WO2016107603A1 - Dérivés hétérocycliques contenant de l'azote substitué et leurs applications - Google Patents
Dérivés hétérocycliques contenant de l'azote substitué et leurs applications Download PDFInfo
- Publication number
- WO2016107603A1 WO2016107603A1 PCT/CN2015/100201 CN2015100201W WO2016107603A1 WO 2016107603 A1 WO2016107603 A1 WO 2016107603A1 CN 2015100201 W CN2015100201 W CN 2015100201W WO 2016107603 A1 WO2016107603 A1 WO 2016107603A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- compound
- mmol
- alkyl
- substituted
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 506
- 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 178
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims abstract description 178
- 238000002360 preparation method Methods 0.000 claims abstract description 90
- 239000003814 drug Substances 0.000 claims abstract description 76
- 210000004185 liver Anatomy 0.000 claims abstract description 35
- 208000031226 Hyperlipidaemia Diseases 0.000 claims abstract description 26
- 102100038955 Proprotein convertase subtilisin/kexin type 9 Human genes 0.000 claims abstract description 26
- 230000014509 gene expression Effects 0.000 claims abstract description 23
- 108010028554 LDL Cholesterol Proteins 0.000 claims abstract description 17
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 15
- 208000035150 Hypercholesterolemia Diseases 0.000 claims abstract description 11
- 201000001421 hyperglycemia Diseases 0.000 claims abstract description 10
- 208000008589 Obesity Diseases 0.000 claims abstract description 9
- 208000006575 hypertriglyceridemia Diseases 0.000 claims abstract description 9
- 235000020824 obesity Nutrition 0.000 claims abstract description 9
- 206010022489 Insulin Resistance Diseases 0.000 claims abstract description 8
- 238000008214 LDL Cholesterol Methods 0.000 claims abstract description 7
- 101001098868 Homo sapiens Proprotein convertase subtilisin/kexin type 9 Proteins 0.000 claims abstract 2
- -1 cyano, carbonyl Chemical group 0.000 claims description 236
- 238000006243 chemical reaction Methods 0.000 claims description 204
- 125000000217 alkyl group Chemical group 0.000 claims description 102
- 239000007858 starting material Substances 0.000 claims description 95
- 125000000623 heterocyclic group Chemical group 0.000 claims description 84
- 125000003118 aryl group Chemical group 0.000 claims description 77
- 125000001424 substituent group Chemical group 0.000 claims description 70
- 125000001072 heteroaryl group Chemical group 0.000 claims description 64
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 58
- 125000003342 alkenyl group Chemical group 0.000 claims description 54
- 125000000304 alkynyl group Chemical group 0.000 claims description 54
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 50
- 239000001257 hydrogen Substances 0.000 claims description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims description 49
- 150000003839 salts Chemical class 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 40
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 39
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 37
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 36
- 125000003545 alkoxy group Chemical group 0.000 claims description 36
- 239000012453 solvate Substances 0.000 claims description 36
- 150000002632 lipids Chemical class 0.000 claims description 32
- 230000001965 increasing effect Effects 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 238000011282 treatment Methods 0.000 claims description 27
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 24
- 206010019708 Hepatic steatosis Diseases 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims description 16
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 16
- 125000004076 pyridyl group Chemical group 0.000 claims description 16
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims description 15
- 125000001624 naphthyl group Chemical group 0.000 claims description 15
- 125000002541 furyl group Chemical group 0.000 claims description 14
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 14
- 125000002883 imidazolyl group Chemical group 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 14
- 125000001544 thienyl group Chemical group 0.000 claims description 14
- 238000005859 coupling reaction Methods 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 230000008878 coupling Effects 0.000 claims description 12
- 238000010168 coupling process Methods 0.000 claims description 12
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 12
- 238000006268 reductive amination reaction Methods 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 11
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 8
- 150000003457 sulfones Chemical class 0.000 claims description 8
- 150000003626 triacylglycerols Chemical class 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 150000007942 carboxylates Chemical class 0.000 claims description 7
- 125000004043 oxo group Chemical group O=* 0.000 claims description 7
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- 125000005493 quinolyl group Chemical group 0.000 claims description 6
- 229910052710 silicon Inorganic materials 0.000 claims description 6
- 239000010703 silicon Substances 0.000 claims description 6
- 150000003376 silicon Chemical class 0.000 claims description 6
- 125000005504 styryl group Chemical group 0.000 claims description 6
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 101001051093 Homo sapiens Low-density lipoprotein receptor Proteins 0.000 claims description 2
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 claims description 2
- 125000003636 chemical group Chemical group 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 7
- 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 abstract description 46
- 108010001831 LDL receptors Proteins 0.000 abstract description 21
- 102000000853 LDL receptors Human genes 0.000 abstract description 21
- 235000012000 cholesterol Nutrition 0.000 abstract description 18
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 abstract description 15
- 229940124597 therapeutic agent Drugs 0.000 abstract description 6
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- 230000007850 degeneration Effects 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 599
- 235000019439 ethyl acetate Nutrition 0.000 description 251
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 228
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 168
- 238000005481 NMR spectroscopy Methods 0.000 description 125
- 238000003756 stirring Methods 0.000 description 124
- 239000000047 product Substances 0.000 description 92
- 238000004809 thin layer chromatography Methods 0.000 description 92
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 90
- 239000000203 mixture Substances 0.000 description 73
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 69
- 229940079593 drug Drugs 0.000 description 57
- 239000007787 solid Substances 0.000 description 56
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 53
- 239000011541 reaction mixture Substances 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- 230000000694 effects Effects 0.000 description 36
- 239000003921 oil Substances 0.000 description 35
- 235000019198 oils Nutrition 0.000 description 35
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
- 239000000243 solution Substances 0.000 description 32
- 239000012265 solid product Substances 0.000 description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 27
- 229920006395 saturated elastomer Polymers 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 108010007622 LDL Lipoproteins Proteins 0.000 description 24
- 102000007330 LDL Lipoproteins Human genes 0.000 description 24
- 101710180553 Proprotein convertase subtilisin/kexin type 9 Proteins 0.000 description 24
- 239000003925 fat Substances 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- 210000004369 blood Anatomy 0.000 description 22
- 239000008280 blood Substances 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 21
- 239000007864 aqueous solution Substances 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- 239000002904 solvent Substances 0.000 description 19
- 0 COP(N(*)*)(N(*)*)=O Chemical compound COP(N(*)*)(N(*)*)=O 0.000 description 17
- 210000003494 hepatocyte Anatomy 0.000 description 17
- 241001465754 Metazoa Species 0.000 description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
- 231100000240 steatosis hepatitis Toxicity 0.000 description 16
- 208000004930 Fatty Liver Diseases 0.000 description 15
- 208000010706 fatty liver disease Diseases 0.000 description 15
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 14
- 238000002474 experimental method Methods 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- 239000011734 sodium Substances 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 235000014113 dietary fatty acids Nutrition 0.000 description 13
- 235000019197 fats Nutrition 0.000 description 13
- 229930195729 fatty acid Natural products 0.000 description 13
- 239000000194 fatty acid Substances 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 125000004093 cyano group Chemical group *C#N 0.000 description 12
- 150000002431 hydrogen Chemical class 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 12
- 239000000546 pharmaceutical excipient Substances 0.000 description 12
- 210000002966 serum Anatomy 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- 208000029078 coronary artery disease Diseases 0.000 description 11
- 125000005843 halogen group Chemical group 0.000 description 11
- 238000002955 isolation Methods 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- 108010011376 AMP-Activated Protein Kinases Proteins 0.000 description 10
- 102000014156 AMP-Activated Protein Kinases Human genes 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 10
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 10
- 206010012601 diabetes mellitus Diseases 0.000 description 10
- 150000004665 fatty acids Chemical class 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- 229960002855 simvastatin Drugs 0.000 description 10
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 230000008901 benefit Effects 0.000 description 8
- 239000012634 fragment Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 238000003753 real-time PCR Methods 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical group ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 7
- 208000024172 Cardiovascular disease Diseases 0.000 description 7
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 7
- 229940093265 berberine Drugs 0.000 description 7
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 description 7
- 238000011161 development Methods 0.000 description 7
- 230000018109 developmental process Effects 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical group COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 7
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 6
- 108010082126 Alanine transaminase Proteins 0.000 description 6
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 6
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 6
- 101150094724 PCSK9 gene Proteins 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 239000003524 antilipemic agent Substances 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 208000026106 cerebrovascular disease Diseases 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 239000006071 cream Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 235000013355 food flavoring agent Nutrition 0.000 description 6
- 235000003599 food sweetener Nutrition 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 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 6
- 239000010410 layer Substances 0.000 description 6
- 229960003512 nicotinic acid Drugs 0.000 description 6
- 235000001968 nicotinic acid Nutrition 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000003755 preservative agent Substances 0.000 description 6
- 238000011552 rat model Methods 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 238000009825 accumulation Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 210000001789 adipocyte Anatomy 0.000 description 5
- 239000003963 antioxidant agent Substances 0.000 description 5
- 235000006708 antioxidants Nutrition 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229940125877 compound 31 Drugs 0.000 description 5
- 229940127573 compound 38 Drugs 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 229940125753 fibrate Drugs 0.000 description 5
- 150000002429 hydrazines Chemical class 0.000 description 5
- 230000008595 infiltration Effects 0.000 description 5
- 238000001764 infiltration Methods 0.000 description 5
- 210000004969 inflammatory cell Anatomy 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 108020004999 messenger RNA Proteins 0.000 description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 239000011664 nicotinic acid Substances 0.000 description 5
- 125000004430 oxygen atom Chemical group O* 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 235000000346 sugar Nutrition 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 150000003573 thiols Chemical class 0.000 description 5
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 208000032928 Dyslipidaemia Diseases 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 108010023302 HDL Cholesterol Proteins 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 208000017170 Lipid metabolism disease Diseases 0.000 description 4
- 229940127355 PCSK9 Inhibitors Drugs 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 4
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 125000004423 acyloxy group Chemical group 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 230000003078 antioxidant effect Effects 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- 125000004104 aryloxy group Chemical group 0.000 description 4
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 description 4
- 239000003613 bile acid Substances 0.000 description 4
- 229940125385 biologic drug Drugs 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 206010008118 cerebral infarction Diseases 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 230000003908 liver function Effects 0.000 description 4
- 239000004530 micro-emulsion Substances 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 150000003904 phospholipids Chemical class 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 3
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 3
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 3
- VWOJSRICSKDKAW-UHFFFAOYSA-N 1-(4-nitrophenyl)piperazine Chemical compound C1=CC([N+](=O)[O-])=CC=C1N1CCNCC1 VWOJSRICSKDKAW-UHFFFAOYSA-N 0.000 description 3
