TW201720796A - 作為apj促效劑之2,4-二羥基菸鹼醯胺 - Google Patents
作為apj促效劑之2,4-二羥基菸鹼醯胺 Download PDFInfo
- Publication number
- TW201720796A TW201720796A TW105133123A TW105133123A TW201720796A TW 201720796 A TW201720796 A TW 201720796A TW 105133123 A TW105133123 A TW 105133123A TW 105133123 A TW105133123 A TW 105133123A TW 201720796 A TW201720796 A TW 201720796A
- Authority
- TW
- Taiwan
- Prior art keywords
- substituted
- independently selected
- alkyl
- group
- substituents
- Prior art date
Links
- 239000000556 agonist Substances 0.000 title abstract description 11
- XUGMSMOGPBQWJC-UHFFFAOYSA-N 4-hydroxy-2-oxo-1h-pyridine-3-carboxamide Chemical class NC(=O)C1=C(O)C=CNC1=O XUGMSMOGPBQWJC-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 226
- 239000003814 drug Substances 0.000 claims abstract description 48
- 125000000217 alkyl group Chemical group 0.000 claims description 161
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 145
- -1 substituted Chemical class 0.000 claims description 126
- 125000000623 heterocyclic group Chemical group 0.000 claims description 98
- 229910052801 chlorine Inorganic materials 0.000 claims description 91
- 229910052731 fluorine Inorganic materials 0.000 claims description 91
- 229910052794 bromium Inorganic materials 0.000 claims description 70
- 150000003839 salts Chemical class 0.000 claims description 65
- 125000002837 carbocyclic group Chemical group 0.000 claims description 64
- 229910052739 hydrogen Inorganic materials 0.000 claims description 60
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 57
- 229910052757 nitrogen Inorganic materials 0.000 claims description 52
- 125000001424 substituent group Chemical group 0.000 claims description 47
- 229910052760 oxygen Inorganic materials 0.000 claims description 42
- 206010019280 Heart failures Diseases 0.000 claims description 40
- 229910052799 carbon Inorganic materials 0.000 claims description 38
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- 125000003342 alkenyl group Chemical group 0.000 claims description 31
- 238000011282 treatment Methods 0.000 claims description 28
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 27
- 229910052717 sulfur Inorganic materials 0.000 claims description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 22
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 19
- 125000004178 (C1-C4) alkyl group Chemical class 0.000 claims description 17
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000003107 substituted aryl group Chemical group 0.000 claims description 15
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 239000003937 drug carrier Substances 0.000 claims description 13
- 150000001721 carbon Chemical group 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
- 206010012601 diabetes mellitus Diseases 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 7
- 208000029078 coronary artery disease Diseases 0.000 claims description 7
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 208000010125 myocardial infarction Diseases 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 208000006011 Stroke Diseases 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 230000002107 myocardial effect Effects 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 206010007572 Cardiac hypertrophy Diseases 0.000 claims description 3
- 208000006029 Cardiomegaly Diseases 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 238000007634 remodeling Methods 0.000 claims description 3
- 206010061216 Infarction Diseases 0.000 claims description 2
- 230000007574 infarction Effects 0.000 claims description 2
- 229910004013 NO 2 Inorganic materials 0.000 claims 10
- 125000003003 spiro group Chemical group 0.000 claims 3
- 206010049694 Left Ventricular Dysfunction Diseases 0.000 claims 2
- 206010007559 Cardiac failure congestive Diseases 0.000 claims 1
- 208000003037 Diastolic Heart Failure Diseases 0.000 claims 1
- 208000008253 Systolic Heart Failure Diseases 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical group 0.000 claims 1
- 238000007675 cardiac surgery Methods 0.000 claims 1
- 208000018578 heart valve disease Diseases 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 113
- 238000000034 method Methods 0.000 description 99
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 74
- 239000000460 chlorine Substances 0.000 description 65
- 235000019439 ethyl acetate Nutrition 0.000 description 55
- 239000003795 chemical substances by application Substances 0.000 description 46
- ZEZJPIDPVXJEME-UHFFFAOYSA-N 2,4-Dihydroxypyridine Chemical compound OC=1C=CNC(=O)C=1 ZEZJPIDPVXJEME-UHFFFAOYSA-N 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 40
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 37
- 101000793362 Homo sapiens Apelin receptor Proteins 0.000 description 36
- 102100030949 Apelin receptor Human genes 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 229940124597 therapeutic agent Drugs 0.000 description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 29
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 28
- 201000010099 disease Diseases 0.000 description 28
- 239000012453 solvate Substances 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 25
- 239000012071 phase Substances 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 23
- 239000000651 prodrug Substances 0.000 description 22
- 229940002612 prodrug Drugs 0.000 description 22
- 230000002829 reductive effect Effects 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 21
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 21
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 21
- 229940095074 cyclic amp Drugs 0.000 description 21
- 238000002360 preparation method Methods 0.000 description 19
- 239000000243 solution Substances 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 230000000670 limiting effect Effects 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 239000002585 base Substances 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 239000004480 active ingredient Substances 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- 108091008803 APLNR Proteins 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 230000002265 prevention Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 206010020772 Hypertension Diseases 0.000 description 9
- 229910004809 Na2 SO4 Inorganic materials 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 230000000747 cardiac effect Effects 0.000 description 9
- 239000003153 chemical reaction reagent Substances 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
- 229920006395 saturated elastomer Polymers 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 7
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 7
- 239000005695 Ammonium acetate Substances 0.000 description 7
- 201000001320 Atherosclerosis Diseases 0.000 description 7
- 208000008589 Obesity Diseases 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 235000019257 ammonium acetate Nutrition 0.000 description 7
- 229940043376 ammonium acetate Drugs 0.000 description 7
- 239000003472 antidiabetic agent Substances 0.000 description 7
- 235000008504 concentrate Nutrition 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 208000028867 ischemia Diseases 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 7
- 235000020824 obesity Nutrition 0.000 description 7
- 125000002971 oxazolyl group Chemical group 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 125000001544 thienyl group Chemical group 0.000 description 7
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 6
- 108010052412 Apelin Proteins 0.000 description 6
- 101100323464 Homo sapiens APLNR gene Proteins 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 125000000842 isoxazolyl group Chemical group 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 125000003226 pyrazolyl group Chemical group 0.000 description 6
- 208000037803 restenosis Diseases 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 6
- PAHBCVGKVFBQCH-UHFFFAOYSA-N 6-butyl-3-[3-(2-chlorophenyl)pyrrolidine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CC(CC1)C1=C(C=CC=C1)Cl)O)C1=C(C=CC=C1OC)OC PAHBCVGKVFBQCH-UHFFFAOYSA-N 0.000 description 5
- QIGKOQAOJOZBKU-SFHVURJKSA-N 6-butyl-5-(3-fluoro-2,6-dimethoxyphenyl)-4-hydroxy-3-[(3R)-3-phenylpyrrolidine-1-carbonyl]-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1C[C@H](CC1)C1=CC=CC=C1)O)C1=C(C(=CC=C1OC)F)OC QIGKOQAOJOZBKU-SFHVURJKSA-N 0.000 description 5
- 206010002383 Angina Pectoris Diseases 0.000 description 5
- 102000018746 Apelin Human genes 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- 206010063837 Reperfusion injury Diseases 0.000 description 5
- 229940125708 antidiabetic agent Drugs 0.000 description 5
- BWVPHIKGXQBZPV-QKFDDRBGSA-N apelin Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N1[C@H](C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2NC=NC=2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=2NC=NC=2)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCSC)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(O)=O)CCC1 BWVPHIKGXQBZPV-QKFDDRBGSA-N 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 125000002541 furyl group Chemical group 0.000 description 5
- 125000001188 haloalkyl group Chemical group 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 5
- 125000002883 imidazolyl group Chemical group 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 208000031225 myocardial ischemia Diseases 0.000 description 5
- 125000000160 oxazolidinyl group Chemical group 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 208000002815 pulmonary hypertension Diseases 0.000 description 5
- 125000003373 pyrazinyl group Chemical group 0.000 description 5
- 125000002098 pyridazinyl group Chemical group 0.000 description 5
- 125000004076 pyridyl group Chemical group 0.000 description 5
- 125000000168 pyrrolyl group Chemical group 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 125000000335 thiazolyl group Chemical group 0.000 description 5
- 125000004306 triazinyl group Chemical group 0.000 description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 4
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 4
- TYNFGDMXKBRIMD-UHFFFAOYSA-N 3-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-4-hydroxy-1H-pyridin-2-one Chemical compound CCOCC1=C(C(O)=C(C(=O)N2CCC(C2)C2=C(F)C=CC=C2F)C(=O)N1)C1=C(OC)C=CC=C1OC TYNFGDMXKBRIMD-UHFFFAOYSA-N 0.000 description 4
- ISWHIVGTKAPCBD-UHFFFAOYSA-N 3-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-4-hydroxy-5-(3-methoxyphenyl)-6-(2-methyl-1,3-thiazol-4-yl)-1H-pyridin-2-one Chemical compound COc1cccc(c1)-c1c(O)c(C(=O)N2CCC(C2)c2ncc(F)cc2F)c(=O)[nH]c1-c1csc(C)n1 ISWHIVGTKAPCBD-UHFFFAOYSA-N 0.000 description 4
- LSQPBZVEEYPZNT-UHFFFAOYSA-N 3-[3-(5-chloropyridin-2-yl)pyrrolidine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-4-hydroxy-1H-pyridin-2-one Chemical compound ClC=1C=CC(=NC=1)C1CN(CC1)C(=O)C=1C(=NC(=C(C=1O)C1=C(C=CC=C1OC)OC)COCC)O LSQPBZVEEYPZNT-UHFFFAOYSA-N 0.000 description 4
- STPCTGAXOIRZLX-UHFFFAOYSA-N 5-(2,6-dimethoxyphenyl)-6-(ethylaminomethyl)-3-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-4-hydroxy-1H-pyridin-2-one Chemical compound COC1=C(C(=CC=C1)OC)C=1C(=C(C(=NC=1CNCC)O)C(=O)N1CC(CC1)C1=C(C=CC=C1)F)O STPCTGAXOIRZLX-UHFFFAOYSA-N 0.000 description 4
- SWMRKJKGMIVBQC-UHFFFAOYSA-N 6-butyl-3-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-4-hydroxy-5-(3-methoxyphenyl)-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CC(CC1)C1=NC=C(C=C1F)F)O)C1=CC(=CC=C1)OC SWMRKJKGMIVBQC-UHFFFAOYSA-N 0.000 description 4
- KNNQFRTUAOSUPW-UHFFFAOYSA-N 6-butyl-3-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CC(CC1)C1=NC=C(C=C1F)F)O)C1=C(C=CC=C1OC)OC KNNQFRTUAOSUPW-UHFFFAOYSA-N 0.000 description 4
- BJRABZGGXKCRFF-UHFFFAOYSA-N 6-butyl-3-[3-(3-chlorophenyl)pyrrolidine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CC(CC1)C1=CC(=CC=C1)Cl)O)C1=C(C=CC=C1OC)OC BJRABZGGXKCRFF-UHFFFAOYSA-N 0.000 description 4
- PQBPXJCTSKAMJZ-UHFFFAOYSA-N 6-butyl-3-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound CCCCC1=C(C(O)=C(C(=O)N2CCC(C2)C2=NC=C(Cl)C=C2F)C(=O)N1)C1=C(OC)C=CC=C1OC PQBPXJCTSKAMJZ-UHFFFAOYSA-N 0.000 description 4
- PFURAOMBNMGHKV-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-3-[3-(5-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CC(CC1)C1=NC=C(C=C1)F)O)C1=C(C=CC=C1OC)OC PFURAOMBNMGHKV-UHFFFAOYSA-N 0.000 description 4
- 229940127291 Calcium channel antagonist Drugs 0.000 description 4
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 208000001145 Metabolic Syndrome Diseases 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 125000006242 amine protecting group Chemical group 0.000 description 4
- 238000002399 angioplasty Methods 0.000 description 4
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000000480 calcium channel blocker Substances 0.000 description 4
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 4
- 239000002934 diuretic Substances 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 4
- 125000004438 haloalkoxy group Chemical group 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 125000002632 imidazolidinyl group Chemical group 0.000 description 4
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 125000002757 morpholinyl group Chemical group 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 125000001715 oxadiazolyl group Chemical group 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 238000011321 prophylaxis Methods 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 238000004007 reversed phase HPLC Methods 0.000 description 4
- 238000012552 review Methods 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- 125000001113 thiadiazolyl group Chemical group 0.000 description 4
- 125000001425 triazolyl group Chemical group 0.000 description 4
- 230000002792 vascular Effects 0.000 description 4
- CUKWUWBLQQDQAC-VEQWQPCFSA-N (3s)-3-amino-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-carboxyethyl]carbamoyl]pyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-ox Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 CUKWUWBLQQDQAC-VEQWQPCFSA-N 0.000 description 3
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 3
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 3
- OWDFUXRQUNAXRE-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-[4-(1-methylimidazol-2-yl)piperazine-1-carbonyl]-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)C=1N(C=CN=1)C)O)C1=C(C=CC=C1OC)OC OWDFUXRQUNAXRE-UHFFFAOYSA-N 0.000 description 3
- 239000005541 ACE inhibitor Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102400000345 Angiotensin-2 Human genes 0.000 description 3
- 206010003658 Atrial Fibrillation Diseases 0.000 description 3
- 206010007556 Cardiac failure acute Diseases 0.000 description 3
- 241000208011 Digitalis Species 0.000 description 3
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 3
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 208000035150 Hypercholesterolemia Diseases 0.000 description 3
- 208000031226 Hyperlipidaemia Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- 208000018262 Peripheral vascular disease Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 230000008484 agonism Effects 0.000 description 3
- 229940083712 aldosterone antagonist Drugs 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 3
- 229950006323 angiotensin ii Drugs 0.000 description 3
- 239000000883 anti-obesity agent Substances 0.000 description 3
- 229940125710 antiobesity agent Drugs 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 3
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 3
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 230000008602 contraction Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 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 3
- NLUNLVTVUDIHFE-UHFFFAOYSA-N cyclooctylcyclooctane Chemical compound C1CCCCCCC1C1CCCCCCC1 NLUNLVTVUDIHFE-UHFFFAOYSA-N 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000002702 enteric coating Substances 0.000 description 3
- 238000009505 enteric coating Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000005956 isoquinolyl group Chemical group 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000000123 paper Substances 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 3
- DPZNOMCNRMUKPS-UHFFFAOYSA-N resorcinol dimethyl ether Natural products COC1=CC=CC(OC)=C1 DPZNOMCNRMUKPS-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- 125000003831 tetrazolyl group Chemical group 0.000 description 3
- 125000004525 thiadiazinyl group Chemical group S1NN=C(C=C1)* 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 2
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 2
- YEWCQODMEFGLMI-UHFFFAOYSA-N 1'-[6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-2-oxo-1H-pyridine-3-carbonyl]spiro[1,3-dihydroquinoline-4,4'-piperidine]-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCC2(CC(NC3=CC=CC=C23)=O)CC1)O)C1=C(C=CC=C1OC)OC YEWCQODMEFGLMI-UHFFFAOYSA-N 0.000 description 2
- 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 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- RKAQGZNSSXXHGN-UHFFFAOYSA-N 3-(4-benzhydrylpiperazine-1-carbonyl)-6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)C(C1=CC=CC=C1)C1=CC=CC=C1)O)C1=C(C=CC=C1OC)OC RKAQGZNSSXXHGN-UHFFFAOYSA-N 0.000 description 2
- DXRLAIHMZMZBHU-UHFFFAOYSA-N 3-[2-butyl-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-4-hydroxy-6-oxo-1H-pyridin-3-yl]-N-propan-2-ylbenzamide Chemical compound C(CCC)C1=NC(=C(C(=C1C=1C=C(C(=O)NC(C)C)C=CC=1)O)C(=O)N1CC(CC1)C1=NC=C(C=C1F)F)O DXRLAIHMZMZBHU-UHFFFAOYSA-N 0.000 description 2
- HQQPPLDRRWXRLW-UHFFFAOYSA-N 3-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-4-hydroxy-1H-pyridin-2-one Chemical compound FC=1C(=NC=C(C=1)F)C1CN(CC1)C(=O)C=1C(=NC(=C(C=1O)C1=C(C=CC=C1OC)OC)COCC)O HQQPPLDRRWXRLW-UHFFFAOYSA-N 0.000 description 2
- ZVIMEZNEMDYJPV-UHFFFAOYSA-N 3-[4-(1,2-benzothiazol-3-yl)piperazine-1-carbonyl]-6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound S1N=C(C2=C1C=CC=C2)N1CCN(CC1)C(=O)C=1C(=NC(=C(C=1O)C1=C(C=CC=C1OC)OC)CCCC)O ZVIMEZNEMDYJPV-UHFFFAOYSA-N 0.000 description 2
- QTMUHSVYJGYWNS-UHFFFAOYSA-N 3-[4-(1,3-benzoxazol-2-yl)piperidine-1-carbonyl]-6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound O1C(=NC2=C1C=CC=C2)C1CCN(CC1)C(=O)C=1C(=NC(=C(C=1O)C1=C(C=CC=C1OC)OC)CCCC)O QTMUHSVYJGYWNS-UHFFFAOYSA-N 0.000 description 2
- AGDFNJVHDNKBLX-UHFFFAOYSA-N 3-[4-[(2,3-dichlorophenyl)methyl]piperazine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-4-hydroxy-1H-pyridin-2-one Chemical compound ClC1=C(C=CC=C1Cl)CN1CCN(CC1)C(=O)C=1C(=NC(=C(C=1O)C1=C(C=CC=C1OC)OC)COCC)O AGDFNJVHDNKBLX-UHFFFAOYSA-N 0.000 description 2
- FWQUFMUGCWUBIT-UHFFFAOYSA-N 4-[1-[6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-2-oxo-1H-pyridine-3-carbonyl]piperidin-4-yl]benzamide Chemical compound CCCCC1=C(C(O)=C(C(=O)N2CCC(CC2)C2=CC=C(C=C2)C(N)=O)C(O)=N1)C1=C(OC)C=CC=C1OC FWQUFMUGCWUBIT-UHFFFAOYSA-N 0.000 description 2
- VRLNCNWNDNXTCM-UHFFFAOYSA-N 5-(2,6-dimethoxyphenyl)-3-[4-[(3-fluorophenyl)methyl]piperazine-1-carbonyl]-4-hydroxy-6-(2-methoxyethyl)-1H-pyridin-2-one Chemical compound COC1=C(C(=CC=C1)OC)C=1C(=C(C(=NC=1CCOC)O)C(=O)N1CCN(CC1)CC1=CC(=CC=C1)F)O VRLNCNWNDNXTCM-UHFFFAOYSA-N 0.000 description 2
- FFVGBTZRGSIQAL-UHFFFAOYSA-N 5-(2,6-dimethoxyphenyl)-6-(4-fluorophenyl)-3-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-4-hydroxy-1H-pyridin-2-one Chemical compound COC1=C(C(=CC=C1)OC)C=1C(=C(C(=NC=1C1=CC=C(C=C1)F)O)C(=O)N1CC(CC1)C1=C(C=CC=C1)F)O FFVGBTZRGSIQAL-UHFFFAOYSA-N 0.000 description 2
- MJRQWNRBGLQROP-UHFFFAOYSA-N 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-4-hydroxy-1H-pyridin-2-one Chemical compound COC1=C(C(=CC=C1)OC)C=1C(=C(C(=NC=1COCC)O)C(=O)N1CC(CC1)C1=C(C=CC=C1)F)O MJRQWNRBGLQROP-UHFFFAOYSA-N 0.000 description 2
- XWAUIQTUAPXBRO-UHFFFAOYSA-N 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-[3-(3-fluorophenyl)pyrrolidine-1-carbonyl]-4-hydroxy-1H-pyridin-2-one Chemical compound COC1=C(C(=CC=C1)OC)C=1C(=C(C(=NC=1COCC)O)C(=O)N1CC(CC1)C1=CC(=CC=C1)F)O XWAUIQTUAPXBRO-UHFFFAOYSA-N 0.000 description 2
- SEXZYTNOKJFQTI-UHFFFAOYSA-N 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-[4-[(2-fluorophenyl)methyl]piperazine-1-carbonyl]-4-hydroxy-1H-pyridin-2-one Chemical compound COC1=C(C(=CC=C1)OC)C=1C(=C(C(=NC=1COCC)O)C(=O)N1CCN(CC1)CC1=C(C=CC=C1)F)O SEXZYTNOKJFQTI-UHFFFAOYSA-N 0.000 description 2
- ZLRDNEZLCPNZKE-UHFFFAOYSA-N 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-[4-[(3-fluorophenyl)methyl]piperazine-1-carbonyl]-4-hydroxy-1H-pyridin-2-one Chemical compound COC1=C(C(=CC=C1)OC)C=1C(=C(C(=NC=1COCC)O)C(=O)N1CCN(CC1)CC1=CC(=CC=C1)F)O ZLRDNEZLCPNZKE-UHFFFAOYSA-N 0.000 description 2
- MORAXWPILAFWAK-SFHVURJKSA-N 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-4-hydroxy-3-[(3R)-3-phenylpyrrolidine-1-carbonyl]-1H-pyridin-2-one Chemical compound COC1=C(C(=CC=C1)OC)C=1C(=C(C(=NC=1COCC)O)C(=O)N1C[C@H](CC1)C1=CC=CC=C1)O MORAXWPILAFWAK-SFHVURJKSA-N 0.000 description 2
- ZLNULAJDQCJLOL-IBGZPJMESA-N 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-4-hydroxy-3-[(3S)-3-phenylmethoxypyrrolidine-1-carbonyl]-1H-pyridin-2-one Chemical compound C(C1=CC=CC=C1)O[C@@H]1CN(CC1)C(=O)C=1C(=NC(=C(C=1O)C1=C(C=CC=C1OC)OC)COCC)O ZLNULAJDQCJLOL-IBGZPJMESA-N 0.000 description 2
- MORAXWPILAFWAK-GOSISDBHSA-N 5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-4-hydroxy-3-[(3S)-3-phenylpyrrolidine-1-carbonyl]-1H-pyridin-2-one Chemical compound COC1=C(C(=CC=C1)OC)C=1C(=C(C(=NC=1COCC)O)C(=O)N1C[C@@H](CC1)C1=CC=CC=C1)O MORAXWPILAFWAK-GOSISDBHSA-N 0.000 description 2
- UAHUYSRHLWEMMI-UHFFFAOYSA-N 6-(ethoxymethyl)-3-[4-[(3-fluorophenyl)methyl]piperazine-1-carbonyl]-4-hydroxy-5-(2-methoxyphenyl)-1H-pyridin-2-one Chemical compound C(C)OCC1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)CC1=CC(=CC=C1)F)O)C1=C(C=CC=C1)OC UAHUYSRHLWEMMI-UHFFFAOYSA-N 0.000 description 2
- MHXSGPZETNDQSO-KRWDZBQOSA-N 6-(ethoxymethyl)-5-(4-fluoro-2,6-dimethoxyphenyl)-4-hydroxy-3-[(3R)-3-phenylpyrrolidine-1-carbonyl]-1H-pyridin-2-one Chemical compound C(C)OCC1=C(C(=C(C(=N1)O)C(=O)N1C[C@H](CC1)C1=CC=CC=C1)O)C1=C(C=C(C=C1OC)F)OC MHXSGPZETNDQSO-KRWDZBQOSA-N 0.000 description 2
- QSHXHZFCIYLKBU-UHFFFAOYSA-N 6-butyl-3-(4-cyclohexylpiperazine-1-carbonyl)-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)C1CCCCC1)O)C1=C(C=CC=C1OC)OC QSHXHZFCIYLKBU-UHFFFAOYSA-N 0.000 description 2
- ZKJPREGZORLOPY-UHFFFAOYSA-N 6-butyl-3-[3-(3-chlorophenyl)azetidine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CC(C1)C1=CC(=CC=C1)Cl)O)C1=C(C=CC=C1OC)OC ZKJPREGZORLOPY-UHFFFAOYSA-N 0.000 description 2
- QLRHTCHILRFJSZ-UHFFFAOYSA-N 6-butyl-3-[3-(5-chloropyridin-2-yl)pyrrolidine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CC(CC1)C1=NC=C(C=C1)Cl)O)C1=C(C=CC=C1OC)OC QLRHTCHILRFJSZ-UHFFFAOYSA-N 0.000 description 2
- VWJYLLQLCPPMLL-UHFFFAOYSA-N 6-butyl-3-[3-[(2,3-difluorophenyl)methoxy]azetidine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CC(C1)OCC1=C(C(=CC=C1)F)F)O)C1=C(C=CC=C1OC)OC VWJYLLQLCPPMLL-UHFFFAOYSA-N 0.000 description 2
- LQCZWCZUQUOOTK-UHFFFAOYSA-N 6-butyl-3-[4-(2-chlorophenyl)piperazine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)C1=C(C=CC=C1)Cl)O)C1=C(C=CC=C1OC)OC LQCZWCZUQUOOTK-UHFFFAOYSA-N 0.000 description 2
- MCQBRBORRICOPD-UHFFFAOYSA-N 6-butyl-3-[4-(3-chlorophenyl)piperidine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCC(CC1)C1=CC(=CC=C1)Cl)O)C1=C(C=CC=C1OC)OC MCQBRBORRICOPD-UHFFFAOYSA-N 0.000 description 2
- TZFFAXXOWWNCHB-UHFFFAOYSA-N 6-butyl-3-[4-(4-chlorophenyl)-4-hydroxypiperidine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCC(CC1)(O)C1=CC=C(C=C1)Cl)O)C1=C(C=CC=C1OC)OC TZFFAXXOWWNCHB-UHFFFAOYSA-N 0.000 description 2
- JXXWGJDDGHLALL-UHFFFAOYSA-N 6-butyl-3-[4-(5-chloropyridin-2-yl)piperazine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)C1=NC=C(C=C1)Cl)O)C1=C(C=CC=C1OC)OC JXXWGJDDGHLALL-UHFFFAOYSA-N 0.000 description 2
- RWSAPGOQPPRPTF-UHFFFAOYSA-N 6-butyl-3-[4-(cyclopropylmethyl)piperazine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)CC1CC1)O)C1=C(C=CC=C1OC)OC RWSAPGOQPPRPTF-UHFFFAOYSA-N 0.000 description 2
- FHZCKUYQJUXHPH-UHFFFAOYSA-N 6-butyl-3-[4-[(2,3-dichlorophenyl)methyl]piperazine-1-carbonyl]-5-(2,5-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)CC1=C(C(=CC=C1)Cl)Cl)O)C1=C(C=CC(=C1)OC)OC FHZCKUYQJUXHPH-UHFFFAOYSA-N 0.000 description 2
- UPWPJDUMNWHYHZ-UHFFFAOYSA-N 6-butyl-3-[4-[(2,3-dichlorophenyl)methyl]piperazine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)CC1=C(C(=CC=C1)Cl)Cl)O)C1=C(C=CC=C1OC)OC UPWPJDUMNWHYHZ-UHFFFAOYSA-N 0.000 description 2
- FFORQQRXYATGPS-UHFFFAOYSA-N 6-butyl-3-[4-[(2,3-difluorophenyl)methyl]piperazine-1-carbonyl]-5-(2,5-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)CC1=C(C(=CC=C1)F)F)O)C1=C(C=CC(=C1)OC)OC FFORQQRXYATGPS-UHFFFAOYSA-N 0.000 description 2
- GVUYOSRUKWPPQX-UHFFFAOYSA-N 6-butyl-3-[4-[(2,3-difluorophenyl)methyl]piperazine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)CC1=C(C(=CC=C1)F)F)O)C1=C(C=CC=C1OC)OC GVUYOSRUKWPPQX-UHFFFAOYSA-N 0.000 description 2
- SYJZPHVLKKFXOW-UHFFFAOYSA-N 6-butyl-3-[4-[(2,4-dichlorophenyl)methyl]piperazine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)CC1=C(C=C(C=C1)Cl)Cl)O)C1=C(C=CC=C1OC)OC SYJZPHVLKKFXOW-UHFFFAOYSA-N 0.000 description 2
- BFAVJIZCJXSCMR-UHFFFAOYSA-N 6-butyl-3-[4-[(4-chlorophenyl)methyl]piperazine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)CC1=CC=C(C=C1)Cl)O)C1=C(C=CC=C1OC)OC BFAVJIZCJXSCMR-UHFFFAOYSA-N 0.000 description 2
- RUJHNKADQHZZDS-QHCPKHFHSA-N 6-butyl-4-hydroxy-3-[(3R)-3-phenylpyrrolidine-1-carbonyl]-5-(3-propan-2-ylphenyl)-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1C[C@H](CC1)C1=CC=CC=C1)O)C1=CC(=CC=C1)C(C)C RUJHNKADQHZZDS-QHCPKHFHSA-N 0.000 description 2
- KPIKYAWKTFSLOT-IBGZPJMESA-N 6-butyl-5-(2,5-dimethoxyphenyl)-4-hydroxy-3-[(3R)-3-phenylpyrrolidine-1-carbonyl]-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1C[C@H](CC1)C1=CC=CC=C1)O)C1=C(C=CC(=C1)OC)OC KPIKYAWKTFSLOT-IBGZPJMESA-N 0.000 description 2
- KPIKYAWKTFSLOT-LJQANCHMSA-N 6-butyl-5-(2,5-dimethoxyphenyl)-4-hydroxy-3-[(3S)-3-phenylpyrrolidine-1-carbonyl]-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1C[C@@H](CC1)C1=CC=CC=C1)O)C1=C(C=CC(=C1)OC)OC KPIKYAWKTFSLOT-LJQANCHMSA-N 0.000 description 2
- IHOOFLBEFRNISQ-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-3-[3-(3-fluoropyridin-2-yl)oxyazetidine-1-carbonyl]-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CC(C1)OC1=NC=CC=C1F)O)C1=C(C=CC=C1OC)OC IHOOFLBEFRNISQ-UHFFFAOYSA-N 0.000 description 2
- UOHRPIGTAUTOKW-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-3-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CC(CC1)C1=NC=CC=C1F)O)C1=C(C=CC=C1OC)OC UOHRPIGTAUTOKW-UHFFFAOYSA-N 0.000 description 2
- FYRCMPVHDQPOHS-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-3-[3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CC(CC1)C1=CC=C(C=C1)F)O)C1=C(C=CC=C1OC)OC FYRCMPVHDQPOHS-UHFFFAOYSA-N 0.000 description 2
- WNKUPNMMDVIAJD-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-3-[4-[(2-fluorophenyl)methyl]piperazine-1-carbonyl]-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)CC1=C(C=CC=C1)F)O)C1=C(C=CC=C1OC)OC WNKUPNMMDVIAJD-UHFFFAOYSA-N 0.000 description 2
- GUFPHRJNZDHUQT-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-3-[4-[(3-fluorophenyl)methyl]piperazine-1-carbonyl]-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)CC1=CC(=CC=C1)F)O)C1=C(C=CC=C1OC)OC GUFPHRJNZDHUQT-UHFFFAOYSA-N 0.000 description 2
- PQKJBACOPZUZLR-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-3-[4-[(3-fluoropyridin-2-yl)methyl]piperazine-1-carbonyl]-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)CC1=NC=CC=C1F)O)C1=C(C=CC=C1OC)OC PQKJBACOPZUZLR-UHFFFAOYSA-N 0.000 description 2
- OPFONQFICDLTDS-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-3-[4-[3-(furan-2-yl)-1H-pyrazol-5-yl]piperidine-1-carbonyl]-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCC(CC1)C1=CC(=NN1)C=1OC=CC=1)O)C1=C(C=CC=C1OC)OC OPFONQFICDLTDS-UHFFFAOYSA-N 0.000 description 2
- SYXJHTYOLFBZRR-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-(4-hydroxy-4-phenylpiperidine-1-carbonyl)-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCC(CC1)(C1=CC=CC=C1)O)O)C1=C(C=CC=C1OC)OC SYXJHTYOLFBZRR-UHFFFAOYSA-N 0.000 description 2
- FOWGPJMHFKCABB-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-(4-hydroxy-4-pyridin-3-ylpiperidine-1-carbonyl)-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCC(CC1)(C=1C=NC=CC=1)O)O)C1=C(C=CC=C1OC)OC FOWGPJMHFKCABB-UHFFFAOYSA-N 0.000 description 2
- QUKFQELSHHQCEQ-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-(4-phenylpiperidine-1-carbonyl)-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCC(CC1)C1=CC=CC=C1)O)C1=C(C=CC=C1OC)OC QUKFQELSHHQCEQ-UHFFFAOYSA-N 0.000 description 2
- GNWHXORETIYCQZ-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-(4-pyridazin-3-ylpiperazine-1-carbonyl)-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)C=1N=NC=CC=1)O)C1=C(C=CC=C1OC)OC GNWHXORETIYCQZ-UHFFFAOYSA-N 0.000 description 2
- KQRRAIWYFKBTNV-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-(4-pyridin-4-ylpiperazine-1-carbonyl)-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)C1=CC=NC=C1)O)C1=C(C=CC=C1OC)OC KQRRAIWYFKBTNV-UHFFFAOYSA-N 0.000 description 2
- TWCXIZHJKPRIMU-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-(4-pyrrolidin-1-ylpiperidine-1-carbonyl)-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCC(CC1)N1CCCC1)O)C1=C(C=CC=C1OC)OC TWCXIZHJKPRIMU-UHFFFAOYSA-N 0.000 description 2
- VGCNPNDZOILGJM-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-(spiro[1H-2-benzofuran-3,4'-piperidine]-1'-carbonyl)-1H-pyridin-2-one Chemical compound CCCCC1=C(C(O)=C(C(=O)N2CCC3(CC2)OCC2=CC=CC=C32)C(O)=N1)C1=C(OC)C=CC=C1OC VGCNPNDZOILGJM-UHFFFAOYSA-N 0.000 description 2
- BCINEYMTISNZFK-IBGZPJMESA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-[(3R)-3-phenylpyrrolidine-1-carbonyl]-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1C[C@H](CC1)C1=CC=CC=C1)O)C1=C(C=CC=C1OC)OC BCINEYMTISNZFK-IBGZPJMESA-N 0.000 description 2
- BCINEYMTISNZFK-LJQANCHMSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-[(3S)-3-phenylpyrrolidine-1-carbonyl]-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1C[C@@H](CC1)C1=CC=CC=C1)O)C1=C(C=CC=C1OC)OC BCINEYMTISNZFK-LJQANCHMSA-N 0.000 description 2
- KUGVUTDBIPOBKB-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-[4-(1-phenyltetrazol-5-yl)-1,4-diazepane-1-carbonyl]-1H-pyridin-2-one Chemical compound CCCCC1=C(C(O)=C(C(=O)N2CCCN(CC2)C2=NN=NN2C2=CC=CC=C2)C(O)=N1)C1=C(OC)C=CC=C1OC KUGVUTDBIPOBKB-UHFFFAOYSA-N 0.000 description 2
- YTGFIQJVXSNSSP-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-[4-(1-phenyltetrazol-5-yl)piperazine-1-carbonyl]-1H-pyridin-2-one Chemical compound CCCCC1=C(C(O)=C(C(=O)N2CCN(CC2)C2=NN=NN2C2=CC=CC=C2)C(O)=N1)C1=C(OC)C=CC=C1OC YTGFIQJVXSNSSP-UHFFFAOYSA-N 0.000 description 2
- IMPRQMRJIGCQIP-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-[4-(2-methoxyphenyl)piperidine-1-carbonyl]-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCC(CC1)C1=C(C=CC=C1)OC)O)C1=C(C=CC=C1OC)OC IMPRQMRJIGCQIP-UHFFFAOYSA-N 0.000 description 2
- WEUGCKQKZYZKNZ-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-[4-(pyridin-2-ylmethyl)piperazine-1-carbonyl]-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)CC1=NC=CC=C1)O)C1=C(C=CC=C1OC)OC WEUGCKQKZYZKNZ-UHFFFAOYSA-N 0.000 description 2
- XMKJTASDRFSEAG-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-[4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carbonyl]-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)C1=NC=CC(=N1)C(F)(F)F)O)C1=C(C=CC=C1OC)OC XMKJTASDRFSEAG-UHFFFAOYSA-N 0.000 description 2
- JHFWPXHWYILCHT-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-[4-[[3-(trifluoromethyl)phenyl]methyl]piperazine-1-carbonyl]-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)CC1=CC(=CC=C1)C(F)(F)F)O)C1=C(C=CC=C1OC)OC JHFWPXHWYILCHT-UHFFFAOYSA-N 0.000 description 2
- KMJMQAPXLDOTGI-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-N-methyl-2-oxo-N-(2-phenoxyethyl)-1H-pyridine-3-carboxamide Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N(CCOC1=CC=CC=C1)C)O)C1=C(C=CC=C1OC)OC KMJMQAPXLDOTGI-UHFFFAOYSA-N 0.000 description 2
- MTKVAWOADACLOC-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-N-methyl-2-oxo-N-(2-pyridin-2-ylethyl)-1H-pyridine-3-carboxamide Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N(CCC1=NC=CC=C1)C)O)C1=C(C=CC=C1OC)OC MTKVAWOADACLOC-UHFFFAOYSA-N 0.000 description 2