- 102000000452 Acetyl-CoA carboxylase Human genes 0.000 description 3
- 108010016219 Acetyl-CoA carboxylase Proteins 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 3
- 201000001320 Atherosclerosis Diseases 0.000 description 3
- 108010018763 Biotin carboxylase Proteins 0.000 description 3
- YKYKBQQBAGNVRU-UHFFFAOYSA-N Cc(cc1)ccc1S(Oc(cc1)ccc1N1CCNCC1)(=O)=O Chemical compound Cc(cc1)ccc1S(Oc(cc1)ccc1N1CCNCC1)(=O)=O YKYKBQQBAGNVRU-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 229910010082 LiAlH Inorganic materials 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-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
- 229940122392 PCSK9 inhibitor Drugs 0.000 description 3
- 235000019483 Peanut oil Nutrition 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 3
- 108090000340 Transaminases Proteins 0.000 description 3
- 102000003929 Transaminases Human genes 0.000 description 3
- 108010069201 VLDL Cholesterol Proteins 0.000 description 3
- 108010062497 VLDL Lipoproteins Proteins 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 3
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 3
- 229920000080 bile acid sequestrant Polymers 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- 125000005366 cycloalkylthio group Chemical group 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000002440 hepatic effect Effects 0.000 description 3
- 208000006454 hepatitis Diseases 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- 210000005228 liver tissue Anatomy 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N n-hexadecyl alcohol Natural products CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 3
- 235000005152 nicotinamide Nutrition 0.000 description 3
- 239000011570 nicotinamide Substances 0.000 description 3
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 3
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 125000002971 oxazolyl group Chemical group 0.000 description 3
- 239000000312 peanut oil Substances 0.000 description 3
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229940126586 small molecule drug Drugs 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 235000011069 sorbitan monooleate Nutrition 0.000 description 3
- 239000001593 sorbitan monooleate Substances 0.000 description 3
- 229940035049 sorbitan monooleate Drugs 0.000 description 3
- 229940124530 sulfonamide Drugs 0.000 description 3
- 150000003456 sulfonamides Chemical class 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- XQJAHBHCLXUGEP-UHFFFAOYSA-N 2-bromo-1-(4-methoxyphenyl)ethanone Chemical compound COC1=CC=C(C(=O)CBr)C=C1 XQJAHBHCLXUGEP-UHFFFAOYSA-N 0.000 description 2
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- 125000005916 2-methylpentyl group Chemical group 0.000 description 2
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000005917 3-methylpentyl group Chemical group 0.000 description 2
- XJZGRBZMXHGFCB-UHFFFAOYSA-N 4-(4-nitrophenyl)piperazin-2-one Chemical compound C1=CC([N+](=O)[O-])=CC=C1N1CC(=O)NCC1 XJZGRBZMXHGFCB-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 102100022900 Actin, cytoplasmic 1 Human genes 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 102000008873 Angiotensin II receptor Human genes 0.000 description 2
- 108050000824 Angiotensin II receptor Proteins 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 108010011485 Aspartame Proteins 0.000 description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 2
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 2
- VKJGBAJNNALVAV-UHFFFAOYSA-M Berberine chloride (TN) Chemical compound [Cl-].C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 VKJGBAJNNALVAV-UHFFFAOYSA-M 0.000 description 2
- UZMBXRMRKKAHQI-UHFFFAOYSA-N COc1ccc(CN(CC2)CCN2c(cc2)ccc2O)cc1OC Chemical compound COc1ccc(CN(CC2)CCN2c(cc2)ccc2O)cc1OC UZMBXRMRKKAHQI-UHFFFAOYSA-N 0.000 description 2
- 229920001268 Cholestyramine Polymers 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-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
- 108010010803 Gelatin Proteins 0.000 description 2
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 2
- 108010010234 HDL Lipoproteins Proteins 0.000 description 2
- 102000015779 HDL Lipoproteins Human genes 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 206010067125 Liver injury Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 102100031545 Microsomal triglyceride transfer protein large subunit Human genes 0.000 description 2
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 2
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 2
- CWKMIEALBOKDCD-UHFFFAOYSA-N O=Cc1ccccc1S(c1ccccc1)(=O)=O Chemical compound O=Cc1ccccc1S(c1ccccc1)(=O)=O CWKMIEALBOKDCD-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 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
- 229920002472 Starch Polymers 0.000 description 2
- 102000001494 Sterol O-Acyltransferase Human genes 0.000 description 2
- 108010054082 Sterol O-acyltransferase Proteins 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 230000009102 absorption Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 239000000605 aspartame Substances 0.000 description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 2
- 235000010357 aspartame Nutrition 0.000 description 2
- 229960003438 aspartame Drugs 0.000 description 2
- 229960005370 atorvastatin Drugs 0.000 description 2
- 125000005602 azabenzimidazolyl group Chemical group 0.000 description 2
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=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
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 210000000941 bile Anatomy 0.000 description 2
- 229940096699 bile acid sequestrants Drugs 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229960000074 biopharmaceutical Drugs 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 230000001906 cholesterol absorption Effects 0.000 description 2
- 229940121657 clinical drug Drugs 0.000 description 2
- 229960001214 clofibrate Drugs 0.000 description 2
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=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 RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 2
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 2
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000006806 disease prevention Effects 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 150000002081 enamines Chemical class 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 2
- 229960000815 ezetimibe Drugs 0.000 description 2
- 201000005577 familial hyperlipidemia Diseases 0.000 description 2
- 150000002191 fatty alcohols Chemical class 0.000 description 2
- 229960002297 fenofibrate Drugs 0.000 description 2
- 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 2
- 239000002319 fibrinogen receptor antagonist Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 229960003765 fluvastatin Drugs 0.000 description 2
- 235000021588 free fatty acids Nutrition 0.000 description 2
- 239000012737 fresh medium Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229960003627 gemfibrozil Drugs 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 231100000234 hepatic damage Toxicity 0.000 description 2
- 231100000304 hepatotoxicity Toxicity 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
- 235000009200 high fat diet Nutrition 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 125000002632 imidazolidinyl group Chemical group 0.000 description 2
- 125000002636 imidazolinyl group Chemical group 0.000 description 2
- 125000005945 imidazopyridyl group Chemical group 0.000 description 2
- 150000003949 imides Chemical class 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- 125000000842 isoxazolyl 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
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 230000008818 liver damage Effects 0.000 description 2
- 208000018191 liver inflammation Diseases 0.000 description 2
- 150000004668 long chain fatty acids Chemical class 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229960004844 lovastatin Drugs 0.000 description 2
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 2
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000000873 masking effect Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000010445 mica Substances 0.000 description 2
- 229910052618 mica group Inorganic materials 0.000 description 2
- 108010038232 microsomal triglyceride transfer protein Proteins 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 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 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229960003966 nicotinamide Drugs 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 230000010399 physical interaction Effects 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 108010094020 polyglycine Proteins 0.000 description 2
- 229920000232 polyglycine polymer Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 229960002965 pravastatin Drugs 0.000 description 2
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 2
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000004059 squalene synthase inhibitor Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 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
- 125000001425 triazolyl group Chemical group 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- WJUFSDZVCOTFON-UHFFFAOYSA-N veratraldehyde Chemical compound COC1=CC=C(C=O)C=C1OC WJUFSDZVCOTFON-UHFFFAOYSA-N 0.000 description 2
- 229940011671 vitamin b6 Drugs 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- FNHHVPPSBFQMEL-KQHDFZBMSA-N (3S)-5-N-[(1S,5R)-3-hydroxy-6-bicyclo[3.1.0]hexanyl]-7-N,3-dimethyl-3-phenyl-2H-1-benzofuran-5,7-dicarboxamide Chemical compound CNC(=O)c1cc(cc2c1OC[C@@]2(C)c1ccccc1)C(=O)NC1[C@H]2CC(O)C[C@@H]12 FNHHVPPSBFQMEL-KQHDFZBMSA-N 0.000 description 1
- OIIOPWHTJZYKIL-PMACEKPBSA-N (5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[[[(2S)-5-oxopyrrolidin-2-yl]methylamino]methyl]pyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one Chemical compound C1(=C(N=C(C2=C(C(C3=CC=CC(=C3Cl)C3=NC(OC)=C(N=C3)CNC[C@H]3NC(=O)CC3)=CC=C2)Cl)C=N1)OC)CNC[C@H]1NC(=O)CC1 OIIOPWHTJZYKIL-PMACEKPBSA-N 0.000 description 1
- RWIUTHWKQHRQNP-ZDVGBALWSA-N (9e,12e)-n-(1-phenylethyl)octadeca-9,12-dienamide Chemical compound CCCCC\C=C\C\C=C\CCCCCCCC(=O)NC(C)C1=CC=CC=C1 RWIUTHWKQHRQNP-ZDVGBALWSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 1
- LYFPBWOBIJJASK-INIZCTEOSA-N (S)-(-)-Canadine Natural products O(C)c1c(OC)ccc2c1C[N+]1[C@H](c3c(cc4OCOc4c3)CC1)C2 LYFPBWOBIJJASK-INIZCTEOSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 1
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 1
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-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
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 125000003562 2,2-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003764 2,4-dimethylpentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- VCUXVXLUOHDHKK-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-4-(2-chloro-4-methoxyphenyl)-1,3-thiazole-5-carboxamide Chemical compound ClC1=CC(OC)=CC=C1C1=C(C(N)=O)SC(C=2N=C(N)N=CC=2)=N1 VCUXVXLUOHDHKK-UHFFFAOYSA-N 0.000 description 1
- VTAKZNRDSPNOAU-UHFFFAOYSA-M 2-(chloromethyl)oxirane;hydron;prop-2-en-1-amine;n-prop-2-enyldecan-1-amine;trimethyl-[6-(prop-2-enylamino)hexyl]azanium;dichloride Chemical compound Cl.[Cl-].NCC=C.ClCC1CO1.CCCCCCCCCCNCC=C.C[N+](C)(C)CCCCCCNCC=C VTAKZNRDSPNOAU-UHFFFAOYSA-M 0.000 description 1
- PAYROHWFGZADBR-UHFFFAOYSA-N 2-[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]propane-1,3-diol Chemical compound C1=C(I)C(OC)=CC(C(C)C)=C1OC1=CN=C(NC(CO)CO)N=C1N PAYROHWFGZADBR-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 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
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- 125000004336 3,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 1
- 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 1
- SRVXSISGYBMIHR-UHFFFAOYSA-N 3-[3-[3-(2-amino-2-oxoethyl)phenyl]-5-chlorophenyl]-3-(5-methyl-1,3-thiazol-2-yl)propanoic acid Chemical compound S1C(C)=CN=C1C(CC(O)=O)C1=CC(Cl)=CC(C=2C=C(CC(N)=O)C=CC=2)=C1 SRVXSISGYBMIHR-UHFFFAOYSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000004337 3-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- OKYSUJVCDXZGKE-UHFFFAOYSA-N 3-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=CC(S(Cl)(=O)=O)=C1 OKYSUJVCDXZGKE-UHFFFAOYSA-N 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- MCFBUIIRFZBRCU-UHFFFAOYSA-N 4-[1-[5-[6-(trifluoromethyl)-1h-benzimidazol-2-yl]pyridin-2-yl]piperidin-4-yl]oxycyclohexane-1-carboxylic acid Chemical compound C1CC(C(=O)O)CCC1OC1CCN(C=2N=CC(=CC=2)C=2NC3=CC(=CC=C3N=2)C(F)(F)F)CC1 MCFBUIIRFZBRCU-UHFFFAOYSA-N 0.000 description 1
- UIADWSXPNFQQCZ-UHFFFAOYSA-N 4-[4-(3,4-dichlorophenyl)-5-phenyl-1,3-oxazol-2-yl]butanoic acid Chemical compound ClC=1C=C(C=CC=1Cl)C=1N=C(OC=1C1=CC=CC=C1)CCCC(=O)O UIADWSXPNFQQCZ-UHFFFAOYSA-N 0.000 description 1
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 1
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 1
- GSDQYSSLIKJJOG-UHFFFAOYSA-N 4-chloro-2-(3-chloroanilino)benzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1NC1=CC=CC(Cl)=C1 GSDQYSSLIKJJOG-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- FCFHJJYTYOPPEM-UHFFFAOYSA-N 4h-berberine n-oxide Chemical compound C12=CC=3OCOC=3C=C2CC[N+]2([O-])C1CC1=CC=C(OC)C(OC)=C1C2 FCFHJJYTYOPPEM-UHFFFAOYSA-N 0.000 description 1
- UICBHOXXGLYZJH-UHFFFAOYSA-N 5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium Chemical compound C1=CC=C2CC[N+]3=CC4=CC=CC=C4C=C3C2=C1 UICBHOXXGLYZJH-UHFFFAOYSA-N 0.000 description 1
- 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 1
- UTCFOFWMEPQCSR-UHFFFAOYSA-N 5-formylsalicylic acid Chemical compound OC(=O)C1=CC(C=O)=CC=C1O UTCFOFWMEPQCSR-UHFFFAOYSA-N 0.000 description 1
- IJRKLHTZAIFUTB-UHFFFAOYSA-N 5-nitro-2-(2-phenylethylamino)benzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1NCCC1=CC=CC=C1 IJRKLHTZAIFUTB-UHFFFAOYSA-N 0.000 description 1
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-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
- XASOHFCUIQARJT-UHFFFAOYSA-N 8-methoxy-6-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one Chemical compound C(N1C(=O)C2=C(OC)C=C(C=3N4C(=NC=3)C=C(C=C4)OCCN3CCOCC3)C=C2CC1)C(F)(F)F XASOHFCUIQARJT-UHFFFAOYSA-N 0.000 description 1