- HPGKGKFIYWCYKF-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-N-methyl-2-oxo-N-(4-phenylbutyl)-1H-pyridine-3-carboxamide Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N(CCCCC1=CC=CC=C1)C)O)C1=C(C=CC=C1OC)OC HPGKGKFIYWCYKF-UHFFFAOYSA-N 0.000 description 2
- SLJMIFFMIFPMMT-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-N-[2-(2-fluorophenyl)ethyl]-4-hydroxy-2-oxo-N-propyl-1H-pyridine-3-carboxamide Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N(CCC)CCC1=C(C=CC=C1)F)O)C1=C(C=CC=C1OC)OC SLJMIFFMIFPMMT-UHFFFAOYSA-N 0.000 description 2
- BQIZDKBOPHTRFY-UHFFFAOYSA-N 6-butyl-5-(3-ethylphenyl)-4-hydroxy-3-[5-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl]-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(N1)=O)C=1OC(=NN=1)CC=1N=C(SC=1)C)O)C1=CC(=CC=C1)CC BQIZDKBOPHTRFY-UHFFFAOYSA-N 0.000 description 2
- HQNPYEHFAWFXRM-UHFFFAOYSA-N 6-butyl-N-[2-(4-chlorophenyl)ethyl]-5-(2,6-dimethoxyphenyl)-4-hydroxy-N-methyl-2-oxo-1H-pyridine-3-carboxamide Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N(C)CCC1=CC=C(C=C1)Cl)O)C1=C(C=CC=C1OC)OC HQNPYEHFAWFXRM-UHFFFAOYSA-N 0.000 description 2
- JDCLSEMPWVJGEQ-UHFFFAOYSA-N 6-cyclopentyl-5-(2,6-dimethoxyphenyl)-3-[3-(3-fluorophenyl)pyrrolidine-1-carbonyl]-4-hydroxy-1H-pyridin-2-one Chemical compound C1(CCCC1)C1=C(C(=C(C(=N1)O)C(=O)N1CC(CC1)C1=CC(=CC=C1)F)O)C1=C(C=CC=C1OC)OC JDCLSEMPWVJGEQ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 108050000824 Angiotensin II receptor Proteins 0.000 description 2
- 101800000733 Angiotensin-2 Proteins 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
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 125000006539 C12 alkyl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 208000031229 Cardiomyopathies Diseases 0.000 description 2
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 2
- 229940097420 Diuretic Drugs 0.000 description 2
- JRWZLRBJNMZMFE-UHFFFAOYSA-N Dobutamine Chemical compound C=1C=C(O)C(O)=CC=1CCNC(C)CCC1=CC=C(O)C=C1 JRWZLRBJNMZMFE-UHFFFAOYSA-N 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- UWWMFNMBWWRCKQ-UHFFFAOYSA-N N-(2-benzamidoethyl)-6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-N-methyl-2-oxo-1H-pyridine-3-carboxamide Chemical compound CCCCC1=C(C(O)=C(C(=O)N(C)CCNC(=O)C2=CC=CC=C2)C(O)=N1)C1=C(OC)C=CC=C1OC UWWMFNMBWWRCKQ-UHFFFAOYSA-N 0.000 description 2
- SNHWZOWXLJFEGD-UHFFFAOYSA-N N-[1-[6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-2-oxo-1H-pyridine-3-carbonyl]azetidin-3-yl]-2,3-difluorobenzenesulfonamide Chemical compound CCCCC1=C(C(O)=C(C(=O)N2CC(C2)NS(=O)(=O)C2=C(F)C(F)=CC=C2)C(O)=N1)C1=C(OC)C=CC=C1OC SNHWZOWXLJFEGD-UHFFFAOYSA-N 0.000 description 2
- MVBNINGALJOTCH-UHFFFAOYSA-N N-[1-[6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-2-oxo-1H-pyridine-3-carbonyl]azetidin-3-yl]benzamide Chemical compound CCCCC1=C(C(O)=C(C(=O)N2CC(C2)NC(=O)C2=CC=CC=C2)C(O)=N1)C1=C(OC)C=CC=C1OC MVBNINGALJOTCH-UHFFFAOYSA-N 0.000 description 2
- VBXHAJWRRCOBEF-UHFFFAOYSA-N N-benzyl-6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-2-oxo-N-propyl-1H-pyridine-3-carboxamide Chemical compound C(C1=CC=CC=C1)N(C(=O)C=1C(=NC(=C(C=1O)C1=C(C=CC=C1OC)OC)CCCC)O)CCC VBXHAJWRRCOBEF-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 229910017917 NH4 Cl Inorganic materials 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 2
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 2
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108010062481 Type 1 Angiotensin Receptor Proteins 0.000 description 2
- 102000010913 Type 1 Angiotensin Receptor Human genes 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- MCNHVBWLINLGIB-UHFFFAOYSA-N [Li].CC(CCCCCCCCCNCCCCCCCCCC(C)(C)C)(C)C Chemical compound [Li].CC(CCCCCCCCCNCCCCCCCCCC(C)(C)C)(C)C MCNHVBWLINLGIB-UHFFFAOYSA-N 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 208000022531 anorexia Diseases 0.000 description 2
- 230000003063 anti-neuropathic effect Effects 0.000 description 2
- 230000003324 anti-retinal effect Effects 0.000 description 2
- 229940125682 antidementia agent Drugs 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 239000003524 antilipemic agent Substances 0.000 description 2
- XXCCRHIAIBQDPX-PEWBXTNBSA-N apelin-13 Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(N)=O)C1=CN=CN1 XXCCRHIAIBQDPX-PEWBXTNBSA-N 0.000 description 2
- 239000002830 appetite depressant Substances 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 2
- BSDOQSMQCZQLDV-UHFFFAOYSA-N butan-1-olate;zirconium(4+) Chemical compound [Zr+4].CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-] BSDOQSMQCZQLDV-UHFFFAOYSA-N 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000011111 cardboard Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 239000003638 chemical reducing agent Substances 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
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000002475 cognitive enhancer Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 2
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 2
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 206010061428 decreased appetite Diseases 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 229940030606 diuretics Drugs 0.000 description 2
- 229960001089 dobutamine Drugs 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 239000006274 endogenous ligand Substances 0.000 description 2
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 229960000346 gliclazide Drugs 0.000 description 2
- 239000003292 glue Substances 0.000 description 2
- 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 2
- 230000036541 health Effects 0.000 description 2
- 210000005003 heart tissue Anatomy 0.000 description 2
- 230000000004 hemodynamic effect Effects 0.000 description 2
- 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 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 201000008980 hyperinsulinism Diseases 0.000 description 2
- 208000006575 hypertriglyceridemia Diseases 0.000 description 2
- 125000005945 imidazopyridyl group Chemical group 0.000 description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 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 2
- 230000003993 interaction Effects 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 239000007937 lozenge 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
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000003695 memory enhancer Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
- 150000002823 nitrates Chemical class 0.000 description 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 2
- 239000002664 nootropic agent Substances 0.000 description 2
- 125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000002093 peripheral 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
- 230000001766 physiological effect Effects 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 150000004032 porphyrins Chemical class 0.000 description 2
- 238000009117 preventive therapy Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000009862 primary prevention Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 125000005493 quinolyl group Chemical group 0.000 description 2
- 239000003087 receptor blocking agent Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000002461 renin inhibitor Substances 0.000 description 2
- 229940086526 renin-inhibitors Drugs 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000009863 secondary prevention Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 150000003413 spiro compounds Chemical class 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- IEHUFJSDRXTNGE-UHFFFAOYSA-N tert-butyl 3-(5-chloropyridin-2-yl)-2,5-dihydropyrrole-1-carboxylate Chemical compound ClC=1C=CC(=NC=1)C=1CN(CC=1)C(=O)OC(C)(C)C IEHUFJSDRXTNGE-UHFFFAOYSA-N 0.000 description 2
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 2
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000000844 transformation Methods 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
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 230000024883 vasodilation Effects 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- DBGIVFWFUFKIQN-VIFPVBQESA-N (+)-Fenfluramine Chemical compound CCN[C@@H](C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-VIFPVBQESA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- GIXSTBOIKJPUKD-QMMMGPOBSA-N (2s)-1-cyclohexylpropan-2-amine Chemical compound C[C@H](N)CC1CCCCC1 GIXSTBOIKJPUKD-QMMMGPOBSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- UZRRTWVCUBAXIJ-UHFFFAOYSA-N (4-fluoro-2,6-dimethoxyphenyl)methyl methanesulfonate Chemical compound CS(=O)(=O)OCC1=C(C=C(C=C1OC)F)OC UZRRTWVCUBAXIJ-UHFFFAOYSA-N 0.000 description 1
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 1
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 1
- 125000006569 (C5-C6) heterocyclic group Chemical group 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
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 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 1
- FIARMZDBEGVMLV-UHFFFAOYSA-N 1,1,2,2,2-pentafluoroethanolate Chemical group [O-]C(F)(F)C(F)(F)F FIARMZDBEGVMLV-UHFFFAOYSA-N 0.000 description 1
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
- LLJFMFZYVVLQKT-UHFFFAOYSA-N 1-cyclohexyl-3-[4-[2-(7-methoxy-4,4-dimethyl-1,3-dioxo-2-isoquinolinyl)ethyl]phenyl]sulfonylurea Chemical compound C=1C(OC)=CC=C(C(C2=O)(C)C)C=1C(=O)N2CCC(C=C1)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 LLJFMFZYVVLQKT-UHFFFAOYSA-N 0.000 description 1
- MMZYCBHLNZVROM-UHFFFAOYSA-N 1-fluoro-2-methylbenzene Chemical compound CC1=CC=CC=C1F MMZYCBHLNZVROM-UHFFFAOYSA-N 0.000 description 1
- IWFKMNAEFPEIOY-UHFFFAOYSA-N 1-fluoro-3,5-dimethoxybenzene Chemical compound COC1=CC(F)=CC(OC)=C1 IWFKMNAEFPEIOY-UHFFFAOYSA-N 0.000 description 1
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- XXMFJKNOJSDQBM-UHFFFAOYSA-N 2,2,2-trifluoroacetic acid;hydrate Chemical compound [OH3+].[O-]C(=O)C(F)(F)F XXMFJKNOJSDQBM-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- QDKSGHXRHXVMPF-UHFFFAOYSA-N 2,2-dimethylundecane Chemical compound CCCCCCCCCC(C)(C)C QDKSGHXRHXVMPF-UHFFFAOYSA-N 0.000 description 1
- HVFJQRZGBBKTPL-UHFFFAOYSA-N 2,3-dichloropentane Chemical compound CCC(Cl)C(C)Cl HVFJQRZGBBKTPL-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- QFBYQIUBLBNTDO-UHFFFAOYSA-N 2-(2,6-dimethoxyphenyl)acetic acid Chemical compound COC1=CC=CC(OC)=C1CC(O)=O QFBYQIUBLBNTDO-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- SPBIXXXFDSLALC-UHFFFAOYSA-N 2-[ethyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]acetic acid Chemical compound OC(=O)CN(CC)C(=O)OC(C)(C)C SPBIXXXFDSLALC-UHFFFAOYSA-N 0.000 description 1
- BZUUVQCSPHPUQA-UHFFFAOYSA-N 2-bromo-5-chloropyridine Chemical compound ClC1=CC=C(Br)N=C1 BZUUVQCSPHPUQA-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- ILPUOPPYSQEBNJ-UHFFFAOYSA-N 2-methyl-2-phenoxypropanoic acid Chemical class OC(=O)C(C)(C)OC1=CC=CC=C1 ILPUOPPYSQEBNJ-UHFFFAOYSA-N 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- RCQFNQQYVSNBOJ-UHFFFAOYSA-N 3-(2-chlorophenyl)pyrrolidine Chemical compound ClC1=CC=CC=C1C1CNCC1 RCQFNQQYVSNBOJ-UHFFFAOYSA-N 0.000 description 1
- RQGYSXVZGVZRPG-UHFFFAOYSA-N 3-(3-fluorophenyl)pyrrolidine Chemical compound FC1=CC=CC(C2CNCC2)=C1 RQGYSXVZGVZRPG-UHFFFAOYSA-N 0.000 description 1
- YZTCGYARZGKANI-UHFFFAOYSA-N 3-(diethylamino)-1-phenylpropan-1-one Chemical compound CCN(CC)CCC(=O)C1=CC=CC=C1 YZTCGYARZGKANI-UHFFFAOYSA-N 0.000 description 1
- JWHIEVXUXFAQDJ-UHFFFAOYSA-N 3-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-4-hydroxy-1H-pyridin-2-one Chemical compound CCOCC1=C(C(O)=C(C(=O)N2CCC(C2)C2=C(F)C=C(F)C=C2)C(=O)N1)C1=C(OC)C=CC=C1OC JWHIEVXUXFAQDJ-UHFFFAOYSA-N 0.000 description 1
- QDSLOWFLSKKPFS-UHFFFAOYSA-N 3-[4-(1,3-benzothiazol-2-yl)piperazine-1-carbonyl]-6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound S1C(=NC2=C1C=CC=C2)N1CCN(CC1)C(=O)C=1C(=NC(=C(C=1O)C1=C(C=CC=C1OC)OC)CCCC)O QDSLOWFLSKKPFS-UHFFFAOYSA-N 0.000 description 1
- KCEASQOKZXDFKA-UHFFFAOYSA-N 3-[4-(1,3-benzoxazol-2-yl)piperazine-1-carbonyl]-6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound O1C(=NC2=C1C=CC=C2)N1CCN(CC1)C(=O)C=1C(=NC(=C(C=1O)C1=C(C=CC=C1OC)OC)CCCC)O KCEASQOKZXDFKA-UHFFFAOYSA-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
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- HOGUCRFULNNZBQ-UHFFFAOYSA-N 4-fluoro-2,6-dimethoxybenzaldehyde Chemical compound COC1=CC(F)=CC(OC)=C1C=O HOGUCRFULNNZBQ-UHFFFAOYSA-N 0.000 description 1
- 125000006042 4-hexenyl group Chemical group 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
- 125000003119 4-methyl-3-pentenyl group Chemical group [H]\C(=C(/C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- IQRUQXXCIDNXLO-UHFFFAOYSA-N 5-(2,6-dimethoxyphenyl)-6-(ethylaminomethyl)-3-[3-(3-fluorophenyl)pyrrolidine-1-carbonyl]-4-hydroxy-1H-pyridin-2-one Chemical compound COC1=C(C(=CC=C1)OC)C=1C(=C(C(=NC=1CNCC)O)C(=O)N1CC(CC1)C1=CC(=CC=C1)F)O IQRUQXXCIDNXLO-UHFFFAOYSA-N 0.000 description 1
- ZDHQVQVNOIWLNX-UHFFFAOYSA-N 5-(7-chloro-10h-benzo[1,2]cyclohepta[2,4-c][1,3]thiazol-10-yl)-1-methyl-4-sulfanylidenepyrimidin-2-one Chemical compound S=C1NC(=O)N(C)C=C1C1C2=CC=C(Cl)C=C2C=CC2=C1N=CS2 ZDHQVQVNOIWLNX-UHFFFAOYSA-N 0.000 description 1
- WZCAHCHVKHKMEO-AWEZNQCLSA-N 5-bromo-6-butyl-4-hydroxy-3-[(3R)-3-phenylpyrrolidine-1-carbonyl]-1H-pyridin-2-one Chemical compound BrC=1C(=C(C(=NC=1CCCC)O)C(=O)N1C[C@H](CC1)C1=CC=CC=C1)O WZCAHCHVKHKMEO-AWEZNQCLSA-N 0.000 description 1
- PWQMQVGCIMNSBY-UHFFFAOYSA-N 5-chloro-3-fluoro-2-pyrrolidin-3-ylpyridine Chemical compound ClC=1C=C(C(=NC=1)C1CNCC1)F PWQMQVGCIMNSBY-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- LQDVDLXIGYHGEY-UHFFFAOYSA-N 6-(ethoxymethyl)-5-(4-fluoro-2,6-dimethoxyphenyl)-4-hydroxy-3-[5-[(2-oxopyridin-1-yl)methyl]-1,3,4-oxadiazol-2-yl]-1H-pyridin-2-one Chemical compound C(C)OCC1=C(C(=C(C(=N1)O)C1=NN=C(O1)CN1C(C=CC=C1)=O)O)C1=C(C=C(C=C1OC)F)OC LQDVDLXIGYHGEY-UHFFFAOYSA-N 0.000 description 1
- FHUQYVQCIQJAHF-UHFFFAOYSA-N 6-butyl-3-[4-[(2,3-difluorophenyl)methyl]piperazine-1-carbonyl]-5-(2,3-dimethoxyphenyl)-4-hydroxy-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)CC1=C(C(=CC=C1)F)F)O)C1=C(C(=CC=C1)OC)OC FHUQYVQCIQJAHF-UHFFFAOYSA-N 0.000 description 1
- GUFNVUDXTINVTO-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-[4-(3-propyl-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl]-1H-pyridin-2-one Chemical compound CCCCC1=C(C(O)=C(C(=O)N2CCC(CC2)C2=NC(CCC)=NO2)C(O)=N1)C1=C(OC)C=CC=C1OC GUFNVUDXTINVTO-UHFFFAOYSA-N 0.000 description 1
- XNAHSRPAEBCQHM-UHFFFAOYSA-N 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-3-[4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carbonyl]-1H-pyridin-2-one Chemical compound C(CCC)C1=C(C(=C(C(=N1)O)C(=O)N1CCN(CC1)C1=NC=CC=C1C(F)(F)F)O)C1=C(C=CC=C1OC)OC XNAHSRPAEBCQHM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 101150059573 AGTR1 gene Proteins 0.000 description 1
- ITZMJCSORYKOSI-AJNGGQMLSA-N APGPR Enterostatin Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N1[C@H](C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)CCC1 ITZMJCSORYKOSI-AJNGGQMLSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 208000026828 Aorta coarctation Diseases 0.000 description 1
- 208000006179 Aortic Coarctation Diseases 0.000 description 1
- 102000016555 Apelin receptors Human genes 0.000 description 1
- 102400000252 Apelin-13 Human genes 0.000 description 1
- 102400000251 Apelin-36 Human genes 0.000 description 1
- 101800001808 Apelin-36 Proteins 0.000 description 1
- 200000000007 Arterial disease Diseases 0.000 description 1
- 206010003225 Arteriospasm coronary Diseases 0.000 description 1
- 241000937413 Axia Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 102000013585 Bombesin Human genes 0.000 description 1
- 108010051479 Bombesin Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- PVAJDEVOHOZSCM-UHFFFAOYSA-N C1(CCCCC1)NC(=O)N.C(C)(=O)C1=CC=CC=C1 Chemical compound C1(CCCCC1)NC(=O)N.C(C)(=O)C1=CC=CC=C1 PVAJDEVOHOZSCM-UHFFFAOYSA-N 0.000 description 1
- 125000006538 C11 alkyl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 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
- 101800001982 Cholecystokinin Proteins 0.000 description 1
- 102100025841 Cholecystokinin Human genes 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- 229920001268 Cholestyramine Polymers 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010009807 Coarctation of the aorta Diseases 0.000 description 1
- 229920002911 Colestipol Polymers 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 102000012289 Corticotropin-Releasing Hormone Human genes 0.000 description 1
- 108010022152 Corticotropin-Releasing Hormone Proteins 0.000 description 1
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 1
- FMGSKLZLMKYGDP-UHFFFAOYSA-N Dehydroepiandrosterone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CC=C21 FMGSKLZLMKYGDP-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 239000004131 EU approved raising agent Substances 0.000 description 1
- 208000037487 Endotoxemia Diseases 0.000 description 1
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)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)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 1
- 108010011459 Exenatide Proteins 0.000 description 1
- UTICCJKOWNGQBL-UHFFFAOYSA-N FC1=CC(=C(C(=C1)OC)CC#N)OC Chemical compound FC1=CC(=C(C(=C1)OC)CC#N)OC UTICCJKOWNGQBL-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102400001370 Galanin Human genes 0.000 description 1
- 101800002068 Galanin Proteins 0.000 description 1
- 102000034354 Gi proteins Human genes 0.000 description 1
- 108091006101 Gi proteins Proteins 0.000 description 1
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 244000020551 Helianthus annuus Species 0.000 description 1
- 235000003222 Helianthus annuus Nutrition 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 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 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 229940122199 Insulin secretagogue Drugs 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- 229910004861 K2 HPO4 Inorganic materials 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- 108010007622 LDL Lipoproteins Proteins 0.000 description 1
- 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 1
- 102000016267 Leptin Human genes 0.000 description 1
- 108010092277 Leptin Proteins 0.000 description 1
- 229940127470 Lipase Inhibitors Drugs 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 239000000637 Melanocyte-Stimulating Hormone Substances 0.000 description 1
- 108010007013 Melanocyte-Stimulating Hormones Proteins 0.000 description 1
- 101710151321 Melanostatin Proteins 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
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- RYQMZBNXEZLSQY-UHFFFAOYSA-N NC(=C(C(=O)OCC)C1=C(C=CC=C1OC)OC)CCCC Chemical compound NC(=C(C(=O)OCC)C1=C(C=CC=C1OC)OC)CCCC RYQMZBNXEZLSQY-UHFFFAOYSA-N 0.000 description 1
- 229910017711 NHRa Inorganic materials 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 102400000064 Neuropeptide Y Human genes 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 102000008052 Nitric Oxide Synthase Type III Human genes 0.000 description 1
- 108010075520 Nitric Oxide Synthase Type III Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 102000023984 PPAR alpha Human genes 0.000 description 1
- 108010016731 PPAR gamma Proteins 0.000 description 1
- 108010044210 PPAR-beta Proteins 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 1
- 108010081690 Pertussis Toxin Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- 108700018615 Pyr(1)- apelin 13 Proteins 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 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 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 208000009982 Ventricular Dysfunction Diseases 0.000 description 1
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- CKUAXEQHGKSLHN-UHFFFAOYSA-N [C].[N] Chemical group [C].[N] CKUAXEQHGKSLHN-UHFFFAOYSA-N 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 239000000785 adrenergic beta-1 receptor agonist Substances 0.000 description 1
- 239000000808 adrenergic beta-agonist Substances 0.000 description 1
- 229940126157 adrenergic receptor agonist Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000002170 aldosterone antagonist Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000006177 alkyl benzyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- IVHKZGYFKJRXBD-UHFFFAOYSA-N amino carbamate Chemical compound NOC(N)=O IVHKZGYFKJRXBD-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 229940125364 angiotensin receptor blocker Drugs 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000002253 anti-ischaemic effect Effects 0.000 description 1
- 230000002946 anti-pancreatic effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 108010040480 apelin-13 peptide Proteins 0.000 description 1
- SVWSKJCJNAIKNH-MJZUAXFLSA-N apelin-17 Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](N)CCCCN)C1=CN=CN1 SVWSKJCJNAIKNH-MJZUAXFLSA-N 0.000 description 1
- BVTLGARMSLXAHI-VDEROMQGSA-N apelin-36 Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)CNC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C)C1=CN=CN1 BVTLGARMSLXAHI-VDEROMQGSA-N 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 125000004935 benzoxazolinyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 102000000072 beta-Arrestins Human genes 0.000 description 1
- 108010080367 beta-Arrestins Proteins 0.000 description 1
- 229960000516 bezafibrate Drugs 0.000 description 1
- IIBYAHWJQTYFKB-UHFFFAOYSA-N bezafibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1CCNC(=O)C1=CC=C(Cl)C=C1 IIBYAHWJQTYFKB-UHFFFAOYSA-N 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 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
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 244000309464 bull Species 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004900 c-terminal fragment Anatomy 0.000 description 1
- 230000001593 cAMP accumulation Effects 0.000 description 1
- 230000003491 cAMP production Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical group 0.000 description 1
- 230000009787 cardiac fibrosis Effects 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 230000001625 cardiomyogenic effect Effects 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 230000009084 cardiovascular function Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000001023 centrifugal evaporation Methods 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- 229960001761 chlorpropamide Drugs 0.000 description 1
- 229940107137 cholecystokinin Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- YZFWTZACSRHJQD-UHFFFAOYSA-N ciglitazone Chemical compound C=1C=C(CC2C(NC(=O)S2)=O)C=CC=1OCC1(C)CCCCC1 YZFWTZACSRHJQD-UHFFFAOYSA-N 0.000 description 1
- 229950009226 ciglitazone Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 208000035850 clinical syndrome Diseases 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
- GMRWGQCZJGVHKL-UHFFFAOYSA-N colestipol Chemical compound ClCC1CO1.NCCNCCNCCNCCN GMRWGQCZJGVHKL-UHFFFAOYSA-N 0.000 description 1
- 229960002604 colestipol Drugs 0.000 description 1
- 239000013066 combination product Substances 0.000 description 1
- 229940127555 combination product Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 1
- 125000002704 decyl 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])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 229960004597 dexfenfluramine Drugs 0.000 description 1
- 201000009101 diabetic angiopathy Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- GRTGGSXWHGKRSB-UHFFFAOYSA-N dichloromethyl methyl ether Chemical compound COC(Cl)Cl GRTGGSXWHGKRSB-UHFFFAOYSA-N 0.000 description 1
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 102000038379 digestive enzymes Human genes 0.000 description 1
- 108091007734 digestive enzymes Proteins 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 150000002085 enols Chemical group 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- NBURZXNJAMAOGH-UHFFFAOYSA-N ethyl 2-(2,6-dimethoxyphenyl)-3-hydroxyhept-2-enoate Chemical compound COC1=C(C(=CC=C1)OC)C(C(=O)OCC)=C(CCCC)O NBURZXNJAMAOGH-UHFFFAOYSA-N 0.000 description 1
- WVVQLGDEFFABLW-UHFFFAOYSA-N ethyl 5-bromo-6-butyl-4-hydroxy-2-oxo-1H-pyridine-3-carboxylate Chemical compound BrC=1C(=NC(=C(C(=O)OCC)C=1O)O)CCCC WVVQLGDEFFABLW-UHFFFAOYSA-N 0.000 description 1
- DCQBNVPTZSEWJX-UHFFFAOYSA-N ethyl 6-butyl-4-hydroxy-2-oxo-5-(3-propan-2-ylphenyl)-1H-pyridine-3-carboxylate Chemical compound CCCCC1=C(C(O)=C(C(=O)OCC)C(=O)N1)C1=CC(=CC=C1)C(C)C DCQBNVPTZSEWJX-UHFFFAOYSA-N 0.000 description 1
- XRLABGSRYMWXES-UHFFFAOYSA-N ethyl 6-butyl-5-(2,6-dimethoxyphenyl)-4-hydroxy-2-oxo-1H-pyridine-3-carboxylate Chemical compound C(CCC)C1=NC(=C(C(=O)OCC)C(=C1C1=C(C=CC=C1OC)OC)O)O XRLABGSRYMWXES-UHFFFAOYSA-N 0.000 description 1
- RREPHPBBMRBCQB-UHFFFAOYSA-N ethyl 6-butyl-5-(3-fluoro-2,6-dimethoxyphenyl)-4-hydroxy-2-oxo-1H-pyridine-3-carboxylate Chemical compound C(CCC)C1=NC(=C(C(=O)OCC)C(=C1C1=C(C(=CC=C1OC)F)OC)O)O RREPHPBBMRBCQB-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229960001519 exenatide Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000013213 extrapolation Methods 0.000 description 1
- 229960002297 fenofibrate Drugs 0.000 description 1
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 239000002319 fibrinogen receptor antagonist Substances 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000010855 food raising agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000009760 functional impairment Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 229960003468 gliquidone Drugs 0.000 description 1
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 229940120105 glynase Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000004995 haloalkylthio group Chemical group 0.000 description 1
- 208000038003 heart failure with preserved ejection fraction Diseases 0.000 description 1
- 208000038002 heart failure with reduced ejection fraction Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 102000047215 human APLNR Human genes 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 208000001286 intracranial vasospasm Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 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
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 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
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 1
- 229940039781 leptin Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process 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
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002394 mineralocorticoid antagonist Substances 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- SLZIZIJTGAYEKK-CIJSCKBQSA-N molport-023-220-247 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CN)[C@@H](C)O)C1=CNC=N1 SLZIZIJTGAYEKK-CIJSCKBQSA-N 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 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 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
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000006070 nanosuspension Substances 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 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
- 230000007935 neutral effect Effects 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
- 229960001243 orlistat Drugs 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- GGMAXEWLXWJGSF-PEWBXTNBSA-N p-Glu-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H]1NC(=O)CC1)C1=CN=CN1 GGMAXEWLXWJGSF-PEWBXTNBSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 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
- 230000003076 paracrine Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 229960003562 phentermine Drugs 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- LYKMMUBOEFYJQG-UHFFFAOYSA-N piperoxan Chemical compound C1OC2=CC=CC=C2OC1CN1CCCCC1 LYKMMUBOEFYJQG-UHFFFAOYSA-N 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960003611 pramlintide Drugs 0.000 description 1
- 108010029667 pramlintide Proteins 0.000 description 1
- NRKVKVQDUCJPIZ-MKAGXXMWSA-N pramlintide acetate Chemical compound C([C@@H](C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)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]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCCCN)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NRKVKVQDUCJPIZ-MKAGXXMWSA-N 0.000 description 1
- 229960002847 prasterone Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000036316 preload Effects 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108010070701 procolipase Proteins 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000010791 quenching Methods 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
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000033300 receptor internalization Effects 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 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
- 229960002354 repaglinide Drugs 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 1
- 229960004937 saxagliptin Drugs 0.000 description 1
- 108010033693 saxagliptin Proteins 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 208000013220 shortness of breath Diseases 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
- 230000011664 signaling Effects 0.000 description 1
- 230000007727 signaling mechanism Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010922 spray-dried dispersion Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 1
- SMPQEXISQMIBEL-UHFFFAOYSA-N tert-butyl 3-(3-fluorophenyl)pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC1C1=CC=CC(F)=C1 SMPQEXISQMIBEL-UHFFFAOYSA-N 0.000 description 1
- HTNUZOGSBIBGCF-UHFFFAOYSA-N tert-butyl 3-(5-chloropyridin-2-yl)pyrrolidine-1-carboxylate Chemical compound ClC=1C=CC(=NC=1)C1CN(CC1)C(=O)OC(C)(C)C HTNUZOGSBIBGCF-UHFFFAOYSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000005403 thiohaloalkoxy group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylene diamine Substances C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 239000002550 vasoactive agent Substances 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 230000006815 ventricular dysfunction Effects 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 239000011726 vitamin B6 Substances 0.000 description 1
- 229960001729 voglibose Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61P9/10—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
-
- 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
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
本發明提供式(I)化合物:□其中所有變數如本說明書中所定義,及包含此新穎化合物中任一者的組合物。此等化合物為APJ促效劑,其可用作藥劑。
Description
本發明提供為APJ促效劑之新穎2,4-二羥基菸鹼醯胺及其類似物、含有其之組合物,及使用其之方法,例如用於治療或預防心臟衰竭、動脈粥樣硬化、缺血性心臟病及相關病狀。
在已開發國家,心臟衰竭(Heart failure;HF)及相關併發症構成主要健康負擔,僅在美國就估計有5,700,000人發病(Roger, V.L.等人,Circulation
, 125(1):e2-e220 (2012))。儘管近二十年來取得重要進步,但預後仍然很差,在診斷5年內存活率僅為~50%(Roger, V.L.等人,JAMA
, 292(3):344-350 (2004))。除不良之存活率以外,生活品質之減弱及反覆性住院構成針對開發新穎治療選擇之顯然尚未滿足的醫學需求。 HF為臨床症候群,其特徵為心臟無法輸送足夠的血液及氧供應來滿足體內器官之代謝需求。與HF相關之主要症狀包括歸因於肺水腫之呼吸短促、疲勞、運動耐力下降及下肢水腫。HF之病因非常複雜,伴有多種相關之風險因素及潛在病因。 HF之主要病因為冠狀動脈疾病及心臟缺血、急性心肌梗塞、內源性心肌病及慢性不受控高血壓。HF會急性地發展(心肌梗塞後之功能損傷)或成為慢性病狀,其特徵為長期不適應之心臟組織重塑、肥大及心臟功能障礙(例如歸因於失控性長期高血壓)。根據診斷準則及心室功能障礙的類型,HF分為兩個主要群:具有「低收縮分率」(HFrEF)之HF或具有「正常收縮分率」(HFpEF)之HF。兩種類型具有類似病徵及症狀,但心室功能損傷的類型不同(Borlaug, B.A.等人,Eur. Heart J.
, 32(6):670-679 (2011))。 APJ受體(APLNR)及其內源性肽配位體愛帕琳(apelin)已經表明為心臟血管功能之重要調節劑及用於治療性地干預HF之候選物(綜述參見Japp, A.G.等人,Biochem. Pharmacol.
, 75(10):1882-1892 (2008))。 從臨床前疾病模型及人類心臟衰竭患者之所累積的證據隱含,愛帕琳及APJ促效作用在HF發展上是有益處的。不具有愛帕琳或APJ基因之小鼠之肌細胞收縮性減弱(Charo, D.N.等人,Am. J. Physiol. Heart Circ. Physiol.
, 297(5):H1904-H1913 (2009))。愛帕琳基因敲除(KO)小鼠隨著衰老罹患漸進式心臟功能障礙,且在反向主動脈縮窄(TAC)之模型中更易罹患HF(Kuba, K.等人,Circ. Res
., 101(4):e32-42 (2007))。慢性HF中之功能損傷為對心臟之長期需求之結果,且與不適應之心臟重塑作用相關,藉由心臟肥大、增加之發炎及間質纖維化體現,最終導致心臟效能降低。 在正常條件下及還有在心臟衰竭之模型中,急性投與愛帕琳會增加囓齒動物心輸出量(Berry, M.F.,Circulation
, 110(11增刊 1):II187-II193 (2004))。直接加強心臟收縮性且動脈及靜脈床中周邊血管阻力下降導致心輸出量增加(Ashley, E.A.,Cardiovasc. Res.,
65(1):73-82 (2005))。血管阻力之降低在心臟上產生更低之前負荷及後負荷,且因此產生更低之工作負荷(Cheng, X.等人,Eur. J. Pharmacol
., 470(3):171-175 (2003))。類似於囓齒動物研究,愛帕琳急性輸注至健康人類個體及患有心臟衰竭之患者產生類似的血液動力學反應,其中心輸出量增加且在周邊及冠狀動脈中血管舒張反應增加(Japp, A.G.等人,Circulation
, 121(16):1818-1827 (2010))。 愛帕琳之基礎心肌收縮作用機制未完全理解,但由於心跳速率不增加,因此似乎不同於臨床上使用之β1
腎上腺素促效劑(多巴酚丁胺)。愛帕琳之血管舒張作用主要經由內皮氧化氮合成酶路徑介導(Tatemoto, K.,Regul. Pept
., 99(2-3):87-92 (2001))。愛帕琳在缺氧條件下會經誘導,促進血管生成,且已證明會限制缺血-再灌注模型中之梗塞大小(Simpkin, J.C.,Basic Res. Cardiol
., 102(6):518-528 (2007))。 除評估愛帕琳之急性投藥之前述研究以外,若干研究已清晰地顯示在HF之許多慢性囓齒動物模型、包括血管收縮素II模型、TAC模型及大鼠Dahl鹽敏感型模型中長期投與愛帕琳產生有益作用(Siddiquee, K.等人,J. Hypertens.