- IRBAWVGZNJIROV-SFHVURJKSA-N 9-(2-cyclopropylethynyl)-2-[[(2s)-1,4-dioxan-2-yl]methoxy]-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one Chemical compound C1=C2C3=CC=C(C#CC4CC4)C=C3CCN2C(=O)N=C1OC[C@@H]1COCCO1 IRBAWVGZNJIROV-SFHVURJKSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 108700038202 AMP-Activated Protein Kinase Kinases Proteins 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 240000002234 Allium sativum Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- IYHHRZBKXXKDDY-UHFFFAOYSA-N BI-605906 Chemical compound N=1C=2SC(C(N)=O)=C(N)C=2C(C(F)(F)CC)=CC=1N1CCC(S(C)(=O)=O)CC1 IYHHRZBKXXKDDY-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- GZRKXKUVVPSREJ-UHFFFAOYSA-N C(C1)NCCN1c1ncccc1 Chemical compound C(C1)NCCN1c1ncccc1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 1
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
- BGGALFIXXQOTPY-NRFANRHFSA-N C1(=C(C2=C(C=C1)N(C(C#N)=C2)C[C@@H](N1CCN(CC1)S(=O)(=O)C)C)C)CN1CCC(CC1)NC1=NC(=NC2=C1C=C(S2)CC(F)(F)F)NC Chemical compound C1(=C(C2=C(C=C1)N(C(C#N)=C2)C[C@@H](N1CCN(CC1)S(=O)(=O)C)C)C)CN1CCC(CC1)NC1=NC(=NC2=C1C=C(S2)CC(F)(F)F)NC BGGALFIXXQOTPY-NRFANRHFSA-N 0.000 description 1
- IDWKOSBHBHKJIF-UHFFFAOYSA-N CC(N(CC1)CCN1c(cc1)ccc1OS(c1ccc(C)cc1)(=O)=O)OC Chemical compound CC(N(CC1)CCN1c(cc1)ccc1OS(c1ccc(C)cc1)(=O)=O)OC IDWKOSBHBHKJIF-UHFFFAOYSA-N 0.000 description 1
- DDFWQWKUSVTOEA-VEDVMXKPSA-N CCC([C@@H](C)N1CCNCC1)O Chemical compound CCC([C@@H](C)N1CCNCC1)O DDFWQWKUSVTOEA-VEDVMXKPSA-N 0.000 description 1
- UHNRLQRZRNKOKU-UHFFFAOYSA-N CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O Chemical compound CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O UHNRLQRZRNKOKU-UHFFFAOYSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- CXJOONIFSVSFAD-UHFFFAOYSA-N COc1ccc(CC(Cl)=O)cc1 Chemical compound COc1ccc(CC(Cl)=O)cc1 CXJOONIFSVSFAD-UHFFFAOYSA-N 0.000 description 1
- NRPFNQUDKRYCNX-UHFFFAOYSA-N COc1ccc(CC(O)=O)cc1 Chemical compound COc1ccc(CC(O)=O)cc1 NRPFNQUDKRYCNX-UHFFFAOYSA-N 0.000 description 1
- QYHYAGJHPLHVKN-UHFFFAOYSA-N COc1ccc(CN(CC2)CCN2c(cc2)ccc2NS(c2cc(C(O)=O)ccc2)(=O)=O)cc1C(O)=O Chemical compound COc1ccc(CN(CC2)CCN2c(cc2)ccc2NS(c2cc(C(O)=O)ccc2)(=O)=O)cc1C(O)=O QYHYAGJHPLHVKN-UHFFFAOYSA-N 0.000 description 1
- PMNKCGAXJUSOQX-UHFFFAOYSA-N COc1ccc(CN(CC2)CCN2c(cc2)ccc2OC(N2CCOCC2)=O)cc1OC Chemical compound COc1ccc(CN(CC2)CCN2c(cc2)ccc2OC(N2CCOCC2)=O)cc1OC PMNKCGAXJUSOQX-UHFFFAOYSA-N 0.000 description 1
- XMFLACULNJLLHA-UHFFFAOYSA-N COc1ccc(CN(CC2)CCN2c(cc2)ccc2OS(C2CCCCC2)(=O)=O)cc1OC Chemical compound COc1ccc(CN(CC2)CCN2c(cc2)ccc2OS(C2CCCCC2)(=O)=O)cc1OC XMFLACULNJLLHA-UHFFFAOYSA-N 0.000 description 1
- ZARHOJSZKYTXAX-UHFFFAOYSA-N COc1ccc(CN(CC2)CCN2c(cc2)ccc2OS(c(cc2)ccc2-c2c[o]cc2)(=O)=O)cc1OC Chemical compound COc1ccc(CN(CC2)CCN2c(cc2)ccc2OS(c(cc2)ccc2-c2c[o]cc2)(=O)=O)cc1OC ZARHOJSZKYTXAX-UHFFFAOYSA-N 0.000 description 1
- PBXBQIBANVJMBX-XEGCMXMBSA-M C[C@@H](C(C1)Cl)Oc(cccc2)c2N=C1N1CCN(Cc(cccc2)c2S(c2ccccc2)([O-])=O)CC1 Chemical compound C[C@@H](C(C1)Cl)Oc(cccc2)c2N=C1N1CCN(Cc(cccc2)c2S(c2ccccc2)([O-])=O)CC1 PBXBQIBANVJMBX-XEGCMXMBSA-M 0.000 description 1
- VWUDGOMDTYXWPK-NRFANRHFSA-N C[C@@H](C1)N(Cc(cc2OC)ccc2OC)CCN1c(cc1)ccc1OS(c1ccc(C)cc1)(=O)=O Chemical compound C[C@@H](C1)N(Cc(cc2OC)ccc2OC)CCN1c(cc1)ccc1OS(c1ccc(C)cc1)(=O)=O VWUDGOMDTYXWPK-NRFANRHFSA-N 0.000 description 1
- WWPKHSOKANNDEF-FCHUYYIVSA-N C[C@@H](C1)N(Cc(cc2OC)ccc2OC)C[C@@H](C)N1c(cc1)ccc1NS(c1ccc(C)cc1)(=O)=O Chemical compound C[C@@H](C1)N(Cc(cc2OC)ccc2OC)C[C@@H](C)N1c(cc1)ccc1NS(c1ccc(C)cc1)(=O)=O WWPKHSOKANNDEF-FCHUYYIVSA-N 0.000 description 1
- WAPKLPYJNKFWPM-FCHUYYIVSA-N C[C@@H](C1)N(Cc(cc2OC)ccc2OC)C[C@@H](C)N1c(cc1)ccc1OS(c1ccc(C)cc1)(=O)=O Chemical compound C[C@@H](C1)N(Cc(cc2OC)ccc2OC)C[C@@H](C)N1c(cc1)ccc1OS(c1ccc(C)cc1)(=O)=O WAPKLPYJNKFWPM-FCHUYYIVSA-N 0.000 description 1
- YPWFGNDASATQAB-KVDNEDBNSA-N C[C@@H]([C@H](C)OS([C@H]1C(C)=CC1)(=O)=O)C(C=C)N1CCN(Cc2ccc(-c3ccc[s]3)[s]2)CC1 Chemical compound C[C@@H]([C@H](C)OS([C@H]1C(C)=CC1)(=O)=O)C(C=C)N1CCN(Cc2ccc(-c3ccc[s]3)[s]2)CC1 YPWFGNDASATQAB-KVDNEDBNSA-N 0.000 description 1
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 description 1
- OUKQTRFCDKSEPL-UHFFFAOYSA-N C[n]1c(C=O)ccc1 Chemical compound C[n]1c(C=O)ccc1 OUKQTRFCDKSEPL-UHFFFAOYSA-N 0.000 description 1
- PJYHYRIEBBIBEP-UHFFFAOYSA-N C[n]1c(CN(CC2)CCN2c(cc2)ccc2O)ccc1 Chemical compound C[n]1c(CN(CC2)CCN2c(cc2)ccc2O)ccc1 PJYHYRIEBBIBEP-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- UPKVRHBRAVWSIC-UHFFFAOYSA-N Cc(cc1)ccc1S(Oc(cc1)ccc1N1CCN(Cc2c(cccc3)c3ncc2)CC1)(=O)=O Chemical compound Cc(cc1)ccc1S(Oc(cc1)ccc1N1CCN(Cc2c(cccc3)c3ncc2)CC1)(=O)=O UPKVRHBRAVWSIC-UHFFFAOYSA-N 0.000 description 1
- HEVNIQOBWMMUIH-UHFFFAOYSA-N Cc(cc1)ccc1S(Oc(ccc(C=O)c1)c1OC)(=O)=O Chemical compound Cc(cc1)ccc1S(Oc(ccc(C=O)c1)c1OC)(=O)=O HEVNIQOBWMMUIH-UHFFFAOYSA-N 0.000 description 1
- ICWARSJXAPFMMW-UHFFFAOYSA-N Cc(cc1)ccc1S(Oc(ccc(CN(CC1)CCC1c1ccccc1)c1)c1OC)(=O)=O Chemical compound Cc(cc1)ccc1S(Oc(ccc(CN(CC1)CCC1c1ccccc1)c1)c1OC)(=O)=O ICWARSJXAPFMMW-UHFFFAOYSA-N 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- QWGDMFLQWFTERH-UHFFFAOYSA-N Clc(cc1)cc2c1Oc(cccc1)c1N=C2N1CCNCC1 Chemical compound Clc(cc1)cc2c1Oc(cccc1)c1N=C2N1CCNCC1 QWGDMFLQWFTERH-UHFFFAOYSA-N 0.000 description 1
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 1
- 229920002905 Colesevelam Polymers 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- XPDXVDYUQZHFPV-UHFFFAOYSA-N Dansyl Chloride Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(Cl)(=O)=O XPDXVDYUQZHFPV-UHFFFAOYSA-N 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- 229920002307 Dextran Polymers 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
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-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
- 235000010469 Glycine max Nutrition 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020751 Hypersensitivity 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
- 208000031773 Insulin resistance syndrome Diseases 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 101150013552 LDLR gene 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
- FZAGOOYMTPGPGF-UHFFFAOYSA-N Lambertine Chemical compound C1=C2C3=CC4=CC=C(OC)C(OC)=C4CN3CCC2=CC2=C1OCO2 FZAGOOYMTPGPGF-UHFFFAOYSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 108010013563 Lipoprotein Lipase Proteins 0.000 description 1
- 102100022119 Lipoprotein lipase Human genes 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- DJJNYEXRPRQXPD-UHFFFAOYSA-N N#Cc(cc1)ccc1N1CCNCC1 Chemical compound N#Cc(cc1)ccc1N1CCNCC1 DJJNYEXRPRQXPD-UHFFFAOYSA-N 0.000 description 1
- SUKXKLNDBLNTSW-UHFFFAOYSA-N N-(4-hydroxycyclohexyl)-6-phenylhexanamide Chemical compound OC1CCC(CC1)NC(CCCCCC1=CC=CC=C1)=O SUKXKLNDBLNTSW-UHFFFAOYSA-N 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- LIMFPAAAIVQRRD-BCGVJQADSA-N N-[2-[(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-yl]-8-[(2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl]-5-propan-2-ylisoquinolin-3-amine Chemical compound F[C@H]1CN(CC[C@H]1OC)C1=NC=CC(=N1)NC=1N=CC2=C(C=CC(=C2C=1)C(C)C)N1[C@@H]([C@H](C1)CS(=O)(=O)C)C LIMFPAAAIVQRRD-BCGVJQADSA-N 0.000 description 1
- POFVJRKJJBFPII-UHFFFAOYSA-N N-cyclopentyl-5-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-methyl-1,3-thiazol-2-amine Chemical compound C1(CCCC1)NC=1SC(=C(N=1)C)C1=NC(=NC=C1F)NC1=NC=C(C=C1)CN1CCN(CC1)CC POFVJRKJJBFPII-UHFFFAOYSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- XMWFMEYDRNJSOO-UHFFFAOYSA-N O=C(N1CCOCC1)Cl Chemical compound O=C(N1CCOCC1)Cl XMWFMEYDRNJSOO-UHFFFAOYSA-N 0.000 description 1
- MGCGJBXTNWUHQE-UHFFFAOYSA-N O=Cc1c(cccc2)c2ncc1 Chemical compound O=Cc1c(cccc2)c2ncc1 MGCGJBXTNWUHQE-UHFFFAOYSA-N 0.000 description 1
- FYBWRAXKYXTOQC-UHFFFAOYSA-N O=Cc1ccc(-c2ccc[s]2)[s]1 Chemical compound O=Cc1ccc(-c2ccc[s]2)[s]1 FYBWRAXKYXTOQC-UHFFFAOYSA-N 0.000 description 1
- MJWVCJUSRGLHFO-UHFFFAOYSA-N O=S(C1CCCCC1)(Cl)=O Chemical compound O=S(C1CCCCC1)(Cl)=O MJWVCJUSRGLHFO-UHFFFAOYSA-N 0.000 description 1
- RWCNTLMXZISAQA-UHFFFAOYSA-N O=S(c1ccccc1)(c1c(CN(CC2)CCN2c2ncccc2)cccc1)=O Chemical compound O=S(c1ccccc1)(c1c(CN(CC2)CCN2c2ncccc2)cccc1)=O RWCNTLMXZISAQA-UHFFFAOYSA-N 0.000 description 1
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 206010035148 Plague Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 206010074268 Reproductive toxicity Diseases 0.000 description 1
- 206010039020 Rhabdomyolysis Diseases 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 238000010818 SYBR green PCR Master Mix Methods 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 206010040914 Skin reaction Diseases 0.000 description 1
- 229940123185 Squalene epoxidase inhibitor Drugs 0.000 description 1
- 229940123495 Squalene synthetase inhibitor Drugs 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- OJFKUJDRGJSAQB-UHFFFAOYSA-N TAK-632 Chemical compound C1=C(NC(=O)CC=2C=C(C=CC=2)C(F)(F)F)C(F)=CC=C1OC(C(=C1S2)C#N)=CC=C1N=C2NC(=O)C1CC1 OJFKUJDRGJSAQB-UHFFFAOYSA-N 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
- PQECCKIOFCWGRJ-UHFFFAOYSA-N Tetrahydro-berberine Natural products C1=C2C3CC4=CC=C(OC)C(O)=C4CN3CCC2=CC2=C1OCO2 PQECCKIOFCWGRJ-UHFFFAOYSA-N 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical group ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- YEPRCPIKTUGVHG-UHFFFAOYSA-N [O-][N+](c1ccc(N2CCNCC2)nc1)=O Chemical compound [O-][N+](c1ccc(N2CCNCC2)nc1)=O YEPRCPIKTUGVHG-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000007488 abnormal function Effects 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 238000011374 additional therapy Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- QBYJBZPUGVGKQQ-SJJAEHHWSA-N aldrin Chemical compound C1[C@H]2C=C[C@@H]1[C@H]1[C@@](C3(Cl)Cl)(Cl)C(Cl)=C(Cl)[C@@]3(Cl)[C@H]12 QBYJBZPUGVGKQQ-SJJAEHHWSA-N 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005236 alkanoylamino group Chemical group 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 125000005262 alkoxyamine group Chemical group 0.000 description 1
- 125000004947 alkyl aryl amino group Chemical group 0.000 description 1
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 1
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 description 1
- 229940087168 alpha tocopherol Drugs 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
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001708 anti-dyslipidemic effect Effects 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000005251 aryl acyl group Chemical group 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000000732 arylene group Chemical group 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
- 238000003556 assay Methods 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- FYBWCLKVKGHJKS-UHFFFAOYSA-L berberine sesquihydrate sulfate Chemical compound O.O.O.[O-]S([O-])(=O)=O.C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2.C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 FYBWCLKVKGHJKS-UHFFFAOYSA-L 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 229940076810 beta sitosterol Drugs 0.000 description 1
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 1
- 235000013734 beta-carotene Nutrition 0.000 description 1
- 239000011648 beta-carotene Substances 0.000 description 1
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 description 1
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 description 1
- 229960002747 betacarotene Drugs 0.000 description 1
- 229960003237 betaine Drugs 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
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000872 buffer Substances 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
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- VZTUIEROBZXUFA-UHFFFAOYSA-N canadine Chemical compound C1=C2C3CC4=CC=C(OC)C(OC)=C4CN3CCC2=CC2=C1OCO2 VZTUIEROBZXUFA-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 229960004203 carnitine Drugs 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000007248 cellular mechanism Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 229940107218 chromium Drugs 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 235000012721 chromium Nutrition 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- FDJOLVPMNUYSCM-UVKKECPRSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(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-2,7, Chemical compound [Co+3].N#[C-].C1([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)[N-]\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 FDJOLVPMNUYSCM-UVKKECPRSA-L 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 235000017471 coenzyme Q10 Nutrition 0.000 description 1
- 229940110767 coenzyme Q10 Drugs 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 229960001152 colesevelam Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 229940126179 compound 72 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 238000011262 co‐therapy Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000005138 cryopreservation Methods 0.000 description 1
- 235000012754 curcumin Nutrition 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 229940109262 curcumin Drugs 0.000 description 1
- 150000001913 cyanates Chemical class 0.000 description 1
- 229960002104 cyanocobalamin Drugs 0.000 description 1
- 235000000639 cyanocobalamin Nutrition 0.000 description 1
- 239000011666 cyanocobalamin Substances 0.000 description 1
- 125000004367 cycloalkylaryl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- CHVJITGCYZJHLR-UHFFFAOYSA-N cyclohepta-1,3,5-triene Chemical compound C1C=CC=CC=C1 CHVJITGCYZJHLR-UHFFFAOYSA-N 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
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- GJYVZUKSNFSLCL-UHFFFAOYSA-N dichloromethanol Chemical compound OC(Cl)Cl GJYVZUKSNFSLCL-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- BJXYHBKEQFQVES-NWDGAFQWSA-N enpatoran Chemical compound N[C@H]1CN(C[C@H](C1)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BJXYHBKEQFQVES-NWDGAFQWSA-N 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-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
- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 125000005313 fatty acid group Chemical group 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 208000001130 gallstones Diseases 0.000 description 1
- 235000004611 garlic Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 229940087603 grape seed extract Drugs 0.000 description 1
- 235000002532 grape seed extract Nutrition 0.000 description 1
- 235000009569 green tea Nutrition 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 125000005253 heteroarylacyl group Chemical group 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 208000020346 hyperlipoproteinemia Diseases 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 208000017169 kidney disease Diseases 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
- 230000003902 lesion Effects 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007056 liver toxicity Effects 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 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
- 239000003550 marker Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229950008446 melinamide Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 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
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- OPECTNGATDYLSS-UHFFFAOYSA-N naphthalene-2-sulfonyl chloride Chemical compound C1=CC=CC2=CC(S(=O)(=O)Cl)=CC=C21 OPECTNGATDYLSS-UHFFFAOYSA-N 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 150000002814 niacins Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 238000013116 obese mouse model Methods 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
- 239000012053 oil suspension Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000006014 omega-3 oil Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 229960003104 ornithine 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
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- IVMHDOBGNQOUHO-UHFFFAOYSA-N oxathiane Chemical compound C1CCSOC1 IVMHDOBGNQOUHO-UHFFFAOYSA-N 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
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229960002797 pitavastatin Drugs 0.000 description 1
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 125000005592 polycycloalkyl group Polymers 0.000 description 1
- 229920001601 polyetherimide Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960003912 probucol Drugs 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
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- BBNQQADTFFCFGB-UHFFFAOYSA-N purpurin Chemical compound C1=CC=C2C(=O)C3=C(O)C(O)=CC(O)=C3C(=O)C2=C1 BBNQQADTFFCFGB-UHFFFAOYSA-N 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 229940026314 red yeast rice Drugs 0.000 description 1
- 239000002461 renin inhibitor Substances 0.000 description 1
- 229940086526 renin-inhibitors Drugs 0.000 description 1
- 230000007696 reproductive toxicity Effects 0.000 description 1
- 231100000372 reproductive toxicity Toxicity 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 229960000672 rosuvastatin Drugs 0.000 description 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 1
- 229940109850 royal jelly Drugs 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol 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)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
- 229950005143 sitosterol Drugs 0.000 description 1
- 231100000430 skin reaction Toxicity 0.000 description 1
- 230000035483 skin reaction Effects 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000007863 steatosis Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 150000005691 triesters Chemical class 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 108010002139 very low density lipoprotein triglyceride Proteins 0.000 description 1
- 231100000925 very toxic Toxicity 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 235000019158 vitamin B6 Nutrition 0.000 description 1
- 239000011726 vitamin B6 Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000001717 vitis vinifera seed extract Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- LQUPKVMEAATBSL-UHFFFAOYSA-L zinc;2,3,4-trichlorophenolate Chemical compound [Zn+2].[O-]C1=CC=C(Cl)C(Cl)=C1Cl.[O-]C1=CC=C(Cl)C(Cl)=C1Cl LQUPKVMEAATBSL-UHFFFAOYSA-L 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- 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
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
- C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
- C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D267/20—[b, f]-condensed
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D471/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
Definitions
- the present technology relates to the treatment of hyperlipidemia (including hypertriglyceridemia and hypercholesterolemia), hepatic steatosis, type II diabetes, hyperglycemia, insulin resistance, obesity, metabolic syndrome and Uses, compounds and compositions in anti-tumor.
- hyperlipidemia including hypertriglyceridemia and hypercholesterolemia
- hepatic steatosis hepatic steatosis
- type II diabetes hepatic steatosis
- hyperglycemia hepatic steatosis
- insulin resistance obesity
- metabolic syndrome Uses, compounds and compositions in anti-tumor.
- Metabolic Syndrome is a pathological state in which a variety of metabolic components are abnormally aggregated. It is a complex metabolic disorder syndrome and is a risk factor for diabetes and cardiovascular and cerebrovascular diseases.
- Cardio-cerebral vascular disease is the number one killer of human health. Its cause is very complicated. Hyperlipidemia is regarded as a very important risk factor by most people. With the improvement of living standards and the acceleration of aging, hyperlipidemia The incidence and mortality of the disease increased significantly, and there are reports in the literature that dyslipidemia is the main cause of atherosclerosis, coronary heart disease, and myocardial infarction.
- Hyperlipidemia is often explained by the fact that fat metabolism or abnormal function causes one or more lipids in plasma to be above normal. Hyperlipidemia is a systemic disease, usually referred to as serum total cholesterol (TC), triglyceride (TG) or high density lipoprotein cholesterol (HDL-C) is too low, modern medicine called dyslipidemia . Lipids are insoluble or sparingly soluble in water, so they must bind to proteins to form lipoproteins. Therefore, hyperlipidemia is also commonly referred to as hyperlipoproteinemia.
- TC serum total cholesterol
- TG triglyceride
- HDL-C high density lipoprotein cholesterol
- Hyperlipidemia and cerebral infarction The increase of cholesterol in the blood is easy to form atherosclerotic plaque. When these plaques accumulate in the arterial wall, the arterial cavity will be narrowed, and the blood will flow into the corresponding part, which will cause kinetic energy defect. When it occurs in the cerebral blood vessels, it can cause cerebral infarction. Medical evidence: long-term lipid-lowering treatment can not only treat cerebral infarction, but also prevent cerebral infarction.
- Coronary heart disease is also known as coronary atherosclerotic heart disease. Coronary artery is the main artery that supplies blood to the heart. If too much fat is deposited, it will cause arteriosclerosis, which will hinder blood flow, cause heart ischemia, and a series of symptoms, namely coronary heart disease. There are many risk factors for coronary heart disease, such as: high blood lipids, smoking, obesity, high blood pressure, lack of physical activity, diabetes, family history of coronary heart disease, etc. Among them, high blood lipids are one of the important risk factors for coronary heart disease. Therefore, the most basic treatment for coronary heart disease is to regulate blood lipids.
- Fatty liver refers to the accumulation of fat in the liver, often accompanied by increased blood lipids.
- the incidence of fatty liver is as high as 5-10%, and about 35% of adult patients with transaminase are fatty liver. Some severe patients can develop cirrhosis. Therefore, fatty liver treatment should also be treated with lipid-lowering.
- Hyperlipidemia and diabetes Hypertension, hyperlipidemia and hyperglycemia are often referred to as “three highs” and are a major factor threatening the health of people with diabetes. The three are closely related, high blood lipids can aggravate the symptoms of diabetes, most diabetic patients with high blood lipids, more likely to cause stroke, coronary heart disease, limb necrosis, fundus lesions, kidney disease, neuropathy, etc., therefore, in addition to treatment of hyperglycemia in diabetic patients In addition, attention should be paid to regulating blood lipids, which is very important to reduce mortality and disability in diabetic patients.
- Hyperlipidemia is defined as a dyslipidemia or dyslipidemia. Usually refers to the body's blood lipid concentration is beyond the normal range. Includes triglyceride (TG), serum total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C) or low-density lipoprotein cholesterol (LDL-C) levels and high-density lipoprotein cholesterol (HDL-C) Level reduction With the in-depth study of hyperlipidemia and cardiovascular disease, people began to realize that hypolipidemicemia is very important for reducing the risk of cardiovascular disease.
- TG triglyceride
- TC serum total cholesterol
- VLDL-C very low-density lipoprotein cholesterol
- LDL-C low-density lipoprotein cholesterol
- HDL-C high-density lipoprotein cholesterol
- the blood lipid-lowering drugs commonly used in the market mainly include statins, fibrates, niacins, and bile acid sequestrants.
- Statins represent drugs: atorvastatin, simvastatin, lovastatin, pravastatin, fluvastatin, and the like. These drugs are the fastest-developing lipid-lowering drugs in recent years, mainly to inhibit the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the serum total cholesterol (TC) synthesis pathway. The activity reduces TC synthesis; increases the number of low-density lipoprotein receptors, accelerates LDL degradation, and increases HDL content, which is beneficial to the clearance and transport of TC.
- HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A
- statins the side effects are inevitable, such as: rhabdomyolysis, myositis and various enzyme activities in the liver, and some patients are not well adapted to the treatment of statins, more important The single statin treatment often does not achieve the desired results.
- the fibrates represent drugs: clofibrate, gemfibrozil, fenofibrate, etc. After long-term clinical application, these drugs have been proven to be a class of drugs that are well tolerated and have good lipid-lowering effects.
- its lipid-lowering pathway increases the activity of lipoprotein lipase, which increases the clearance of triglyceride (TG); lowers blood sugar, which makes the synthesis of glucose and free fatty acids tend to glucose. Lipid synthesis is reduced.
- Niacin represents a drug: niacin, inositol niacin, acyclovir and the like. These drugs inhibit the synthesis of glycerol by the liver mainly by inhibiting the decomposition of fat and the formation of free fatty acids. Triester (TG) and very low density lipoprotein (VLD-L) to lower blood lipids.
- TG Triester
- VLD-L very low density lipoprotein
- Inadequacies The effect of lowering blood lipids in diabetic patients is not obvious. Side effects such as: liver poisoning, high blood sugar is more obvious, and skin reactions such as skin plague and itching often occur.
- the bile acid sequestrants represent drugs: Ezetimibe, polyunsaturated fatty acids, and the like. Such lipid-lowering drugs can be classified into two types: cholesterol absorption inhibitors and polyunsaturated fatty acids.
- Cholesterol absorption inhibitor (Yibei Maibu): combined with bile acid, hinders the reabsorption of bile acid, thereby promoting the conversion of cholesterol into bile acid, which is excreted in the intestine and the drug.
- LDL low-density lipoprotein
- LDLR low-density lipoprotein receptor
- PCSK9 proprotein convertase subtilisin/kexin type 9
- PCSK9 is a serine protease that is mainly synthesized in the liver, which can reduce the amount of LDLR in hepatocytes. After binding to LDLR located on the cell surface, PCSK9 internalizes into cells and promotes LDLR degradation in lysosomes. Inhibition of PCSK9 activity increases the number of LDLRs and decreases plasma LDL levels.
- PCSK9 inhibitors are an important direction for large multinational pharmaceutical companies to develop new cardiovascular disease drugs. It is expected that these drugs will surpass statin mature lipid-lowering drugs. Large pharmaceutical companies are working hard to promote the development of PCSK9 inhibitor drugs.
- the current research work focuses on the development of biologic drugs (including protein drugs and long-chain nucleic acid drugs) (see table below), biologic drugs and small molecules. When the drug is used to treat the same disease, the biopharmaceutical is costly, and only a limited preparation method such as an injection preparation can be used. At present, no small molecule PCSK9 inhibitor has become a clinical drug candidate.
- a series of patent applications for small molecule compounds of PCSK9 inhibitors are disclosed, including WO2010075469, WO2011006000, WO2011051961, WO2011152508, WO2012090220, JP2013136572, WO2013132509, WO2013137371, WO2014017569, WO2014002105, WO2014002106, WO2014150326, WO2014150395, WO2014139008, and the like.
- the object of the present invention is to provide a compound of the formula (V), and their tautomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolism Precursor or prodrug.
- Compound of formula V is to provide a compound of the formula (V), and their tautomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolism Precursor or prodrug.
- Y is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are independently hydrogen, halo, substituted or unsubstituted silicon, amino, nitro, oxo, Thio, sulfone, cyano, carbonyl, sulfonyloxy, phosphoryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl , heteroarylalkyl, heterocyclyl or heterocyclylalkyl;
- M is a nitrogen atom, or a carbon atom
- W is a nitrogen atom, or a carbon atom
- Z is -O-, -S-, -NH-, -CR 5 R 6 -, -C(O)O-, -C(O)NR 5 -, -SO 2 O-, -SO 2 NR 5 - , -P(O)R 5 R 6 or Z is not an atom (ie, the chemical group attached to Z is directly linked by a chemical bond);
- Ring X is a 3- to 10-membered ring, and the 3- to 10-membered ring X is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein
- R' and R" are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaryl Alkyl, heterocyclic or heterocyclylalkyl,
- n 1, 2, 3;
- the present invention relates to a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, including the compound (VI) of the formula
- R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently hydrogen, halo, substituted or unsubstituted silicon, amino, nitro, oxo, Thio, sulfone, cyano, carbonyl, sulfonyloxy, phosphoryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl , heteroarylalkyl, heterocyclyl or heterocyclylalkyl;
- R 5 , R 6 , R 7 , R 8 , Z, M, q, t, ring X and ring Y are as described above.
- the present invention relates to a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, including a compound of the formula (VII),
- R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently hydrogen, halo, substituted or unsubstituted silicon, amino, nitro, oxy, sulphur , sulfone, cyano, carbonyl, sulfonyloxy, phosphoryloxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl group;
- R 5 , R 6 , R 7 , R 8 , R', R", Z, ring X, M, m, n, q, t are as described above.