, 29(4):724-731 (2011);Scimia, M.C.等人,Nature
, 488(7411):394-398 (2012);Koguchi, W.等人,Circ. J
., 76(1):137-144 (2012))。在此等研究中,長期輸注愛帕琳會降低心臟肥大及心臟纖維化,且與心臟效能之改善相關。 基因跡象亦顯示APJ基因之多形現象與HF之較慢進展相關(Sarzani, R.等人,J. Card. Fail.
, 13(7):521-529 (2007))。重要的是,雖然APJ及愛帕琳之表現可能隨HF進展降低或顯著變化,但愛帕琳之心臟血管血液動力學作用在罹患HF並接受標準照護療法之患者中會持久(Japp, A.G.等人,Circulation
, 121(16):1818-1827 (2010))。 概言之,大量跡象指示APJ受體促效作用在HF中起心臟保護作用且對HF患者而言將具有潛在益處。愛帕琳在循環中之極短半衰期限制其治療效用,且因此需要具有改進藥物動力學及信號傳導概況同時保持或促進內源性APJ促效劑愛帕琳之有益作用的APJ受體促效劑。
本發明提供適用作APJ促效劑之2,4-二羥基菸鹼醯胺及其類似物,包括其立體異構體、互變異構體、醫藥學上可接受之鹽或溶劑合物。 本發明亦提供用於製備本發明化合物或其立體異構體、互變異構體、醫藥學上可接受之鹽或溶劑合物之方法及中間物。 本發明亦提供醫藥組合物,其包含醫藥學上可接受之載劑及本發明化合物或其立體異構體、互變異構體、醫藥學上可接受之鹽或溶劑合物中之至少一者。 本發明化合物可用於治療及/或預防與APJ相關之多種疾病或病症,諸如心臟衰竭、冠狀動脈疾病、心肌症、糖尿病及相關病狀,包括(但不限於)急性冠狀動脈症候群、心肌缺血、高血壓、肺高血壓、冠狀動脈痙攣、腦血管痙攣、缺血/再灌注損傷、心絞痛、腎病、代謝症候群及胰島素抗性。 本發明化合物可用於療法中。 本發明化合物可用於製造供治療及/或預防與APJ相關之多種疾病或病症用之藥劑。 本發明化合物可單獨使用,與本發明之其他化合物組合使用或與一或多種其他藥劑組合使用。 本發明之其他特徵及優勢將自以下實施方式及申請專利範圍而顯而易見。
相關申請案之交叉參考 本申請案主張2015年10月14日申請之美國臨時申請案第62/241,367號及2015年12月22日申請之美國臨時申請案第62/270,659號之優先權。 I. 本發明化合物 在第一態樣中,本發明尤其提供式(I)化合物:或其立體異構體、對映異構體、非對映異構體、互變異構體、醫藥學上可接受之鹽、前藥或溶劑合物,其中: alk為經0至5個Re
取代之C1-6
烷基; 環B獨立地選自C3-6
環烷基、C3-6
環烯基、芳基、雙環碳環基及6員雜芳基; R1
獨立地選自鹵素、NO2
、-(CH2
)n
ORb
、(CH2
)n
S(O)p
Rc
、-(CH2
)n
C(=O)Rb
、-(CH2
)n
NRa
Ra
、-(CH2
)n
CN、-(CH2
)n
C(=O)NRa
Ra
、-(CH2
)n
NRa
C(=O)Rb
、-(CH2
)n
NRa
C(=O)NRa
Ra
、-(CH2
)n
NRa
C(=O)ORb
、-(CH2
)n
OC(=O)NRa
Ra
、-(CH2
)n
C(=O)ORb
、-(CH2
)n
S(O)p
NRa
Ra
、-(CH2
)n
NRa
S(O)p
NRa
Ra
、-(CH2
)n
NRa
S(O)p
Rc
、經0至3個Re
取代之C1-4
烷基、經0至3個Re
取代之-(CH2
)n
-C3-6
碳環基及經0至3個Re
取代之-(CH2
)n
-雜環基; R2
獨立地選自經0至3個Re
取代之C1-5
烷基;經0至3個Re
取代之C1-5
烯基;經0至3個Re
取代之芳基;經0至3個Re
取代之雜環基及經0至3個Re
取代之C3-6
環烷基;其限制條件為當R2
為C1-5
烷基時,除了連接至吡啶環之碳原子以外的碳原子及連接至其上之基團可經O、N及S置換; R3
及R4
獨立地選自經0至3個R6
取代之C1-5
烷基;經0至3個R6
取代之-(CH2
)n
-C3-6
碳環基及經0至3個R6
取代之-(CH2
)n
-雜環基; 或者,R3
及R4
連同其共同連接之氮原子一起形成包含碳原子及額外1至4個選自NR5a
、O及S之雜原子且經0至5個R5
取代之雜環或螺雜環; R5
在每次出現時獨立地選自OH、鹵素、-(CR7
R7
)n
-C3-10
碳環、-(CR7
R7
)n-
雜環,且各自經0至3個R6
取代; R5a
在每次出現時獨立地選自-C(=O)ORb
、C(=O)NRa
Ra
、-S(O)p
Rc
、-(CR7
R7
)n
-C3-10
碳環、-C(=O)-C3-10
碳環、-(CR7
R7
)n-
雜環,各自經0至3個R6
取代; R6
獨立地選自H、鹵素、=O、-(CH2
)n
ORb
、(CH2
)n
S(O)p
Rc
、-(CH2
)n
C(=O)Rb
、-(CH2
)n
NRa
Ra
、-(CH2
)n
CN、-(CH2
)n
C(=O)NRa
Ra
、-(CH2
)n
NRa
C(=O)Rb
、-(CH2
)n
NRa
C(=O)NRa
Ra
、-(CH2
)n
NRa
C(=O)ORb
、-(CH2
)n
OC(=O)NRa
Ra
、-(CH2
)n
C(=O)ORb
、-(CH2
)n
S(O)p
NRa
Ra
、-(CH2
)n
NRa
S(O)p
NRa
Ra
、-(CH2
)n
NRa
S(O)p
Rc
、經0至3個Re
取代之C1-5
烷基、經0至3個Re
取代之(CH2
)n
-C3-6
碳環基及經0至3個Re
取代之-(CH2
)n
-雜環基; R7
在每次出現時獨立地選自H、C1-4
烷基及經0至3個Re
取代之(CH2
)n
-C3-12
碳環基; Ra
在每次出現時獨立地選自H、經0至5個Re
取代之C1-6
烷基、經0至5個Re
取代之C2-6
烯基、經0至5個Re
取代之C2-6
炔基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基;或Ra
及Ra
連同其共同連接之氮原子一起形成經0至5個Re
取代之雜環; Rb
在每次出現時獨立地選自H、經0˗5個Re
取代之C1˗6
烷基、經0˗5個Re
取代之C2˗6
烯基、經0˗5個Re
取代之C2˗6
炔基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基; Rc
在每次出現時獨立地選自經0至5個Re
取代之C1-6
烷基、經0至5個Re
取代之C2-6
烯基、經0至5個Re
取代之C2-6
炔基、C3˗6
碳環基及雜環基; Rd
在每次出現時獨立地選自H及經0至5個Re
取代之C1-4
烷基; Re
在每次出現時獨立地選自經0至5個Rf
取代之C1-6
烷基、C2-6
烯基、C2-6
炔基、-(CH2
)n
-C3-6
環烷基、-(CH2
)n
-C4-6
雜環基、-(CH2
)n
-芳基、-(CH2
)n
-雜芳基、F、Cl、Br、CN、NO2
、=O、CO2
H、-(CH2
)n
ORf
、S(O)p
Rf
、C(=O)NRf
Rf
、NRf
C(=O)Rf
、S(O)p
NRf
Rf
、NRf
S(O)p
Rf
、NRf
C(=O)ORf
、OC(=O)NRf
Rf
及-(CH2
)n
NRf
Rf
; Rf
在每次出現時獨立地選自H、F、Cl、Br、CN、OH、C1-5
烷基(最佳經鹵素及OH取代)、C3-6
環烷基及苯基,或Rf
及Rf
連同其共同連接之氮原子一起形成視情況經C1-4
烷基取代之雜環; n獨立地選自0、1、2、3及4;且 p在每次出現時獨立地選自0、1及2。 在第二態樣中,本發明提供一種式(II)化合物:或其立體異構體、對映異構體、非對映異構體、互變異構體、醫藥學上可接受之鹽、前藥或溶劑合物,以上者在第一態樣之範疇內,其中: 環B獨立地選自、及6員雜芳基; R1
獨立地選自F、Cl、Br、NO2
、-(CH2
)n
ORb
、-(CH2
)n
C(=O)Rb
、-(CH2
)n
NRa
Ra
、-(CH2
)n
C(=O)NRa
Ra
、-(CH2
)n
NRa
C(=O)Rb
、經0至3個Re
取代之C1-4
烷基及經0至3個Re
取代之C3-6
環烷基; R2
獨立地選自經0至3個Re
取代之C1-5
烷基、C1-5
烯基、經0至3個Re
取代之芳基、經0至3個Re
取代之雜環基及C3-6
環烷基;其限制條件為當R2
為C1-5
烷基時,除了連接至吡啶環之碳原子以外的碳原子及連接至其上之基團可經O、N及S置換; R3
及R4
連同其共同連接之氮原子一起形成選自以下之雜環或螺雜環:; R5
在每次出現時獨立地選自OH、-(CH2
)n
-芳基、-(CH2
)n
-C3-6
環烷基及-(CH2
)n
-雜環,各自經0至3個R6
取代; R5a
在每次出現時獨立地選自-(CR7
R7
)n
-C3-10
碳環及-(CR7
R7
)n
-雜環、-C(=O)-C3-10
碳環,各自經0至3個R6
取代; R6
獨立地選自H、F、Cl、Br、-ORb
、=O、-(CH2
)n
C(=O)Rb
、-(CH2
)n
C(=O)ORb
、-(CH2
)n
NRa
Ra
、CN、-(CH2
)n
C(=O)NRa
Ra
、-NHC(=O)ORb
、經0至3個Re
取代之C1-4
烷基、經0至3個Re
取代之(CH2
)n
-C3-6
碳環基及經0至3個Re
取代之-(CH2
)n
-雜環基; R7
在每次出現時獨立地選自H、C1-4
烷基及經0至3個Re
取代之(CH2
)n
-C3-12
碳環基; Ra
在每次出現時獨立地選自H、經0至5個Re
取代之C1-6
烷基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基;或Ra
及Ra
連同其共同連接之氮原子一起形成經0至5個Re
取代之雜環; Rb
在每次出現時獨立地選自H、經0˗5個Re
取代之C1˗6
烷基、經0˗5個Re
取代之C2˗6
烯基、經0˗5個Re
取代之C2˗6
炔基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基; Re
在每次出現時獨立地選自經0至5個Rf
取代之C1-6
烷基、C2-6
烯基、C2-6
炔基、-(CH2
)n
-C3-6
環烷基、-(CH2
)n
-C4-6
雜環基、-(CH2
)n
-芳基、-(CH2
)n
-雜芳基、F、Cl、Br、CN、NO2
、=O、CO2
H、-(CH2
)n
ORf
、S(O)p
Rf
、C(=O)NRf
Rf
、NRf
C(=O)Rf
、S(O)p
NRf
Rf
、NRf
S(O)p
Rf
、NRf
C(=O)ORf
、OC(=O)NRf
Rf
及-(CH2
)n
NRf
Rf
; Rf
在每次出現時獨立地選自H、F、Cl、Br、CN、OH、C1-5
烷基(最佳經鹵素及OH取代)、C3-6
環烷基及苯基; n獨立地選自0、1、2、3及4;且 p在每次出現時獨立地選自0、1及2。 在第三態樣中,本發明提供一種式(III)化合物:或其立體異構體、對映異構體、非對映異構體、互變異構體、醫藥學上可接受之鹽、前藥或溶劑合物,以上者在第一或第二態樣之範疇內,其中: R1
獨立地選自F、Cl、OH及OC1-4
烷基; R1a
獨立地選自F、Cl及C1-2
烷基; R2
獨立地選自經0至3個Re
取代之C1-5
烷基、C1-5
烯基、經0至3個Re
取代之芳基、經0至3個Re
取代之雜芳基、C3-6
環烷基及-(CH2
)1-4
OC1-5
烷基及-(CH2
)1-3
OC3-6
環烷基; R3
及R4
連同其共同連接之氮原子一起形成選自以下之雜環或螺雜環:; R5
在每次出現時獨立地選自OH、-(CH2
)n
-芳基、-(CH2
)n
-C3-6
環烷基及-(CH2
)n
-雜環,各自經0至3個R6
取代; R5a
在每次出現時獨立地選自-(CR7
R7
)n
-C3-10
碳環及-(CR7
R7
)n
-雜環、-C(=O)-C3-10
碳環,各自經0至3個R6
取代; R6
獨立地選自H、F、Cl、Br、-ORb
、=O、-(CH2
)n
C(=O)Rb
、-(CH2
)n
C(=O)ORb
、-(CH2
)n
NRa
Ra
、CN、-(CH2
)n
C(=O)NRa
Ra
、經0至3個Re
取代之C1-4
烷基、經0至3個Re
取代之(CH2
)n
-C3-6
碳環基及經0至3個Re
取代之-(CH2
)n
-雜環基; R7
在每次出現時獨立地選自H、C1-4
烷基及經0至3個Re
取代之(CH2
)n
-C3-12
碳環基; Ra
在每次出現時獨立地選自H、經0至5個Re
取代之C1-6
烷基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基;或Ra
及Ra
連同其共同連接之氮原子一起形成經0至5個Re
取代之雜環; Rb
在每次出現時獨立地選自H、經0˗5個Re
取代之C1˗6
烷基、經0˗5個Re
取代之C2˗6
烯基、經0˗5個Re
取代之C2˗6
炔基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基; Re
在每次出現時獨立地選自C1-6
烷基(視情況經F及Cl取代)、OH、OCH3
、OCF3
、-(CH2
)n
-C3-6
環烷基、-(CH2
)n
-C4-6
雜環基、-(CH2
)n
-芳基、-(CH2
)n
-雜芳基、F、Cl、Br、CN、NO2
、=O、CO2
H;且 n獨立地選自0、1、2、3及4。 在第四態樣中,本發明提供一種式(III)化合物或其立體異構體、對映異構體、非對映異構體、互變異構體、醫藥學上可接受之鹽、前藥或溶劑合物,以上者在第一、第二及第三態樣中之任一者之範疇內,其中: R5
在每次出現時獨立地選自 ; R6
獨立地選自H、F、Cl、Br、-OCH3
、-OCF3
、=O、CN、CH3
、CF3
-(CH2
)n
-芳基、經0至3個Re
取代之-(CH2
)n
-C3-6
環烷基及經0至3個Re
取代之-(CH2
)n
-雜環基; R6a
獨立地選自H、CH3
、經0至3個Re
取代之芳基及經0至3個Re
取代之雜環基; Ra
在每次出現時獨立地選自H、經0至5個Re
取代之C1-6
烷基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基; Re
在每次出現時獨立地選自C1-6
烷基(視情況經F及Cl取代)、OH、OCH3
、OCF3
、-(CH2
)n
-C3-6
環烷基、-(CH2
)n
-C4-6
雜環基、-(CH2
)n
-芳基、-(CH2
)n
-雜芳基、F、Cl、Br、CN、NO2
、=O、CO2
H;且 n獨立地選自0、1、2及3。 在第五態樣中,本發明提供一種式(III)化合物或其立體異構體、對映異構體、非對映異構體、互變異構體、醫藥學上可接受之鹽、前藥或溶劑合物,以上者在第一、第二及第三態樣中之任一者之範疇內,其中: R3
及R4
連同其共同連接之氮原子一起形成選自以下之雜環或螺雜環:; R5a
在每次出現時獨立地選自 ; R6
獨立地選自H、F、Cl、Br、-OCH3
、-O(CH2
)1-3
OCH3
、-OCF3
、=O、CN、CH3
、CF3
-(CH2
)n
-芳基、經0至3個Re
取代之-(CH2
)n
-C3-6
環烷基及經0至3個Re
取代之-(CH2
)n
-雜環基; R6a
獨立地選自H、CH3
、經0至3個Re
取代之芳基及經0至3個Re
取代之雜環基; Re
在每次出現時獨立地選自C1-6
烷基(視情況經F及Cl取代)、OH、OCH3
、OCF3
、-(CH2
)n
-C3-6
環烷基、-(CH2
)n
-C4-6
雜環基、-(CH2
)n
-芳基、-(CH2
)n
-雜芳基、F、Cl、Br、CN、NO2
、=O、CO2
H;且 n獨立地選自0、1、2及3。 在第六態樣中,本發明提供一種式(III)化合物或其立體異構體、對映異構體、非對映異構體、互變異構體、醫藥學上可接受之鹽、前藥或溶劑合物,以上者在第一、第二及第三態樣中之任一者之範疇內,其中: R1
獨立地選自F、Cl、OH及OC1-4
烷基; R1a
獨立地選自F、Cl及C1-2
烷基; R2
獨立地選自經0至3個Re
取代之C1-5
烷基、C1-5
烯基、經0至3個Re
取代之苯基、經0至3個Re
取代之6員雜芳基、C3-6
環烷基及CH2
O(CH2
)1-3
CH3
; R3
及R4
連同其共同連接之氮原子一起形成選自以下之雜環或螺雜環:; R5
在每次出現時獨立地選自OH、 ; R6
獨立地選自H、F、Cl、Br、-OCH3
、-OCF3
、=O、CN、CH3
、CF3
、-C(=O)NH2
、經0至3個Re
取代之-(CH2
)n
-芳基、經0至3個Re
取代之-(CH2
)n
-C3-6
環烷基及經0至3個Re
取代之-(CH2
)n
-雜環基; R6a
獨立地選自H、CH3
、經0至3個Re
取代之芳基及經0至3個Re
取代之雜環基; Ra
在每次出現時獨立地選自H、經0至5個Re
取代之C1-6
烷基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基; Re
在每次出現時獨立地選自C1-6
烷基(視情況經F及Cl取代)、OH、OCH3
、OCF3
、-(CH2
)n
-C3-6
環烷基、-(CH2
)n
-C4-6
雜環基、-(CH2
)n
-芳基、-(CH2
)n
-雜芳基、F、Cl、Br、CN、NO2
、=O、CO2
H;且 n獨立地選自0、1、2及3。 在第七態樣中,本發明提供一種化合物或其立體異構體、對映異構體、非對映異構體、互變異構體、醫藥學上可接受之鹽、前藥或溶劑合物,以上者在第一、第二及第三態樣之範疇內,其中: R1
獨立地選自-CH2
OH、-OCH3
、-OCF3
、OCH2
Ph、-C(=O)NRa
Ra
、-NRa
Ra
、CH3
、CH2
CH3
、CH(CH3
)2
及環丙基; R2
獨立地選自經0至3個Re
取代之C1-5
烷基、C1-5
烯基、經0至3個Re
取代之苯基、經0至3個Re
取代之6員雜芳基、C3-6
環烷基及CH2
O(CH2
)1-3
CH3
; R3
及R4
獨立地選自經0至3個R6
取代之C1-5
烷基;經0至3個R6
取代之-(CH2
)n
-C3-6
碳環基及經0至3個R6
取代之-(CH2
)n
-雜環基; R6
獨立地選自H、鹵素、-(CH2
)n
ORb
、-(CH2
)n
NRa
Ra
、-(CH2
)n
C(=O)NRa
Ra
、-(CH2
)n
NRa
C(=O)Rb
、-(CH2
)n
NRa
C(=O)ORb
、-(CH2
)n
OC(=O)NRa
Ra
、-(CH2
)n
C(=O)ORb
、-(CH2
)n
S(O)p
NRa
Ra
、-(CH2
)n
NRa
S(O)p
NRa
Ra
、經0至3個Re
取代之C1-5
烷基、經0至3個Re
取代之苯基及經0至3個Re
取代之雜環基; Ra
在每次出現時獨立地選自H、經0至5個Re
取代之C1-6
烷基、經0至5個Re
取代之-(CH2
)n
-苯基及經0至5個Re
取代之-(CH2
)n
-雜芳基; Rb
在每次出現時獨立地選自H、經0至5個Re
取代之C1-6
烷基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基; Re
在每次出現時獨立地選自C1-6
烷基(視情況經F及Cl取代)、OH、OCH3
、OCF3
、-(CH2
)n
-C3-6
環烷基、-(CH2
)n
-C4-6
雜環基、-(CH2
)n
-芳基、-(CH2
)n
-雜芳基、F、Cl、Br、CN、NO2
、=O、CO2
H;且 n獨立地選自0、1、2、3及4。 在第八態樣中,本發明提供一種選自例示性實例之化合物或其立體異構體、對映異構體、非對映異構體、互變異構體、醫藥學上可接受之鹽、前藥或溶劑合物。 在另一態樣中,本發明提供式(I)化合物或其立體異構體、對映異構體、非對映異構體、互變異構體、醫藥學上可接受之鹽、溶劑合物或前藥,其中: alk為經0至5個Re
取代之C1-6
烷基; 環B獨立地選自C3-6
環烷基、C3-6
環烯基、芳基、雙環碳環基及6員雜芳基; R1
獨立地選自鹵素、NO2
、-(CH2
)n
ORb
、(CH2
)n
S(O)p
Rc
、-(CH2
)n
C(=O)Rb
、-(CH2
)n
NRa
Ra
、-(CH2
)n
CN、-(CH2
)n
C(=O)NRa
Ra
、-(CH2
)n
NRa
C(=O)Rb
、-(CH2
)n
NRa
C(=O)NRa
Ra
、-(CH2
)n
NRa
C(=O)ORb
、-(CH2
)n
OC(=O)NRa
Ra
、-(CH2
)n
C(=O)ORb
、-(CH2
)n
S(O)p
NRa
Ra
、-(CH2
)n
NRa
S(O)p
NRa
Ra
、-(CH2
)n
NRa
S(O)p
Rc
、經0至3個Re
取代之C1-4
烷基、經0至3個Re
取代之-(CH2
)n
-C3-6
碳環基及經0至3個Re
取代之-(CH2
)n
-雜環基; R2
獨立地選自經0至3個Re
取代之C1-5
烷基;經0至3個Re
取代之C1-5
烯基;經0至3個Re
取代之芳基;經0至3個Re
取代之雜環基及經0至3個Re
取代之C3-6
環烷基;其限制條件為當R2
為C1-5
烷基時,除了連接至吡啶環之亞甲基單元以外的亞甲基單元可經O、N及S置換; R3
及R4
獨立地選自H、經0至3個R6
取代之C1-5
烷基、經0至3個R6
取代之-(CH2
)n
-C3-6
碳環基及經0至3個R6
取代之-(CH2
)n
-雜環基;其限制條件為R3
及R4
不均為H; 或者,R3
及R4
連同其共同連接之氮原子一起形成包含碳原子及0至4個選自N、NR5a
、O及S之雜原子且經0至5個R5
取代之雜環或螺雜環; R5
在每次出現時獨立地選自OH、鹵素、-(CR7
R7
)n
-C3-10
碳環、-(CR7
R7
)n-
雜環,且各自經0至3個R6
取代; R5a
在每次出現時獨立地選自-C(=O)ORb
、C(=O)NRa
Ra
、-S(O)p
Rc
、-(CR7
R7
)n
-C3-10
碳環、-C(=O)-C3-10
碳環、-(CR7
R7
)n
-雜環、-C(=O)-雜環,各自經0至3個R6
取代; R6
獨立地選自H、鹵素、=O、-(CH2
)n
ORb
、(CH2
)n
S(O)p
Rc
、-(CH2
)n
C(=O)Rb
、-(CH2
)n
NRa
Ra
、-(CH2
)n
CN、-(CH2
)n
C(=O)NRa
Ra
、-(CH2
)n
NRa
C(=O)Rb
、-(CH2
)n
NRa
C(=O)NRa
Ra
、-(CH2
)n
NRa
C(=O)ORb
、-(CH2
)n
OC(=O)NRa
Ra
、-(CH2
)n
C(=O)ORb
、-(CH2
)n
S(O)p
NRa
Ra
、-(CH2
)n
NRa
S(O)p
NRa
Ra
、-(CH2
)n
NRa
S(O)p
Rc
、經0至3個Re
取代之C1-5
烷基、經0至3個Re
取代之(CH2
)n
-C3-6
碳環基及經0至3個Re
取代之-(CH2
)n
-雜環基; R7
在每次出現時獨立地選自H、C1-4
烷基及經0至3個Re
取代之(CH2
)n
-C3-12
碳環基; Ra
在每次出現時獨立地選自H、經0至5個Re
取代之C1-6
烷基、經0至5個Re
取代之C2-6
烯基、經0至5個Re
取代之C2-6
炔基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基;或Ra
及Ra
連同其共同連接之氮原子一起形成經0至5個Re
取代之雜環; Rb
在每次出現時獨立地選自H、經0˗5個Re
取代之C1˗6
烷基、經0˗5個Re
取代之C2˗6
烯基、經0˗5個Re
取代之C2˗6
炔基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基; Rc
在每次出現時獨立地選自經0至5個Re
取代之C1-6
烷基、經0至5個Re
取代之C2-6
烯基、經0至5個Re
取代之C2-6
炔基、經0至5個Re
取代之C3-6
碳環基及經0至5個Re
取代之雜環基; Rd
在每次出現時獨立地選自H及經0至5個Re
取代之C1-4
烷基; Re
在每次出現時獨立地選自經0至5個Rg
取代之C1-6
烷基、C2-6
烯基、C2-6
炔基、-(CH2
)n
-C3-6
環烷基、-(CH2
)n
-C4-6
雜環基、-(CH2
)n
-芳基、-(CH2
)n
-雜芳基、F、Cl、Br、CN、NO2
、=O、-(CH2
)n
CO2
Rf
、-(CH2
)n
ORf
、-(CH2
)n
S(O)p
Rf
、-(CH2
)n
C(=O)NRf
Rf
、-(CH2
)n
NRf
C(=O)Rf
、-(CH2
)n
S(O)p
NRf
Rf
、-(CH2
)n
NRf
S(O)p
Rf
、-(CH2
)n
NRf
C(=O)ORf
、-(CH2
)n
OC(=O)NRf
Rf
及-(CH2
)n
NRf
Rf
; Rf
在每次出現時獨立地選自H、C1-5
烷基(最佳經鹵素及OH取代)、C3-6
環烷基及苯基,或Rf
及Rf
連同其共同連接之氮原子一起形成視情況經C1-4
烷基取代之雜環; Rg
在每次出現時獨立地選自H、F、Cl、Br、CN、OH、C1-5
烷基(最佳經鹵素及OH取代)、C3-6
環烷基及苯基; n獨立地選自0、1、2、3及4;且 p在每次出現時獨立地選自0、1及2。 在另一態樣中,本發明提供式(II)化合物或其立體異構體、對映異構體、非對映異構體、互變異構體、醫藥學上可接受之鹽、溶劑合物或前藥,其中: 環B獨立地選自、及6員雜芳基; R1
獨立地選自F、Cl、Br、NO2
、-(CH2
)n
ORb
、-(CH2
)n
C(=O)Rb
、-(CH2
)n
NRa
Ra
、-(CH2
)n
CN、-(CH2
)n
C(=O)NRa
Ra
、-(CH2
)n
NRa
C(=O)Rb
、經0至3個Re
取代之C1-4
烷基及經0至3個Re
取代之C3-6
環烷基; R2
獨立地選自經0至3個Re
取代之C1-5
烷基;經0至3個Re
取代之C1-5
烯基;經0至3個Re
取代之芳基;經0至3個Re
取代之雜環基及經0至3個Re
取代之C3-6
環烷基;其限制條件為當R2
為C1-5
烷基時,除了連接至吡啶環之亞甲基單元以外的亞甲基單元可經O、N及S置換; R3
及R4
獨立地選自H及經0至3個R6
取代之C1-5
烷基;其限制條件為R3
及R4
不均為H; 或者,R3
及R4
連同其共同連接之氮原子一起形成選自以下之雜環或螺雜環:; R5
在每次出現時獨立地選自OH、-(CH2
)n
-芳基、-(CH2
)n
-C3-6
環烷基及-(CH2
)n
-雜環,各自經0至3個R6
取代; R5a
在每次出現時獨立地選自-(CR7
R7
)n
-C3-10
碳環及-(CR7
R7
)n
-雜環、-C(=O)-C3-10
碳環,各自經0至3個R6
取代; R6
獨立地選自H、F、Cl、Br、-ORb
、=O、-(CH2
)n
C(=O)Rb
、-(CH2
)n
C(=O)ORb
、-(CH2
)n
NRa
Ra
、CN、-(CH2
)n
C(=O)NRa
Ra
、-NHC(=O)ORb
、經0至3個Re
取代之C1-4
烷基、經0至3個Re
取代之(CH2
)n
-C3-6
碳環基及經0至3個Re
取代之-(CH2
)n
-雜環基; R7
在每次出現時獨立地選自H、C1-4
烷基及經0至3個Re
取代之(CH2
)n
-C3-12
碳環基; Ra
在每次出現時獨立地選自H、經0至5個Re
取代之C1-6
烷基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基;或Ra
及Ra
連同其共同連接之氮原子一起形成經0至5個Re
取代之雜環; Rb
在每次出現時獨立地選自H、經0˗5個Re
取代之C1˗6
烷基、經0˗5個Re
取代之C2˗6
烯基、經0˗5個Re
取代之C2˗6
炔基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基; Re
在每次出現時獨立地選自經0至5個Rg
取代之C1-6
烷基、C2-6
烯基、C2-6
炔基、-(CH2
)n
-C3-6
環烷基、-(CH2
)n
-C4-6
雜環基、-(CH2
)n
-芳基、-(CH2
)n
-雜芳基、F、Cl、Br、CN、NO2
、=O、CO2
Rf
、-(CH2
)n
ORf
、S(O)p
Rf
、C(=O)NRf
Rf
、NRf
C(=O)Rf
、S(O)p
NRf
Rf
、NRf
S(O)p
Rf
、NRf
C(=O)ORf
、OC(=O)NRf
Rf
及-(CH2
)n
NRf
Rf
; Rf
在每次出現時獨立地選自H、C1-5
烷基(最佳經鹵素及OH取代)、C3-6
環烷基及苯基; Rg
在每次出現時獨立地選自H、F、Cl、Br、CN、OH、C1-5
烷基(最佳經鹵素及OH取代); n獨立地選自0、1、2、3及4;且 p在每次出現時獨立地選自0、1及2。 在另一態樣中,本發明提供式(IIIa)化合物:或其立體異構體、對映異構體、非對映異構體、互變異構體或醫藥學上可接受之鹽,其中: R1
獨立地選自F、Cl、-(CH2
)n
OH、C(=O)NRa
Ra
、C1-4
烷基及OC1-4
烷基; R2
獨立地選自經0至3個Re
取代之C1-5
烷基、C1-5
烯基、經0至3個Re
取代之芳基、經0至3個Re
取代之雜芳基、C3-6
環烷基及-(CH2
)1-4
OC1-5
烷基及-(CH2
)1-3
OC3-6
環烷基; R3
及R4
獨立地選自H及經0至3個R6
取代之C1-5
烷基;其限制條件為R3
及R4
不均為H; 或者,R3
及R4
連同其共同連接之氮原子一起形成選自以下之雜環或螺雜環:; R5
在每次出現時獨立地選自OH、-(CH2
)n
-芳基、-(CH2
)n
-C3-6
環烷基及-(CH2
)n
-雜環,各自經0至3個R6
取代; R5a
在每次出現時獨立地選自-(CR7
R7
)n
-C3-10
碳環及-(CR7
R7
)n
-雜環、-C(=O)-C3-10
碳環,各自經0至3個R6
取代; R6
獨立地選自H、F、Cl、Br、-ORb
、=O、-(CH2
)n
C(=O)Rb
、-(CH2
)n
C(=O)ORb
、-(CH2
)n
NRa
Ra
、CN、-(CH2
)n
C(=O)NRa
Ra
、經0至3個Re
取代之C1-4
烷基、經0至3個Re
取代之(CH2
)n
-C3-6
碳環基及經0至3個Re
取代之-(CH2
)n
-雜環基; R7
在每次出現時獨立地選自H、C1-4
烷基及經0至3個Re
取代之(CH2
)n
-C3-12
碳環基; Ra
在每次出現時獨立地選自H、經0至5個Re
取代之C1-6
烷基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基;或Ra
及Ra
連同其共同連接之氮原子一起形成經0至5個Re
取代之雜環; Rb
在每次出現時獨立地選自H、經0˗5個Re
取代之C1˗6
烷基、經0˗5個Re
取代之C2˗6
烯基、經0˗5個Re
取代之C2˗6
炔基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基; Re
在每次出現時獨立地選自C1-6
烷基(視情況經F及Cl取代)、OH、OCH3
、OCF3
、-(CH2
)n
-C3-6
環烷基、-(CH2
)n
-C4-6
雜環基、-(CH2
)n
-芳基、-(CH2
)n
-雜芳基、F、Cl、Br、CN、NO2
、=O、CO2
H;且 n獨立地選自0、1、2、3及4。 在另一態樣中,本發明提供式(IIIb)化合物:或其立體異構體、對映異構體、非對映異構體、互變異構體或醫藥學上可接受之鹽,其中: R1
為-OCH3
; R2
獨立地選自經0至3個Re
取代之C1-5
烷基、C1-5
烯基、經0至3個Re
取代之苯基、經0至3個Re
取代之6員雜芳基、C3-6
環烷基及CH2
O(CH2
)1-3
CH3
; R3
及R4
獨立地選自H及經0至3個R6
取代之C1-5
烷基;其限制條件為R3
及R4
不均為H; 或者,R3
及R4
連同其共同連接之氮原子一起形成選自以下之雜環: ; R5a
在每次出現時獨立地選自 ; R5
在每次出現時獨立地選自OH、 ; R6
獨立地選自H、F、Cl、Br、-OCH3
、-OCF3
、=O、CN、CH3
、CF3
、-C(=O)NH2
、經0至3個Re
取代之-(CH2
)n
-芳基、經0至3個Re
取代之-(CH2
)n
-C3-6
環烷基及經0至3個Re
取代之-(CH2
)n
-雜環基; R6a
獨立地選自H、CH3
、經0至3個Re
取代之芳基及經0至3個Re
取代之雜環基; Ra
在每次出現時獨立地選自H、經0至5個Re
取代之C1-6
烷基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基; Re
在每次出現時獨立地選自C1-6
烷基(視情況經F及Cl取代)、OH、OCH3
、OCF3
、-(CH2
)n
-C3-6
環烷基、-(CH2
)n
-C4-6
雜環基、-(CH2
)n
-芳基、-(CH2
)n
-雜芳基、F、Cl、Br、CN、NO2
、=O、CO2
H;且 n獨立地選自0、1、2及3。 在另一態樣中,本發明提供式(IIIa)或(IIIb)之化合物或其立體異構體、對映異構體、非對映異構體、互變異構體、醫藥學上可接受之鹽、溶劑合物或前藥,其中: R3
及R4
連同其共同連接之氮原子一起形成選自以下之雜環或螺雜環:; R5a
在每次出現時獨立地選自R6
獨立地選自H、F、Cl、Br、-OCH3
、-O(CH2
)1-3
OCH3
、-OCF3
、=O、CN、CH3
、CF3
-(CH2
)n
-芳基、經0至3個Re
取代之-(CH2
)n
-C3-6
環烷基及經0至3個Re
取代之-(CH2
)n
-雜環基; R6a
獨立地選自H、CH3
、經0至3個Re
取代之芳基及經0至3個Re
取代之雜環基; Re
在每次出現時獨立地選自C1-6
烷基(視情況經F及Cl取代)、OH、OCH3
、OCF3
、-(CH2
)n
-C3-6
環烷基、-(CH2
)n
-C4-6
雜環基、-(CH2
)n
-芳基、-(CH2
)n
-雜芳基、F、Cl、Br、CN、NO2
、=O、CO2
H;且 n獨立地選自0、1、2及3。 在另一態樣中,本發明提供式(IIIb)化合物或其立體異構體、對映異構體、非對映異構體、互變異構體或醫藥學上可接受之鹽,其中: R1
為-OCH3
; R2
獨立地選自經0至3個Re
取代之C1-5
烷基、C1-5
烯基、經0至3個Re
取代之苯基、經0至3個Re
取代之6員雜芳基、C3-6
環烷基及CH2
O(CH2
)1-3
CH3
; R3
獨立地選自H及C1-5
烷基; R4
獨立地選自經0至3個R6
取代之C1-5
烷基; R6
獨立地選自-ORb
、-C(=O)Rb
、-C(=O)NRa
Ra
、-NRa
C(=O)Rb
、經0至3個Re
取代之C3-6
環烷基、經0至3個Re
取代之芳基及經0至3個Re
取代之雜芳基; Ra
在每次出現時獨立地選自H、經0至5個Re
取代之C1-6
烷基、經0至5個Re
取代之C2-6
烯基、經0至5個Re
取代之C2-6
炔基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基;或Ra
及Ra
連同其共同連接之氮原子一起形成經0至5個Re
取代之雜環; Rb
在每次出現時獨立地選自H、經0至5個Re
取代之C1-6
烷基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基; Re
在每次出現時獨立地選自經0至5個Rg
取代之C1-6
烷基、C2-6
烯基、C2-6
炔基、-(CH2
)n
-C3-6
環烷基、-(CH2
)n
-C4-6
雜環基、-(CH2
)n
-芳基、-(CH2
)n
-雜芳基、F、Cl、Br、CN、NO2
、=O、CO2
Rf
、-(CH2
)n
ORf
、S(O)p
Rf
、C(=O)NRf
Rf
、NRf
C(=O)Rf
、S(O)p
NRf
Rf
、NRf
S(O)p
Rf
、NRf
C(=O)ORf
、OC(=O)NRf
Rf
及-(CH2
)n
NRf
Rf
; Rf
在每次出現時獨立地選自H、C1-5
烷基(最佳經鹵素及OH取代)、C3-6
環烷基及苯基,或Rf
及Rf
連同其共同連接之氮原子一起形成視情況經C1-4
烷基取代之雜環; n獨立地選自0、1、2、3及4;且 p在每次出現時獨立地選自0、1及2。 在另一態樣中,本發明提供式(IV)化合物:或其立體異構體、對映異構體、非對映異構體、互變異構體或醫藥學上可接受之鹽,其中: R1