- the present invention relates to the compound of the formula (VII) wherein R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently -H, halo, substituted or unsubstituted Substituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocycloalkyl base;
- R 17 , R 18 , R 19 , R 20 , R 21 are independently -H, halo, -OH, -NO 2 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R' , -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R", substituted or unsubstituted amino, alkyl, alkane Oxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, also selected from :
- R 27 is selected from phenyl, C 1-6 alkyl, cyclo(C 3-8 )alkyl, thienyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinoline , phenylethynyl, benzyl, styryl, naphthyl, substituted amino, morpholinyl, piperidinyl, N-methylpiperazinyl, tetrahydropyrrolyl, hexahydropyridyl, camphoralkyl, P-tolyl,
- C 1-6 alkyl is optionally substituted by 0 to 13 substituents
- thienyl, furyl and imidazolyl groups are optionally substituted by 0 to 3 substituents,
- the pyridyl group is optionally substituted with from 0 to 4 substituents.
- pyrimidinyl and pyridazinyl are optionally substituted by 0 to 3 substituents,
- the phenyl group is optionally substituted with from 0 to 5 substituents.
- quinolyl and isoquinolinylnaphthyl are optionally substituted with from 0 to 6 substituents,
- the naphthyl group is optionally substituted with from 0 to 7 substituents.
- substituents are selected from the group consisting of: hydroxy, halogen, cyano, nitro, silyl, -COOH, carboxylate, substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, ring
- R 28 is selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl A group, a heterocyclic group or a heterocyclic group.
- the present invention relates to a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, including a compound of the formula (VIII),
- the present invention relates to the compound of the formula (VIII), wherein R 22 , R 23 , R 24 , R 25 , R 26 are independently -H, halo, -OH, -NO 2 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R", -OC(O)OR', -OC(O)NR'R", Substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hetero A cycloalkyl or heterocyclylalkyl group, also selected from the group consisting of:
- R 27 is selected from phenyl, C 1-6 alkyl, cyclo(C 3-8 )alkyl, thienyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinoline , phenylethynyl, benzyl, styryl, naphthyl, substituted amino, morpholinyl, piperidinyl, N-methylpiperazinyl, tetrahydropyrrolyl, hexahydropyridyl, camphoralkyl, P-tolyl,
- C 1-6 alkyl is optionally substituted by 0 to 13 substituents
- thienyl, furyl and imidazolyl groups are optionally substituted by 0 to 3 substituents,
- the pyridyl group is optionally substituted with from 0 to 4 substituents.
- pyrimidinyl and pyridazinyl are optionally substituted by 0 to 3 substituents,
- the phenyl group is optionally substituted with from 0 to 5 substituents.
- quinolyl and isoquinolinylnaphthyl are optionally substituted with from 0 to 6 substituents,
- the naphthyl group is optionally substituted with from 0 to 7 substituents.
- substituents are selected from the group consisting of: hydroxy, halogen, cyano, nitro, silyl, -COOH, carboxylate, substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, ring
- R 28 is selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl A group, a heterocyclic group or a heterocyclic group.
- the present invention relates to a compound of the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, including the compound (IX) of the formula
- R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 are as described above;
- R 22 , R 23 , R 24 , R 25 , R 26 are as described above;
- R 5 , R 6 , R 7 , R 8 , M, q, t are as described above.
- the present invention relates to the compound of the formula (IX), wherein R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 are independently -H, halogen, -OH, -NO 2 , -CN, -(CH 2 ) 0-6 COOR', -C(O)R', -OC(O)R', -C(O)NR'R", -OC( O) OR', -OC(O)NR'R", substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, An aralkyl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group or a heterocyclic alkyl group, further selected from the group consisting of:
- R 27 is selected from phenyl, C 1-6 alkyl, cyclo(C 3-8 )alkyl, thienyl, furyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinoline , phenylethynyl, benzyl, styryl, naphthyl, substituted amino, morpholinyl, piperidinyl, N-methylpiperazinyl, tetrahydropyrrolyl, hexahydropyridyl, camphoralkyl, P-tolyl,
- C 1-6 alkyl is optionally substituted by 0 to 13 substituents
- thienyl, furyl and imidazolyl groups are optionally substituted by 0 to 3 substituents,
- the pyridyl group is optionally substituted with from 0 to 4 substituents.
- pyrimidinyl and pyridazinyl are optionally substituted by 0 to 3 substituents,
- the phenyl group is optionally substituted with from 0 to 5 substituents.
- quinolyl and isoquinolinylnaphthyl are optionally substituted with from 0 to 6 substituents,
- the naphthyl group is optionally substituted with from 0 to 7 substituents.
- substituents are selected from the group consisting of: hydroxy, halogen, cyano, nitro, silyl, -COOH, carboxylate, substituted or unsubstituted amino, alkyl, alkoxy, alkenyl, alkynyl, ring
- R 28 is selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl A group, a heterocyclic group or a heterocyclic group.
- the present invention relates to a compound selected from the following compounds, but is not limited to the following compound ranges:
- the present invention relates to a compound represented by the formula (V), a stereoisomer thereof, a tautomer thereof, a solvate thereof and a pharmaceutically acceptable salt thereof, wherein a preparation method comprises the steps of:
- X1 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound V;
- Another preparation method includes the following steps:
- X1 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature.
- V is prepared by reacting X1 and X3 under a certain reaction condition by reductive amination.
- the present invention relates to a compound of the formula (V), which comprises a pharmaceutical composition comprising a compound of any one and a pharmaceutically acceptable carrier.
- the present invention relates to a pharmaceutical composition consisting of a compound of the formula (V), which comprises a compound which is administered to any one of a therapeutically effective amount of a patient in need of treatment.
- the present invention relates to the use of any one of the compounds of the formula (V) for the preparation of a medicament for lowering the lipid level of a patient's plasma and/or liver.
- the present invention relates to a compound of any one of the compounds represented by the general formula (V) for use in the treatment of hyperlipemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, metabolic syndrome, antitumor drugs. the use of.
- the present invention relates to the use of any one of the compounds of the general formula (V) for the preparation of a medicament for increasing LDLR expression and/or reducing PCSK9 expression.
- the present invention relates to a compound of the formula (V), and the compounds disclosed herein have the following beneficial effects:
- the small molecule compound of the general formula (V) disclosed in the present invention is expected to be a new generation of lipid-lowering drug in inhibiting the expression of PCSK9 gene, increasing the expression of LDLR and enhancing the uptake of hepatocytes to LDL.
- PCSK9 inhibitors as lipid-lowering drugs is an important direction for large multinational pharmaceutical companies to develop new cardiovascular disease drugs. It is expected that these drugs will surpass statin mature lipid-lowering drugs. Large pharmaceutical companies are working hard to promote the development of PCSK9 inhibitor drugs.
- biologic drugs including protein drugs and long-chain nucleic acid drugs.
- PCSK9 inhibitors have been developed. Clinical drug candidates. The following table:
- the biopharmaceutical is expensive, and only a limited preparation method such as an injection preparation can be used, and the small molecule drug has the advantages of low manufacturing cost, various preparation methods, and the like, and the present invention discloses
- the small molecule compound of the general formula (V) exhibits significant inhibition of PCSK9 gene expression at the cellular level and enhances the significant function of hepatocytes to uptake of LDL, and is expected to have a new generation of lipid-lowering drugs.
- the formulation of small molecule drugs is more extensive than that of biomacromolecules, which is conducive to the development of a variety of drug formulations for later drug development. Compared to biomacromolecular drugs, it can be provided for a wide range of formulation types. satisfy people's demands.
- the compound of the general formula (V) disclosed in the present invention has a novel structure and a novel structural feature, and is expected to have a novel effect on PCSK9, compared with a compound disclosed in the prior patent document which is a target of PCSK9.
- the candidate drug of the mechanism and eventually become a new generation of lipid-lowering drugs with a novel mechanism of action.
- Patent Application WO2014139008 reports a class of small molecule compounds, some of which are mainly characterized by the inclusion of "borate and boric acid” structural fragments, although multiple bone marrows are currently available.
- Tumor treatment drug - bortezomib containing “boric acid” structural fragments
- the application of "boric acid” drugs in non-tumor treatment areas is still limited, mainly because Potential neurotoxic side effects of boron drugs, as well as their potential for "irreversible binding" to biological organisms (Chem. Res. Toxicol., 2013, 26(4), pp 608-615), the chemical properties of the drug
- the potential “carcinogenicity” that may be caused by molecular design, “reproductive toxicity” has been widely recognized by pharmaceutical chemists.
- the compound of the formula (V) disclosed in the present invention has novel structure and novel unique structural features, and indicates that the compound disclosed in the present invention
- the novel molecular structure features may bring unexpected "drug-like characteristics", and it is expected to become a candidate drug with a novel mechanism of action for PCSK9, and eventually become a new generation of lipid-lowering drugs with novel mechanism of action.
- the compound of the formula (V) disclosed in the invention has the advantages that the raw materials are easy to obtain, the preparation process is simple, and the cost is low.
- the small molecule compound of the formula (V) disclosed in the present invention is mainly prepared by using a commercially available intermediate, and then subjected to a fragment coupling reaction by a simple chemical reaction.
- a commercially available starting material having a functional group such as "amine”, “aldehyde” or “halogenated hydrocarbon” can be used to prepare a target compound by one-step chemical reaction. Therefore, the compound of the formula (V) disclosed in the present invention has the advantages that the raw materials are easily available, the preparation process is simple, and the cost is low.
- the compound of the general formula (V) disclosed in the present invention has the activity of activating AMPK kinase, suggesting that the compound of the present invention can not only be developed into a new generation of lipid-lowering drugs, but also can play a role in controlling blood sugar, and is a comprehensive metabolic synthesis.
- the comprehensive benefits of patients with lipid-lowering and hypoglycemic agents are more advantageous than the existing single-acting drugs.
- X1 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound V;
- Another preparation method includes the following steps:
- X1 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature.
- V is prepared by reacting X1 and X3 under a certain reaction condition by reductive amination.
- X4 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X4 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound VI;
- Another preparation method includes the following steps:
- X4 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VI is prepared by reacting X4 and X3 under a certain reaction condition by reductive amination.
- a compound represented by the formula (VII) of the present invention, a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof, wherein one of the preparations includes the following steps:
- X5 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound VII;
- Another preparation method includes the following steps:
- X5 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VII is obtained by reacting X5 and X3 under a certain reaction condition by reductive amination.
- X1 and X6 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X6 at a certain reaction temperature, in the presence of a certain alkaline reagent, by coupling to obtain compound VIII;
- Another preparation method includes the following steps:
- X1 and X7 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VIII is prepared by reacting X1 and X7 under a certain reaction condition by reductive amination.
- X5 and X8 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X8 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound IX;
- Another preparation method includes the following steps:
- X5 and X9 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X9 are prepared by a reductive amination reaction under certain reaction conditions to obtain IX.
- Figure 1 shows the effect of the fluorescence intensity observed under the microscope on the ability of the sample to take up LDL by hepatocytes after compound treatment.
- Fig. 2 is a graph showing the comparison of serum low-density lipoprotein cholesterol (LDL-C) in high-fat SD rats after oral administration of some of the compounds of the present invention for four weeks.
- LDL-C serum low-density lipoprotein cholesterol
- Fig. 3 shows a comparison of the results of determination of total cholesterol (TC) in serum of a high-fat SD rat after oral administration of a part of the compound of the present invention for four weeks.
- Figure 4 is a graph showing the comparison of serum alanine aminotransferase (ALT) levels in high-fat SD rats after oral administration of some of the compounds of the present invention for four weeks.
- Fig. 5 is a graph showing the comparison of the results of serum aspartate aminotransferase (AST) in high-fat SD rats after oral administration of some of the compounds of the present invention for four weeks.
- AST serum aspartate aminotransferase
- the present technology provides novel compounds, and the use of the compounds in reducing plasma and/or liver lipid levels, as well as in the treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, Uses in hepatic steatosis, type 2 diabetes, hyperglycemia, insulin resistance, obesity, and metabolic syndrome.
- the compounds provided herein can be formulated into pharmaceutical compositions and medicaments for use in the methods disclosed herein.
- the invention also provides the use of the compound for the preparation of a pharmaceutical formulation and a medicament, the use of the compound for lowering lipid levels in plasma and/or liver, and the compound in the treatment of hyperlipidemia, hypercholesterolemia Use in disease, hypertriglyceridemia, hepatic steatosis, type 2 diabetes, hyperglycemia, insulin resistance, obesity, and metabolic syndrome.
- an element such as hydrogen or H
- R group is defined to include hydrogen or H, it also includes ruthenium and osmium.
- Compound comprises a radioisotope (e.g., tritium, C 14, P 32 and S 35) is therefore also within the scope of the present invention. Means for inserting such markers into the compounds of the invention will be apparent to those skilled in the art based on the disclosure herein.
- substituted means an organic group (e.g., an alkyl group) as defined below wherein one or more hydrogen-bonded bonds are replaced by a bond to a non-hydrogen atom or a non-carbon atom.
- Substituted groups also include groups in which one or more bonds to a carbon or hydrogen atom are replaced by one or more bonds (including double or triple bonds) linking the heteroatoms.
- a substituted group is substituted with one or more substituents. In some embodiments, the substituent is substituted with 1, 2, 3, 4, 5 or 6 substituents.
- substituents examples include halogen (i.e., F, Cl, Br, and I), a hydroxyl group, an alkoxy group, an alkenyloxy group, an aryloxy group, an aralkyloxy group, a heterocyclic oxygen group, and a heterocyclic alkoxy group.
- halogen i.e., F, Cl, Br, and I
- a hydroxyl group an alkoxy group, an alkenyloxy group, an aryloxy group, an aralkyloxy group, a heterocyclic oxygen group, and a heterocyclic alkoxy group.
- Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclic, and heteroaryl, also include ring and ring systems in which a bond to a hydrogen atom is replaced by a bond to a carbon atom.
- the substituted cycloalkyl, aryl, heterocyclic and heteroaryl groups may also be substituted by substituted or unsubstituted alkyl, alkenyl and alkynyl groups as defined below.
- the alkyl group includes a linear or branched group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 12 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,
- lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
- the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ring Alkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -C(O)R', -C(O)OR', -S(O) m R', - NR'R", -C(O)NR'R", -NR'C(O)R", -NR'S(O) m R" or -S(O) m NR'R".
- a cycloalkylalkyl group means an alkyl group substituted with a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, and the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 Up to 10 carbon atoms.
- Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
- a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
- Alkenyl refers to an unsaturated alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- Butyl group and the like.
- the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, -C(O)R', -C(O)OR', -S(O) m R', -NR'R", -C(O)NR'R", -NR'C (O) R", -NR'S(O) m R" or -S(O) m NR'R".
- Cycloalkenyl refers to an unsaturated cycloalkyl group as defined above having at least one double bond between two carbon atoms.
- a cycloalkenyl group can have one, two or three double bonds but does not include an aromatic compound.
- the cycloalkenyl group contains 4 to 14 carbon atoms or, in some embodiments, 5 to 14 carbon atoms, preferably 5 to 10 carbon atoms, more preferably 5, 6, 7 or 8 carbon atoms.
- Examples of the cycloalkenyl group include a cyclohexenyl group, a cyclopentenyl group, a cyclohexadienyl group, a butadienyl group, a pentadienyl group, and a hexadienyl group.
- alkynyl group means an unsaturated alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like.
- the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, -C(O)R', -C(O)OR', -S(O) m R', -NR'R", -C(O)NR'R", -NR'C (O) R", -NR'S(O) m R" or -S(O) m NR'R".
- the aryl group is a cyclic aromatic hydrocarbon containing no hetero atoms.
- Aryl groups include monocyclic, bicyclic, and tricyclic systems herein.
- aryl groups include, but are not limited to, phenyl, methoxyheptyl, diphenyl, indenyl, phenanthryl, anthracenyl, fluorenyl, indanyl, cyclopentadienyl, and naphthyl.
- the aryl group contains 6-14 carbons, preferably 6 to 12, more preferably 6-10 carbon atoms in the ring portion of the group.
- the aryl group is phenyl or naphthyl.
- aryl includes groups containing a fused ring (eg, a fused aromatic-aliphatic ring system) (eg, indanyl, tetrahydronaphthyl, and the like), it does not include having members with rings
- An aryl group of one of the other groups bonded for example, an alkyl group or a halogenated group.
- a group such as a tolyl group is referred to as a substituted aryl group.
- Representative substituted aryl groups can be monosubstituted or substituted more than once.
- monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5- or 6-substituted phenyl or naphthyl groups, which may be substituted, for example, with the substituents listed above.
- Aralkyl is an alkyl group as defined above wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined above.
- the aralkyl group contains from 7 to 16 carbon atoms, preferably from 7 to 14 carbon atoms, more preferably from 7 to 10 carbon atoms.
- the substituted aralkyl group may be substituted at the alkyl group, the aryl group, or both the alkyl group and the aryl moiety.
- Representative aralkyl groups include, but are not limited to, benzyl and phenethyl and fused (cycloalkylaryl)alkyl (eg, 4-indolylethyl).
- Representative substituted aralkyl groups can be substituted one or several times with, for example, the substituents listed above.
- Heterocyclyl includes aromatic (also referred to as heteroaryl) and non-aromatic cyclic compounds containing three or more ring members, wherein one or more of the ring members are heteroatoms such as, but not limited to, N. , O and S.
- a heterocyclic group contains 1, 2, 3 or 4 heteroatoms.
- heterocyclyl includes mono, di, and tricyclic rings having from 3 to 16 ring members.
- Heterocyclyl groups include aromatic, partially unsaturated and saturated ring systems such as imidazolyl, imidazolinyl and imidazolidinyl.
- heterocyclyl includes fused ring species, including those containing fused aromatic and non-aromatic groups, such as benzotriazolyl, 2,3-dihydrobenzo[1,4]. Dioxoalkyl and benzo[1,3]dioxolyl.
- the phrase also includes bridged polycyclic systems containing heteroatoms such as, but not limited to, quinuclidinyl. However, the phrase does not include heterocyclic groups having other groups (eg, alkyl, oxo or halo groups) bonded to one of the ring members.
- Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, Furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl , thiazolinyl, isothiazolyl, thiadiazo, oxadiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetra
- substituted heterocyclic groups may be monosubstituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5- or 6-substituted or substituted by various substituents such as those listed above A disubstituted pyridyl or morpholinyl group.
- a heteroaryl group is an aromatic ring compound containing five or more ring member atoms, wherein one or more ring members are heteroatoms such as, but not limited to, N, O and S.
- Heteroaryl groups include, but are not limited to, the following groups, for example, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl , pyrazinyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, fluorenyl, azaindolyl (pyrrolopyridinyl), oxazolyl, benzimidazolyl, Imidazopyridyl (azabenzimidazolyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzox
- Heteroaryl groups include fused ring compounds in which all of the rings are aromatic, such as fluorenyl groups, which also include fused ring compounds in which only one ring is aromatic, such as 2,3-dihydroindenyl.
- heteroaryl includes fused ring compounds, the phrase does not include heteroaryl groups having other groups (eg, alkyl groups) bonded to one of the ring members.
- a heteroaryl group having such a substitution is referred to as a "substituted heteroaryl group.”
- Representative substituted heteroaryl groups can be substituted one or several times with, for example, the various substituents listed above.
- Heterocyclylalkyl is an alkyl group as defined above, but wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to a heterocyclic group as defined above.
- the substituted heterocyclic alkyl group may be substituted at the alkyl group or the heterocyclic group or at both the alkyl group and the heterocyclic group.
- Representative heterocyclylalkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazole-4- Base-methyl, pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl and ind-2-yl-propyl.
- Representative substituted heterocyclylalkyl groups can be substituted one or several times with, for example, the substituents listed above.
- Heteroarylalkyl is an alkyl group as defined above wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined above.
- the substituted heteroarylalkyl group may be substituted at the alkyl or heteroaryl portion or at both the alkyl and heteroaryl portions.
- Representative substituted heteroarylalkyl groups can be substituted one or several times with, for example, the substituents listed above.
- the groups described herein having two or more points of attachment are designated by the prefix "sub".
- the divalent alkyl group is an alkylene group
- the divalent aryl group is an arylene group
- the divalent heteroaryl group is a heteroarylene group, and the like.
- Substituted groups having a single point of attachment to a compound of the invention do not use a "sub" designation.
- chloroethyl is not referred to herein as chloroethylene.
- An oxo group means a substituent group formed by linking with an oxygen atom, wherein the group bonded to the oxygen atom is a substituted or unsubstituted alkyl group, an aryl group, a heteroaryl group, a cycloalkyl group, an alkyl group. , aryl acyl, heteroaryl acyl.
- the above group may be bonded to an oxygen atom to form an alkoxy group, an aryloxy group, a heteroaryloxy group, a cycloalkyloxy group, an alkyl acyloxy group, an aryl acyloxy group, a heteroaryl acyloxy group, and a ring.
- Alkyl acyloxy Alkyl acyloxy.
- the alkoxy group is a substituent in which a bond to a hydrogen atom in a hydroxyl group (-OH) is replaced by a bond to a carbon atom of the substituted or unsubstituted alkyl group defined above.
- linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like.
- branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy and the like.
- cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
- Representative substituted alkoxy groups can be substituted one or several times with, for example, the substituents listed above.
- alkanoyl and “alkanoyloxy” as used herein mean -C(O)-alkyl and -O-C(O)-alkyl, respectively, each of which contains from 2 to 5 carbon atoms.
- aryloxy and arylalkoxy mean, respectively, a substituent formed by bonding a substituted or unsubstituted aryl group to an oxygen atom, a substituted or unsubstituted aralkyl group and an oxygen atom.
- a substituent formed by bonding examples include, but are not limited to, phenoxy, naphthyloxy, and benzyloxy.
- Representative substituted aryloxy and arylalkoxy groups can be substituted one or several times with, for example, the substituents listed above.
- carboxylic acid refers to a -COOH group.
- Carboxylate refers to a -COOR' group.
- R' is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclic group as defined herein.
- amide includes both C-amide and N-amide groups, i.e., -C(O)NR'R” and -NR'C(O)R” groups, respectively.
- R' and R" are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocycle as defined herein.
- the amide group thus includes, but is not limited to, a carbamoyl group (-C(O)NH 2 ) and a carboxamide group (-NHC(O)H).
- the amide is -NR'C(O) -(C 1-5 alkyl), this group is referred to as "carbonylamino", in other embodiments, the amide is -NHC(O)-alkyl, the group is referred to as "alkanoylamino" .
- nitrile or "cyano” as used herein refers to a -CN group.
- Carbamates include N-carbamate groups and O-carbamate groups, i.e., -NR'C(O)OR” and -OC(O)NR'R” groups, respectively.
- R' and R" are independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group, as defined herein.
- R' can also be H.
- amine refers to a radical -NR'R", wherein R' and R" are, independently, hydrogen or substituted or unsubstituted alkyl, as defined herein, Alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclic.
- the amine is an alkylamino, dialkylamino, arylamino or alkylarylamino group.
- the amine is NH 2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino or benzylamino.
- sulfonamide includes both S-sulfonamide groups and N-sulfonamide groups, i.e., -SO 2 NR'R" and -NR'SO 2 R” groups, respectively.
- R' and R" are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocycle as defined herein.
- the sulfonamide group thus includes, but is not limited to, a sulfonyl group (-SO 2 NH 2 ).
- the sulfonamide is -NHSO 2 -alkyl, which is referred to as "alkylsulfonylamino" .
- thiol refers to the -SH group, while the sulfide includes the -SR' group, the sulfoxide includes the -S(O)R' group, the sulfone includes the -SO 2 R' group, and the sulfonyloxy group includes -OSO 2 R', the sulfonic acid oxy group includes -OSO 2 OR'.
- R' is independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl group, as defined herein.
- the sulfide is an alkyl thiol group, -S-alkyl.
- urea refers to a -NR'-C(O)-NR'R” group.
- the R' and R" groups are independently hydrogen or substituted or unsubstituted alkyl, alkenyl as defined herein. , alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl.
- ⁇ refers to -C(NR')NR'R" and -NR'C(NR')R", wherein R' and R" are each independently hydrogen as defined herein or substituted or not Substituted alkyl, cycloalkyl, alkenyl, alkynyl, arylarylalkyl, heterocyclyl or heterocyclylalkyl.
- ⁇ refers to -NR'C(NR')NR'R", wherein R' and R" are each independently hydrogen or substituted or unsubstituted alkyl, cycloalkyl, as defined herein, Alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl.
- halo refers to bromo, chloro, fluoro or iodo. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.
- hydroxy refers to -OH, or may be an ionized form as used herein -O -.
- imide refers to -C(O)NR'C(O)R", wherein R' and R" are each independently hydrogen or substituted or unsubstituted alkyl, ring, as defined herein. Alkyl, alkenyl, alkynyl, arylarylalkyl, heterocyclyl or heterocyclylalkyl.
- nitrogen-containing heterocyclic group refers to a ring system containing a nitrogen atom which may "couple” aromatic and non-aromatic ring systems, or link other ring systems through “spirocarbon atoms", such as the following structure:
- the term "imine” refers to a -CR' (NR") and -N (CR'R”) group, wherein R' and R" are each independently hydrogen or substituted or unsubstituted as defined herein.
- An alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an arylarylalkyl group, a heterocyclic group or a heterocyclic alkyl group, and satisfies: R' and R" are not hydrogen at the same time.
- nitro means -NO 2 when used herein.
- trifluoromethyl refers to a -CF 3.
- salts of the compounds described herein are within the scope of the invention and include such acid addition or base addition salts which retain the desired pharmacological activity and are not biologically potential Poor effects (eg, salts are not excessively toxic, sensitizing or irritating, and are bioavailable).
- the compound of the present invention has a basic group (for example, an amino group), it can be combined with a mineral acid (for example, hydrochloric acid, borohydride, nitric acid, sulfuric acid, and phosphoric acid), an organic acid (for example, alginate, formic acid, acetic acid, benzoic acid, Gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and p-toluenesulfonic acid) or acidic amino acids (eg aspartame)
- a mineral acid for example, hydrochloric acid, borohydride, nitric acid, sulfuric acid, and phosphoric acid
- an organic acid for example, alginate, formic acid, acetic acid, benzoic acid, Gluconic acid, fumaric
- the compound of the present invention When the compound of the present invention has an acidic group such as a carboxylic acid group, it can be combined with a metal such as an alkali metal and an alkaline earth metal (for example, Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ) ), ammonia or organic amines (such as dicyclohexylamine, trimethylamine, triethylamine, pyridine, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (such as arginine, lysine and ornithine) ) form a salt.
- a metal such as an alkali metal and an alkaline earth metal (for example, Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ )
- ammonia or organic amines such as dicyclohexylamine, trimethylamine, triethylamine, pyridine, ethanolamine,
- the compounds of the invention may exhibit tautomerism, conformational isomerism, geometric isomerism and/or stereoisomerism.
- formulae in the specification and claims represent only one of the possible tautomeric, conformational, stereoisomeric or geometric isomeric forms, it is to be understood that the invention includes a compound having one of the ones described herein or Any tautomeric, conformational, stereoisomeric, and/or geometric isomeric form for a variety of uses, as well as mixtures of these various forms.
- Stereoisomers of the compounds including all chiral, diastereomeric and racemic forms of the structure, unless explicitly indicated for stereochemistry.