獨立地選自-CH2
OH、-OCH3
、-OCF3
、OCH2
Ph、-C(=O)NRa
Ra
、-NRa
Ra
、CH3
、CH2
CH3
、CH(CH3
)2
及環丙基; R2
獨立地選自經0至3個Re
取代之C1-5
烷基、C1-5
烯基、經0至3個Re
取代之苯基、經0至3個Re
取代之6員雜芳基、C3-6
環烷基及CH2
O(CH2
)1-3
CH3
; R3
及R4
連同其共同連接之氮原子一起形成選自以下之雜環: ; R5a
在每次出現時獨立地選自 ; R5
在每次出現時獨立地選自OH、 ; R6
獨立地選自H、F、Cl、Br、-OCH3
、-OCF3
、=O、CN、CH3
、CF3
、-C(=O)NH2
、經0至3個Re
取代之-(CH2
)n
-芳基、經0至3個Re
取代之-(CH2
)n
-C3-6
環烷基及經0至3個Re
取代之-(CH2
)n
-雜環基; R6a
獨立地選自H、CH3
、經0至3個Re
取代之芳基及經0至3個Re
取代之雜環基; Ra
在每次出現時獨立地選自H、經0至5個Re
取代之C1-6
烷基、經0至5個Re
取代之-(CH2
)n
-C3-10
碳環基及經0至5個Re
取代之-(CH2
)n
-雜環基; Re
在每次出現時獨立地選自C1-6
烷基(視情況經F及Cl取代)、OH、OCH3
、OCF3
、-(CH2
)n
-C3-6
環烷基、-(CH2
)n
-C4-6
雜環基、-(CH2
)n
-芳基、-(CH2
)n
-雜芳基、F、Cl、Br、CN、NO2
、=O、CO2
H;且 n獨立地選自0、1、2及3。 在另一態樣中,本發明提供式(IV)化合物或其立體異構體、對映異構體、非對映異構體、互變異構體、醫藥學上可接受之鹽、溶劑合物或前藥,其中: R1
獨立地選自-CH2
OH、--C(=O)NHCH(CH3
)2
、CH3
、CH2
CH3
及CH(CH3
)2
; R2
獨立地選自CH2
(CH2
)1-3
CH3
及CH2
O(CH2
)1-3
CH3
; R3
及R4
連同其共同連接之氮原子一起形成; R5a
為; R6
獨立地選自H、F、Cl、Br、CH3
及CF3
;且 R7
獨立地選自H、C1-4
烷基及苯基。 在另一態樣中,本發明提供式(IV)化合物或其立體異構體、對映異構體、非對映異構體、互變異構體、醫藥學上可接受之鹽、溶劑合物或前藥,其中: R1
獨立地選自-CH2
OH、--C(=O)NHCH(CH3
)2
、CH3
、CH2
CH3
及CH(CH3
)2
; R2
獨立地選自CH2
(CH2
)1-3
CH3
及CH2
O(CH2
)1-3
CH3
; R3
及R4
連同其共同連接之氮原子一起形成; R5a
為; R6
獨立地選自H、F、Cl、Br、CH3
及CF3
。 在另一態樣中,本發明提供式(IV)化合物或其立體異構體、對映異構體、非對映異構體、互變異構體、醫藥學上可接受之鹽、溶劑合物或前藥,其中: R1
獨立地選自-CH2
OH、--C(=O)NHCH(CH3
)2
、CH3
、CH2
CH3
及CH(CH3
)2
; R2
獨立地選自CH2
(CH2
)1-3
CH3
及CH2
O(CH2
)1-3
CH3
; R3
及R4
連同其共同連接之氮原子一起形成; R5
在每次出現時獨立地選自; R6
獨立地選自H、F、Cl、Br、CH3
、CF3
、經0至3個Re
取代之芳基;且Re
在每次出現時獨立地選自C1-6
烷基、OH、OCH3
、OCF3
。 在一個非限制性實施例中,環B為;R1
為OC1-4
烷基;R2
獨立地選自經0至3個Re
取代之C1-5
烷基;其中C1-5
烷基之亞甲基單元(除了直接連接至吡啶環之亞甲基單元以外)可經O、N及S置換;R3
及R4
連同其共同連接之氮原子一起形成;R5
在每次出現時獨立地選自 ;且 R6
獨立地選自H、F、Cl、Br、CH3
及CF3
。 在另一非限制性實施例中,環B為;R1
獨立地選自OC1- 4
烷基;R1a
獨立地選自F及Cl;R2
獨立地選自經0至3個Re
取代之C1-5
烷基;其中C1-5
烷基之亞甲基單元(除了直接連接至吡啶環之亞甲基單元以外)可經O、N及S置換;R3
及R4
連同其共同連接之氮原子一起形成; R5
在每次出現時獨立地選自 ;且 R6
獨立地選自H、F、Cl、Br、CH3
及CF3
。 在另一非限制性實施例中,環B為;R1
獨立地選自OC1-4
烷基;R1a
獨立地選自F及Cl;R2
獨立地選自-CH2
CH2
CH2
CH3
及-CH2
OCH2
C H3
;R3
及R4
連同其共同連接之氮原子一起形成; R5
在每次出現時獨立地選自 ;且 R6
獨立地選自H、F、Cl、Br、CH3
及CF3
。 在另一非限制性實施例中,環B為;R1
獨立地選自OC1-4
烷基;R2
獨立地選自經0至3個Re
取代之C1-5
烷基;其中C1-5
烷基之亞甲基單元(除了直接連接至吡啶環之亞甲基單元以外)可經O、N及S置換;R3
及R4
連同其共同連接之氮原子一起形成; R5
在每次出現時獨立地選自 ;且 R6
獨立地選自H、F、Cl、Br、CH3
及CF3
。 在另一非限制性實施例中,環B為;R1
獨立地選自OC1-4
烷基;R2
獨立地選自-CH2
CH2
CH2
CH3
及-CH2
OCH2
CH3
;R3
及R4
連同其共同連接之氮原子一起形成; R5
在每次出現時獨立地選自 ;且 R6
獨立地選自H、F、Cl、Br、CH3
及CF3
。 在另一非限制性實施例中,環B為;R1
為OC1-4
烷基;R2
獨立地選自經0至3個Re
取代之C1-5
烷基;其中C1-5
烷基之亞甲基單元(除了直接連接至吡啶環之亞甲基單元以外)可經O、N及S置換;R3
及R4
連同其共同連接之氮原子一起形成;R5
在每次出現時獨立地選自;且 R6
獨立地選自H、F、Cl、Br、CH3
及CF3
。 在另一非限制性實施例中,環B為;R1
為OC1-4
烷基;R2
獨立地選自-CH2
CH2
CH2
CH3
及-CH2
OCH2
CH3
;R3
及R4
連同其共同連接之氮原子一起形成;R5
在每次出現時獨立地選自;且 R6
獨立地選自H、F、Cl、Br、CH3
及CF3
。 在另一非限制性實施例中,環B為;R1
為OC1-4
烷基;R2
獨立地選自經0至3個Re
取代之C1-5
烷基;其中C1-5
烷基之亞甲基單元(除了直接連接至吡啶環之亞甲基單元以外)可經O、N及S置換;R3
及R4
連同其共同連接之氮原子一起形成;R5a
為;且 R6
獨立地選自H、F、Cl、Br、CH3
及CF3
;且 R7
獨立地選自H、C1-4
烷基及苯基。 在另一非限制性實施例中,環B為;R1
為OC1-4
烷基;R2
獨立地選自-CH2
CH2
CH2
CH3
及-CH2
OCH2
CH3
;R3
及R4
連同其共同連接之氮原子一起形成;R5a
為; R6
獨立地選自H、F、Cl、Br、CH3
及CF3
;且 R7
獨立地選自H、C1-4
烷基及苯基。 在另一非限制性實施例中,環B為;R1
為OC1-4
烷基;R2
獨立地選自-CH2
CH2
CH2
CH3
及-CH2
OCH2
CH3
;R3
及R4
連同其共同連接之氮原子一起形成;R5a
為; R6
獨立地選自H、F、Cl、Br、CH3
及CF3
;且 R7
獨立地選自H、C1-4
烷基及苯基。 在另一非限制性實施例中,環B為;R1
為OC1-4
烷基;R2
獨立地選自-CH2
CH2
CH2
CH3
及-CH2
OCH2
CH3
;R3
及R4
連同其共同連接之氮原子一起形成;R5a
為; R6
獨立地選自H、F、Cl、Br、CH3
及CF3
;且 在另一非限制性實施例中,環B為;R1
為OC1-4
烷基;R2
獨立地選自經0至3個Re
取代之C1-5
烷基;其中C1-5
烷基之亞甲基單元(除了直接連接至吡啶環之亞甲基單元以外)可經O、N及S置換;R3
及R4
連同其共同連接之氮原子一起形成;R5a
獨立地選自; R6
獨立地選自H、F、Cl、Br、CH3
及CF3
。 在另一非限制性實施例中,環B為;R1
為OC1-4
烷基;R2
獨立地選自經0至3個Re
取代之C1-5
烷基;其中C1-5
烷基之亞甲基單元(除了直接連接至吡啶環之亞甲基單元以外)可經O、N及S置換;R3
及R4
連同其共同連接之氮原子一起形成;R5a
獨立地選自; R6
獨立地選自H、F、Cl、Br、CH3
及CF3
;且 R6a
獨立地選自H、CH3
及苯基。 在另一非限制性實施例中,環B為;R1
為OC1-4
烷基;R2
獨立地選自C1-5
烷基;其中C1-5
烷基的亞甲基單元(除了直接連接至吡啶環之亞甲基單元以外)可經O、N及S置換;R3
為H,R4
為經1-3個R6
取代之C1-3
烷基;R6
獨立地選自C(=O)NHRa
及-(CH2
)n
-C3-6
環烷基;Ra
為經0至5個Re
取代之C1-3
烷基,Re
為-(CH2
)n
CO2
Rf
;Rf
獨立地選自H及C1-5
烷基;n獨立地選自0、1及2。 在另一非限制性實施例中,環B為;R1
為OC1-4
烷基;R2
獨立地選自C1-5
烷基;其中C1-5
烷基的亞甲基單元(除了直接連接至吡啶環之亞甲基單元以外)可經O、N及S置換;R3
為C1-3
烷基,R4
為經1-3個R6
取代之C1-3
烷基;R6
獨立地選自-ORb
、NHC(=O)Rb
、芳基及雜芳基;Rb
獨立地選自-(CH2
)n
-C3-10
碳環基及-(CH2
)n
-雜環基;n獨立地選自0、1及2。 在另一態樣中,本發明提供一種選自以下清單的化合物: 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(4-甲氧基苯甲醯基)哌嗪-1-羰基]吡啶-2,4-二醇(1); 6-丁基-5-(2,6-二甲氧基苯基)-2,4-二羥基-N-甲基-N-(4-苯基丁基)吡啶-3-甲醯胺(2); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(1-甲基-1H-咪唑-2-基)哌嗪-1-羰基]吡啶-2,4-二醇(3); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-羥基-4-(吡啶-3-基)哌啶-1-羰基]吡啶-2,4-二醇(4); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(3-丙基-1,2,4-噁二唑-5-基)哌啶-1-羰基]吡啶-2,4-二醇(5); 6-丁基-3-[4-(5-氯吡啶-2-基)哌嗪-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(6); 6-丁基-5-(2,6-二甲氧基苯基)-3-{4-[4-(2-甲氧基乙氧基)苯基]哌嗪-1-羰基}吡啶-2,4-二醇(7); 6-丁基-5-(2,6-二甲氧基苯基)-3-[2-(吡啶-2-基)吡咯啶-1-羰基]吡啶-2,4-二醇(8); 6-丁基-3-{3-[4-(2-氯-4-甲氧基-5-甲基苯基)-5-甲基-1,3-噻唑-2-基]吡咯啶-1-羰基}-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(9); N-(4-{4-[6-丁基-5-(2,6-二甲氧基苯基)-2,4-二羥基吡啶-3-羰基]哌嗪-1-基}苯基)胺基甲酸甲酯(10); 6-丁基-5-(2,6-二甲氧基苯基)-3-{4-[3-(三氟甲基)吡啶-2-基]哌嗪-1-羰基}吡啶-2,4-二醇(11); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(2-甲氧基苯基)哌嗪-1-羰基]吡啶-2,4-二醇(12); 6-丁基-5-(2,6-二甲氧基苯基)-3-{4-[4-(三氟甲基)嘧啶-2-基]哌嗪-1-羰基}吡啶-2,4-二醇(13); 3-(4-苯甲基哌啶-1-羰基)-6-丁基-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(14); 6-丁基-5-(2,6-二甲氧基苯基)-2,4-二羥基-N-甲基-N-[2-(吡啶-2-基)乙基]吡啶-3-甲醯胺(15); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(二苯基甲基)哌嗪-1-羰基]吡啶-2,4-二醇(16); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(4-甲基-1H-咪唑-5-基)哌啶-1-羰基]吡啶-2,4-二醇(17); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(4-甲氧基苯基)哌嗪-1-羰基]吡啶-2,4-二醇(18); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(2-甲氧基苯基)哌啶-1-羰基]吡啶-2,4-二醇(19); 6-丁基-5-(2,6-二甲氧基苯基)-3-{4-[3-(呋喃-2-基)-1H-吡唑-5-基]哌啶-1-羰基}吡啶-2,4-二醇(20); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(噠嗪-3-基)哌嗪-1-羰基]吡啶-2,4-二醇(21); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(吡啶-4-基)哌嗪-1-羰基]吡啶-2,4-二醇(22); 6-丁基-3-[4-(2-氯苯基)哌啶-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(23); 4-{1-[6-丁基-5-(2,6-二甲氧基苯基)-2,4-二羥基吡啶-3-羰基]哌啶-4-基}苯甲醯胺(24); 5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)-3-[(3S)-3-苯基吡咯啶-1-羰基]吡啶-2,4-二醇(25); 5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)-3-[(3R)-3-苯基吡咯啶-1-羰基]吡啶-2,4-二醇(26); 6-丁基-N-[2-(4-氯苯基)乙基]-5-(2,6-二甲氧基苯基)-2,4-二羥基-N-甲基吡啶-3-甲醯胺(27); 6-丁基-5-(2,6-二甲氧基苯基)-3-[(3R)-3-苯基吡咯啶-1-羰基]吡啶-2,4-二醇(28); 6-丁基-5-(2,6-二甲氧基苯基)-3-[(3S)-3-苯基吡咯啶-1-羰基]吡啶-2,4-二醇(29); 6-丁基-5-(2,6-二甲氧基苯基)-3-(4-苯基哌嗪-1-羰基)吡啶-2,4-二醇(30); 6-丁基-3-{4-[(4-氯苯基)甲基]哌嗪-1-羰基}-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(31); 3-[4-(1,3-苯并噁唑-2-基)哌啶-1-羰基]-6-丁基-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(32); N-苯甲基-6-丁基-5-(2,6-二甲氧基苯基)-2,4-二羥基-N-丙基吡啶-3-甲醯胺(33); 6-丁基-3-[3-(3-氯苯基)氮雜環丁烷-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(34); 6-丁基-3-[3-(2-氯苯基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(35); 6-丁基-3-[3-(3-氯苯基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(37); 6-丁基-3-[3-(3-氯苯基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(38); 6-丁基-5-(2,6-二甲氧基苯基)-3-[3-(4-氟苯基)吡咯啶-1-羰基]吡啶-2,4-二醇(39); 6-丁基-5-(2,6-二甲氧基苯基)-3-[3-(4-氟苯基)吡咯啶-1-羰基]吡啶-2,4-二醇(40); 3-(4-苯甲醯基哌嗪-1-羰基)-6-丁基-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(41); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(3-氟苯甲醯基)哌嗪-1-羰基]吡啶-2,4-二醇(42); 6-丁基-5-(2,6-二甲氧基苯基)-3-{4-[(4-氟苯基)甲基]哌嗪-1-羰基}吡啶-2,4-二醇(43); 6-丁基-5-(2,6-二甲氧基苯基)-3-{4-[(2-氟苯基)甲基]哌嗪-1-羰基}吡啶-2,4-二醇(44); 6-丁基-5-(2,6-二甲氧基苯基)-3-{4-[(3-氟苯基)甲基]哌嗪-1-羰基}吡啶-2,4-二醇(45); 6-丁基-5-(2,6-二甲氧基苯基)-3-(4-羥基-4-苯基哌啶-1-羰基)吡啶-2,4-二醇(46); 6-丁基-3-[4-(4-氯苯基)-4-羥基哌啶-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(47); 3-[4-(1,3-苯并噻唑-2-基)哌啶-1-羰基]-6-丁基-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(48); 3-[4-(1,2-苯并噻唑-3-基)哌嗪-1-羰基]-6-丁基-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(49); 1'-[6-丁基-5-(2,6-二甲氧基苯基)-2,4-二羥基吡啶-3-羰基]-1,2-二氫螺[3,1-苯并噁嗪-4,4'-哌啶]-2-酮(50); 3-[4-(1,3-苯并噁唑-2-基)哌嗪-1-羰基]-6-丁基-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(51); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(1-苯基-1H-1,2,3,4-四唑-5-基)哌嗪-1-羰基]吡啶-2,4-二醇(52); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(1-苯基-1H-1,2,3,4-四唑-5-基)-1,4-二氮雜環庚烷-1-羰基]吡啶-2,4-二醇(53); 3-[4-(1,3-苯并噻唑-2-基)哌嗪-1-羰基]-6-丁基-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(54); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(1H-咪唑-4-基)哌啶-1-羰基]吡啶-2,4-二醇(55); 6-丁基-3-[4-(3-氯苯基)哌啶-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(56); 6-丁基-3-[4-(2-氯苯基)哌嗪-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(57); 6-丁基-3-[4-(3-氯苯基)哌嗪-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(58); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(吡啶-2-基)哌嗪-1-羰基]吡啶-2,4-二醇(59); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(3-苯基-1,2,4-噻二唑-5-基)哌嗪-1-羰基]吡啶-2,4-二醇(60); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(吡咯啶-1-基)哌啶-1-羰基]吡啶-2,4-二醇(61); 6-丁基-5-(2,6-二甲氧基苯基)-3-(4-苯基哌啶-1-羰基)吡啶-2,4-二醇(62); 6-丁基-3-(4-環己基哌嗪-1-羰基)-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(63); 6-丁基-5-(2,6-二甲氧基苯基)-3-({3H-螺[2-苯并呋喃-1,4'-哌啶]-1'-基}羰基)吡啶-2,4-二醇(64); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(6-氟-1,2-苯并噁唑-3-基)哌啶-1-羰基]吡啶-2,4-二醇(65); 1-[6-丁基-5-(2,6-二甲氧基苯基)-2,4-二羥基吡啶-3-羰基]-2',3'-二氫-1'H-螺[哌啶-4,4'-喹啉]-2'-酮(66); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(5-苯基-1H-吡唑-3-基)哌啶-1-羰基]吡啶-2,4-二醇(67); 6-丁基-3-[4-(4-氯苯基)哌嗪-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(68); 6-丁基-5-(2,6-二甲氧基苯基)-3-{4-[3-(吡啶-3-基)-1,2,4-噁二唑-5-基]哌啶-1-羰基}吡啶-2,4-二醇(69); 6-(乙氧基甲基)-5-(4-氟-2,6-二甲氧基苯基)-3-[(3R)-3-苯基吡咯啶-1-羰基]吡啶-2,4-二醇) (70); 6-丁基-5-(3-氟-2,6-二甲氧基苯基)-3-[(3R)-3-苯基吡咯啶-1-羰基]吡啶-2,4-二醇(71); 6-丁基-3-[3-(2-氯苯基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(72); (6-丁基-5-(2,6-二甲氧基苯基)-2,4-二羥基吡啶-3-基)(3-(5-氯吡啶-2-基)吡咯啶-1-基)甲酮(74); 6-丁基-3-[3-(5-氯吡啶-2-基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(75); 3-[3-(5-氯吡啶-2-基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)吡啶-2,4-二醇(76); 3-[3-(5-氯吡啶-2-基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)吡啶-2,4-二醇(77); 6-丁基-5-(2,6-二甲氧基苯基)-3-[3-(3-氟吡啶-2-基)吡咯啶-1-羰基]吡啶-2,4-二醇(78); 6-丁基-5-(2,6-二甲氧基苯基)-3-[3-(5-氟吡啶-2-基)吡咯啶-1-羰基]吡啶-2,4-二醇(79); 6-丁基-5-(2,6-二甲氧基苯基)-3-[3-(5-氟吡啶-2-基)吡咯啶-1-羰基]吡啶-2,4-二醇(80); 6-丁基-5-(2,6-二甲氧基苯基)-3-[3-(3-氟吡啶-2-基)吡咯啶-1-羰基]吡啶-2,4-二醇(81); 6-丁基-3-[3-(3,5-二氟吡啶-2-基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(82); 6-丁基-3-[3-(3,5-二氟吡啶-2-基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(83); 3-[3-(3,5-二氟吡啶-2-基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)吡啶-2,4-二醇(84); 3-[3-(3,5-二氟吡啶-2-基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)吡啶-2,4-二醇(85); (5-(2,6-二甲氧基苯基)-6-(4-氟苯基)-2,4-二羥基吡啶-3-基)(3-(2-氟苯基)吡咯啶-1-基)甲酮(86); (3-(3,5-二氟吡啶-2-基)吡咯啶-1-基)(5-(2,6-二甲氧基苯基)-6-(4-氟苯基)-2,4-二羥基吡啶-3-基)甲酮(87); 5-(2,6-二甲氧基苯基)-3-{4-[(3-氟苯基)甲基]哌嗪-1-羰基}-6-(2-甲氧基乙基)吡啶-2,4-二醇(88); 5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)-3-{4-[(2-氟苯基)甲基]哌嗪-1-羰基}吡啶-2,4-二醇(89); 5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)-3-{4-[(3-氟苯基)甲基]哌嗪-1-羰基}吡啶-2,4-二醇(90); 6-(乙氧基甲基)-3-{4-[(3-氟苯基)甲基]哌嗪-1-羰基}-5-(2-甲氧基苯基)吡啶-2,4-二醇(91); 6-丁基-5-(2,6-二甲氧基苯基)-3-(4-苯氧基哌啶-1-羰基)吡啶-2,4-二醇(92); 6-丁基-3-{4-[(2,4-二氯苯基)甲基]哌嗪-1-羰基}-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(93); 6-丁基-3-{4-[(2,3-二氯苯基)甲基]哌嗪-1-羰基}-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(94); N-(2-{1-[6-丁基-5-(2,6-二甲氧基苯基)-2,4-二羥基吡啶-3-基]-N-甲基甲醯胺基}乙基)苯甲醯胺(95); 6-丁基-5-(2,5-二甲氧基苯基)-3-[(3S)-3-苯基吡咯啶-1-羰基]吡啶-2,4-二醇(96); 6-丁基-5-(2,5-二甲氧基苯基)-3-[(3R)-3-苯基吡咯啶-1-羰基]吡啶-2,4-二醇(97); N-{1-[6-丁基-5-(2,6-二甲氧基苯基)-2,4-二羥基吡啶-3-羰基]氮雜環丁-3-基}苯甲醯胺(98); 6-丁基-5-(2,6-二甲氧基苯基)-2,4-二羥基-N-甲基-N-(2-苯氧基乙基)吡啶-3-甲醯胺(99); 6-丁基-3-{4-[(5-氯吡啶-2-基)氧基]哌啶-1-羰基}-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(100); 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(吡啶-2-基甲基)哌嗪-1-羰基]吡啶-2,4-二醇(101); 6-丁基-N-{2-[(5-氯-3-氟吡啶-2-基)胺基]乙基}-5-(2,6-二甲氧基苯基)-2,4-二羥基-N-甲基吡啶-3-甲醯胺(102); 6-丁基-3-{4-[(2,3-二氯苯基)甲基]哌嗪-1-羰基}-5-(2,5-二甲氧基苯基)吡啶-2,4-二醇(103); 3-{4-[(2,3-二氯苯基)甲基]哌嗪-1-羰基}-5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)吡啶-2,4-二醇(104); 6-丁基-3-[4-(5-氯吡啶-2-羰基)哌嗪-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(105); 6-丁基-5-(2,6-二甲氧基苯基)-3-{4-[(2-甲基苯基)甲基]哌啶-1-羰基}吡啶-2,4-二醇(106); 6-丁基-5-(2,6-二甲氧基苯基)-3-(4-{[3-(三氟甲基)苯基]甲基}哌嗪-1-羰基)吡啶-2,4-二醇(107); 6-丁基-3-{4-[(2,3-二氟苯基)甲基]哌嗪-1-羰基}-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(108); 6-丁基-3-[4-(環己基甲基)哌嗪-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(109); 6-丁基-3-{4-[(2,3-二氟苯基)甲基]哌嗪-1-羰基}-5-(2,5-二甲氧基苯基)吡啶-2,4-二醇(110); 6-丁基-3-[4-(環丙基甲基)哌嗪-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(111); 6-丁基-3-{4-[(2,3-二氯苯基)甲基]哌嗪-1-羰基}-5-(2,3-二甲氧基苯基)吡啶-2,4-二醇(112); 3-{4-[(2-溴-5-氟苯基)甲基]哌啶-1-羰基}-6-丁基-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(113); 3-{4-[(2,3-二氟苯基)甲基]哌嗪-1-羰基}-5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)吡啶-2,4-二醇(114); 6-丁基-5-(2,6-二甲氧基苯基)-3-{3-[(3-氟吡啶-2-基)氧基]氮雜環丁烷-1-羰基}吡啶-2,4-二醇(115); 6-丁基-3-{3-[(2,3-二氟苯基)甲氧基]氮雜環丁烷-1-羰基}-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(116); 6-丁基-5-(2,6-二甲氧基苯基)-N-[2-(2-氟苯基)乙基]-2,4-二羥基-N-丙基吡啶-3-甲醯胺(117); N-{1-[6-丁基-5-(2,6-二甲氧基苯基)-2,4-二羥基吡啶-3-羰基]氮雜環丁-3-基}-2,3-二氟苯-1-磺醯胺 (118); 6-丁基-3-[4-(2,3-二氟苯甲醯基)哌嗪-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(119); 6-丁基-5-(2,6-二甲氧基苯基)-3-{4-[(3-氟吡啶-2-基)甲基]哌嗪-1-羰基}吡啶-2,4-二醇(120); 6-丁基-5-(2,6-二甲氧基苯基)-3-{4-[(2-氟-3-甲基苯基)甲基]哌嗪-1-羰基}吡啶-2,4-二醇(121); 6-丁基-3-{4-[(2,5-二氟苯基)甲基]哌嗪-1-羰基}-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(122); 6-丁基-3-{4-[(6-氯吡啶-2-基)甲基]哌嗪-1-羰基}-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(123); 5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)-3-[3-(3-氟苯基)吡咯啶-1-羰基]吡啶-2,4-二醇(124); 6-環戊基-5-(2,6-二甲氧基苯基)-3-[3-(3-氟苯基)吡咯啶-1-羰基]吡啶-2,4-二醇(125); 5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)-3-[3-(2-氟苯基)吡咯啶-1-羰基]吡啶-2,4-二醇(126); 5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)-3-[3-(2-氟苯基)吡咯啶-1-羰基]吡啶-2,4-二醇(127); 3-[3-(3,5-二氟吡啶-2-基)吡咯啶-1-羰基]-5-(3-甲氧基苯基)-6-(2-甲基-1,3-噻唑-4-基)吡啶-2,4-二醇(128); 3-[3-(3,5-二氟吡啶-2-基)吡咯啶-1-羰基]-5-(3-甲氧基苯基)-6-(2-甲基-1,3-噻唑-4-基)吡啶-2,4-二醇(129); 6-丁基-3-[3-(5-氯-3-氟吡啶-2-基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)-4-羥基-1,2-二氫吡啶-2-酮(130); 3-[3-(2,4-二氟苯基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)-4-羥基-1,2-二氫吡啶-2-酮(131); 3-[3-(2,4-二氟苯基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)-4-羥基-1,2-二氫吡啶-2-酮(132); 3-[3-(2,6-二氟苯基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)-4-羥基-1,2-二氫吡啶-2-酮(133); 3-[3-(2,6-二氟苯基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)-4-羥基-1,2-二氫吡啶-2-酮(134); 6-丁基-3-[3-(5-氯-3-氟吡啶-2-基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)-4-羥基-1,2-二氫吡啶-2-酮(135); 3-[(3S)-3-(苯甲氧基)吡咯啶-1-羰基]-6-丁基-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(136); 3-[(3S)-3-(苯甲氧基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)-6-(乙氧基甲基)吡啶-2,4-二醇(137); 6-丁基-5-(3-乙基苯基)-4-羥基-3-{5-[(2-甲基-1,3-噻唑-4-基)甲基]-1,3,4-噁二唑-2-基}-1,2-二氫吡啶-2-酮(138); 2-[3-(2-丁基-5-{4-[(2,3-二氟苯基)甲基]哌嗪-1-羰基}-4,6-二羥基吡啶-3-基)苯基]乙腈(139); 6-丁基-3-[3-(3,5-二氟吡啶-2-基)吡咯啶-1-羰基]-5-[3-(丙-2-基)苯基]吡啶-2,4-二醇(140); 6-丁基-3-[3-(3,5-二氟吡啶-2-基)吡咯啶-1-羰基]-5-[3-(丙-2-基)苯基]吡啶-2,4-二醇(141); 6-丁基-3-[3-(3,5-二氟吡啶-2-基)吡咯啶-1-羰基]-5-(3-甲氧基苯基)吡啶-2,4-二醇(142); 6-丁基-3-[3-(3,5-二氟吡啶-2-基)吡咯啶-1-羰基]-5-(3-甲氧基苯基)吡啶-2,4-二醇(143); 6-丁基-3-[3-(3,5-二氟吡啶-2-基)吡咯啶-1-羰基]-5-[3-(羥基甲基)苯基]吡啶-2,4-二醇(144); 3-{2-丁基-5-[3-(3,5-二氟吡啶-2-基)吡咯啶-1-羰基]-4,6-二羥基吡啶-3-基}-N-(丙-2-基)苯甲醯胺(145); 3-{2-丁基-5-[3-(3,5-二氟吡啶-2-基)吡咯啶-1-羰基]-4,6-二羥基吡啶-3-基}-N-(丙-2-基)苯甲醯胺(146); 6-丁基-3-[3-(3,5-二氟吡啶-2-基)吡咯啶-1-羰基]-5-[3-(羥基甲基)苯基]吡啶-2,4-二醇(147); 6-丁基-3-[(3R)-3-苯基吡咯啶-1-羰基]-5-[3-(丙-2-基)苯基]吡啶-2,4-二醇(148); 5-(2,6-二甲氧基苯基)-6-[(乙基胺基)甲基]-3-[3-(3-氟苯基)吡咯啶-1-羰基]吡啶-2,4-二醇(149); 5-(2,6-二甲氧基苯基)-6-[(乙基胺基)甲基]-3-[3-(2-氟苯基)吡咯啶-1-羰基]吡啶-2,4-二醇(150); 5-(2,6-二甲氧基苯基)-6-[(乙基胺基)甲基]-3-[3-(2-氟苯基)吡咯啶-1-羰基]吡啶-2,4-二醇(151); (S)-(2-(6-丁基-5-(2,6-二甲氧基苯基)-4-羥基-2-側氧基-1,2-二氫吡啶-3-甲醯胺基)-3-環己基丙醯基)甘胺酸甲酯(152); 6-丁基-3-[4-(2,3-二氯苯甲醯基)哌嗪-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇(153); 6-丁基-3-{4-[(2,3-二氟苯基)甲基]哌嗪-1-羰基}-5-(2,3-二甲氧基苯基)吡啶-2,4-二醇(154)。 本發明可在不偏離其精神或基本屬性之情況下以其他特定形式來實施。本發明亦涵蓋本文中所指出之本發明替代態樣的所有組合。應理解,本發明之任何及所有實施例可聯合任何其他實施例來描述本發明的額外實施例。此外,一實施例之任何元素(包括個別可變定義)意欲與任何實施例之任何及所有其他元素組合來描述額外實施例。本發明亦提供一種醫藥組合物,其包含式I化合物或對映異構體、非對映異構體或醫藥學上可接受之鹽及因而醫藥學上可接受之載劑。 在另一實施例中,使用本文中所揭示之APJ hcAMP分析,本發明化合物之EC50