- compounds useful in the present invention include optical isomers that are enriched or resolved at any or all of the asymmetric atoms. Racemic and diastereomeric mixtures, as well as optical isomers, may be isolated or synthesized to be substantially free of their corresponding isomers or diastereomers, and these stereoisomers are also Within the scope of the invention.
- the compounds of the invention may exist as solvates, especially as hydrates.
- the hydrate can be formed during the manufacture of the compound or composition comprising the compound, or the hydrate can be formed over time due to the hygroscopic nature of the compound.
- the compounds of the invention may also exist as organic solvates, including ethers and alcohol solvates, and the like. Identification and preparation of any particular solvate is known to those of ordinary skill in the art of synthetic organic or pharmaceutical chemistry.
- Lipids include both synthetic and naturally occurring fat-soluble compounds, including both neutral and amphiphilic molecules.
- Amphoteric lipids typically comprise a hydrophilic component and a hydrophobic component.
- Exemplary lipid package include fatty acids, triglycerides, neutral fats, phospholipids, glycolipids, fatty alcohols, waxes, hydrazines, steroids such as cholesterol, and surfactants.
- Lipid-lowering agent refers to a compound that has one or more of the following effects when administered to a patient: increased liver expression of LDLR; increased half-life of LDLR mRNA in hepatocytes; increased liver to plasma LDL, cholesterol Or uptake of triglycerides; enhance fatty acid oxidation in the liver, reduce triglyceride synthesis and secretion in the liver, and lower total cholesterol, LDL-cholesterol, VLDL-cholesterol or triglyceride levels in plasma and/or liver.
- the lipid reducing agents disclosed herein include the compounds of the invention.
- the invention provides the use of a compound of the invention for the manufacture of a medicament for lowering lipid levels in a patient's plasma and/or liver, comprising administering to said patient a reduced effective amount of a compound as described herein or combination.
- the reduced lipid level may be one or more of total cholesterol, LDL-cholesterol (LDL-C), triglyceride (TG), and unesterified long-chain fatty acids.
- the compounds and compositions described herein are useful for the prevention or treatment of diseases including, for example, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver (hepatic steatosis), type 2 diabetes, hyperglycemia Disease, obesity or insulin resistance and metabolic syndrome.
- a method of treatment comprises administering to a subject in need of treatment a therapeutically effective amount of a compound or composition described herein.
- the compounds of the invention are also useful in the treatment or prevention of disease states or conditions characterized by elevated plasma or hepatic cholesterol or triglycerides or associated with elevated plasma or hepatic cholesterol or triglycerides.
- the present technology also provides for the treatment or prevention of diseases using the compounds of the invention (eg, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver, type II diabetes, hyperglycemia, obesity or insulin)
- diseases eg, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver, type II diabetes, hyperglycemia, obesity or insulin
- the use of an effective amount of a drug for resistance or metabolic syndrome eg, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, fatty liver, type II diabetes, hyperglycemia, obesity or insulin.
- the compounds and compositions disclosed herein increase the stability of LDLR mRNA by increasing the LDLR mRNA stability by increasing the transcription of the LDLR gene by inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9). ) mediated degradation of LDLR proteins or all of the above possible cellular mechanisms to reduce lipid levels.
- Increased levels of LDLR in the liver increase uptake and processing of plasma LDL-C, resulting in decreased plasma levels of cholesterol, LDL-C, and triglycerides.
- compounds can increase phosphorylation of acetyl CoA carboxylase (ACC) by activating AMP-activated protein kinase (AMPK), a key molecule of bioenergy metabolism regulation.
- ACC acetyl CoA carboxylase
- AMPK AMP-activated protein kinase
- Increased phosphorylation of ACC enhances fatty acid oxidation in the liver, resulting in reduced TG accumulation in the liver and TG secretion in VLDL, which also helps reduce TG, LDL-C, total cholesterol, and unesterified long chains. Plasma levels of fatty acids, thereby preventing or treating diseases associated with hyperlipidemia.
- AMPK is essential for the body to maintain glucose balance, and that compounds can ultimately treat type 2 diabetes, hyperglycemia, obesity or insulin resistance or metabolism by activating AMPK. Syndrome.
- the compounds provided herein have the use of increasing LDLR expression comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition described herein, thereby increasing LDLR in said subject expression.
- the invention provides a use of a compound of the invention to reduce plasma LDL-cholesterol and/or plasma triglycerides, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein or The composition thereby reducing plasma LDL-cholesterol in the patient.
- the invention provides a lipid lowering agent comprising a compound and a composition thereof.
- the compounds and compositions are useful in the methods and treatments of reducing lipids described herein.
- the invention provides a compound of formula V, a stereoisomer thereof, a tautomer thereof, a solvate thereof, and/or a pharmaceutically acceptable salt thereof.
- the present technology provides pharmaceutical compositions and medicaments comprising any of the compounds disclosed herein and a pharmaceutically acceptable carrier or one or more excipients or fillers.
- a pharmaceutical composition for treating a condition selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome is provided.
- Such compositions include a lipid reducing effective amount of any of the compounds described herein.
- the pharmaceutical composition is packaged in unit dosage form.
- the unit dosage form is effective in reducing blood lipids and/or lipid levels in the liver (eg, total cholesterol, LDL-cholesterol, triglycerides, and unesterified long-chain fatty acids) when administered to a subject in need thereof. At least one).
- blood lipids and/or lipid levels in the liver eg, total cholesterol, LDL-cholesterol, triglycerides, and unesterified long-chain fatty acids
- compositions By diluting one or more compounds of the present invention, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, dilutions Agents and the like are mixed to prepare a pharmaceutical composition to prevent or treat a condition associated with increased plasma and/or liver lipid levels.
- pharmaceutically acceptable carriers eg, hyperlipidemia, hypercholesterolemia, hepatic steatosis, and metabolic syndrome
- compositions may be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions or solutions.
- the compositions of the present invention may be formulated in a variety of forms for a variety of routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration or by implantation of a reservoir.
- Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular, injection.
- the dosage forms described below are given as examples and should not be construed as limiting the techniques of the present invention.
- the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
- Oral compositions can be prepared by any of the methods known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
- excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic and a lubricant such as magnesium stearate, stearic acid or talc.
- These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
- water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.
- an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
- a water-soluble carrier such as polyethylene
- a glycol or oil vehicle such as peanut oil, liquid paraffin or olive oil mixed soft gelatin capsules provides an oral formulation.
- the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
- excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecylethyleneoxy cetyl alcohol , or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitan monooleate, or a partial ester of ethylene oxide with a fatty acid and a hexitol anhydride Condensation products such as polyethylene oxide sorbitan
- the aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
- preservatives such as ethylparaben or n-propylparaben
- coloring agents such as ethylparaben or n-propylparaben
- flavoring agents such as sucrose, saccharin or aspartame.
- the oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
- the above sweeteners and flavoring agents may be added to provide a palatable preparation.
- These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.
- the dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweeteners, flavoring agents, and coloring agents can also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
- the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
- the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
- Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, For example, polyethylene oxide sorbitol monooleate.
- the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants.
- Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
- sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
- Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
- the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
- the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
- the active ingredient is dissolved in a mixture of soybean oil and lecithin.
- the oil solution is then added to a mixture of water and glycerin to form a microemulsion.
- the injection or microemulsion can be injected into the bloodstream of the patient by a local injection.
- the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.
- the pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
- the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension, such as a solution prepared in 1,3-butanediol, in a non-toxic parenterally acceptable diluent or solvent.
- sterile fixed oils may conveniently be employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used.
- fatty acids such as oleic acid can also be prepared as an injection.
- Dosage forms for topical (including buccal and sublingual) or transdermal administration of a compound of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches.
- the active component can be mixed under sterile conditions with apharmaceutically acceptable carrier or excipient and with any preservative or buffers which may be required.
- Powders and sprays can be prepared, for example, with excipients such as sugars, mica, silicic acid, sodium hydroxide, calcium silicates and polyamine powders or mixtures of these materials.
- Ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, waxes, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones. , bentonite, silicic acid, mica and zinc oxide or a mixture thereof.
- Absorption enhancers can also be used to increase the flow of the compounds of the invention through the skin. The rate of such flow can be controlled by providing a rate controlling membrane (e.g., as part of a transdermal patch) or by dispersing the compound in a polymer matrix or gel.
- the compounds of the invention may be administered in the form of a suppository for rectal administration.
- These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
- suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
- the compounds of the invention may also be administered with other conventional therapeutic agents useful in the treatment or prevention of hyperlipemia.
- exemplary therapeutic agents for combination therapy with one or more compounds of the invention include, but are not limited to, anti-inflammatory drugs, therapeutic antibodies, and cholesterol lowering drugs, for example, statins.
- Useful additional therapeutic agents useful in combination formulations and co-therapy include, for example, anti-hyperlipidemic agents; anti-dyslipidemic agents; anti-diabetic agents including, but not limited to, cholesterol biosynthesis inhibitors, such as HMG-CoA reductase Inhibitors (also known as statins, lovastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin, pitavastatin and atorvastatin); HMG-CoA reduction synthase inhibitors; Squalene epoxidase inhibitor or squalene synthetase inhibitor (also known as squalene synthase inhibitor); microsomal triglyceride transfer protein (MTP) inhibitor; bile acid sequestrant anion exchange resin, These include, but are not limited to, cholestyramine, cholestyramine, colesevelam or dialkylaminoalkyl derivatives of cross-linked dextran; LDL
- Additional therapies may also include increased exercise, surgery, and changing diets (eg, becoming a low-cholesterol diet).
- Some botanicals are also effective for combination formulations and collaborative therapies to treat hyperlipidemia, such as curcumin, gum ketone , garlic, soy, soluble fiber, fish oil, green tea, carnitine, chromium, coenzyme Q10, grape seed extract, dimeric pantothenic acid, red yeast rice and royal jelly.
- Berberine and related compounds can also be used as a second therapeutic agent in combination with the lipid lowering agent of the present invention.
- berberine sulfate, berberine hydrochloride, berberine chloride, berberine, dihydroberberine, 8-cyanodihydroberberine, tetrahydroberberine N-oxide can be used.
- Compounds of the invention may also be modified, for example by covalently linking organic structural fragments or conjugates, to improve pharmacokinetic properties, toxicity or bioavailability (e.g., increased in vivo half-life).
- the conjugate can be a linear or branched hydrophilic polymeric group, a fatty acid group or a fatty acid ester group.
- the polymeric group can comprise a molecular weight that can be adjusted by one skilled in the art to improve, for example, pharmacokinetic properties, toxicity, or bioavailability.
- Exemplary conjugates can include polyalkanols (eg, polyethylene glycol (PEG), polypropylene glycol (PPG)), carbohydrate polymers, amino acid polymers or polyvinylpyrrolidone, and fatty acid or fatty acid ester groups, which Each may independently comprise from about 8 to about 70 carbon atoms.
- Conjugates for use with the compounds of the invention may also be used as linkers, for example, for any suitable substituent or group, radiolabel (marker or tag), halogen, protein, enzyme, polypeptide, other therapeutic agent (eg drugs or drugs), nucleosides, dyes, oligonucleotides, lipids, phospholipids and/or liposomes.
- the conjugate can include polyvinylamine (PEI), polyglycine, a hybrid of PEI and polyglycine, polyethylene glycol (PEG), or methoxypolyethylene glycol (mPEG).
- PI polyvinylamine
- PEG polyethylene glycol
- mPEG methoxypolyethylene glycol
- Conjugates The compounds of the invention may also be linked to, for example, labeled (fluorescing or luminescent) or a label (radioactive, radioisotope and/or isotope) to comprise a probe of the invention. Conjugates for use with the compounds of the invention may improve in vivo half-life in one aspect.
- linking and/or “binding” may refer to a chemical or physical interaction, such as between a compound of the invention and a target of interest. Examples of linkages or interactions include covalent bonds, ionic bonds, hydrophilic-hydrophobic interactions, hydrophobic-hydrophobic interactions, and complexes. "Links” may also generally be referred to as “binding” or “affinity,” each of which may be used to describe a variety of chemical or physical interactions. Measuring binding or affinity is also a routine technique for those skilled in the art.
- X1 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound V;
- Another preparation method includes the following steps:
- X1 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature.
- V is prepared by reacting X1 and X3 under a certain reaction condition by reductive amination.
- X4 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X4 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound VI;
- Another preparation method includes the following steps:
- X4 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VI is prepared by reacting X4 and X3 under a certain reaction condition by reductive amination.
- X5 and X2 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X2 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound VII;
- Another preparation method includes the following steps:
- X5 and X3 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VII is obtained by reacting X5 and X3 under a certain reaction condition by reductive amination.
- X1 and X6 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X1 and X6 at a certain reaction temperature, in the presence of a certain alkaline reagent, by coupling to obtain compound VIII;
- Another preparation method includes the following steps:
- X1 and X7 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. VIII is prepared by reacting X1 and X7 under a certain reaction condition by reductive amination.
- X5 and X8 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X8 under certain reaction temperature conditions, in the presence of a certain alkaline reagent, by coupling to obtain compound IX;
- Another preparation method includes the following steps:
- X5 and X9 are the starting materials for this scheme and can be obtained by commercially available products or prepared according to methods reported in the literature. X5 and X9 are prepared by a reductive amination reaction under certain reaction conditions to obtain IX.
- the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
- NMR nuclear magnetic resonance
- MS mass spectrometry
- the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethyl.
- DMSO-d 6 dimethyl sulfoxide
- CDCl 3 deuterated chloroform
- CD 3 OD deuterated methanol
- TMS silane
- chemical shift is given in units of 10 -6 (ppm).
- Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
- the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
- the specification for thin layer chromatography separation and purification is 0.4mm ⁇ 0.5mm silica gel plate.