值≤ 10 µM,較佳地EC50
值≤ 5 µM,更佳地EC50
值≤ 1 µM,甚至更佳地EC50
值≤ 0.5 µM,甚至更佳地EC50
值≤ 0.1 µM,甚至更佳地EC50
值≤ 0.01 µM。 在另一態樣中,本發明提供選自本申請案中所例示化合物之任何子集清單的化合物。 在另一態樣中,本發明提供選自APJ hcAMP EC50
效能範圍為A之子集之化合物。 在另一態樣中,本發明提供選自APJ hcAMP EC50
效能範圍為B之子集之化合物。 在另一態樣中,本發明提供APJ hcAMP EC50
效能範圍為C之子集之化合物。 II. 本發明之其他實施例 在另一實施例中,本發明提供一種組合物,其包含本發明化合物或其立體異構體、互變異構體、醫藥學上可接受之鹽或溶劑合物中之至少一者。 在另一實施例中,本發明提供一種醫藥組合物,其包含醫藥學上可接受之載劑及本發明化合物或其立體異構體、互變異構體、醫藥學上可接受之鹽或溶劑合物中之至少一者。 在另一實施例中,本發明提供一種醫藥組合物,其包含醫藥學上可接受之載劑及治療有效量之本發明化合物或其立體異構體、互變異構體、醫藥學上可接受之鹽或溶劑合物中之至少一者。 在另一實施例中,本發明提供一種用於製備本發明化合物或其立體異構體、互變異構體、醫藥學上可接受之鹽或溶劑合物之方法。 在另一實施例中,本發明提供一種用於製備本發明化合物或其立體異構體、互變異構體、醫藥學上可接受之鹽或溶劑合物的中間物。 本發明提供一種進一步包含額外治療劑之醫藥組合物。在一較佳實施例中,本發明提供醫藥組合物,其中額外治療劑為例如血管收縮素轉化酶(ACE)抑制劑、β-腎上腺素受體阻斷劑、血管收縮素II受體阻斷劑、利尿劑、醛固酮拮抗劑及洋地黃(digitalis)化合物。 在另一實施例中,本發明提供一種用於治療及/或預防與APJ或愛帕琳活性相關之多種疾病或病症之方法,其包含向需要此類治療及/或預防之患者投與治療有效量之單獨或視情況與另一本發明化合物及/或至少一種其他類型的治療劑組合之本發明化合物中之至少一者。 與可根據本發明經預防、調節或治療之與APJ及愛帕琳之活性相關的疾病或病症之實例包括(但不限於)心臟衰竭,諸如急性失代償心臟衰竭(ADHF)、心房顫動、冠狀動脈疾病、周邊血管疾病、動脈粥樣硬化、糖尿病、代謝症候群、高血壓、肺高血壓、腦血管病症及其後遺症、心臟血管病症、心絞痛、缺血、中風、心肌梗塞、急性冠狀動脈症候群、再灌注損傷、血管成形再狹窄、糖尿病之血管併發症及肥胖。 在另一實施例中,本發明提供一種用於治療及/或預防以下疾病之方法:心臟衰竭、冠狀動脈疾病、周邊血管疾病、動脈粥樣硬化、糖尿病、代謝症候群、高血壓、肺高血壓、心房顫動、心絞痛、缺血、中風、心肌梗塞、急性冠狀動脈症候群、再灌注損傷、血管成形再狹窄、糖尿病之血管併發症、肥胖,該方法包含向需要此類治療及/或預防之患者投與治療有效量之單獨或視情況與另一本發明化合物及/或至少一種其他類型的治療劑組合之本發明化合物中之至少一者。 在另一實施例中,本發明提供一種用於治療及/或預防諸如ADHF之心臟衰竭之方法,其包含向需要此類治療及/或預防之患者投與治療有效量之單獨或視情況與另一本發明化合物及/或至少一種其他類型的治療劑組合之本發明化合物中之至少一者。 在另一實施例中,本發明提供一種用於治療及/或預防糖尿病及肥胖之方法,其包含向需要此類治療及/或預防之患者投與治療有效量之單獨或視情況與另一本發明化合物及/或至少一種其他類型的治療劑組合之本發明化合物中之至少一者。 在另一實施例中,本發明提供一種用於治療及/或預防高血壓之方法,其包含向需要此類治療及/或預防之患者投與治療有效量之單獨或視情況與另一本發明化合物及/或至少一種其他類型的治療劑組合之本發明化合物中之至少一者。 在另一實施例中,本發明提供一種用於治療及/或預防肺高血壓之方法,其包含向需要此類治療及/或預防之患者投與治療有效量之單獨或視情況與另一本發明化合物及/或至少一種其他類型的治療劑組合之本發明化合物中之至少一者。 在另一實施例中,本發明提供一種用於治療及/或預防急性冠狀動脈症候群及心臟缺血之方法,其包含向需要此類治療及/或預防之患者投與治療有效量之單獨或視情況與另一本發明化合物及/或至少一種其他類型的治療劑組合之本發明化合物中之至少一者。 在另一實施例中,本發明提供一種用於療法之本發明化合物。 在另一實施例中,本發明提供一種用於療法以治療及/或預防與APJ及愛帕琳相關之多種疾病或病症之本發明化合物。 在另一實施例中,本發明亦提供本發明化合物之用途,其用於製造供治療及/或預防與APJ及愛帕琳相關之多種疾病或病症用之藥劑。 在另一實施例中,本發明提供一種用於治療及/或預防與APJ及愛帕琳相關之多種疾病或病症之方法,其包含向有需要的患者投與治療有效量之第一及第二治療劑,其中第一治療劑為本發明化合物。較佳地,第二治療劑例如選擇心肌收縮劑,諸如β-腎上腺素促效劑(例如多巴酚丁胺)。 在另一實施例中,本發明提供一種同時、分開或依序用於療法中的本發明化合物與額外治療劑之組合製劑。 在另一實施例中,本發明提供一種同時、分開或依序用於治療及/或預防與APJ及愛帕琳相關之多種疾病或病症的本發明化合物與額外治療劑之組合製劑。 需要時,本發明化合物可與一或多種其他類型之心臟血管劑及/或一或多種其他類型之治療劑組合使用,其可以相同劑型、以各別口服劑型經口投與,或藉由注射投與。可視情況與本發明之APJ促效劑組合使用之其他類型的心臟血管劑可為以相同劑型、以各別口服劑型經口投與或藉由注射投與而產生額外藥理學效益的一種、兩種、三種或更多種心臟血管劑。 本發明化合物可與選自一或多種、較佳一至三種以下治療劑之額外治療劑組合使用:抗高血壓劑、ACE抑制劑、鹽皮質素受體拮抗劑、血管收縮素受體阻斷劑、鈣離子通道阻斷劑、β-腎上腺素受體阻斷劑、利尿劑、諸如硝酸鹽之血管舒張劑、抗動脈粥樣硬化劑、抗脂質異常性劑、抗糖尿病劑、抗高血糖劑、抗高胰島素血症性劑、抗栓塞劑、抗視網膜病性劑、抗神經病性劑、抗腎病劑、抗缺血性劑、鈣離子通道阻斷劑、抗肥胖劑、抗高脂質血症劑、抗高甘油三酯血症劑、抗高膽固醇血症劑、抗再狹窄劑、抗胰臟劑、脂質降低劑、厭食劑、記憶增強劑、抗癡呆劑、認知促進劑、食慾抑制劑、用於治療心臟衰竭之藥劑、用於治療周邊動脈疾病之藥劑、用於治療惡性腫瘤之藥劑及抗發炎劑。 在另一實施例中,在治療心臟衰竭中,用於組合醫藥組合物或組合方法或組合用途之額外治療劑選自一或多種、較佳一至三種以下治療劑:ACE抑制劑、β-阻斷劑、利尿劑、鹽皮質素受體拮抗劑、腎素抑制劑、鈣離子通道阻斷劑、血管收縮素II受體拮抗劑、硝酸鹽、洋地黃化合物、心肌收縮劑。 本發明可在不偏離其精神或基本屬性之情況下以其他特定形式來實施。本發明涵蓋本文中所指出之本發明較佳態樣的所有組合。應理解,本發明之任何及所有實施例可聯合任何其他實施例以描述額外實施例。亦應理解,實施例之各個別要素為其自身的獨立實施例。此外,一實施例之任何要素意欲與任何實施例之任何及所有其他要素組合以描述額外實施例。 III. 化學 在通篇說明書及隨附申請專利範圍中,既定化學式或名稱應涵蓋其所有立體異構體及光學異構體及外消旋物(若此類異構體存在)。除非另外指示,否則所有對掌性(對映異構體及非對映異構體)及外消旋形式在本發明之範疇內。化合物中亦可存在C=C雙鍵、C=N雙鍵、環系統及其類似者之多種幾何異構體,且所有此類穩定異構體均涵蓋於本發明中。本發明化合物之順式及反式(或E
型及Z
型)幾何異構體已經描述且可以異構體混合物形式或以經分離之異構體形式分離。本發明化合物可以光學活性或外消旋形式分離。光學活性形式可藉由解析外消旋形式或藉由自光學活性起始物質合成來製備。用於製備本發明化合物之所有方法及其中製造之中間物視為本發明之一部分。製備對映異構體或非對映異構體產物時,其可藉由習知方法分離,例如藉由層析或分步結晶加以分離。視方法條件而定,本發明之最終產物係以游離(中和)形式或鹽形式獲得。此等最終產物之游離形式與鹽均在本發明之範疇內。如此需要時,可將化合物之一種形式轉化成另一形式。游離鹼或酸可轉化成鹽;鹽可轉化成游離化合物或另一種鹽;本發明之異構化合物之混合物可分離成個別異構體。本發明化合物、其游離形式及鹽可以多種互變異構體形式存在,其中氫原子轉置至分子之其他部分且分子中之原子之間的化學鍵因此重排。應理解,所有互變異構體形式只要可能存在則均包括於本發明內。 如本文中所使用,術語「烷基」或「伸烷基」意欲包括具有指定數目之碳原子的分支鏈與直鏈飽和脂族烴基。舉例而言,「C1
至C12
烷基」或「C1-12
烷基」(或伸烷基)意欲包括C1
、C2
、C3
、C4
、C5
、C6
、C7
、C8
、C9
、C10
、C11
及C12
烷基;「C4
至C18
烷基」或「C4-18
烷基」(或伸烷基)意欲包括C4
、C5
、C6
、C7
、C8
、C9
、C10
、C11
、C12
、C13
、C14
、C15
、C16
、C17
及C18
烷基。此外,例如「C1
至C6
烷基」或「C1
˗C6
烷基」表示具有1至6個碳原子之烷基。烷基可未經取代或使至少一個氫經另一化學基團置換而經取代。烷基實例包括(但不限於)甲基(Me)、乙基(Et)、丙基(例如正丙基及異丙基)、丁基(例如正丁基、異丁基、第三丁基)及戊基(例如正戊基、異戊基、新戊基)。當使用「C0
烷基」或「C0
伸烷基」時,其意欲表示直接鍵。 「烯基」或「伸烯基」意欲包括具有指定數目的碳原子及一或多個、較佳一至兩個碳-碳雙鍵的直鏈或分支鏈組態的烴鏈,該等碳-碳雙鍵可出現在沿鏈的任何穩定點處。舉例而言,「C2
至C6
烯基」或「C2-6
烯基」(或伸烯基)意欲包括C2
、C3
、C4
、C5
及C6
烯基。烯基之實例包括(但不限於)乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基及4-甲基-3-戊烯基。 「炔基」或「伸炔基」意欲包括具有一或多個、較佳一至三個碳-碳參鍵的直鏈或分支鏈組態的烴鏈,該等碳-碳參鍵可出現在沿鏈的任何穩定點處。舉例而言,「C2
至C6
炔基」或「C2-6
炔基」(或伸炔基)意欲包括C2
、C3
、C4
、C5
及C6
炔基;諸如乙炔基、丙炔基、丁炔基、戊炔基及己炔基。 除非另外規定,否則當使用術語「烴鏈」時,意欲包括「烷基」、「烯基」及「炔基」。 術語「烷氧基」或「烷基氧基」係指-O-烷基。舉例而言,「C1
至C6
烷氧基」或「C1-6
烷氧基」(或烷基氧基)意欲包括C1
、C2
、C3
、C4
、C5
及C6
烷氧基。烷氧基實例包括(但不限於)甲氧基、乙氧基、丙氧基(例如正丙氧基及異丙氧基)及第三丁氧基。類似地,「烷基硫基」或「硫基烷氧基」表示經由硫橋連接的具有指定數目碳原子之如上文所定義之烷基;例如,甲基-S-及乙基-S-。 「鹵基」或「鹵素」包括氟、氯、溴及碘。「鹵烷基」意欲包括經1個或更多個鹵素取代之具有指定數目碳原子之分支鏈及直鏈飽和脂族烴基。鹵烷基之實例包括(但不限於)氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基及七氯丙基。鹵烷基之實例亦包括「氟烷基」,其意欲包括經1個或更多個氟原子取代之具有指定數目碳原子之分支鏈及直鏈飽和脂族烴基。 「鹵烷氧基」或「鹵烷基氧基」表示經由氧橋連接的具有指定數目碳原子之如上文所定義之鹵烷基。舉例而言,「C1-6
鹵烷氧基」意欲包括C1
、C2
、C3
、C4
、C5
及C6
鹵烷氧基。鹵烷氧基之實例包括(但不限於)三氟甲氧基、2,2,2-三氟乙氧基及五氟乙氧基。類似地,「鹵烷基硫基」或「硫基鹵烷氧基」表示經由硫橋連接的具有指定數目碳原子之如上所定義之鹵烷基;例如三氟甲基-S-及五氟乙基-S-。 術語「環烷基」係指環化烷基,包括單環狀、二環狀或多環狀環系統。舉例而言,「C3
至C6
環烷基」或「C3-6
環烷基」意欲包括C3
、C4
、C5
及C6
環烷基。環烷基實例包括(但不限於)環丙基、環丁基、環戊基、環己基及降冰片烷基。分支鏈環烷基,諸如1-甲基環丙基及2-甲基環丙基包括於「環烷基」之定義中。術語「環烯基」係指環化烯基。C4-6
環烯基意欲包括C4
、C5
及C6
環烯基。環烯基實例包括(但不限於)環丁烯基、環戊烯基及環己烯基。 如本文中所使用,「碳環」、「碳環基」或「碳環殘基」欲意謂任何穩定3、4、5、6、7或8員單環或雙環或7、8、9、10、11、12或13員雙環或三環烴環,其中任一者可為飽和、部分不飽和、不飽和或芳族的。此類碳環之實例包括(但不限於)環丙基、環丁基、環丁烯基、環戊基、環戊烯基、環己基、環庚烯基、環庚基、環庚烯基、金剛烷基、環辛基、環辛烯基、環辛二烯基、[3.3.0]二環辛烷、[4.3.0]二環壬烷、[4.4.0]二環癸烷(十氫萘)、[2.2.2]二環辛烷、茀基、苯基、萘基、二氫茚基、金剛烷基、蒽基及四氫萘基(萘滿)。如上文所示,橋接環亦包括於碳環之定義中(例如[2.2.2]二環辛烷)。除非另外規定,否則較佳碳環為環丙基、環丁基、環戊基、環己基、苯基、二氫茚基及四氫萘基。當使用術語「碳環」時,意欲包括「芳基」。當一或多個,較佳一至三個碳原子鍵聯兩個不相鄰碳原子時,產生橋接環。較佳橋鍵為一或兩個碳原子。應指出,一個橋總是將單環轉變成三環。當環橋接時,該環中所敍述取代基亦可存在於橋上。 如本文中所使用,術語「雙環碳環」或「雙環碳環基」欲意謂含有兩個稠環且由碳原子組成的穩定9或10員碳環環系統。兩個稠環中,一個環為稠合至第二環之苯并環;且第二環為5或6員飽和、部分不飽和或不飽和碳環。雙環碳環基可在產生穩定結構之任何碳原子處連接至其側基。若所得化合物穩定,則本文中所描述之雙環碳環基可在任何碳上經取代。雙環碳環基之實例為(但不限於)萘基、1,2-二氫萘基、1,2,3,4-四氫萘基及二氫茚基。 「芳基」係指單環或雙環芳族烴,包括例如苯基及萘基。芳基部分已為所熟知且描述於例如Lewis, R.J.編,Hawley's Condensed Chemical Dictionary
, 第15版, John Wiley & Sons, Inc., New York (2007)中。「C6- 10
芳基」係指苯基及萘基。 如本文中所使用,術語「苯甲基」係指一個氫原子置換為苯基的甲基。 如本文中所使用,術語「雜環」、「雜環基」或「雜環基團」欲意謂穩定的3、4、5、6或7員單環或雙環或7、8、9、10、11、12、13或14員多環雜環,其為飽和、部分不飽和或完全不飽和的且含有碳原子及1、2、3或4個獨立地選自由N、O及S組成之群的雜原子;且包括其中任何上文所定義之雜環稠合至苯環的任何多環基團。氮及硫雜原子可視情況經氧化(亦即N→O及S(O)p,其中p為0、1或2)。氮原子可經取代或未經取代(亦即N或NR,其中R為H或另一取代基(若定義))。雜環可在產生穩定結構之任何雜原子或碳原子處連接至其側基。若所得化合物穩定,則本文中所描述之雜環可在碳原子或氮原子上經取代。雜環中之氮可視情況經四級銨化。當雜環中之S及O原子總數超過1時,則此等雜原子較佳彼此不相鄰。雜環中之S及O原子之總數較佳不超過1。當使用術語「雜環」時,意欲包括雜芳基。 雜環之實例包括(但不限於)吖啶基、氮雜環丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并異噁唑基、苯并異噻唑基、苯并咪唑啉基、咔唑基、4aH
-咔唑基、咔啉基、烷基、烯基、啉基、十氫喹啉基、2H
,6H
-1,5,2-二噻嗪基、二氫呋喃并[2,3-b
]四氫呋喃、呋喃基、呋呫基、咪唑啶基、咪唑啉基、咪唑基、1H
-吲唑基、咪唑并吡啶基、吲哚烯基、吲哚啉基、吲哚嗪基、吲哚基、3H
-吲哚基、靛紅醯基、異苯并呋喃基、異烷基、異吲唑基、異吲哚啉基、異吲哚基、異喹啉基、異噻唑基、異噻唑并吡啶基、異噁唑基、異噁唑并吡啶基、亞甲基二氧基苯基、嗎啉基、萘啶基、八氫異喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑啶基、噁唑基、噁唑并吡啶基、噁唑啶基呸啶基、羥吲哚基、嘧啶基、啡啶基、啡啉基、啡嗪基、啡噻嗪基、啡噁噻基、啡噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、向日葵基、喋啶基、嘌呤基、哌喃基、吡嗪基、吡唑啶基、吡唑啉基、吡唑并吡啶基、吡唑基、噠嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯啶基、吡咯啉基、2-吡咯啶酮基、2H
-吡咯基、吡咯基、喹唑啉基、喹啉基、4H
-喹嗪基、喹噁啉基、奎寧環基、四唑基、四氫呋喃基、四氫異喹啉基、四氫喹啉基、6H
-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻嗯基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基及基。亦包括含有例如以上雜環的稠環及螺化合物。 5至10員雜環之實例包括(但不限於)吡啶基、呋喃基、噻吩基、吡咯基、吡唑基、吡嗪基、哌嗪基、哌啶基、咪唑基、咪唑啶基、吲哚基、四唑基、異噁唑基、嗎啉基、噁唑基、噁二唑基、噁唑啶基、四氫呋喃基、噻二嗪基、噻二唑基、噻唑基、三嗪基、三唑基、苯并咪唑基、1H
-吲唑基、苯并呋喃基、苯并硫呋喃基、苯并四唑基、苯并三唑基、苯并異噁唑基、苯并噁唑基、羥吲哚基、苯并噁唑啉基、苯并噻唑基、苯并異噻唑基、靛紅醯基、異喹啉基、八氫異喹啉基、四氫異喹啉基、四氫喹啉基、異噁唑并吡啶基、喹唑啉基、喹啉基、異噻唑并吡啶基、噻唑并吡啶基、噁唑并吡啶基、咪唑并吡啶基及吡唑并吡啶基。 5至6員雜環之實例包括(但不限於)吡啶基、呋喃基、噻吩基、吡咯基、吡唑基、吡嗪基、哌嗪基、哌啶基、咪唑基、咪唑啶基、吲哚基、四唑基、異噁唑基、嗎啉基、噁唑基、噁二唑基、噁唑啶基、四氫呋喃基、噻二嗪基、噻二唑基、噻唑基、三嗪基及三唑基。亦包括含有例如以上雜環的稠環及螺化合物。 如本文中所使用,術語「雙環雜環」或「雙環雜環基」欲意謂穩定的9或10員雜環系統,其含有兩個稠環且由碳原子及1、2、3或4個獨立地選自由N、O及S組成之群的雜原子構成。在兩個稠環中,一個環為5或6員單環芳族環,其包含5員雜芳基環、6員雜芳基環或苯并環,各自稠合至第二環。第二環為5或6員單環,其為飽和、部分不飽和或不飽和的,且包含5員雜環、6員雜環或碳環(限制條件為若第二環為碳環,則第一環不為苯并)。 雙環雜環基可在產生穩定結構之任何雜原子或碳原子處連接至其側基。若所得化合物穩定,則本文中所描述之雙環雜環基可在碳原子或氮原子上經取代。當雜環中之S及O原子總數超過1時,則此等雜原子較佳彼此不相鄰。雜環中之S及O原子之總數較佳不超過1。 雙環雜環基之實例為(但不限於)喹啉基、異喹啉基、酞嗪基、喹唑啉基、吲哚基、異吲哚基、吲哚啉基、1H
-吲唑基、苯并咪唑基、1,2,3,4-四氫喹啉基、1,2,3,4-四氫異喹啉基、5,6,7,8-四氫喹啉基、2,3-二氫-苯并呋喃基、烷基、1,2,3,4-四氫喹噁啉基及1,2,3,4-四氫喹唑啉基。 如本文中所使用,術語「芳族雜環基」或「雜芳基」欲意謂穩定的單環及多環芳族烴,其包括至少一個雜原子環成員,諸如硫、氧或氮。雜芳基包括(但不限於)吡啶基、嘧啶基、吡嗪基、噠嗪基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、異噁唑基、吡唑基、三唑基、四唑基、吲唑基、1,2,4-噻二唑基、異噻唑基、嘌呤基、咔唑基、苯并咪唑基、吲哚啉基、苯并二氧雜環戊基及苯并二噁烷。雜芳基經取代或未經取代。氮原子經取代或未經取代(亦即N或NR,其中R為H或另一取代基(若經定義))。氮及硫雜原子可視情況經氧化(亦即N→O及S(O)p,其中p為0、1或2)。 5至6員雜芳基之實例包括(但不限於)吡啶基、呋喃基、噻吩基、吡咯基、吡唑基、吡嗪基、咪唑基、咪唑啶基、四唑基、異噁唑基、噁唑基、噁二唑基、噁唑啶基、噻二嗪基、噻二唑基、噻唑基、三嗪基及三唑基。 橋接環亦包括於雜環之定義中。當一或多個、較佳一至三個原子(亦即C、O、N或S)連接兩個不相鄰碳或氮原子時,發生橋接環。橋接環之實例包括(但不限於)一個碳原子、兩個碳原子、一個氮原子、兩個氮原子及一個碳-氮基團。應指出,一個橋總是將單環轉變成三環。當環橋接時,該環中所述取代基亦可存在於橋上。 術語「相對離子」用以表示帶負電物質,諸如氯離子、溴離子、氫氧根、乙酸根及硫酸根;或帶正電物質,諸如鈉(Na+)、鉀(K+)、銨(Rn
NHm
+,其中n=0-4且m=0-4);及其類似物質。 當在環結構內使用虛線環時,此指示該環結構可為飽和、部分飽和或不飽和的。 如本文中所使用,術語「胺保護基」意謂有機合成技術中已知的用於保護胺基的任何基團,其對酯還原劑、二取代之肼、R4-M及R7-M、親核試劑、肼還原劑、活化劑、強鹼、受阻胺鹼及環化劑具有穩定性。符合此等準則之此類胺保護基包括列於以下者中之彼等胺保護基:Wuts, P.G.M.等人,Protecting Groups in Organic Synthesis
, 第4版, Wiley (2007)及The Peptides: Analysis, Synthesis, Biology
, 第3卷, Academic Press, New York (1981),其揭示內容以引用的方式併入本文中。胺保護基之實例包括(但不限於)以下∶(1)醯基型,諸如甲醯基、三氟乙醯基、酞醯基及對甲苯磺醯基;(2)芳族胺基甲酸酯型,諸如苯甲氧基羰基(Cbz)及經取代之苯甲氧基羰基、1-(對聯二苯)-1-甲基乙氧基羰基及9-茀基甲氧基羰基(Fmoc);(3)脂族胺基甲酸酯型,諸如第三丁氧基羰基(Boc)、乙氧基羰基、二異丙基甲氧基羰基及烯丙氧基羰基;(4)環狀烷基胺基甲酸酯型,諸如環戊基氧基羰基及金剛烷氧羰基;(5)烷基型,諸如三苯基甲基及苯甲基;(6)三烷基矽烷,諸如三甲基矽烷;(7)含硫醇型,諸如苯硫基羰基及二硫雜丁二醯基;及(8)烷基型,諸如三苯基甲基、甲基及苯甲基;及經取代之烷基型,諸如2,2,2-三氯乙基、2-苯基乙基及第三丁基;及三烷基矽烷型,諸如三甲基矽烷。 如本文中所提及,術語「經取代」意謂至少一個氫原子經非氫基團置換,其限制條件為維持正常價數且取代產生穩定化合物。如本文中所使用,環雙鍵為形成於兩個相鄰環原子之間的雙鍵(例如C=C、C=N或N=N)。 在本發明化合物上存在氮原子(例如胺)的情況下,此等物可藉由氧化劑(例如mCPBA及/或過氧化氫)處理而轉化成N-氧化物,得到本發明其他化合物。因此,所展示及所主張之氮原子視為涵蓋所展示之氮及其N-氧化物(N→O)衍生物。 當任何變數在化合物之任何組分或式中出現多於一次時,其在每次出現時的定義獨立於其在其他每次出現時的定義。因此,例如,若基團展示經0至3個R取代,則該基團可視情況經至多三個R基團取代,且R在每次出現時獨立地選自R定義。 若連至取代基之一鍵經展示與連接環中之兩個原子的一鍵交叉,則此類取代基可鍵結至該環上的任何原子。當取代基在未指出此類取代基鍵結至既定式化合物之其餘部分的原子的情況下列出時,則此類取代基可經由此類取代基中之任何原子鍵結。 取代基及/或變數之組合僅當此類組合產生穩定化合物時才為允許的。 片語「醫藥學上可接受」在本文中用於指在合理醫學判斷範疇內,適用於與人類及動物之組織接觸而無過度毒性、刺激、過敏反應或其他問題或併發症、與合理益處/風險比相匹配之化合物、物質、組合物及/或劑型。 如本文中所使用,「醫藥學上可接受之鹽」係指所揭示化合物之衍生物,其中母體化合物藉由製成其酸鹽或鹼鹽而改質。醫藥學上可接受之鹽之實例包括(但不限於)鹼基(諸如胺)之礦物酸鹽或有機酸鹽;及酸基(諸如羧酸)之鹼金屬鹽或有機鹽。醫藥學上可接受之鹽包括例如由無毒性無機酸或有機酸形成之母體化合物的習知無毒性鹽或四級銨鹽。舉例而言,此類習知無毒性鹽包括衍生自無機酸之鹽,該等無機酸諸如鹽酸、氫溴酸、硫酸、胺磺酸、磷酸及硝酸;及由有機酸製備之鹽,該等有機酸諸如乙酸、丙酸、丁二酸、乙醇酸、硬脂酸、乳酸、蘋果酸、酒石酸、檸檬酸、抗壞血酸、帕莫酸、順丁烯二酸、羥基順丁烯二酸、苯乙酸、麩胺酸、苯甲酸、水楊酸、對胺基苯磺酸、2-乙醯氧基苯甲酸、反丁烯二酸、甲苯磺酸、甲烷磺酸、乙烷二磺酸、草酸及羥乙基磺酸,及其類似物。 本發明之醫藥學上可接受之鹽可由含有鹼性或酸性部分之母化合物藉由習知化學方法合成。一般而言,此類鹽可由此等化合物之游離酸或鹼形式與化學計量之量的適當鹼或酸在水中或在有機溶劑中或在兩者之混合物中反應來製備;一般而言,非水性介質(如乙醚、乙酸乙酯、乙醇、異丙醇或乙腈)較佳。適合鹽之清單見於Allen, Jr., L.V.編,Remington: The Science and Practice of Pharmacy
, 第22版, Pharmaceutical Press, London, UK (2012),其揭示內容以引用的方式併入本文中。 另外,式I化合物可具有前藥形式。在活體內轉化而得到生物活性劑(亦即式I化合物)的任何化合物為在本發明之範疇及精神內的前藥。各種形式之前藥在此項技術中為熟知的。關於此類前藥衍生物之實例,參見: a) Bundgaard, H.編,Design of Prodrugs
, Elsevier (1985), 及Widder, K. 等人編,Methods in Enzymology
, 112:309-396, Academic Press (1985); b) Bundgaard, H., 第5章, 「Design and Application of Prodrugs」, Krosgaard-Larsen, P.等人編,A Textbook of Drug Design and Development
, 第113-191頁, Harwood Academic Publishers (1991); c) Bundgaard, H.,Adv. Drug Deliv. Rev.
, 8:1-38 (1992); d) Bundgaard, H.等人,J. Pharm. Sci.
, 77:285 (1988); e) Kakeya, N.等人,Chem. Pharm. Bull.
, 32:692 (1984);及 f) Rautio, J.編,Prodrugs and Targeted Delivery (Methods and Principles in Medicinal Chemistry)
, 第47卷, Wiley-VCH (2011)。 含有羧基之化合物可形成生理上可水解之酯,其充當藉由在體內水解產生式I化合物本身之前藥。此類前藥較佳經口投與,因為許多情況下水解主要在消化酶之影響下發生。在酯本身具有活性的情況下或在水解發生於血液中的彼等情況下,可使用非經腸投藥。式I化合物之生理學上可水解之酯的實例包括C1-6
烷基、C1-6
烷基苯甲基、4-甲氧基苯甲基、二氫茚基、酞醯基、甲氧基甲基、C1-6
烷醯基氧基-C1-6
烷基(例如乙醯氧基甲基、特戊醯氧基甲基或丙醯氧基甲基)、C1-6
烷氧基羰氧基-C1-6
烷基(例如甲氧基羰氧基甲基或乙氧基羰氧基甲基、甘胺醯氧基甲基、苯基甘胺醯氧基甲基、(5-甲基-2-側氧基-1,3-二氧雜環戊烯-4-基)-甲基),及用於例如青黴素(penicillin)及頭孢菌素(cephalosporin)技術中之其他熟知的生理學上可水解之酯。此類酯可藉由此項技術中已知之習知技術來製備。 前藥之製備在此項技術中為熟知的且描述於例如King, F.D.編,Medicinal Chemistry: Principles and Practice
, The Royal Society of Chemistry, Cambridge, UK (第2版,複製版(2006));Testa, B.等人,Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology
, VCHA and Wiley-VCH, Zurich, Switzerland (2003);Wermuth, C.G.編,The Practice of Medicinal Chemistry
, 第3版, Academic Press, San Diego, CA (2008)中。 本發明意欲包括存在於本發明化合物中之原子之所有同位素。同位素包括原子數相同但質量數不同之彼等原子。作為一般實例但非限制性地,氫之同位素包括氘及氚。氘在其核中具有一個質子及一個中子,且質量為普通氫之兩倍。氘可由諸如「2
H」或「D」之符號表示。本文中本身或用以改質化合物或基團的術語「氘化」係指連接至碳(一或多個)之一或多個氫原子經氘原子置換。碳之同位素包括13
C及14
C。 本發明之同位素標記化合物通常可藉由熟習此項技術者已知之習知技術或藉由類似於本文所描述之方法、使用適當同位素標記試劑替代以其他方式採用之非標記試劑來製備。此類化合物具有多種潛在用途,例如作為測定潛在醫藥化合物結合至標靶蛋白或受體之能力的標準品及試劑或用於使活體內或活體外結合至生物受體之本發明化合物成像。 術語「溶劑合物」意謂本發明化合物與一或多個溶劑分子(不論有機或無機)之物理性締合。此物理性締合包括氫鍵結。在某些情況下,例如當一或多個溶劑分子併入結晶固體之晶格時溶劑合物將能夠分離。溶劑合物中之溶劑分子可以有序排列及/或無序排列而存在。溶劑合物可包含化學計量或非化學計量之量的溶劑分子。「溶劑合物」涵蓋溶液相與可分離溶劑合物。例示性溶劑合物包括(但不限於)水合物、乙醇合物、甲醇合物及異丙醇合物。溶劑化方法一般在此項技術中已知。 如本文所使用之縮寫定義如下:「1×」表示一次,「2×」表示兩次,「3×」表示三次,「℃」表示攝氏度,「eq」表示當量,「g」表示公克,「mg」表示毫克,「L」表示公升,「mL」表示毫升,「μL」表示微升,「N」表示當量濃度,「M」表示莫耳濃度,「mmol」表示毫莫耳,「min」表示分鐘,「h」表示小時,「rt」表示室溫,「RT」表示滯留時間,「atm」表示大氣壓,「psi」表示磅每平方吋,「conc.」表示濃縮物,「aq」表示「水性」,「sat」或「sat'd」表示飽和,「MW」表示分子量,「mp」表示熔點,「MS」或「Mass Spec」表示質譜分析,「ESI」表示電噴霧電離質譜分析,「HR」表示高解析度,「HRMS」表示高解析度質譜分析,「LCMS」表示液相層析質譜分析,「HPLC」表示高壓液相層析,「RP HPLC」表示逆相HPLC,「TLC」或「tlc」表示薄層層析,「NMR」表示核磁共振光譜,「nOe」表示核奧氏效應(nuclear Overhauser effect)光譜分析,「1
H」表示質子,「δ」表示δ,「s」表示單峰,「d」表示二重峰,「t」表示三重峰,「q」表示四重峰,「m」表示多重峰,「br」表示寬峰,「Hz」表示赫茲,且「α」、「β」、「R」、「S」、「E」、「Z」及「ee」為熟習此項技術者所熟悉之立體化學名稱。
本發明化合物可以熟習此項有機合成技術者已知的許多方式來製備。本發明化合物可使用下文所描述之方法以及有機合成化學技術中已知之合成方法或藉由如熟習此項技術者所瞭解之其變化形式來合成。較佳方法包括(但不限於)下文所描述之方法。反應在適於所採用之試劑及物質且適合於實現轉換的溶劑或溶劑混合物中進行。熟習此項有機合成技術者應理解,分子上存在之官能基應與所提出之轉換相符。有時此將需要作出判斷以修改合成步驟次序或選擇一種特定方法流程而非另一種,從而獲得所需本發明化合物。 本發明之新穎化合物可使用此部分中所描述之反應及技術來製備。另外,在下文所描述之合成方法的描述中,應理解所提出之所有反應條件(包括溶劑選擇、反應氛圍、反應溫度、實驗持續時間及處理程序)均選擇為熟習此項技術者容易識別的該反應之標準條件。對與反應條件相容之取代基的限制對於熟習此項技術者而言將顯而易見,且於是須使用替代方法。 合成 式(I)化合物可藉由以下流程及實施例中描述之例示性方法以及熟習此項技術者使用的相關公開文獻程序來製備。用於此等反應之例示性試劑及程序呈現於下文及實施例中。下文方法中之保護及去保護可藉由此項技術中一般已知之程序進行(參見例如Wuts, P.G.M.等人,Protecting Groups in Organic Synthesis
, 第4版, Wiley (2007))。有機合成及官能基轉換的通用方法可見於:Trost, B.M.等人編,Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry
, Pergamon Press, New York, NY (1991);Smith, M.B.等人,March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure
. 第6版, Wiley & Sons, New York, NY (2007);Katritzky, A.R.等人編,Comprehensive Organic Functional Groups Transformations II
, 第2版, Elsevier Science Inc., Tarrytown, NY (2004);Larock, R.C.,Comprehensive Organic Transformations
, VCH Publishers, Inc., New York, NY (1999)及其中之參考文獻。 式(I)化合物可如流程1中所描述製備。 流程1步驟1描述式G1b化合物之製備,此係藉由式G1a之酯與酸R2
CO-LG縮合,其中LG表示離去基(諸如鹵素及其類似基團)。較佳之溶劑為醚(諸如四氫呋喃、二噁烷及其類似物)及極性非質子性溶劑(諸如N,N-二甲基甲醯胺)。較佳之鹼為金屬醯胺(諸如雙(三甲基矽烷基)胺基鋰及二異丙胺基鋰及其類似物)及金屬氫化物(諸如氫化鈉及其類似物)。 步驟2描述式G1c化合物之製備,此係藉由式G1b化合物與氨縮合。較佳之氨源為氨(氣)或其鹽(諸如乙酸銨、甲酸銨及其類似物)。較佳之溶劑為醇(諸如甲醇、乙醇及其類似物)。 步驟3描述式G1d之吡啶化合物之製備,此係藉由式G1c化合物與丙二酸酯衍生物R b
OCOCH2
CO-LG在鹼存在下縮合,其中LG表示離去基(諸如鹵素或烷氧化物,諸如乙氧化物及其類似者)。該方法可以單步驟進行或逐步地進行。用於兩步驟方法之第一步之較佳溶劑為鹵化溶劑(諸如DCM及其類似物)、醚(諸如四氫呋喃、二噁烷及其類似物)及水。用於兩步驟方法之第一步之較佳鹼為三級胺(諸如TEA、DIEA及其類似物)及鹼金屬碳酸鹽、鹼金屬碳酸氫鹽、鹼金屬氫氧化物(諸如碳酸鈉、碳酸氫鈉、氫氧化鈉及其類似物)。用於第二步及單步驟方法之較佳溶劑為醇(諸如MeOH及EtOH及其類似物)。用於第二步及單步驟方法之較佳鹼為鹼金屬烷氧化物(諸如乙醇鈉及其類似物)。 步驟4描述由式G1d之相對應酯與NHR3
R4
之胺製備式(I)化合物。較佳反應條件為在高溫(諸如100℃至160℃)下藉助於微波反應器加熱,且較佳溶劑為乙醇及DMF。或者,式(I)化合物可使用催化劑由式G1d之相對應酯及NHR3
R4
之胺來製備。較佳之催化劑為1-羥基-7-氮雜苯并三唑(HOAT)及第三丁醇鋯(IV) (Zr(Ot
Bu)4
)且較佳溶劑為甲苯。 或者,流程1中之式G1d化合物可如流程2中所描述製備。 流程2步驟1描述由式G2a化合物(如W2007/197478中所描述製備)製備式G2b化合物,其中LG表示離去基(諸如鹵素,較佳為溴)。用於併入離去基中之較佳試劑為溴源(諸如元素溴及NBS及其類似物)。較佳之溶劑為鹵化溶劑(諸如DCM及其類似物)。 步驟2描述式G1d化合物之製備,此係藉由有機金屬試劑M-(alk)0-2
-Ⓑ-(R1
)1-4
與式G2b化合物偶合。有機金屬試劑M-(alk)0-2
-Ⓑ-(R1
)1-4
較佳藉由烷基酸或酯B(OR)2
-(alk)0-2
-Ⓑ-(R1
)1-4
(R = H或烷基)與過渡金屬催化劑(諸如Pd(PPh3
)4
及Pd(OAc)2
及其類似物)反應而產生。較佳之溶劑為醚(諸如四氫呋喃、二噁烷及其類似物)、非質子性溶劑(諸如甲苯及其類似物)及水。較佳之鹼為鹼金屬碳酸鹽、鹼金屬碳酸氫鹽(諸如碳酸鈉、碳酸氫鈉及其類似物)。 或者,流程1中之式G1c化合物可如流程3中所描述製備。 流程3步驟1描述式G3b化合物之製備,此係藉由溴化式G3a之酯。較佳之溴源為元素溴及NBS及其類似物。較佳之溶劑為醚(諸如四氫呋喃、二噁烷及其類似物)。較佳之鹼為金屬醯胺(諸如雙(三甲基矽烷基)胺基鋰及二異丙胺基鋰及其類似物)及金屬氫化物(諸如氫化鈉及其類似物)。 步驟2描述式G1c化合物之製備,此由式G3b化合物在過渡金屬存在下經由與腈R2
-CN縮合進行。較佳之過渡金屬為鋅,且可使用助催化劑(氧化鋅、烷基磺酸及其類似物)。可使用諸如醚(諸如四氫呋喃、二噁烷及其類似物)之惰性溶劑及非質子性溶劑(諸如甲苯及其類似物),較佳地反應在淨條件下執行。 IV. 生物學 APJ受體在1993年發現為孤兒G蛋白偶合之受體(GPCR),且隨後發現其將愛帕琳肽識別為其內源性配位體。其屬於A類GPCR且具有經典的7-跨膜域結構,呈現與血管收縮素AT1受體之最大的序列同源性(綜述參見Pitkin, S.L.等人,Pharmacol. Rev.
, 62(3):331-342 (2010))。APJ在多種周邊組織及CNS中表現,且在胎盤、心肌、血管內皮細胞、平滑肌細胞以及心肌細胞中具有相對高之表現(Kleinz, J.M.等人,Pharmacol. Ther
., 107(2):198-211(2005))。愛帕琳肽最初在牛胃提取物中經鑑別且到目前為止仍為唯一已知之APJ受體之內源性配位體及促效劑(Tatemoto, K.等人,Biochem. Biophys. Res. Commun
., 255:471-476 (1998))。愛帕琳基因之組織表現緊密地反映出APJ表現模態且已假定以自分泌或旁分泌方式起作用,常常藉由參照「愛帕琳-APJ系統」來例示。愛帕琳基因編碼77個胺基酸前驅肽,其經裂解以形成成熟之分泌肽,進一步進行蛋白水解分裂,形成更短的C-末端片段。愛帕琳-36、-17及-13表示主要活性形式,其中愛帕琳-13之焦麩胺酸鹽化形式為存在於心臟組織中之最穩定且最為常見之形式(Maguire, J.J.等人,Hypertension
, 54(3):598-604 (2009))。愛帕琳在循環中具有極短的半衰期,估計小於5分鐘(Japp, A.G.等人,Circulation
, 121(16):1818-1827 (2010))。 已知APJ受體之活化以百日咳毒素敏感性方式抑制經毛喉素(forskolin)刺激之環AMP (cAMP)的含量,指示偶合至Gi蛋白。cAMP分析中,愛帕琳之結合親和力及EC50
值據報導在亞奈莫耳範圍內(綜述參見Pitkin, S.L.等人,Pharmacol. Rev.
, 62(3):331-342(2010))。除cAMP抑制以外,APJ受體活化亦引起β-抑制蛋白募集、受體內化及胞外調節激酶(ERK)之活化(綜述參見Kleinz, J.M.等人,Pharmacol. Ther
.,107(2):198-211 (2005))。此等信號傳導機制中,促進調節愛帕琳之下游生理作用之機制目前尚不清楚。已顯示APJ受體與AT1受體相互作用。雖然愛帕琳不結合AT1且血管收縮素II不結合APJ,但已假定愛帕琳之某些生理作用至少部分地經由血管收縮素II之功能拮抗作用及AT1受體路徑介導(Chun, A.J.等人,J. Clin. Invest.
, 118(10):3343-3354 (2008))。 在作為實例給出且不意欲為限制性之以下類別中之一或多者中尋找與已知HF治療劑相比較具有有利及改良特徵之化合物亦合乎需要且為較佳的:(a)藥物動力學特性,包括口服生物可用性、半衰期及清除率;(b)醫藥特性;(c)給藥需求;(d)降低血液藥物濃度峰谷特徵之因素;(e)增加受體處活性藥物之濃度之因素;(f)降低臨床藥物-藥物相互作用之傾向之因素;(g)降低不利副作用之可能性之因素,包括相較於其他生物標靶之選擇性;及(h)所提高之治療指數。 如本文中所使用,術語「患者」涵蓋所有哺乳動物物種。 如本文中所使用,術語「個體」係指可能潛在受益於APJ促效劑治療的任何人類或非人類生物體。例示性個體包括具有罹患以下風險因素之任何年齡的人類:心臟衰竭及其後遺症、心絞痛、缺血、心臟缺血、心肌梗塞、再灌注損傷、血管成形再狹窄、高血壓、糖尿病之血管併發症、肥胖或內毒素血症、中風以及動脈粥樣硬化、冠狀動脈疾病、急性冠狀動脈症候群及/或血脂異常。 如本文中所使用,「治療(treating或treatment)」涵蓋治療哺乳動物(尤其人類)之疾病病況且包括:(a)抑制疾病病況,亦即遏制其發展;及/或(b)緩解疾病病況,亦即使疾病病況消退。 如本文中所使用,「預防」為疾病病況之防護性治療以藉由投與患者治療有效量之本發明化合物或其立體異構體、互變異構體、醫藥學上可接受之鹽或溶劑合物中之至少一者來減少疾病病況之風險及/或使風險達最小及/或降低疾病病況復發之風險。患者可基於已知相較於一般群體增加罹患臨床疾病病況之風險的因素而選用於預防療法。對於預防治療,臨床疾病病況之病狀可呈現或可尚未呈現。「預防」治療可分成(a)初級預防及(b)次級預防。初級預防定義為治療以減少尚未呈現臨床疾病病況之患者的疾病病況之風險或使該風險達最小,而次級預防定義為使相同或類似臨床疾病病況之復發或第二次發生的風險達最小或降低該風險。 如本文中所使用,「預防」涵蓋哺乳動物、尤其人類之亞臨床疾病病況之預防性治療,旨在降低臨床疾病病況之發生機率。患者基於已知相較於一般群體增加罹患臨床疾病病況之風險的因素而選用於預防療法。 「治療有效量」意欲包括當單獨或以組合方式投與以調節APJ及/或預防或治療本文所列病症時有效的本發明化合物的量。當應用於組合時,該術語係指無論以組合方式、依序或同時投與,產生預防或治療作用的活性成分的組合量。 A. 分析方法 胞內cAMP積累分析 穩定地表現人類APJ受體之HEK293細胞用以分析化合物之活性。將經培養細胞剝離且再懸浮於cAMP均質時差式螢光(HTRF)分析緩衝液(Cisbio;目錄號62AM4PEJ)中。根據製造商提供之分析方案在384孔分析培養盤(Perkin-Elmer;目錄號6008289)中進行分析。將化合物以及含有0.2 nM IBMX及2 μM毛喉素之分析緩衝液之連續稀釋液添加至含有5,000個細胞之各孔中且在室溫下培育30分鐘。隨後將cAMP D2試劑添加於裂解緩衝液中,之後添加EuK抗體(Cisbio;目錄號62AM4PEJ)且培育60分鐘。使用螢光計量測螢光發射比。藉由使用已知cAMP濃度自標準曲線外推來計算胞內cAMP濃度(對毛喉素介導之cAMP產生的經化合物刺激之抑制)。藉由將資料擬合成具有可變斜率之S形濃度反應曲線來獲得EC50
值。各化合物之經毛喉素誘導之cAMP含量的最大可實現抑制(Ymax
)表示為使用焦麩胺酸鹽化之愛帕琳-13 ((Pyr1)愛帕琳-13)肽獲得之相對抑制百分比,其設定成100%。 在上文所描述之APJ活體外分析中測試下文所揭示之實例,且發現其具有人類APJ環AMP (hcAMP)活性。各化合物之EC50
值在實例描述結束時呈現。 本發明化合物具有作為APJ受體之促效劑之活性,且因而可用於治療與APJ活性相關之疾病。因此,本發明化合物可投與至哺乳動物、較佳人類以用於治療多種病狀及病症,包括但不限於治療、預防或減緩以下之進展:心臟衰竭、冠狀動脈疾病、周邊血管疾病、動脈粥樣硬化、糖尿病、代謝症候群及其後遺症、高血壓、肺高血壓、腦血管病症、心房顫動、心絞痛、缺血、中風、心肌梗塞、急性冠狀動脈症候群、再灌注損傷、血管成形再狹窄、糖尿病之血管併發症及肥胖。 藉由上文所描述之分析確定的本發明之例示性化合物之生物活性在各實例結束時展示。APJ cAMP EC50
效能範圍如下:A = 0.01-10 nM;B = 10.01-100 nM;C = 100.01-300 nM。 V. 醫藥組合物、調配物及組合 本發明化合物可藉由任何適合之手段投與以用於本文所描述之任何用途,任何適合之手段例如經口,諸如錠劑、膠囊(其各自包括持續釋放或定時釋放調配物)、丸劑、散劑、顆粒、酏劑、酊劑、懸浮液(包括奈米懸浮液、微懸浮液、噴霧乾燥分散液)、糖漿及乳液;舌下;經頰;非經腸,諸如藉由皮下、靜脈內、肌肉內或胸骨內注射,或輸注技術(例如呈無菌可注射水溶液或非水溶液或懸浮液形式);經鼻,包括向鼻膜投與,諸如藉由吸入噴霧;局部,諸如以乳霜或軟膏形式;或經直腸,諸如以栓劑形式。其可單獨投與,但一般將與基於所選投藥途徑及標準醫藥實踐選擇的醫藥載劑一起投與。 術語「醫藥組合物」意謂包含本發明化合物以及至少一種額外醫藥學上可接受之載劑的組合物。「醫藥學上可接受之載劑」係指此項技術中一般可接受用於向動物,尤其哺乳動物遞送生物活性劑的介質,視投藥模式之性質及劑型而定包括亦即佐劑、賦形劑或媒劑,諸如稀釋劑、防腐劑、填充劑、流動調節劑、崩解劑、濕潤劑、乳化劑、懸浮劑、甜味劑、調味劑、芳香劑、抗細菌劑、抗真菌劑、潤滑劑及施配劑。 醫藥學上可接受之載劑根據一般技術者範圍內的多個因素調配。此等包括(但不限於):所調配之活性劑的類型及性質;投與含該藥劑之組合物的個體;組合物之預期投藥途徑;及所靶向之治療適應症。醫藥學上可接受之載劑包括水性及非水性液體介質,以及多種固體及半固體劑型。除活性劑以外,此類載劑可包括多種不同成分及添加劑,此類額外成分出於一般技術者熟知之多種原因(例如使活性劑、黏合劑等穩定)包括於調配物中。對適合的醫藥學上可接受之載劑及涉及其選擇之因素的描述見於多種可容易獲得之來源,例如Allen, Jr., L.V.等人,Remington: The Science and Practice of Pharmacy
(2卷), 第22版, Pharmaceutical Press (2012)。 本發明化合物之給藥方案將當然將視已知因素而變化,諸如特定藥劑之藥力學特徵及其投藥模式及途徑;接受者之物種、年齡、性別、健康狀況、醫學病狀及體重;症狀之性質及程度;同時發生之治療的種類;治療頻率;投藥途徑、患者之腎功能及肝功能以及所需作用。 藉助於一般指導,各活性成分在用於所指示作用時的每日口服劑量將在每天約0.001至約5000 mg之間,較佳每天約0.01至約1000 mg之間,且最佳每天約0.1至約250 mg之間範圍內。靜脈內投與時,在恆定速率輸注期間最佳劑量將在每分鐘約0.01至約10 mg/kg之範圍內。本發明化合物可以單次日劑量投與,或每日總劑量可以每日兩次、三次或四次之分次劑量投與。 化合物通常以與針對預期投藥形式(例如口服錠劑、膠囊、酏劑及糖漿)適當選擇且與習知醫藥實踐相符的適合醫藥稀釋劑、賦形劑或載劑(在本文中統稱為醫藥載劑)之混雜物形式投與。 適合於投與之劑型(醫藥組合物)可含有每劑量單位約1毫克至約2000毫克之活性成分。在此等醫藥組合物中,活性成分通常將以按該組合物之總重量計約0.1-95重量%之量存在。 用於口服投藥之典型膠囊含有本發明化合物中之至少一者(250 mg)、乳糖(75 mg)及硬脂酸鎂(15 mg)。混合物通過60目篩且裝入1號明膠膠囊中。 藉由將本發明化合物中之至少一者(250 mg)無菌置入小瓶中,無菌冷凍-乾燥及密封來製造典型可注射製劑。對於使用,將小瓶的內含物與2 mL生理食鹽水混合以產生可注射製劑。 本發明在其範疇內包括醫藥組合物,該等醫藥組合物包含治療有效量之單獨或與醫藥載劑組合的本發明化合物中之至少一者作為活性成分。視情況,本發明化合物可單獨、與本發明之其他化合物組合或與一或多種其他治療劑、例如用於治療心臟衰竭之藥劑或其他醫藥活性物質組合而使用。 本發明化合物可與其他APJ促效劑或一或多種其他適合之治療劑(適用於治療前述病症)組合使用,該等治療劑包括:用於治療心臟衰竭之藥劑、抗高血壓劑、抗動脈粥樣硬化劑、抗脂質異常性劑、抗糖尿病劑、抗高血糖劑、抗高胰島素血症性劑、抗栓塞劑、抗視網膜病性劑、抗神經病性劑、抗腎病劑、抗缺血性劑、抗肥胖劑、抗高脂質血症劑、抗高甘油三酯血症劑、抗高膽固醇血症劑、抗再狹窄劑、抗胰臟劑、脂質降低劑、厭食劑、記憶增強劑、抗癡呆劑、認知促進劑、食慾抑制劑及用於治療周邊動脈疾病之藥劑。 在治療心臟衰竭及冠狀動脈疾病中,本發明化合物可與選自一或多種、較佳一至三種以下治療劑的額外治療劑組合使用:ACE抑制劑、β-阻斷劑、利尿劑、鹽皮質素受體拮抗劑、腎素抑制劑、鈣離子通道阻斷劑、血管收縮素II受體拮抗劑、硝酸鹽、洋地黃化合物、心肌收縮劑及β-受體促效劑、抗高脂質血症劑、血漿HDL升高劑、抗高膽固醇血症劑、膽固醇生物合成抑制劑(諸如HMG CoA還原酶抑制劑)、LXR促效劑、普羅布可(probucol)、雷諾昔酚(raloxifene)、菸鹼酸、菸鹼醯胺、膽固醇吸收抑制劑、膽酸錯隔劑(諸如陰離子交換樹脂或四級胺(例如,消膽胺或考來替潑(colestipol))、低密度脂蛋白受體誘導劑、氯貝特(clofibrate)、非諾貝特(fenofibrate)、苯并貝特(benzofibrate)、環丙貝特(cipofibrate)、gemfibrizol、維生素B6
、維生素B12
、抗氧化劑維生素、抗糖尿病劑、血小板凝集抑制劑、血纖維蛋白原受體拮抗劑、阿司匹林(aspirin)及纖維酸衍生物。 本發明化合物可視所需靶向療法而定與一或多種、較佳一至三種以下抗糖尿病劑組合使用。研究表明糖尿病及高脂質血症調節可藉由將第二劑添加至治療方案中而進一步改進。抗糖尿病劑之實例包括(但不限於)磺醯脲(諸如氯磺丙脲、甲苯磺丁尿、乙醯苯磺醯環己脲、甲磺氮卓脲、格列本脲、格列齊特(gliclazide)、格列農(glynase)、格列美脲(glimepiride)及格列吡嗪);雙胍(諸如二甲雙胍);噻唑啶二酮(諸如環格列酮(ciglitazone)、吡格列酮(pioglitazone)、曲格列酮(troglitazone)及羅格列酮(rosiglitazone))及相關胰島素敏化劑,諸如PPARα、PPARβ及PPARγ之選擇性及非選擇性活化劑;脫氫表雄酮(亦稱作DHEA或其結合之硫酸酯,DHEA-SO4
);抗糖皮質激素;TNFα抑制劑;二肽基肽酶IV (DPP4)抑制劑(諸如西他列汀(sitagliptin)、沙格列汀(saxagliptin));GLP-1促效劑或類似物(諸如艾塞那肽(exenatide));α葡糖苷酶抑制劑(諸如阿卡波糖(acarbose)、米格列醇及伏格列波糖(voglibose));普蘭林肽(pramlintide) (人類激素澱粉素之合成類似物);其他胰島素促泌素(諸如瑞格列奈(repaglinide)、格列喹酮(gliquidone)及那格列奈(nateglinide));胰島素以及以上所論述用於治療心臟衰竭及動脈粥樣硬化之治療劑。 本發明化合物可與一或多種、較佳一至三種以下抗肥胖劑組合使用,該等抗肥胖劑選自苯丙醇胺、苯丁胺、二乙胺苯丙酮、氯苯咪吲哚、氟苯丙胺、右芬氟拉明(dexfenfluramine)、酚妥拉明(phentiramine)、β3
腎上腺素受體促效劑、諾美婷(sibutramine)、胃腸脂肪酶抑制劑(諸如羅氏鮮(orlistat)及瘦素。用於治療肥胖或肥胖相關病症之其他藥劑包括神經肽Y、腸抑素、膽囊收縮素、鈴蟾素、澱粉素、組胺H3
受體、多巴胺D2
受體調節劑、黑色素細胞刺激激素、促腎上腺皮質激素釋放因子、甘丙胺素及γ胺基丁酸(GABA)。 以上其他治療劑與本發明化合物組合使用時可以例如Physicians' Desk Reference
(如以上所陳述的專利中)中所指示的量或另外由一般技術者確定的量使用。 尤其當以單個劑量單位形式提供時,組合之活性成分之間可能存在化學相互作用。因此,當本發明化合物及第二治療劑以單個劑量單位組合時,儘管活性成分以單個劑量單位組合,但仍對其進行調配,使活性成分之間的物理接觸降至最低(亦即降低)。舉例而言,一種活性成分可包覆腸溶包衣。藉由對活性成分中之一者包覆腸溶包衣,不僅可使組合之活性成分之間的接觸降至最低,而且可控制此等組分中之一者在胃腸道中的釋放,使得此等組分中之一者不在胃中釋放,而是在腸道中釋放。活性成分中之一者亦可包覆有影響在整個胃腸道中之持續釋放的物質,且亦用以使組合之活性成分之間的物理接觸降至最低。此外,持久釋放之組分可額外包覆腸溶包衣,使得此組分之釋放僅在腸道中發生。另一方法將涉及組合產物之調配,其中一種組分包覆有持續及/或腸釋放聚合物,且另一組分亦包覆有諸如低黏度級別之羥丙基甲基纖維素(HPMC)的聚合物或此項技術中已知的其他適當物質,以進一步分隔活性組分。聚合物包衣用以形成針對與另一組分之相互作用的額外屏障。 只要與本發明相符,熟習此項技術者將容易顯而易知使本發明之組合產物的組分之間的接觸降至最低之此等以及其他方式,而不論是以單個劑型投與還是以各別形式但同時藉由相同方式投與。 本發明化合物可單獨投與或與一或多種額外治療劑組合投與。「組合投與」或「組合療法」意謂本發明化合物及一或多種額外治療劑同時投與所治療之哺乳動物。當組合投與時,各組分可同時投與或以任何順序依序在不同時間點投與。因此,各組分可分開但時間上充分接近地投與,以便提供所需治療作用。 在涉及APJ受體及愛帕琳活性之測試或分析中,本發明化合物亦適用作標準或參考化合物,例如作為品質標準品或對照。此類化合物可以商業套組形式提供以例如用於涉及APJ及愛帕琳或抗心臟衰竭活性之醫藥研究。舉例而言,本發明化合物可在分析中用作參考物以使其已知活性與具有未知活性的化合物相比較。此將確保實驗者正確進行分析且提供比較基礎,當測試化合物為參考化合物之衍生物時尤其如此。當研發新的分析或方案時,根據本發明之化合物可用以測試其有效性。 本發明化合物亦可用於涉及APJ及愛帕琳之診斷分析中。 本發明亦涵蓋製品。如本文中所使用,製品意欲包括(但不限於)套組及封裝。本發明之製品包含:(a)第一容器;(b)位於第一容器內之醫藥組合物,其中該組合物包含第一治療劑,其包含本發明化合物或其醫藥學上可接受之鹽形式;及(c)陳述醫藥組合物可用於治療及/或預防與APJ及愛帕琳相關之多種疾病或病症(如先前所定義)之藥品說明書。在另一實施例中,藥品說明書陳述醫藥組合物可用於與第二治療劑組合使用(如先前所定義)以治療及/或預防與APJ及愛帕琳相關之多種疾病或病症。製品可進一步包含:(d)第二容器,其中組分(a)及(b)位於第二容器內,且組分(c)位於第二容器內或外部。位於第一及第二容器內意謂各別容器將條目保持於其邊界內。 第一容器為用以容納醫藥組合物之盛器。此容器可用於製造、儲存、運送及/或個別/整體出售。第一容器意欲涵蓋瓶、罐、小瓶、燒瓶、注射器、管(例如對於乳霜製劑)或任何其他用以製造、容納、儲存或分配醫藥產品之容器。 第二容器為用以容納第一容器及視情況藥品說明書的容器。第二容器之實例包括(但不限於)盒(例如卡紙板或塑膠)、板條箱、紙盒、袋(例如紙袋或塑膠袋)、小袋及大袋。藥品說明書可經由膠帶、膠水、卡釘或另一附著方法物理附著於第一容器之外部,或其可留在第二容器內部而不藉助於任何物理方式附著於第一容器。或者,藥品說明書位於第二容器之外部上。當位於第二容器之外部上時,藥品說明書較佳經膠帶、膠水、卡釘或另一附著方法物理附著。或者,其可與第二容器外部相鄰或接觸但不物理附著。 藥品說明書為敍述與位於第一容器內之醫藥組合物相關之資訊的標記、標籤、標記物等。所敍述資訊通常將由控管出售製品之地區的監管機構(例如美國食品與藥物管理局(United States Food and Drug Administration))決定。較佳地,藥品說明書具體敍述醫藥組合物已審批通過之適應症。藥品說明書可由任何材料製成,個人可從上面讀取其中或其上所含之資訊。較佳地,藥品說明書為上面已形成所需資訊(例如經列印或塗覆)的可列印材料(例如紙、塑膠、卡紙板、箔、背面黏性紙或塑膠等)。 本發明之其他特徵在例示性實施例的以下描述中將變得顯而易知,該等例示性實施例為了說明本發明而給出且不意欲對其進行限制。 VI. 實例 以下提供之實例為說明性的,作為部分範疇及本發明之具體實施例且不欲限制本發明之範疇。除非另外指示,否則縮寫及化學符號具有其常見及慣用含義。除非另外指示,否則本文中所描述之化合物已使用本文中所揭示之流程及其他方法製備、分離及表徵或可使用其製備。 作為一般熟習此項技術者,將能夠理解分子形式之吡啶酮可互變異構化成如以下等式中所展示之其酮基及烯醇形式,其中R1
、R2
、R3
及R4
如上所定義,本發明意欲涵蓋所有可能的互變異構體,即使當結構僅描繪其中之一者時亦如此。分析型LCMS方法的描述 方法A:管柱:Waters Acquity UPLC BEH C18,2.1 × 50 mm,1.7 μm顆粒;移動相A:5:95 CAN:具有10 mM NH4
OAc之水;移動相B:95:5 ACN:具有10 mM NH4
OAc之水;溫度:50℃;梯度:3分鐘內0-100% B,隨後100% B下保持0.75分鐘;流速:1.11 mL/min;偵測:UV,220 nm。 方法B:管柱:Waters Acquity UPLC BEH C18,2.1 × 50 mm,1.7 μm顆粒;移動相A:5:95 ACN:具有0.1% TFA之水;移動相B:95:5 ACN:具有0.1% TFA之水;溫度:50℃;梯度:3分鐘內0-100% B,隨後在100% B下保持0.75分鐘;流速:1.11 mL/min;偵測:UV,220 nm。 方法C:管柱:PHENOMENEX®
Luna 3 μm C18 (2.0 × 30 mm);移動相A:10:90甲醇:具有0.1% TFA之水;移動相B:90:10 MeOH:具有0.1% TFA之水;梯度:2分鐘內0-100% B,隨後在100% B下保持1分鐘;流速:1 mL/min;偵測:UV,220 nm。 方法D: Waters Acquity UPLC BEH C18,2.1 × 50 mm,1.7 μm顆粒;移動相A:具有0.1% TFA之水;移動相B:具有0.1% TFA之ACN;梯度:1分鐘內2-98% B,隨後在98% B下保持0.5分鐘;流速:0.8 mL/min;偵測:UV,220 nm。 方法E:管柱:Phenomenex Luna 3u C18 (2) 2.0 × 30 mm;移動相A:10:90 MeOH:具有10 mM NH4
OAc之水;移動相B:90:10 MeOH:具有10 mM NH4
OAc之水;梯度:2分鐘內0-100% B;流速:1.11 mL/min;偵測:UV,220 nm。 實例1 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(4-甲氧基苯甲醯基)哌嗪-1-羰基]吡啶-2,4-二醇化合物1a. 2-(2,6-二甲氧基苯基)乙酸乙酯 歷經10分鐘時間段向1,3-二甲氧基苯(3.3 mL,25 mmol)於THF (40 mL)中之溶液中逐滴添加2.5M nBuLi之己烷(10 mL,25 mmol)溶液,隨後攪拌混合物2小時。緩慢添加經壓碎碘化銅(I) (2.38 g,12.5 mmol),隨後攪拌反應混合物1小時,變為均勻。將混合物冷卻至-78℃,隨後歷經20分鐘逐滴添加溴乙酸乙酯(2.8 mL,25 mmol)。移除冷浴且將混合物升溫至室溫。藉由添加水來淬滅混合物,隨後添加Et2
O且混合物經由矽藻土過濾。將過濾物用1.5N K2
HPO4
稀釋且用Et2
O (2×)萃取。將經合併之有機萃取物用鹽水洗滌,乾燥(MgSO4
),過濾且在減壓下濃縮。藉由矽膠層析用0至15% EtOAc/己烷溶離來純化殘餘物,得到呈淡棕色油狀之化合物1a (4.8 g,86%產率),其在靜置後固化。LCMS (方法E) Rt = 1.90。MSm/z
= 225.1 (M+H)。1
H NMR (500MHz, CDCl3
) δ 7.23 (t,J
=8.4 Hz, 1H), 6.58 (d,J
=8.3 Hz, 2H), 4.17 (q,J
=7.2 Hz, 2H), 3.83 (s, 6H), 3.71 (s, 2H), 1.27 (t,J
=7.2 Hz, 3H)。 化合物1b. 2-(2,6-二甲氧基苯基)-3-羥基庚-2-烯酸乙酯 在-78℃下向化合物1a (1.50 g,6.7 mmol)於THF (14 mL)中之溶液中逐滴添加1.0M LHMDS之THF (16.7 mL,16.7 mmol)溶液,且攪拌混合物10分鐘。移除冷浴且在室溫下攪拌反應混合物1小時。將混合物冷卻至-78℃,隨後逐滴添加戊醯氯(1.34 mL,11.0 mmol),且使混合物升溫至0℃且攪拌15分鐘。混合物藉由添加飽和NH4
Cl淬滅且用EtOAc (3×)萃取。將經合併之萃取物用鹽水洗滌,乾燥(Na2
SO4
),過濾且在減壓下濃縮。藉由矽膠層析用0至30% EtOAc/己烷溶離來純化殘餘物,得到呈透明無色油狀之化合物1b之異構體混合物(1.80 g,88%產率)。LCMS (方法C) Rt = 2.21。MSm/z
= 309.1 (M+H)。主要異構體之1
H NMR (400MHz, CDCl3
) δ 13.22 (s, 1H), 7.26 - 7.22 (m, 1H), 6.56 (d,J
=8.6 Hz, 2H), 4.14 (q,J
=7.0 Hz, 2H), 3.75 (s, 5H), 2.05 - 1.96 (m, 2H), 1.51 - 1.42 (m, 2H), 1.22 - 1.17 (m, 2H), 1.14 (t,J
=7.2 Hz, 3H), 0.77 (t,J
=7.3 Hz, 3H)。 化合物1c. 3-胺基-2-(2,6-二甲氧基苯基)庚-2-烯酸乙酯 向化合物1b (1.8 g,5.9 mmol)及甲酸銨(1.8 g,29 mmol)於無水乙醇(35 mL)中之混合物中添加分子篩,隨後在回流下加熱混合物10小時。使混合物冷卻至室溫,隨後過濾且在減壓下濃縮。將殘餘物溶解於水中且用EtOAc (3×)萃取。將萃取物乾燥(Na2
SO4
),過濾且在減壓下濃縮。藉由矽膠層析用0至35% EtOAc/己烷溶離來純化殘餘物,得到呈透明無色油狀之化合物1c (1.2 g,68 %產率)。LCMS (方法C) Rt = 1.84 min。MSm/z
= 308.1 (M+H)。1
H NMR (400MHz, CDCl3
) δ 7.21 (t,J
=8.4 Hz, 1H), 6.55 (d,J
=8.4 Hz, 2H), 4.05 (q,J
=7.0 Hz, 2H), 3.75 (s, 6H), 1.98 - 1.88 (m, 2H), 1.43 - 1.31 (m, 2H), 1.18 (dt,J
=15.0, 7.5 Hz, 2H), 1.09 (t,J
=7.0 Hz, 3H), 0.73 (t,J
=7.4 Hz, 3H)。 化合物1d. 6-丁基-5-(2,6-二甲氧基苯基)-2,4-二羥基菸鹼酸乙酯 向化合物1c (1.20 g,4.0 mmol)於DCM (20 mL)與1N NaHCO3
(24 mL,24 mmol)之混合物中之溶液中逐滴添加乙基丙二醯氯(1.5 mL,12 mmol)於DCM (5 mL)中之溶液,且攪拌混合物10分鐘。用DCM稀釋混合物,分離各層,且用DCM (2×)萃取水層。將經合併之有機萃取物用飽和NH4
Cl及鹽水洗滌,乾燥(Na2
SO4
),過濾且在減壓下濃縮。將殘餘物溶解於無水EtOH (20 mL)中,隨後添加2.5M乙醇鈉之乙醇(6.4 mL,16 mmol)溶液且攪拌混合物24小時,產生沈澱物。在減壓下將混合物蒸發至乾燥,隨後用飽和NH4
Cl稀釋且用DCM (3×)萃取含水部分。將經合併之萃取物用鹽水洗滌,乾燥(Na2
SO4
),傾析且在減壓下於矽藻土上濃縮。藉由矽膠層析用5至75% EtOAc/DCM溶離來純化殘餘物,得到呈白色固體狀之化合物1d (0.52 g,35 %產率)。LCMS (方法C) Rt = 1.95 min。MSm/z
= 376.1 (M+H)。1
H NMR (400MHz, DMSO-d6
) δ 7.33 (t,J
=8.4 Hz, 1H), 6.70 (d,J
=8.4 Hz, 2H), 4.30 (q,J
=6.8 Hz, 2H), 3.68 (s, 6H), 2.09 (t,J
=7.2 Hz, 2H), 1.37 - 1.23 (m, 5H), 1.12 - 0.99 (m, 2H), 0.65 (t,J
=7.4 Hz, 3H)。 實例1. 6-丁基-5-(2,6-二甲氧基苯基)-3-[4-(4-甲氧基苯甲醯基)哌嗪-1-羰基]吡啶-2,4-二醇 向化合物1d (25 mg,0.067 mmol)於乙醇(0.5 mL)中之懸浮液中添加(4-甲氧基苯基)(哌嗪-1-基)甲酮HCl鹽(21 mg,0.080 mmol)。在150℃下在微波照射下加熱所得混合物3小時。在減壓下濃縮混合物且藉由逆相HPLC來純化,得到實例1 (28 mg,77%產率)。LCMS (方法C) Rt = 1.79 min,m/z
= 550.1 (M+H)。1
H NMR (500MHz, DMSO-d6) δ 7.42 (d, J=8.3 Hz, 2H), 7.33 (t, J=8.3 Hz, 1H), 7.00 (d, J=8.5 Hz, 2H), 6.70 (d, J=8.3 Hz, 2H), 3.81 (s, 3H), 3.69 (s, 6H), 3.57 (br. s., 8H), 2.10 - 2.04 (m, 2H), 1.31 (d, J=6.1 Hz, 2H), 1.09 - 0.99 (m, 2H), 0.65 (t, J=7.3 Hz, 3H)。人類APJ cAMP EC50
效能範圍C。 藉由針對實例1所描述之通用程序製備以下化合物:實例2至7、10至34及41至69。 表1
實例70. 6-(乙氧基甲基)-5-(4-氟-2,6-二甲氧基苯基)-3-[(3R)-3-苯基吡咯啶-1-羰基]吡啶-2,4-二醇)化合物70a. 4-氟-2,6-二甲氧基苯甲醛 在0℃下歷經15分鐘向1-氟-3,5-二甲氧基苯(3.00g,19.2 mmol)於二氯甲烷(45 mL)中之攪拌溶液中緩慢添加TiCl4
於二氯甲烷(38.4 mL,38.4 mmol)中之1.0 M溶液。將混合物冷卻至-78℃且用二氯(甲氧基)甲烷(2.26 mL,25.0 mmol)逐滴處理。在-78℃下攪拌反應混合物30分鐘且使其升溫至0℃。1小時後,將混合物倒入冷稀HCl溶液中,且用乙酸乙酯(2×)萃取水相。將有機溶離份合併,經Na2
SO4
乾燥,過濾且在減壓下濃縮。在矽膠層析上用0%至30% ACN/DCM溶離來純化殘餘物,得到呈白色固體狀之化合物70a (1.60 g,45%)。MSm/z
= 184.9 (M+H)。1
H NMR (400MHz, CDCl3
) δ 10.42 (s, 1H), 6.34 (s, 1H), 6.31 (s, 1H), 3.91 (s, 6H) 化合物70b. (4-氟-2,6-二甲氧基苯基)甲醇 在0℃向化合物70a (2.52 g,13.7 mmol)於乙醇(60 mL)中之懸浮液中添加硼氫化鈉(0.35 g,9.1 mmol)。移除冰浴且繼續攪拌20分鐘。將混合物冷卻至0℃,隨後藉由添加飽和氯化銨溶液淬滅。將所得懸浮液濃縮且再溶解於EtOAc/水混合物中。分離各層且將有機溶離份用鹽水洗,經Na2
SO4
乾燥且濃縮,得到呈白色固體之化合物70b (2.3g,90%),其不經進一步純化即使用。LCMS (方法C) Rt = 1.38 min。1
H NMR (400MHz, CDCl3
) δ 6.33 (s, 1H), 6.31 (s, 1H), 4.74 (m, 2H), 3.85 (s, 6H) 化合物70c. 甲磺酸4-氟-2,6-二甲氧基苯甲酯 向化合物70b (2.3g,13 mmol)於二氯甲烷(80 mL)中之溶液中添加TEA (3.5 mL,25 mmol)。將混合物冷卻至0℃且用含甲磺醯氯(7.4 mL,0.095 mol)之二氯甲烷 (25 mL)處理。30分鐘後,用二氯甲烷(100 mL)稀釋混合物且用水(3 × 50 mL)洗有機相。將有機層經Na2
SO4
乾燥且在減壓下濃縮,得到化合物70c (2.7 g,82%),其不經進一步純化即使用。LCMS (方法C) Rt = 1.64 min。1
H NMR (400MHz, CDCl3
) δ 6.23 (s, 1H), 6.20 (s, 1H), 4.64 (s, 2H), 3.78 (s, 6H) 化合物70d. 2-(4-氟-2,6-二甲氧基苯基)乙腈 向化合物70c (2.7 g,10 mmol)於DMF (40 mL)中之溶液中添加氰化鈉(1.0 g,20 mmol),且攪拌混合物30分鐘。將混合物用水(800 mL)稀釋且用30%乙酸乙酯於己烷中(3 × 200 mL)萃取。合併之有機層經Na2
SO4
乾燥且在減壓下濃縮。藉由矽膠層析用0%至5%乙酸乙酯於己烷中溶離來純化殘餘物,得到化合物70d (1.8 g,88%)。LCMS (方法C) Rt = 1.57,MSm/z
= 196.0 (M+H)。1
H NMR (400MHz, DMSO-d6
) δ 6.67 (s, 1H), 6.64 (s, 1H), 3.85 (s, 6H), 3.65 (s, 2H) 化合物70e. 2-(4-氟-2,6-二甲氧基苯基)乙酸乙酯 向化合物70d (1.75g,8.97mmol)於EtOH (40mL)中之溶液中鼓泡HCl氣體2h時間段。在減壓下濃縮混合物,且將殘餘物用水(50 mL)稀釋且在40℃下加熱隔夜。冷卻至室溫後,用乙酸乙酯(3 × 50 mL)萃取反應混合物。將合併之有機層經Na2
SO4
乾燥且在減壓下濃縮,得到化合物70e (1.6 g,76%)。LCMS (方法C) Rt = 1.86。MSm/z
= 243.1 (M+H)。1
H NMR (400MHz, DMSO-d6
) δ 6.58 (s, 1H), 6.55 (s, 1H), 4.05 (q,J
=7.0 Hz, 2H), 3.76 (s, 6H), 3.49 (s, 2H), 1.17 (t,J
=7.2 Hz, 3H) 實例70. 1-({5-[6-(乙氧基甲基)-5-(4-氟-2,6-二甲氧基苯基)-2,4-二羥基吡啶-3-基]-1,3,4-噁二唑-2-基}甲基)-1,2-二氫吡啶-2-酮 使用針對實例1所描述之方法由化合物70e製備實例70 (12%)。LCMS (方法C) Rt = 1.86 min,m/z
= 497.1 (M+H)。1
H NMR (400MHz, 氯仿-d) δ 7.33 (m, 5H), 6.38 (m, 2H), 4.16 (s, 2H), 3.87 - 3.77 (m, 2H), 3.74 (s, 6H), 3.71 - 3.64 (m, 2H), 3.54 (m, 3H), 2.44 - 2.28 (m, 2H), 1.24 (t, J=6.8 Hz, 3H)。人類APJ cAMP EC50
效能範圍B。 實例71. 6-丁基-5-(3-氟-2,6-二甲氧基苯基)-3-[(3R)-3-苯基吡咯啶-1-羰基]吡啶-2,4-二醇化合物71a. 6-丁基-5-(3-氟-2,6-二甲氧基苯基)-2,4-二羥基菸鹼酸乙酯 在0℃下向化合物1d (650 mg,1.73 mmol)於DMF (7.5 mL)中之溶液中緩慢添加1-氯甲基-4-氟-1,4-二氮雜雙環[2.2.2]辛烷雙(四氟硼酸鹽),N
-氯甲基-N
'-氟三伸乙基二銨雙(四氟硼酸鹽) (F-TEDA,613 mg,1.73 mmol)。在0℃下攪拌一分鐘後,移除冰浴且在室溫下繼續攪拌16小時。用EtOAc稀釋混合物,用水(3×)洗滌有機相,隨後用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮。用EtOAc (3×)濕磨所得固體。在減壓下蒸發磨碎物且藉由矽膠層析用0-100%乙酸乙酯/己烷溶離來純化殘餘物,得到呈白色固體狀之化合物71a (170 mg,25%)。LCMS (方法C) Rt = 1.75。MSm/z
= 394.1.0 (M+H)。1
H NMR (400MHz, CDCl3
) δ 7.10 (dd,J
=11.2, 9.2 Hz, 1H), 6.69 - 6.54 (m, 1H), 4.41 (q,J
=7.0 Hz, 2H), 3.82 (m, 3H), 3.72 (s, 3H), 2.35 (t,J
=7.8 Hz, 2H), 1.52 (td,J
=7.5, 2.5 Hz, 2H), 1.40 (t,J
=7.0 Hz, 3H), 0.78 (t,J
=7.3 Hz, 3H) 實例71.6-丁基-5-(3-氟-2,6-二甲氧基苯基)-3-[(3R)-3-苯基吡咯啶-1-羰基]吡啶-2,4-二醇 使用針對實例1所描述之方法由化合物71a製備實例71 (13%)。LCMS (方法C) Rt = 2.04 min,m/z
= 495.1 (M+H)。1
H NMR (400MHz, 氯仿-d) δ 7.33 (m, 5H), 6.38 (m, 2H), 4.16 (s, 2H), 3.87 - 3.77 (m, 2H), 3.74 (s, 6H), 3.71 - 3.64 (m, 2H), 3.54 (m, 3H), 2.44 - 2.28 (m, 2H), 1.24 (t, J=6.8 Hz, 3H)。人類APJ cAMP EC50
效能範圍A。 實例72. 6-丁基-3-[3-(2-氯苯基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)吡啶-2,4-二醇藉由針對實例1所描述之通用程序由化合物1d及3-(2-氯苯基)吡咯啶製備實例72。使用對掌性SFC層析(管柱:Chiralpak OD-H,30 × 250 mm,5微米,管柱:Chiralpak OD-H,30 × 250 mm,5微米,移動相:35% MeOH/65% CO2
,流動條件:85 mL/min,150巴,40℃,偵測器波長:220 nm,注射:0.5 mL之~6.5mg/mL於MeOH:ACN (1:1)中)分離外消旋物質。分離兩個峰。實例72 (42%產率)指定為峰2 (峰2滯留時間= 13.6,對掌性分析HPLC:管柱:Chiralpak OD-H,4.6 × 250 mm,5微米,移動相:35% MeOH/65% CO2
,流動條件:2.0 mL/min,150巴,40℃,偵測器波長:220 nm,注射:10 μl之~1mg/mL於MeOH中)。LCMS (方法C) Rt = 2.07 min,m/z
= 511.1 (M+H)。1
H NMR (500MHz, DMSO-d6) δ 7.50 (br. s., 2H), 7.34 (dd, J=14.3, 6.9 Hz, 3H), 6.71 (d, J=8.0 Hz, 2H), 3.91 (br. s., 1H), 3.69 (br. s., 6H), 2.26 (br. s., 1H), 2.08 (br. s., 3H), 1.50 (br. s., 2H), 1.38 - 1.21 (m, 2H), 1.07 (br. s., 2H), 1.00 - 0.84 (m, 2H), 0.65 (br. s., 3H)。人類APJ cAMP EC50
效能範圍A。 藉由針對實例72所描述之通用程序製備以下化合物:實例8、9、35及實例37至40。 表2
實例74. (6-丁基-5-(2,6-二甲氧基苯基)-2,4-二羥基吡啶-3-基)(3-(5-氯吡啶-2-基)吡咯啶-1-基)甲酮化合物74a. 3-(5-氯吡啶-2-基)-2,5-二氫-1H-吡咯-1-甲酸第三丁酯 使3-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-2,5-二氫-1H-吡咯-1-甲酸第三丁酯(106 mg,0.360 mmol)、2-溴-5-氯吡啶(76 mg,0.40 mmol)、碳酸銫(350 mg,1.10 mmol)及PdCl2
(dppf)-CH2
Cl2
(18 mg,0.022 mmol)於二噁烷(2.4 mL)及水(0.5 mL)中之混合物脫氣,且在90℃下加熱14小時。將混合物用EtOAc稀釋,用鹽水洗滌,經硫酸鈉乾燥,過濾且在減壓下濃縮。使殘基經歷用0-100% EtOAc/己烷溶離的矽膠層析,得到呈黃色固體狀之74a (50 mg,0.18 mmol,50%產率)。1
H NMR (400MHz, 氯仿-d) δ 8.62 - 8.41 (m, 1H), 7.82 - 7.57 (m, 1H), 7.40 - 7.16 (m, 1H), 6.60 - 6.32 (m, 1H), 4.60 - 4.49 (m, 2H), 4.41 - 4.27 (m, 2H), 1.52 - 1.45 (m, 9H)。 化合物74b. 3-(5-氯吡啶-2-基)吡咯啶-1-甲酸第三丁酯 在氫氣氛圍(氣球)下攪拌74a (530 mg,1.90 mmol)及5% Rh/C (390 mg,0.190 mmol)於EtOH (8 mL)中之混合物4小時。經由矽藻土過濾混合物且在減壓下濃縮。使用矽膠層析用0-100% EtOAc/己烷溶離、隨後使用對掌性SFC製備型HPLC (管柱:Chiralpak IC,30 × 250 mm,5微米;移動相:10% IPA/0.1% DEA/90% CO2
;流動條件:85 mL/min,150巴,40℃;波長:220 nm)來純化殘餘物,得到化合物74b (指定為峰1,110 mg,21%產率)。峰1滯留時間= 11.87 min (Chiralpak IC,4.6 × 250 mm,5微米;移動相:10% IPA/0.1% DEA/90% CO2
;流動條件:2.0 mL/min,150巴,40℃;波長:220 nm)。LCMS (方法B) Rt = 0.96 min,m/z
= 283.2 (M+H)。1
H NMR (400MHz, 氯仿-d) δ 8.52 (d, J=2.2 Hz, 1H), 7.64 - 7.56 (m, 1H), 7.14 (d, J=8.4 Hz, 1H), 3.97 - 3.29 (m, 5H), 2.34 - 2.05 (m, 2H), 1.50 - 1.44 (m, 9H)。 化合物74c. 3-(5-氯吡啶-2-基)-2,5-二氫-1H-吡咯-1-甲酸第三丁酯 在室溫下攪拌化合物74b (110 mg,0.38 mmol)及4N HCl/二噁烷(1.0 mL,4.0 mmol)5小時。用乙醚稀釋混合物,且藉由過濾收集沈澱物,得到呈白色固體狀之化合物74c (89 mg,0.35 mmol,91%產率)。LCMS (方法B) Rt = 0.47 min,m/z
= 183.1 (M+H)。1
H NMR (500MHz, DMSO-d6) δ 7.79 (d, J=2.5 Hz, 1H), 7.24 - 6.97 (m, 1H), 6.83 - 6.56 (m, 1H), 3.01 (s, 1H), 2.83 (s, 2H), 2.77 - 2.67 (m, 1H), 2.54 (br. s., 2H), 1.85 - 1.57 (m, 1H), 1.53 - 1.14 (m, 1H)。 實例74.(6-丁基-5-(2,6-二甲氧基苯基)-2,4-二羥基吡啶-3-基)(3-(5-氯吡啶-2-基)吡咯啶-1-基)甲酮 使用針對實例1所描述之方法由化合物1d及化合物74c製備實例74 (35%產率)。LCMS (方法B) Rt = 0.89 min,m/z
= 512.3 (M+H)。1
H NMR (500MHz, DMSO-d6) δ 8.56 (br. s., 1H), 7.92 - 7.83 (m, 1H), 7.51 - 7.38 (m, 1H), 7.32 (s, 1H), 6.69 (d, J=8.3 Hz, 2H), 3.66 (br. s., 10H), 2.89 (s, 1H), 2.35 - 2.17 (m, 1H), 2.08 (br. s., 3H), 1.37 - 1.22 (m, 2H), 1.08 - 0.98 (m, 2H), 0.69 - 0.50 (m, 3H)。人類APJ cAMP EC50
效能範圍A。 藉由針對實例74所描述之通用程序製備以下化合物:實例75至實例87。 表3
藉由針對實例1所描述之通用程序製備以下化合物:實例88至實例123,及實例153-154。 表4
藉由針對實例74所描述之通用程序製備以下化合物:實例124至實例129。 表5
實例130. 6-丁基-3-[3-(5-氯-3-氟吡啶-2-基)吡咯啶-1-羰基]-5-(2,6-二甲氧基苯基)-4-羥基-1,2-二氫吡啶-2-酮將1-羥基-7-氮雜苯并三唑(HOAT,6.5 mg,0.048 mmol)及第三丁醇鋯(IV) (0.02 mL,0.05 mmol)添加到含化合物1d及5-氯-3-氟-2-(吡咯啶-3-基)吡啶(使用針對化合物74c之製備所描述之通用途徑由對掌性3-(5-氯-3-氟吡啶-2-基)吡咯啶-1-甲酸第三丁酯製備,異構體2,Rt = 8.20,對掌性分析HPLC:Whelko (4.6 × 250 mm,5微米;移動相:10%IPA/90% CO2
;流動條件:3.0 mL/min,140巴,40℃;波長:220 nm。))之甲苯(1.5mL)中。在100℃下加熱反應混合物。16小時後,使反應混合物冷卻且用1N HCl (4 mL)稀釋,用DCM (3 × 5mL)萃取,將經合併之有機部分經Na2
SO4
乾燥,濃縮且經由製備型LC/MS在以下條件下純化:管柱:XBridge C18,19×200 mm,5 μm粒子;移動相A:5:95乙腈:具有0.1%TFA之水;移動相B:95:5乙腈:具有0.1%TFA之水;梯度:歷經25分鐘20-60% B,隨後在100% B下保持5分鐘;流速:20 mL/min。將含有所需產物之溶離份合併且濃縮,得到實例130 (13mg,31%產率)。LCMS (方法D) Rt = 0.98,m/z = 530.0 (M+H)。1
H NMR (500MHz, DMSO-d6) δ 8.49 (br. s., 1H), 8.06 (br. s., 1H), 7.32 (t, J=8.3 Hz, 1H), 6.70 (d, J=8.4 Hz, 2H), 3.67 (s, 6H), 3.93-3.70 (m, 2H), 3.65-3.38 (m, 3H) , 2.35 - 2.22 (m, 1H), 2.18 - 1.96 (m, 3H), 1.33 - 1.24 (m, 2H), 1.14 - 0.98 (m, 2H), 0.64 (t, J=6.6 Hz, 3H)。人類cAMP 效能範圍A。 藉由針對實例130所描述之通用程序製備以下化合物:實例131至實例137。 表6
實例138. 6-丁基-5-(3-乙基苯基)-4-羥基-3-{5-[(2-甲基-1,3-噻唑-4-基)甲基]-1,3,4-噁二唑-2-基}-1,2-二氫吡啶-2-酮化合物138a. 5-溴-6-丁基-2,4-二羥基菸鹼酸乙酯 將溴(0.55 mL,11 mmol)添加至含化合物138a (1.7 g,7.1 mmol;如W2007/197478中所描述製備)之DCM (40 mL)中。15分鐘後,在減壓下濃縮反應混合物,且藉由矽膠層析用0至5%甲醇/DCM溶離來純化,得到呈白色固體狀之化合物138b (2.2g,99%產率)。LCMS (方法D) Rt = 0.90 min,m/z
= 320.0 [M+H]+
。1
H NMR (500MHz, CDCl3
) δ 14.28 (s, 1H), 12.09 - 11.75 (m, 1H), 4.45 (q,J
=7.0 Hz, 2H), 2.95 - 2.71 (m, 2H), 1.80 - 1.64 (m, 2H), 1.52 - 1.37 (m, 5H), 0.98 (t,J
=7.4 Hz, 3H)。 化合物138b. 6-丁基-4-羥基-5-(3-異丙基苯基)-2-側氧基-1,2-二氫吡啶-3-甲酸乙酯 用氮氣淨化含化合物138a (100 mg,0.31 mmol)、(3-異丙基苯基)酸(77 mg,0.47 mmol)及Pd(PPh3
)4
(110 mg,0.094 mmol)之2M Na2
CO3
(2 mL)/二噁烷(4 mL),且加熱至100℃。2小時後,過濾反應混合物,用DMF/甲醇稀釋且使用逆相HPLC (Phenomemenx Luna AXIA 5微米C18,30 × 100 mm,歷經10分鐘30至100%B,有5分鐘保持時間,溶劑A:90%水/10%甲醇/0.1%TFA,溶劑B:90%甲醇/10%水/0.1% TFA,流動速率40 mL/min;254下之偵測器)純化,以分離化合物138b (25 mg,22%產率)。LCMS (方法D)。Rt = 1.05,m/z = 384.0 [M+H]+
。1
H NMR (500MHz, 氯仿-d) δ 7.50 - 7.35 (m, 1H), 7.35 - 7.23 (m, 1H), 7.15 - 6.96 (m, 2H), 4.48 (d,J
=6.6 Hz, 2H), 2.97 (dt,J
=13.8, 6.9 Hz, 1H), 2.48 (t,J
=7.7 Hz, 2H), 1.62 - 1.51 (m, 2H), 1.45 (t,J
=6.6 Hz, 3H), 1.34 - 1.21 (m, 8H), 0.81 (t,J
=7.3 Hz, 3H)。 實例138. 6-丁基-5-(3-乙基苯基)-4-羥基-3-{5-[(2-甲基-1,3-噻唑-4-基)甲基]-1,3,4-噁二唑-2-基}-1,2-二氫吡啶-2-酮 使用針對實例1所描述之方法由化合物138b製備實例138 (8.5%)。LCMS (方法A)。Rt = 2.23,m/z = 524.0 [M+H]+
。1
H NMR (500MHz, DMSO-d6) d 7.35 - 7.15 (m, 5H), 7.08 - 6.92 (m, 2H), 3.26 - 3.02 (m, 2H), 2.98 - 2.76 (m, 1H), 2.53 (m, 8H), 2.19 (br. s., 2H), 1.47 - 1.33 (m, 2H), 1.28 - 1.14 (m, 6H), 1.13 - 1.01 (m, 2H), 0.66 (t, J=7.2 Hz, 3H)。人類cAMP效能範圍A。 藉由針對實例138及74所描述之通用程序製備以下化合物:實例139至實例147。 表7
實例148. 6-丁基-3-[(3R)-3-苯基吡咯啶-1-羰基]-5-[3-(丙-2-基)苯基]吡啶-2,4-二醇化合物148a. (R)-(5-溴-6-丁基-2,4-二羥基吡啶-3-基)(3-苯基吡咯啶-1-基)甲酮 使用針對實例1所描述之方法由化合物138b製備化合物148a (35%產率)。LCMS (方法D)。Rt = 0.97, m/z = 421.0 [M+H]+
。1
H NMR (400MHz, 氯仿-d) δ 7.45 - 7.21 (m, 5H), 4.10 - 3.64 (m, 4H), 3.42 (br. s., 1H), 2.91 - 2.74 (m, 2H), 2.37 (br. s., 1H), 2.17 - 2.05 (m, 1H), 1.71 (quin,J
=7.6 Hz, 2H), 1.46 (dq,J
=14.8, 7.4 Hz, 2H), 1.06 - 0.89 (m, 3H)。 實例148. 6-丁基-3-[(3R)-3-苯基吡咯啶-1-羰基]-5-[3-(丙-2-基)苯基]吡啶-2,4-二醇 使用針對實例138所描述之方法由化合物148a製備實例148 (4%產率)。LCMS (方法D)。Rt = 2.31,m/z = 459.0 [M+H]+
。1
H NMR (500MHz, DMSO-d6) d 7.42 - 7.18 (m, 7H), 7.10 - 6.98 (m, 2H), 3.89 - 3.32 (m, 4H), 2.90 (br. s., 1H), 2.24 (br. s., 3H), 2.11 - 1.90 (m, 1H), 1.40 (br. s., 2H), 1.26 - 1.14 (m, 7H), 1.08 (br. s., 2H), 0.66 (br. s., 3H)。人類cAMP效能範圍A。 實例149. 5-(2,6-二甲氧基苯基)-6-[(乙基胺基)甲基]-3-[3-(3-氟苯基)吡咯啶-1-羰基]吡啶-2,4-二醇化合物149a. (2-(1H-咪唑-1-基)-2-側氧基乙基)(乙基)胺基甲酸第三丁酯 在室溫下將羰基二咪唑(176 mg,1.10 mmol)添加到含2-((第三丁氧基羰基)(乙基)胺基)乙酸(200 mg,0.98 mmol)之THF (10 mL)中。18小時後,用H2
O洗滌反應混合物,將有機部分分離且經MgSO4
乾燥,過濾且在減壓下濃縮,得到呈黃色油狀之化合物149a (220 mg,88%產率)。LCMS (方法E) Rt = 1.57 min,m/z
= 252.2 [M+H]+
。1
H NMR (500MHz, 氯仿-d) δ 8.24 (br. s., 1H), 7.52 (t,J
=1.5 Hz, 1H), 7.21 - 7.09 (m, 1H), 4.54 (s, 1H), 4.45 (br. s., 1H), 3.47 (d,J
=6.3 Hz, 1H), 3.43 - 3.28 (m, 1H), 1.52 (s, 5H), 1.45 (d,J
=5.0 Hz, 1H), 1.40 (br. s., 3H), 1.24 - 1.08 (m, 3H) 化合物149b. 4-((第三丁氧基羰基)(乙基)胺基)-2-(2,6-二甲氧基苯基)-3-側氧基丁酸乙酯 將LiHMDS (1.0 mL,1.0 mmol,1M THF溶液)添加到冷卻至-78℃之含化合物1a (160 mg,0.71 mmol)之THF (1 mL)中。10分鐘後,在室溫下攪拌反應混合物。1小時後,將反應混合物冷卻至-78℃且添加二乙基鋅(2M溶液,0.5 mL,1 mmol)。經40分鐘之時段使反應混合物升溫至-20℃。添加化合物149a (217 mg,0.856 mmol)之THF (0.5 mL)溶液,且20分鐘後,將反應混合物用1N HCl稀釋,用DCM (2×)萃取,經MgSO4
乾燥,在減壓下濃縮且使用矽膠層析純化,得到化合物149b (70 mg,24%產率)。LCMS (方法E) Rt = 2.02 min,m/z
= 410.4 [M+H]+
。1
H NMR (500MHz, 氯仿-d) δ 7.32 - 7.10 (m, 1H), 6.65 - 6.41 (m, 2H), 5.07 - 5.06 (m, 1H) 4.22 - 3.98 (m, 2H), 3.97 - 3.84 (m, 2H), 3.77 - 3.56 (m, 6H), 3.32 - 2.88 (m, 2H), 1.45 - 1.31 (m, 9H), 1.21 - 1.01 (m, 4H), 1.01 - 0.77 (m, 3H)。 化合物149c. 6-(((第三丁氧基羰基)(乙基)胺基)甲基)-5-(2,6-二甲氧基苯基)-2,4-二羥基菸鹼酸乙酯 使用描述於實例1中之通用方法由化合物149b製備化合物149c,產率為17%。LCMS (方法E) Rt = 0.95 min,m/z
= 477.3 [M+H]+
。1
H NMR (500MHz, 氯仿-d) δ 7.39 (t,J
=8.4 Hz, 1H), 6.66 (d,J
=8.5 Hz, 2H), 4.46 (q,J
=7.2 Hz, 2H), 4.06 (br. s., 2H), 3.89 - 3.67 (m, 6H), 3.07 (d,J
=6.9 Hz, 2H), 1.49 (s, 9H), 1.47 - 1.41 (m, 3H), 0.91 (t,J
=7.0 Hz, 3H)。 化合物149d. ((3-(2,6-二甲氧基苯基)-5-(3-(3-氟苯基)吡咯啶-1-羰基)-4,6-二羥基吡啶-2-基)甲基)(乙基)胺基甲酸第三丁酯 使用描述於實例1中之方法由化合物149c及3-(3-氟苯基)吡咯啶(使用針對化合物74c之製備所描述之通用途徑由對掌性3-(3-氟苯基)吡咯啶-1-甲酸第三丁酯製備,異構體2,Rt = 10.72,對掌性分析HPLC:Whelko (4.6 × 250 mm,5微米;移動相:10% IPA/90% CO2
;流動條件:3.0 mL/min,140巴,40℃;波長:220 nm))製備化合物149d (8%產率)。LCMS (方法A) Rt = 1.96 min,m/z
= 596.0 [M+H]+
。1
H NMR (500MHz, DMSO-d6
) δ 7.37 (d,J
=6.1 Hz, 1H), 7.28 (br. s., 1H), 7.19 (br. s., 1H), 7.15 (br. s., 1H), 7.06 (t,J
=8.2 Hz, 1H), 6.76 - 6.61 (m, 2H), 3.90 - 3.84 (m, 2H), 3.65 (br. m., 3H), 2.89 - 2.73 (m, 3H), 2.51 (br. s., 6H), 2.26 (br. s., 1H), 1.98 - 1.89 (br. m., 2H), 1.33-1.26 (br. m., 9H), 0.75 (br. s., 3H) 實例149. 5-(2,6-二甲氧基苯基)-6-[(乙基胺基)甲基]-3-[3-(3-氟苯基)吡咯啶-1-羰基]吡啶-2,4-二醇 在室溫下將TFA (0.1 mL)添加到含化合物149d (12 mg,0.020 mmol)之DCM (1 mL)中。3小時後,在減壓下濃縮反應混合物,且經由製備型LC/MS在以下條件下純化:管柱:XBridge C18,19 × 200 mm,5 μm粒子;移動相A:5:95乙腈:具有10 mM乙酸銨之水;移動相B:95:5乙腈:具有10 mM乙酸銨之水;梯度:歷經15分鐘0-100%B,隨後在100% B下保持3分鐘;流速:20 mL/min,得到實例149 (2.5 mg,25%)。LCMS (方法A) Rt = 1.094 min,m/z
= 496.4 [M+H]+
。1
H NMR (500MHz, DMSO-d6
) δ 7.44 - 7.27 (m, 2H), 7.18 (d,J
=9.3 Hz, 2H), 7.07 (t,J
=7.9 Hz, 1H), 6.71 (d,J
=8.2 Hz, 2H), 3.68 (br s, 6H), 3.17 (br s, 2H), 2.56-2.53 (m, 2H), 2.40-2.14 (m., 3H), 2.13 - 1.95 (m, 1H), 1.90 (br s, 3H), 0.85 (br s, 3H)。人類cAMP效能範圍C。 藉由針對實例149及74所描述之通用程序製備以下化合物:實例150至實例151。 表8
實例152. (S)-(2-(6-丁基-5-(2,6-二甲氧基苯基)-4-羥基-2-側氧基-1,2-二氫吡啶-3-甲醯胺基)-3-環己基丙醯基)甘胺酸甲酯化合物152a. (S)-2-(6-丁基-5-(2,6-二甲氧基苯基)-4-羥基-2-側氧基-1,2-二氫吡啶-3-甲醯胺基)-3-環己基丙酸甲酯 向化合物1d (50 mg,0.13 mmol)於DMF (2 mL)中之攪拌溶液中添加(S)-2-胺基-3-環己基丙酸甲酯(30 mg,0.16 mmol)及Et3
N (0.037 mL,0.27 mmol)。在微波照射下於密封反應容器中將反應混合物加熱至150℃,維持1小時,使其冷卻至室溫,在真空中濃縮且用EtOAc稀釋。將有機層用0.1M HCl洗滌,經MgSO4
乾燥,過濾且在真空中濃縮。將殘餘物添加到矽膠(12g)管柱中且用0-100% EtOAc/己烷溶離。將含有化合物152a之溶離份作為透明液體收集且在減壓下移除溶劑,產生呈無色油狀之化合物152a (30 mg,44%產率)。LCMS (方法A) 滯留時間= 2.50 min,m/z
= 514.9 (M+H)。1
H NMR (500MHz, DMSO-D6) δ 10.63 (d,J
= 7.3 Hz, 1H), 7.34 (t,J
= 8.5 Hz, 1H), 6.71 (d,J
= 8.5 Hz, 2H), 4.51-4.55 (m, 1H), 3.66 (s, 6H), 3.52 (s, 3H), 3.17 (d,J
= 5.2 Hz, 1H), 2.14 (t,J
= 7.6 Hz, 2H), 1.54-1.76 (m, 7H), 1.28-1.36 (m, 3H), 1.04-1.24 (m, 5H), 0.86-1.01 (m, 2H), 0.64 (t,J
= 7.3 Hz, 3H)。 化合物152b. (S)-2-(6-丁基-5-(2,6-二甲氧基苯基)-4-羥基-2-側氧基-1,2-二氫吡啶-3-甲醯胺基)-3-環己基丙酸 向化合物152a (25 mg,0.049 mmol)於THF(5 mL)中之攪拌溶液中添加於水(3 mL)中之氫氧化鋰單一水合物(6.1 mg,0.15 mmol)。在室溫下攪拌反應混合物16小時,隨後在真空中濃縮且將殘餘物溶解於EtOAc中。用0.1 M HCl (pH=4)洗滌有機層。用EtOAc 5×萃取水層。將合併之有機層經MgSO4
乾燥,過濾且在真空中濃縮,得到呈白色固體狀之化合物152b (23mg,95%產率)。LCMS (方法A) 滯留時間= 1.72 min,m/z
= 501.0 (M+H)。1
H NMR (500MHz, DMSO-D6) δ 10.53 (d,J
= 7.6 Hz, 1H), 7.95 (s, 1H), 7.34 (t,J
= 8.2 Hz, 1H), 6.71 (d,J
= 8.2 Hz, 2H), 4.38-4.45 (m, 1H), 3.68 (s, 6H), 2.14 (t,J
= 7.3 Hz, 2H), 1.55-1.79 (m, 7H), 1.28-1.40 (m, 3H), 1.05-1.23 (m, 5H), 0.86-1.01 (m, 2H), 0.66 (t,J
= 7.0 Hz, 3H)。 實例152. (S)-(2-(6-丁基-5-(2,6-二甲氧基苯基)-4-羥基-2-側氧基-1,2-二氫吡啶-3-甲醯胺基)-3-環己基丙醯基)甘胺酸甲酯 向化合物152b (30 mg,0.060 mmol)於THF(3 mL)中之攪拌溶液添加BOP (29 mg,0.066 mmol)及Et3
N (0.025 mL,0.18 mmol)。15分鐘後,添加2-胺基乙酸甲酯鹽酸鹽(9.0 mg,0.072 mmol)之THF(1 mL)溶液且攪拌反應混合物2小時。反應混合物在真空中濃縮且用EtOAc稀釋。用飽和NaHCO3
、飽和NH4
Cl洗滌有機層。有機層經MgSO4
乾燥,過濾且在真空中濃縮。經由製備型LC/MS在以下條件下純化殘餘物:管柱:XBridge C18,19 × 200 mm,5 μm粒子;移動相A:5:95乙腈:具有10 mM乙酸銨之水;移動相B:95:5乙腈:具有10 mM乙酸銨之水;梯度:歷經20分鐘40-80%B,隨後在100% B下保持5分鐘;流速:20 mL/min。合併含有化合物152之溶離份且經由離心蒸發乾燥。經由製備型LC/MS在以下條件下進一步純化殘餘物:管柱:XBridge C18,19 × 200 mm,5 μm粒子;移動相A:5:95乙腈:具有10 mM乙酸銨之水;移動相B:95:5乙腈:具有10 mM乙酸銨之水;梯度:歷經19分鐘40-80%B,隨後在100% B下保持5分鐘;流速:20 mL/min。合併含有實例152 (16mg,50%)之溶離份且經由離心蒸發乾燥。LCMS (方法A) Rt = 2.18 min,m/z
= 572.5 [M+H]+
。1
H NMR (500MHz, DMSO-d6) δ 10.55 (br s, 1H), 8.62 (br s, 1H), 7.34 (t, J = 7.6 Hz, 1H), 6.71 (d, J = 8.2 Hz, 2H), 4.57 (br s, 1H), 3.83-3.89 (m, 2H), 3.68 (s, 6H), 3.63 (s, 3H), 2.14 (br s, 2H), 1.70-1.80 (m, 2H), 1.51-1.70 (m, 5H), 1.27-1.40 (m, 3H), 1.05-1.26 (m, 5H), 0.89-0.97 (m, 2H), 0.64 (t, J = 7.3 Hz, 3H)。人類cAMP效能範圍A。
無
Claims (15)
- 一種式(I)化合物:或其立體異構體、對映異構體、非對映異構體、互變異構體或醫藥學上可接受之鹽,其中: alk為經0至5個Re 取代之C1-6 烷基; 環B獨立地選自C3-6 環烷基、C3-6 環烯基、芳基、雙環碳環基及6員雜芳基; R1 獨立地選自鹵素、NO2 、-(CH2 )n ORb 、(CH2 )n S(O)p Rc 、-(CH2 )n C (=O)Rb 、-(CH2 )n NRa Ra 、-(CH2 )n CN、-(CH2 )n C(=O)NRa Ra 、-(CH2 )n NRa C(=O)Rb 、-(CH2 )n NRa C(=O)NRa Ra 、-(CH2 )n NRa C(=O)ORb 、-(CH2 )n OC(=O)NRa Ra 、-(CH2 )n C(=O)ORb 、-(CH2 )n S(O)p NRa Ra 、-(CH2 )n NRa S(O)p NRa Ra 、-(CH2 )n NRa S(O)p Rc 、經0至3個Re 取代之C1-4 烷基、經0至3個Re 取代之-(CH2 )n -C3-6 碳環基及經0至3個Re 取代之-(CH2 )n -雜環基; R2 獨立地選自經0至3個Re 取代之C1-5 烷基;經0至3個Re 取代之C1-5 烯基;經0至3個Re 取代之芳基;經0至3個Re 取代之雜環基及經0至3個Re 取代之C3-6 環烷基;限制條件為當R2 為C1-5 烷基時,除了連接至吡啶環之亞甲基單元以外的亞甲基單元可經O、N及S置換; R3 及R4 獨立地選自H、經0至3個R6 取代之C1-5 烷基、經0至3個R6 取代之-(CH2 )n -C3-6 碳環基及經0至3個R6 取代之-(CH2 )n -雜環基;限制條件為R3 及R4 不均為H; 或者,R3 及R4 連同其共同連接之氮原子一起形成包含碳原子及0至4個選自N、NR5a 、O及S之雜原子且經0至5個R5 取代之雜環或螺雜環; R5 獨立地選自OH、鹵素、-(CR7 R7 )n -C3-10 碳環、-(CR7 R7 )n- 雜環,且各自經0至3個R6 取代; R5a 獨立地選自-C(=O)ORb 、C(=O)NRa Ra 、-S(O)p Rc 、-(CR7 R7 )n -C3- 10 碳環、-C(=O)-C3-10 碳環、-(CR7 R7 )n -雜環、-C(=O)-雜環,各自經0至3個R6 取代; R6 獨立地選自H、鹵素、=O、-(CH2 )n ORb 、(CH2 )n S(O)p Rc 、-(CH2 )n C (=O)Rb 、-(CH2 )n NRa Ra 、-(CH2 )n CN、-(CH2 )n C(=O)NRa Ra 、-(CH2 )n NRa C(=O)Rb 、-(CH2 )n NRa C(=O)NRa Ra 、-(CH2 )n NRa C(=O)ORb 、-(CH2 )n OC(=O)NRa Ra 、-(CH2 )n C(=O)ORb 、-(CH2 )n S(O)p NRa Ra 、-(CH2 )n NRa S(O)p NRa Ra 、-(CH2 )n NRa S(O)p Rc 、經0至3個Re 取代之C1-5 烷基、經0至3個Re 取代之(CH2 )n -C3-6 碳環基及經0至3個Re 取代之-(CH2 )n -雜環基; R7 獨立地選自H、C1-4 烷基及經0至3個Re 取代之(CH2 )n -C3-12 碳環基; Ra 獨立地選自H、經0至5個Re 取代之C1-6 烷基、經0至5個Re 取代之C2-6 烯基、經0至5個Re 取代之C2-6 炔基、經0至5個Re 取代之-(CH2 )n -C3-10 碳環基及經0至5個Re 取代之-(CH2 )n -雜環基;或Ra 及Ra 連同其共同連接之氮原子一起形成經0至5個Re 取代之雜環; Rb 獨立地選自H、經0至5個Re 取代之C1-6 烷基、經0至5個Re 取代之C2-6 烯基、經0至5個Re 取代之C2-6 炔基、經0至5個Re 取代之-(CH2 )n -C3-10 碳環基及經0至5個Re 取代之-(CH2 )n -雜環基; Rc 獨立地選自經0至5個Re 取代之C1-6 烷基、經0至5個Re 取代之C2-6 烯基、經0至5個Re 取代之C2-6 炔基、經0至5個Re 取代之C3-6 碳環基及經0至5個Re 取代之雜環基; Rd 獨立地選自H及經0至5個Re 取代之C1-4 烷基; Re 獨立地選自經0至5個Rg 取代之C1-6 烷基、C2-6 烯基、C2-6 炔基、-(CH2 )n -C3-6 環烷基、-(CH2 )n -C4-6 雜環基、-(CH2 )n -芳基、-(CH2 )n -雜芳基、F、Cl、Br、CN、NO2 、=O、-(CH2 )n CO2 Rf 、-(CH2 )n ORf 、-(CH2 )n S(O)p Rf 、-(CH2 )n C(=O)NRf Rf 、-(CH2 )n NRf C(=O)Rf 、-(CH2 )n S(O)p NRf Rf 、-(CH2 )n NRf S(O)p Rf 、-(CH2 )n NRf C(=O)ORf 、-(CH2 )n OC(=O)NRf Rf 及-(CH2 )n NRf Rf ; Rf 獨立地選自H、C1-5 烷基(最佳經鹵素及OH取代)、C3-6 環烷基及苯基,或Rf 及Rf 連同其共同連接之氮原子一起形成視情況經C1-4 烷基取代之雜環; Rg 獨立地選自H、F、Cl、Br、CN、OH、C1-5 烷基(最佳經鹵素及OH取代)、C3-6 環烷基及苯基; n獨立地選自0、1、2、3及4;及 p獨立地選自0、1及2。
- 如請求項1之化合物,其具有式(II):或其立體異構體、對映異構體、非對映異構體、互變異構體或醫藥學上可接受之鹽,其中: 環B獨立地選自、及6員雜芳基; R1 獨立地選自F、Cl、Br、NO2 、-(CH2 )n ORb 、-(CH2 )n C(=O)Rb 、-(CH2 )n NRa Ra 、-(CH2 )n CN、-(CH2 )n C(=O)NRa Ra 、-(CH2 )n NRa C(=O)Rb 、經0至3個Re 取代之C1-4 烷基及經0至3個Re 取代之C3-6 環烷基; R2 獨立地選自經0至3個Re 取代之C1-5 烷基;經0至3個Re 取代之C1-5 烯基;經0至3個Re 取代之芳基;經0至3個Re 取代之雜環基及經0至3個Re 取代之C3-6 環烷基;限制條件為當R2 為C1-5 烷基時,除了連接至吡啶環之亞甲基單元以外的亞甲基單元可經O、N及S置換; R3 及R4 連同其共同連接之氮原子一起形成選自以下之雜環或螺雜環 ; R5 獨立地選自OH、-(CH2 )n -芳基、-(CH2 )n -C3-6 環烷基及-(CH2 )n -雜環,各自經0至3個R6 取代; R5a 獨立地選自-(CR7 R7 )n -C3-10 碳環及-(CR7 R7 )n -雜環、-C(=O)-C3-10 碳環,各自經0至3個R6 取代; R6 獨立地選自H、F、Cl、Br、-ORb 、=O、-(CH2 )n C(=O)Rb 、-(CH2 )n C(=O)ORb 、-(CH2 )n NRa Ra 、CN、-(CH2 )n C(=O)NRa Ra 、-NHC(=O)ORb 、經0至3個Re 取代之C1-4 烷基、經0至3個Re 取代之(CH2 )n -C3-6 碳環基及經0至3個Re 取代之-(CH2 )n -雜環基; R7 獨立地選自H、C1-4 烷基及經0至3個Re 取代之(CH2 )n -C3-12 碳環基; Ra 獨立地選自H、經0至5個Re 取代之C1-6 烷基、經0至5個Re 取代之-(CH2 )n -C3-10 碳環基及經0至5個Re 取代之-(CH2 )n -雜環基;或Ra 及Ra 連同其共同連接之氮原子一起形成經0至5個Re 取代之雜環; Rb 獨立地選自H、經0至5個Re 取代之C1-6 烷基、經0至5個Re 取代之C2-6 烯基、經0至5個Re 取代之C2-6 炔基、經0至5個Re 取代之-(CH2 )n -C3-10 碳環基及經0至5個Re 取代之-(CH2 )n -雜環基; Re 獨立地選自經0至5個Rg 取代之C1-6 烷基、C2-6 烯基、C2-6 炔基、-(CH2 )n -C3-6 環烷基、-(CH2 )n -C4-6 雜環基、-(CH2 )n -芳基、-(CH2 )n -雜芳基、F、Cl、Br、CN、NO2 、=O、CO2 Rf 、-(CH2 )n ORf 、S(O)p Rf 、C(=O)NRf Rf 、NRf C(=O)Rf 、S(O)p NRf Rf 、NRf S(O)p Rf 、NRf C(=O)ORf 、OC(=O)NRf Rf 及-(CH2 )n NRf Rf ; Rf 獨立地選自H、C1-5 烷基(最佳經鹵素及OH取代)、C3-6 環烷基及苯基; Rg 獨立地選自H、F、Cl、Br、CN、OH、C1-5 烷基(最佳經鹵素及OH取代); n獨立地選自0、1、2、3及4;及 p獨立地選自0、1及2。
- 如請求項2之化合物,其具有式(IIIa):或其立體異構體、對映異構體、非對映異構體、互變異構體或醫藥學上可接受之鹽,其中: R1 獨立地選自F、Cl、-(CH2 )n OH、C(=O)NRa Ra 、C1-4 烷基及OC1-4 烷基; R2 獨立地選自經0至3個Re 取代之C1-5 烷基、C1-5 烯基、經0至3個Re 取代之芳基、經0至3個Re 取代之雜芳基、C3-6 環烷基及-(CH2 )1-4 OC1-5 烷基及-(CH2 )1-3 OC3-6 環烷基; R3 及R4 連同其共同連接之氮原子一起形成選自以下之雜環或螺雜環 ; R5 獨立地選自OH、-(CH2 )n -芳基、-(CH2 )n -C3-6 環烷基及-(CH2 )n -雜環,各自經0至3個R6 取代; R5a 獨立地選自-(CR7 R7 )n -C3-10 碳環及-(CR7 R7 )n -雜環、-C(=O)-C3-10 碳環,各自經0至3個R6 取代; R6 獨立地選自H、F、Cl、Br、-ORb 、=O、-(CH2 )n C(=O)Rb 、-(CH2 )n C(=O)ORb 、-(CH2 )n NRa Ra 、CN、-(CH2 )n C(=O)NRa Ra 、經0至3個Re 取代之C1-4 烷基、經0至3個Re 取代之(CH2 )n -C3-6 碳環基及經0至3個Re 取代之-(CH2 )n -雜環基; R7 獨立地選自H、C1-4 烷基及經0至3個Re 取代之(CH2 )n -C3-12 碳環基; Ra 獨立地選自H、經0至5個Re 取代之C1-6 烷基、經0至5個Re 取代之-(CH2 )n -C3-10 碳環基及經0至5個Re 取代之-(CH2 )n -雜環基;或Ra 及Ra 連同其共同連接之氮原子一起形成經0至5個Re 取代之雜環; Rb 獨立地選自H、經0至5個Re 取代之C1-6 烷基、經0至5個Re 取代之 C2-6 烯基、經0至5個Re 取代之C2-6 炔基、經0至5個Re 取代之-(CH2 )n -C3-10 碳環基及經0至5個Re 取代之-(CH2 )n -雜環基; Re 獨立地選自C1-6 烷基(視情況經F及Cl取代)、OH、OCH3 、OCF3 、-(CH2 )n -C3-6 環烷基、-(CH2 )n -C4-6 雜環基、-(CH2 )n -芳基、-(CH2 )n -雜芳基、F、Cl、Br、CN、NO2 、=O、CO2 H;及 n獨立地選自0、1、2、3及4。
- 如請求項3之化合物或其立體異構體、對映異構體、非對映異構體、互變異構體或醫藥學上可接受之鹽,其中: R5 獨立地選自 ; R6 獨立地選自H、F、Cl、Br、-OCH3 、-OCF3 、=O、CN、CH3 、CF3 -(CH2 )n -芳基、經0至3個Re 取代之-(CH2 )n -C3-6 環烷基及經0至3個Re 取代之-(CH2 )n -雜環基; R6a 獨立地選自H、CH3 、經0至3個Re 取代之芳基及經0至3個Re 取代之雜環基; Ra 獨立地選自H、經0至5個Re 取代之C1-6 烷基、經0至5個Re 取代之-(CH2 )n -C3-10 碳環基及經0至5個Re 取代之-(CH2 )n -雜環基; Re 獨立地選自C1-6 烷基(視情況經F及Cl取代)、OH、OCH3 、OCF3 、-(CH2 )n -C3-6 環烷基、-(CH2 )n -C4-6 雜環基、-(CH2 )n -芳基、-(CH2 )n -雜芳基、F、Cl、Br、CN、NO2 、=O、CO2 H;及 n獨立地選自0、1、2及3。
- 如請求項3之化合物或其立體異構體、對映異構體、非對映異構體、互變異構體或醫藥學上可接受之鹽,其中: R3 及R4 連同其共同連接之氮原子一起形成選自以下之雜環或螺雜環; R5a 獨立地選自 ; R6 獨立地選自H、F、Cl、Br、-OCH3 、-O(CH2 )1-3 OCH3 、-OCF3 、=O、CN、CH3 、CF3 -(CH2 )n -芳基、經0至3個Re 取代之-(CH2 )n -C3-6 環烷基及經0至3個Re 取代之-(CH2 )n -雜環基; R6a 獨立地選自H、CH3 、經0至3個Re 取代之芳基及經0至3個Re 取代之雜環基; Re 獨立地選自C1-6 烷基(視情況經F及Cl取代)、OH、OCH3 、OCF3 、-(CH2 )n -C3-6 環烷基、-(CH2 )n -C4-6 雜環基、-(CH2 )n -芳基、-(CH2 )n -雜芳基、F、Cl、Br、CN、NO2 、=O、CO2 H;及 n獨立地選自0、1、2及3。
- 如請求項3之化合物或其立體異構體、對映異構體、非對映異構體、互變異構體或醫藥學上可接受之鹽,其中: R1 獨立地選自F、Cl、OH及OC1-4 烷基; R1a 獨立地選自F、Cl及C1-2 烷基; R2 獨立地選自經0至3個Re 取代之C1-5 烷基、C1-5 烯基、經0至3個Re 取代之苯基、經0至3個Re 取代之6員雜芳基、C3-6 環烷基及CH2 O(CH2 )1-3 CH3 ; R3 及R4 連同其共同連接之氮原子一起形成選自以下之雜環; R5 獨立地選自OH、 ; R6 獨立地選自H、F、Cl、Br、-OCH3 、-OCF3 、=O、CN、CH3 、CF3 、-C(=O)NH2 、經0至3個Re 取代之-(CH2 )n -芳基、經0至3個Re 取代之-(CH2 )n -C3-6 環烷基及經0至3個Re 取代之-(CH2 )n -雜環基; R6a 獨立地選自H、CH3 、經0至3個Re 取代之芳基及經0至3個Re 取代之雜環基; Ra 獨立地選自H、經0至5個Re 取代之C1-6 烷基、經0至5個Re 取代之-(CH2 )n -C3-10 碳環基及經0至5個Re 取代之-(CH2 )n -雜環基; Re 獨立地選自C1-6 烷基(視情況經F及Cl取代)、OH、OCH3 、OCF3 、-(CH2 )n -C3-6 環烷基、-(CH2 )n -C4-6 雜環基、-(CH2 )n -芳基、-(CH2 )n -雜芳基、F、Cl、Br、CN、NO2 、=O、CO2 H;及 n獨立地選自0、1、2及3。
- 如請求項3之化合物或其立體異構體、對映異構體、非對映異構體、互變異構體或醫藥學上可接受之鹽,其中: R1 獨立地選自-CH2 OH、-OCH3 、-OCF3 、OCH2 Ph、-C(=O)NRa Ra 、-NRa Ra 、CH3 、CH2 CH3 、CH(CH3 )2 及環丙基; R2 獨立地選自經0至3個Re 取代之C1-5 烷基、C1-5 烯基、經0至3個Re 取代之苯基、經0至3個Re 取代之6員雜芳基、C3-6 環烷基及CH2 O(CH2 )1- 3 CH3 ; R3 及R4 獨立地選自經0至3個R6 取代之C1-5 烷基;經0至3個R6 取代之-(CH2 )n -C3-6 碳環基及經0至3個R6 取代之-(CH2 )n -雜環基; R6 獨立地選自H、鹵素、-(CH2 )n ORb 、-(CH2 )n NRa Ra 、-(CH2 )n C(= O)NRa Ra 、-(CH2 )n NRa C(=O)Rb 、-(CH2 )n NRa C(=O)ORb 、-(CH2 )n OC(=O)NRa Ra 、-(CH2 )n C(=O)ORb 、-(CH2 )n S(O)p NRa Ra 、-(CH2 )n NRa S(O)p NRa Ra 、經0至3個Re 取代之C1-5 烷基、經0至3個Re 取代之苯基及經0至3個Re 取代之雜環基; Ra 獨立地選自H、經0至5個Re 取代之C1-6 烷基、經0至5個Re 取代之-(CH2 )n -苯基及經0至5個Re 取代之-(CH2 )n -雜芳基; Rb 獨立地選自H、經0至5個Re 取代之C1-6 烷基、經0至5個Re 取代之-(CH2 )n -C3-10 碳環基及經0至5個Re 取代之-(CH2 )n -雜環基; Re 獨立地選自C1-6 烷基(視情況經F及Cl取代)、OH、OCH3 、OCF3 、-(CH2 )n -C3-6 環烷基、-(CH2 )n -C4-6 雜環基、-(CH2 )n -芳基、-(CH2 )n -雜芳基、F、Cl、Br、CN、NO2 、=O、CO2 H;及 n獨立地選自0、1、2、3及4。
- 如請求項3之化合物,其具有式(IV):或其立體異構體、對映異構體、非對映異構體、互變異構體或醫藥學上可接受之鹽,其中: R1 獨立地選自-CH2 OH、-OCH3 、-OCF3 、OCH2 Ph、-C(=O)NRa Ra 、-NRa Ra 、CH3 、CH2 CH3 、CH(CH3 )2 及環丙基; R2 獨立地選自經0至3個Re 取代之C1-5 烷基、C1-5 烯基、經0至3個Re 取代之苯基、經0至3個Re 取代之6員雜芳基、C3-6 環烷基及CH2 O(CH2 )1-3 CH3 ; R3 及R4 連同其共同連接之氮原子一起形成選自以下之雜環 ; R5a 獨立地選自 ; R5 獨立地選自OH、 ; R6 獨立地選自H、F、Cl、Br、-OCH3 、-OCF3 、=O、CN、CH3 、CF3 、-C(=O)NH2 、經0至3個Re 取代之-(CH2 )n -芳基、經0至3個Re 取代之-(CH2 )n -C3-6 環烷基及經0至3個Re 取代之-(CH2 )n -雜環基; R6a 獨立地選自H、CH3 、經0至3個Re 取代之芳基及經0至3個Re 取代之雜環基; Ra 獨立地選自H、經0至5個Re 取代之C1-6 烷基、經0至5個Re 取代之-(CH2 )n -C3-10 碳環基及經0至5個Re 取代之-(CH2 )n -雜環基; Re 獨立地選自C1-6 烷基(視情況經F及Cl取代)、OH、OCH3 、OCF3 、-(CH2 )n -C3-6 環烷基、-(CH2 )n -C4-6 雜環基、-(CH2 )n -芳基、-(CH2 )n -雜芳基、F、Cl、Br、CN、NO2 、=O、CO2 H;及 n獨立地選自0、1、2及3。
- 如請求項8之化合物或其立體異構體、對映異構體、非對映異構體、互變異構體或醫藥學上可接受之鹽,其中: R1 獨立地選自-CH2 OH、-C(=O)NHCH(CH3 )2 、CH3 、CH2 CH3 及CH(CH3 )2 ; R2 獨立地選自CH2 (CH2 )1-3 CH3 及CH2 O(CH2 )1-3 CH3 ; R3 及R4 連同其共同連接之氮原子一起形成; R5a 為;及 R6 獨立地選自H、F、Cl、Br、CH3 及CF3 。
- 如請求項8之化合物或其立體異構體、對映異構體、非對映異構體、互變異構體或醫藥學上可接受之鹽,其中: R1 獨立地選自-CH2 OH、--C(=O)NHCH(CH3 )2 、CH3 、CH2 CH3 及CH(CH3 )2 ; R2 獨立地選自CH2 (CH2 )1-3 CH3 及CH2 O(CH2 )1-3 CH3 ; R3 及R4 連同其共同連接之氮原子一起形成; R5 獨立地選自;及 R6 獨立地選自H、F、Cl、Br、CH3 及CF3 。
- 如請求項1之化合物,其中該化合物係選自例示性實例或其立體異構體、對映異構體、非對映異構體、互變異構體或醫藥學上可接受之鹽。
- 一種醫藥組合物,其包含醫藥學上可接受之載劑,及如請求項1至11中任一項之化合物或其立體異構體、互變異構體或醫藥學上可接受之鹽。
- 如請求項12之醫藥組合物,其用於療法。
- 一種如請求項12之醫藥組合物之用途,其用於製造供治療心血管疾病之藥劑。
- 如請求項14之用途,其中該等心血管疾病為冠心病、中風、心臟衰竭、收縮性心臟衰竭、舒張性心臟衰竭、糖尿病性心臟衰竭、正常收縮分率之心臟衰竭(heart failure with preserved ejection fraction)、心肌症、心肌梗塞、左心室功能障礙、心肌梗塞後之左心室功能障礙、心臟肥大、心肌重塑、梗塞後或心臟手術後之心肌重塑及心臟瓣膜病。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562241367P | 2015-10-14 | 2015-10-14 | |
US201562270659P | 2015-12-22 | 2015-12-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW201720796A true TW201720796A (zh) | 2017-06-16 |
Family
ID=57178558
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW105133123A TW201720796A (zh) | 2015-10-14 | 2016-10-13 | 作為apj促效劑之2,4-二羥基菸鹼醯胺 |
Country Status (20)
Country | Link |
---|---|
US (1) | US10392347B2 (zh) |
EP (1) | EP3362442B1 (zh) |
JP (1) | JP6837482B2 (zh) |
KR (1) | KR20180067599A (zh) |
CN (1) | CN108368087B (zh) |
AU (1) | AU2016340264B2 (zh) |
BR (1) | BR112018007395A2 (zh) |
CA (1) | CA3001974A1 (zh) |
CL (1) | CL2018000953A1 (zh) |
CO (1) | CO2018004968A2 (zh) |
EA (1) | EA034857B1 (zh) |
ES (1) | ES2774945T3 (zh) |
IL (1) | IL258577B (zh) |
MX (1) | MX2018004344A (zh) |
PE (1) | PE20181197A1 (zh) |
SG (1) | SG10201908839QA (zh) |
TW (1) | TW201720796A (zh) |
UY (1) | UY36949A (zh) |
WO (1) | WO2017066402A1 (zh) |
ZA (1) | ZA201802451B (zh) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ME03733B (me) | 2015-05-20 | 2021-01-20 | Amgen Inc | Agonisti triazola apj receptora |
US10011594B2 (en) | 2015-06-03 | 2018-07-03 | Bristol-Myers Squibb Company | 4-hydroxy-3-(heteroaryl)pyridine-2-one APJ agonists |
ES2858312T3 (es) | 2015-12-04 | 2021-09-30 | Bristol Myers Squibb Co | Agonistas del receptor de apelina y métodos de uso |
JP6948322B2 (ja) | 2015-12-16 | 2021-10-13 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Apj受容体のapjアゴニストとしてのヘテロアリールヒドロキシピリミジノン |
CN109195963B (zh) | 2016-03-24 | 2021-04-23 | 百时美施贵宝公司 | 作为apj激动剂的6-羟基-4-氧代-1,4-二氢嘧啶-5-甲酰胺 |
EP3452466B1 (en) | 2016-05-03 | 2020-08-12 | Amgen Inc. | Heterocyclic triazole compounds as agonists of the apj receptor |
ES2863903T3 (es) | 2016-06-14 | 2021-10-13 | Bristol Myers Squibb Co | 6-hidroxi-5-(fenil/heteroarilsulfonil)pirimidin-4(1H)-ona como agonistas de APJ |
WO2017218617A1 (en) | 2016-06-14 | 2017-12-21 | Bristol-Myers Squibb Company | 4-hydroxy-3-sulfonylpyridin-2(1h)-ones as apj receptor agonists |
US10669258B2 (en) | 2016-10-14 | 2020-06-02 | Bristol-Myers Squibb Company | 3-sulfonyl-5-aminopyridine-2,4-diol APJ agonists |
WO2018093580A1 (en) | 2016-11-16 | 2018-05-24 | Amgen Inc. | Triazole pyridyl compounds as agonists of the apj receptor |
EP3541810B1 (en) | 2016-11-16 | 2020-12-23 | Amgen Inc. | Triazole phenyl compounds as agonists of the apj receptor |
MA46824A (fr) | 2016-11-16 | 2019-09-25 | Amgen Inc | Composés de triazole substitués par alkyle en tant qu'agonistes du récepteur apj |
US11046680B1 (en) | 2016-11-16 | 2021-06-29 | Amgen Inc. | Heteroaryl-substituted triazoles as APJ receptor agonists |
US11020395B2 (en) | 2016-11-16 | 2021-06-01 | Amgen Inc. | Cycloalkyl substituted triazole compounds as agonists of the APJ receptor |
EP3541792B1 (en) | 2016-11-16 | 2020-12-23 | Amgen Inc. | Triazole furan compounds as agonists of the apj receptor |
US11149040B2 (en) | 2017-11-03 | 2021-10-19 | Amgen Inc. | Fused triazole agonists of the APJ receptor |
US11807624B2 (en) | 2018-05-01 | 2023-11-07 | Amgen Inc. | Substituted pyrimidinones as agonists of the APJ receptor |
Family Cites Families (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH602664A5 (en) | 1973-06-14 | 1978-07-31 | Sandoz Ag | 2-Tert. amino-alkylamino-pyrimidine derivs. |
ZA835878B (en) * | 1982-08-23 | 1985-03-27 | Warner Lambert Co | Cardiotonic agents |
GB2263639A (en) | 1992-01-28 | 1993-08-04 | Merck & Co Inc | Substituted pyrimidinones as neurotensin antagonists |
DE4425616A1 (de) * | 1994-07-20 | 1996-01-25 | Basf Ag | Hydroxypyridoncarbonsäureamide, deren Herstellung und Verwendung |
BR9711098B1 (pt) | 1996-07-01 | 2011-10-04 | compostos heterocìclicos, processo para sua preparação e composições farmacêuticas contendo os mesmos e seu uso no tratamento de diabetes e doenças relacionadas. | |
WO2002006242A2 (en) | 2000-07-18 | 2002-01-24 | Neurogen Corporation | 5-substituted 2-aryl-4-pyrimidinones |
TW200300349A (en) | 2001-11-19 | 2003-06-01 | Sankyo Co | A 4-oxoqinoline derivative |
CA2485148A1 (en) | 2002-05-09 | 2003-11-20 | Cytokinetics, Inc. | Pyrimidinone compounds, compositions and methods |
CA2483627A1 (en) | 2002-05-23 | 2003-12-04 | Merck & Co., Inc. | Mitotic kinesin inhibitors |
JP2004339159A (ja) | 2003-05-16 | 2004-12-02 | Sankyo Co Ltd | 4−オキソキノリン誘導体を含有する医薬組成物 |
JP2007505121A (ja) | 2003-09-08 | 2007-03-08 | 武田薬品工業株式会社 | ジペプチジルぺプチダーゼ阻害剤 |
US20050197327A1 (en) | 2003-11-03 | 2005-09-08 | Gustave Bergnes | Compounds, compositions, and methods |
CA2547209A1 (en) | 2003-12-19 | 2005-07-07 | Merck & Co., Inc. | Mitotic kinesin inhibitors |
WO2007033196A1 (en) | 2005-09-14 | 2007-03-22 | Bristol-Myers Squibb Company | Met kinase inhibitors |
WO2007037543A1 (ja) | 2005-09-29 | 2007-04-05 | Banyu Pharmaceutical Co., Ltd. | ビアリールアミド誘導体 |
AU2006320580B2 (en) | 2005-11-30 | 2011-06-23 | Vertex Pharmaceuticals Incorporated | Inhibitors of c-Met and uses thereof |
US8367845B2 (en) | 2006-04-21 | 2013-02-05 | The Trustees Of Boston University | Ionic viscoelastics and viscoelastic salts |
JP2007308441A (ja) * | 2006-05-22 | 2007-11-29 | Sumitomo Chemical Co Ltd | 含複素環化合物及びその用途 |
WO2008052861A2 (de) | 2006-10-10 | 2008-05-08 | Proionic Production Of Ionic Substances Gmbh & Co Keg | Verfahren zur herstellung von 1,3 -hetero-aromatischen carbonaten |
EP2079707B1 (de) | 2006-10-10 | 2014-12-03 | proionic GmbH & Co KG | Verfahren zur umsetzung von 1,3-hetero-aromatischen 2-carboxylaten mit wasser |
TW200845994A (en) | 2007-01-12 | 2008-12-01 | Smithkline Beecham Corp | N-substituted glycine derivatives: prolyl hydroxylase inhibitors |
JP2010519204A (ja) | 2007-02-16 | 2010-06-03 | アムジエン・インコーポレーテツド | 窒素含有複素環ケトン類およびそれらのc−Met阻害薬としての使用 |
WO2009129120A2 (en) | 2008-04-15 | 2009-10-22 | Rfs Pharma, Llc | Nucleoside derivatives for treatment of caliciviridae infections, including norovirus infections |
US20110253929A1 (en) | 2008-12-22 | 2011-10-20 | Basf Se | Mixtures of hydrophobic and hydrophilic ionic liquids and use thereof in liquid ring compressors |
CA2762680C (en) | 2009-05-21 | 2018-04-17 | Chlorion Pharma, Inc. | Methyl sulfanyl pyrmidmes useful as antiinflammatories, analgesics, and antiepileptics |
CN103140221A (zh) | 2010-08-10 | 2013-06-05 | 盐野义制药株式会社 | 新型杂环衍生物和含有其的药物组合物 |
EP2715858A1 (en) | 2011-05-31 | 2014-04-09 | Merck Patent GmbH | Electrolyte formulations |
US9518068B2 (en) | 2011-05-31 | 2016-12-13 | Merck Patent Gmbh | Compounds containing hydrido-tricyano-borate anions |
US20140005181A1 (en) * | 2012-06-21 | 2014-01-02 | Sanford-Burnham Medical Research Institute | Small molecule antagonists of the apelin receptor for the treatment of disease |
WO2014004676A1 (en) | 2012-06-26 | 2014-01-03 | Ironwood Pharmaceuticals, Inc. | Use of faah inhibitors as neuroprotective agents in the cns |
LT2897939T (lt) * | 2012-09-21 | 2017-05-10 | Sanofi | Benzimidazolo karboksirūgšties amido dariniai metabolinių arba širdies ir kraujagyslių ligų gydymui |
DE102012021452A1 (de) | 2012-10-31 | 2014-04-30 | Merck Patent Gmbh | Salze mit Trihydroperfluoralkoxybutansulfonat- oder Trihydroperfluoralkoxypropansulfonat-Anion |
CN105358531B (zh) | 2013-03-14 | 2017-11-14 | 利兰-斯坦福大学初级学院的董事会 | 线粒体醛脱氢酶‑2调节剂和其使用方法 |
WO2014207100A1 (en) | 2013-06-27 | 2014-12-31 | Basf Se | A process for coating paper with cellulose using a solution containing cellulose |
HRP20230546T1 (hr) | 2013-06-27 | 2023-08-04 | Pfizer Inc. | Heteroaromatski spojevi i njihova upotreba kao dopaminskih d1 liganada |
EP2997106B1 (de) | 2013-11-29 | 2019-03-06 | proionic GmbH | Verfahren zum aushärten eines klebstoffs mittels mikrowellenbestrahlung |
US10570128B2 (en) | 2014-05-28 | 2020-02-25 | Sanford Burnham Prebys Medical Discovery Institute | Agonists of the apelin receptor and methods of use thereof |
BR112016028119A2 (pt) | 2014-06-06 | 2017-08-22 | Res Triangle Inst | Agonistas receptores de apelina (apj) e usos dos mesmos |
WO2016074757A1 (de) | 2014-11-11 | 2016-05-19 | Merck Patent Gmbh | Verfahren zur herstellung von mono- und bis(perfluoralkyl)fluorophosphatsalzen und deren säuren |
RU2683245C1 (ru) | 2015-04-24 | 2019-03-27 | Сионоги Энд Ко., Лтд. | 6-членные гетероциклические производные и содержащая их фармацевтическая композиция |
ME03733B (me) | 2015-05-20 | 2021-01-20 | Amgen Inc | Agonisti triazola apj receptora |
US10011594B2 (en) | 2015-06-03 | 2018-07-03 | Bristol-Myers Squibb Company | 4-hydroxy-3-(heteroaryl)pyridine-2-one APJ agonists |
KR101711744B1 (ko) | 2015-07-16 | 2017-03-02 | 경희대학교 산학협력단 | 옥사디아졸 유도체, 이의 제조방법 및 이를 포함하는 전자수송층 |
EP3380970B1 (en) | 2015-11-24 | 2023-01-04 | Sanford Burnham Prebys Medical Discovery Institute | Novel azole derivatives as apelin receptor agonist |
ES2858312T3 (es) | 2015-12-04 | 2021-09-30 | Bristol Myers Squibb Co | Agonistas del receptor de apelina y métodos de uso |
JP6948322B2 (ja) | 2015-12-16 | 2021-10-13 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Apj受容体のapjアゴニストとしてのヘテロアリールヒドロキシピリミジノン |
CN109195963B (zh) | 2016-03-24 | 2021-04-23 | 百时美施贵宝公司 | 作为apj激动剂的6-羟基-4-氧代-1,4-二氢嘧啶-5-甲酰胺 |
ES2863903T3 (es) | 2016-06-14 | 2021-10-13 | Bristol Myers Squibb Co | 6-hidroxi-5-(fenil/heteroarilsulfonil)pirimidin-4(1H)-ona como agonistas de APJ |
WO2017218617A1 (en) | 2016-06-14 | 2017-12-21 | Bristol-Myers Squibb Company | 4-hydroxy-3-sulfonylpyridin-2(1h)-ones as apj receptor agonists |
US10669258B2 (en) | 2016-10-14 | 2020-06-02 | Bristol-Myers Squibb Company | 3-sulfonyl-5-aminopyridine-2,4-diol APJ agonists |
-
2016
- 2016-10-13 CA CA3001974A patent/CA3001974A1/en not_active Abandoned
- 2016-10-13 WO PCT/US2016/056769 patent/WO2017066402A1/en active Application Filing
- 2016-10-13 US US15/767,364 patent/US10392347B2/en active Active
- 2016-10-13 BR BR112018007395A patent/BR112018007395A2/pt not_active IP Right Cessation
- 2016-10-13 EP EP16784732.6A patent/EP3362442B1/en active Active
- 2016-10-13 PE PE2018000536A patent/PE20181197A1/es unknown
- 2016-10-13 ES ES16784732T patent/ES2774945T3/es active Active
- 2016-10-13 UY UY0001036949A patent/UY36949A/es unknown
- 2016-10-13 MX MX2018004344A patent/MX2018004344A/es active IP Right Grant
- 2016-10-13 CN CN201680072835.5A patent/CN108368087B/zh active Active
- 2016-10-13 EA EA201890858A patent/EA034857B1/ru not_active IP Right Cessation
- 2016-10-13 KR KR1020187013119A patent/KR20180067599A/ko active IP Right Grant
- 2016-10-13 SG SG10201908839Q patent/SG10201908839QA/en unknown
- 2016-10-13 AU AU2016340264A patent/AU2016340264B2/en not_active Ceased
- 2016-10-13 JP JP2018519425A patent/JP6837482B2/ja active Active
- 2016-10-13 TW TW105133123A patent/TW201720796A/zh unknown
-
2018
- 2018-04-09 IL IL258577A patent/IL258577B/en active IP Right Grant
- 2018-04-13 CL CL2018000953A patent/CL2018000953A1/es unknown
- 2018-04-13 ZA ZA2018/02451A patent/ZA201802451B/en unknown
- 2018-05-10 CO CONC2018/0004968A patent/CO2018004968A2/es unknown
Also Published As
Publication number | Publication date |
---|---|
UY36949A (es) | 2017-04-28 |
EP3362442A1 (en) | 2018-08-22 |
MX2018004344A (es) | 2018-05-01 |
EA034857B1 (ru) | 2020-03-30 |
ES2774945T3 (es) | 2020-07-23 |
WO2017066402A1 (en) | 2017-04-20 |
ZA201802451B (en) | 2020-01-29 |
EA201890858A1 (ru) | 2018-09-28 |
BR112018007395A2 (pt) | 2018-10-23 |
CA3001974A1 (en) | 2017-04-20 |
KR20180067599A (ko) | 2018-06-20 |
CN108368087B (zh) | 2022-04-12 |
CN108368087A (zh) | 2018-08-03 |
IL258577A (en) | 2018-05-31 |
SG10201908839QA (en) | 2019-10-30 |
CL2018000953A1 (es) | 2018-08-24 |
AU2016340264B2 (en) | 2021-01-07 |
AU2016340264A1 (en) | 2018-05-31 |
US20180297954A1 (en) | 2018-10-18 |
US10392347B2 (en) | 2019-08-27 |
PE20181197A1 (es) | 2018-07-23 |
IL258577B (en) | 2020-07-30 |
JP6837482B2 (ja) | 2021-03-03 |
EP3362442B1 (en) | 2020-01-29 |
JP2018530591A (ja) | 2018-10-18 |
CO2018004968A2 (es) | 2018-10-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6837482B2 (ja) | Apjアゴニストとしての2,4−ジヒドロキシ−ニコチンアミド | |
KR102433280B1 (ko) | Apj 효능제로서의 6-히드록시-4-옥소-1,4-디히드로피리미딘-5-카르복스아미드 | |
JP6948322B2 (ja) | Apj受容体のapjアゴニストとしてのヘテロアリールヒドロキシピリミジノン | |
KR102384668B1 (ko) | Apj 효능제로서의 6-히드록시-5-(페닐/헤테로아릴술포닐)피리미딘-4(1h)-온 | |
KR102066336B1 (ko) | 심혈관 장애의 치료에 사용하기 위한 4-히드록시-3-(헤테로아릴)피리딘-2-온 apj 효능제 | |
JP6962941B2 (ja) | Apj受容体アゴニストとしての4−ヒドロキシ−3−スルホニルピリジン−2(1h)−オン | |
CN110072850B (zh) | 3-磺酰基-5-氨基吡啶-2,4-二醇apj激动剂 | |
TW201722920A (zh) | 新穎愛帕琳(apelin)受體促效劑及使用方法 |