- the known starting materials of the present invention may be synthesized by or with reference to methods known in the art, or may be purchased from companies such as GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, TCI Chemicals, Angie Chemicals, and the like.
- An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon balloon or a nitrogen balloon having a volume of about 1 L.
- the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
- the hydrogenation reaction was usually evacuated, charged with hydrogen, and operated three times.
- reaction temperature is room temperature, and the temperature range is 20 ° C to 30 ° C.
- the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
- TLC thin layer chromatography
- the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane And the acetone system, D: n-hexane, E: ethyl acetate, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine and an acidic or alkaline reagent.
- the system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane and acetone
- the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine and an acidic or alkaline reagent.
- the compound 3C (1.5 g, 5 mmol) was weighed in a round bottom flask, THF was added, dissolved, and then the material was added 3D (0.81 g, 5 mmol), stirred for 10 min, then STAB (1.27 g, 6 mmol) was added and reacted at room temperature for 3 h. After the reaction of the thin layer is completed, the reaction is quenched by the addition of a saturated aqueous solution of ammonium chloride, and the mixture is extracted three times with ethyl acetate. The organic phase is combined, washed sequentially with saturated brine, dried over anhydrous sodium sulfate Product 3 (1.6 g, 72%) was obtained.
- 16D (330 mg, 0.92 mmol) was added to a 50 ml round bottom flask, and ethanol (20 ml) was dissolved. Then, Pd/C (10 mg, 0.09 mmol) was added thereto, and the mixture was purged with H 2 for 5 times (atmospheric pressure), and allowed to react at room temperature overnight. Filtration, washing the filter cake with ethanol, collecting the filtrate, and evaporating the solvent to give a crude product 16E.
- 46C (126.6 mg, 0.718 mmol) and 46D (200 mg, 0.653 mmol) were dissolved in 1,2-dichloroethane, and sodium triacetoxyborohydride (208 mg, 0.980 mmol) was slowly added in an ice bath.
- 57A (225mg, 1.5mmol) was added to a 50ml round bottom flask, dissolved in dichloromethane (10ml), then oxalyl chloride (213 ⁇ l, 2.5mmol) and N,N-dimethylformamide (1 drop) were added and reacted at room temperature. overnight. The solvent and an excess of oxalyl chloride were evaporated to give a crude material.
- the compound 70A (200 mg, 0.609 mmol) was added to a 50 mL round bottom flask, which was dissolved in dichloromethane (10 mL), and the mixture was stirred and stirred for 5 min, pyridine (0.5 mL) was added and the mixture was stirred for 10 min. After stirring at room temperature for 30 min, compound acetic anhydride (2 mL) was added and stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the layers were separated, and the organic phase was combined, washed with water, dried over anhydrous sodium sulfate, and the residue was purified by column chromatography ( petroleum ether: ethyl acetate 5:1).
- 74A (2g, 24.1mmol) and 74B (400mg, 2.41mmol) were dissolved in 10ml of methanol, stirred at room temperature for 12h, then sodium borohydride (109.4, 2.892mmol) was added slowly, after 15min reaction, filtered by diatomite After the solvent was removed by pressure, the mixture was extracted with EtOAc EtOAc EtOAc EtOAc (EtOAc) ).
- 74C (188.5 mg, 0.798 mmol) and 74D (222 mg, 0.725 mg) were dissolved in 5 ml of 1,2-dichloroethane, and sodium triacetoxyborohydride (230 mg, 1.09 mmol) was slowly added at room temperature under ice bath.
- 75A (90mg, 0.731mmol), thionyl chloride (1mL) was added to a 50mL round bottom flask, refluxed in an oil bath of 80 ° C for 2h, spin dry to give 75B, then add 75C (200mg, 0.609mmol), THF (20 mL), DMAP (10 mg), EtOAc (EtOAc, EtOAc, EtOAc (EtOAc) The residue was purified by column chromatography (dichloromethane: methanol: 100:1) to afford white solid compound 75 (28 mg, yield: 10.6%).
- the compound 91A (2000 mg, 10.34 mmol), the compound 91B (2118 mg, 11.37 mmol), potassium carbonate (2140 mg, 15.51 mmol), DMF (5 ml) was added to a 100 ml round bottom flask, and the reaction was cooled after stirring at 70 ° C overnight. The mixture was diluted with EtOAc (3 mL).
- the compound 16E was obtained according to the preparation of Example 16 and the compound 16E was dissolved in 15 mL of dichloromethane, then 140 ⁇ L (1.01 mmol) of triethylamine was added thereto, and stirred at room temperature, and then compound 148B 223 mg (1.01 mmol) was added portionwise. After the addition, the reaction was carried out overnight at room temperature. The reaction mixture was solid and precipitated. The obtained cake was purified by silica gel column chromatography (dichloromethane: methanol: 10:1) to give a white solid.
- Compound 16E was prepared according to Example 16 and Compound 16E 300 mg (0.916 mmol) was dissolved in 15 mL of dichloromethane, then, then, triethylamine, 140 ⁇ L (1.01 mmol), and stirred at room temperature, and then added 149B 223 mg (1.01 mmol) ), after the addition, the reaction was carried out overnight at room temperature. The reaction mixture was solid and precipitated. The obtained cake was purified by silica gel column chromatography (dichloromethane: methanol: 10:1) to give a white solid. The methyl chloride was washed, and the cake was collected.
- 5-formylsalicylic acid 151A (1.66 g, 10.0 mM) was dissolved in N,N-dimethylformamide (30 mL), potassium carbonate (4.14 g, 30 mM) and methyl iodide (2.18 mL, 35 mM) , overnight at room temperature. The reaction was completed by TLC. EtOAc was evaporated.
- Example 151E was obtained as in Example 151.
- Compound 151E 300 mg (0.879 mmol) was dispersed in 15 mL of water, then 242 mg (1.76 mmol) of potassium carbonate was added, and stirred at room temperature, then danyl chloride 155B 283 mg (1.05 mmol) was added portionwise, and the reaction was carried out overnight at room temperature.
- the reaction solution was adjusted to pH 3 with 2M HCl, and a solid was precipitated, suction filtered, washed with water, dried, washed with a mixed solvent (dichloromethane:methanol 5:1), and the organic solvent was collected and evaporated to dryness.
- Example 151E was obtained as in Example 151.
- Compound 151E 300 mg (0.879 mmol) was dispersed in 15 mL of water, then 242 mg (1.76 mmol) of potassium carbonate was added, and stirred at room temperature, then 2-naphthalenesulfonyl chloride 156B 239 mg (1.05 mmol) was added portionwise, and the reaction was carried out overnight at room temperature. .
- the reaction solution was adjusted to pH 3 with 2M HCl, and a solid was precipitated, suction filtered, washed with water, dried, washed with a mixed solvent (dichloromethane:methanol 5:1), and the organic solvent was collected and evaporated to dryness.
- 1-(4-Nitrophenyl)piperazine 157A (1.036 g, 5 mM) was dissolved in methanol (10 mL), and di-tert-butyl dicarbonate (1.24 mL, 5.4 mM) was slowly added dropwise at 0 °C. A solution of methanol (5 mL). The reaction was completely monitored by TLC, the solvent was evaporated, and then purified with petroleum ether/ethyl acetate (20/1), filtered and dried to give product 157B.
- 1-(4-Nitrophenyl)piperazine 158A (1.036 g, 5 mM) was dissolved in methanol (10 mL), and di-tert-butyl dicarbonate (1.24 mL, 5.4 mM) was slowly added dropwise at 0 °C. A solution of methanol (5 mL). The reaction was completely monitored by TLC, the solvent was evaporated, and then purified with petroleum ether/ethyl acetate (20/1), filtered and dried to give product 158B.
- 160F (10 mmol, 1.41 g), 160 g (15 mmol, 1.5 g) and triethylamine (15 mmol, 2.08 ml) were added to a 50 ml round bottom flask, dissolved in DMSO (15 ml), and reacted at 100 ° C for 10 h. After cooling to room temperature, 100 ml of water was added, and a solid was precipitated. Then, 50 ml of ethyl acetate was further added and the mixture was stirred for 10 min, filtered, and washed three times with water to give compound 160H, a yellow solid, 1.67 g, yield 75.6%.
- 3,4-Dimethoxybenzaldehyde 160A (499 mg, 3.0 mM) was dissolved in methanol (10 mL), sodium borohydride (170 mg, 4.5 mM) was added in portions and stirred at room temperature for 15 min. The mixture was diluted with a saturated aqueous solution of ammonium chloride, and the mixture was evaporated, evaporated, evaporated, evaporated.
- the above product 160E was dissolved in dichloromethane (15 mL), triethylamine (58 ⁇ L, 0.42 mM) and 4-diphenylsulfonyl chloride (71 mg, 0.28 mM) were added and reacted for 2.5 h, and the reaction was completely monitored by TLC.
- the aqueous solution of citric acid was extracted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate %).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention concerne un composé représenté par la formule (V), son procédé de préparation et ses applications pharmaceutiques. Spécifiquement, l'invention concerne des dérivés représentés par la formule (V), leur procédé de préparation et leurs utilisations en tant qu'agents thérapeutiques pour prévenir et traiter l'hyperlipidémie, l'hypercholestérolémie, l'hypertriglycéridémie, la dégénérescence graisseuse du foie, le diabète de type 2, l'hyperglycémie, l'obésité ou la résistance à l'insuline, le syndrome métabolique et les cancers. Les composés de l'invention peuvent également réduire les niveaux de cholestérol total, de cholestérol LDL et de triglycérides, et réguler positivement l'expression du récepteur LDL du foie et négativement l'expression de PCSK9.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510001596.1 | 2015-01-01 | ||
CN201510001596 | 2015-01-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2016107603A1 true WO2016107603A1 (fr) | 2016-07-07 |
Family
ID=56284316
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2015/100201 WO2016107603A1 (fr) | 2015-01-01 | 2015-12-31 | Dérivés hétérocycliques contenant de l'azote substitué et leurs applications |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN105753814A (fr) |
WO (1) | WO2016107603A1 (fr) |
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9732080B2 (en) | 2006-11-03 | 2017-08-15 | Vertex Pharmaceuticals Incorporated | Azaindole derivatives as CFTR modulators |
US10071979B2 (en) | 2010-04-22 | 2018-09-11 | Vertex Pharmaceuticals Incorporated | Process of producing cycloalkylcarboxamido-indole compounds |
WO2018165718A1 (fr) | 2017-03-17 | 2018-09-20 | Cardio Therapeutics Pty Ltd | Inhibiteurs hétérocycliques de pcsk9 |
US10081621B2 (en) | 2010-03-25 | 2018-09-25 | Vertex Pharmaceuticals Incorporated | Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide |
US10206877B2 (en) | 2014-04-15 | 2019-02-19 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases |
US10556013B2 (en) | 2017-06-20 | 2020-02-11 | Imbria Pharmaceuticals, Inc. | Compositions and methods for increasing efficiency of cardiac metabolism |
US10568882B2 (en) | 2015-08-21 | 2020-02-25 | Srx Cardio, Llc | Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use |
US10821106B2 (en) | 2015-08-21 | 2020-11-03 | Srx Cardio, Llc | Composition and methods of use of novel phenylalanine small organic compounds to directly modulate PCSK9 protein activity |
US11034669B2 (en) | 2018-11-30 | 2021-06-15 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
US11214625B2 (en) | 2015-10-29 | 2022-01-04 | Min Chen | Application of PCSK9 inhibitors in the preparation of drugs for the treatment of inflammatory immune diseases |
US11285153B2 (en) | 2017-09-29 | 2022-03-29 | Sunshine Lake Pharma Co., Ltd. | Substituted pyrimidine piperazine compound and use thereof |
US11530184B2 (en) | 2020-06-30 | 2022-12-20 | Imbria Pharmaceuticals, Inc. | Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate |
CN116283819A (zh) * | 2023-03-22 | 2023-06-23 | 中国科学院长春应用化学研究所 | 一种异噻唑-5(2h)-亚胺类化合物的制备方法及其应用 |
CN109776509B (zh) * | 2018-01-30 | 2023-07-07 | 成都麻沸散医药科技有限公司 | 一种n-取代咪唑甲酸酯类衍生物及其用途 |
US11780811B2 (en) | 2020-06-30 | 2023-10-10 | Imbria Pharmaceuticals, Inc. | Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate |
US11795173B1 (en) | 2022-04-28 | 2023-10-24 | Xinthera, Inc. | Substituted pyridines as PARP1 inhibitors |
US11802128B2 (en) | 2021-10-01 | 2023-10-31 | Xinthera, Inc. | Azetidine and pyrrolidine PARP1 inhibitors and uses thereof |
US11873298B2 (en) | 2017-10-24 | 2024-01-16 | Janssen Pharmaceutica Nv | Compounds and uses thereof |
US11883396B2 (en) | 2021-05-03 | 2024-01-30 | Imbria Pharmaceuticals, Inc. | Methods of treating kidney conditions using modified forms of trimetazidine |
US11891369B2 (en) | 2016-02-23 | 2024-02-06 | Srx Cardio, Llc | Compounds for binding proprotein convertase subtilisin/kexin type 9 |
US11939329B2 (en) | 2022-01-21 | 2024-03-26 | Xinthera, Inc. | PARP1 inhibitors and uses thereof |
US11945782B2 (en) | 2015-08-21 | 2024-04-02 | Srx Cardio, Llc | Composition and methods of use of tetrahydroisoquinoline small molecules to bind and modulate PCSK9 protein activity |
US11970486B2 (en) | 2016-10-24 | 2024-04-30 | Janssen Pharmaceutica Nv | Compounds and uses thereof |
US12098146B2 (en) | 2020-01-24 | 2024-09-24 | Janssen Pharmaceutica Nv | Compounds and uses thereof |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106866575A (zh) * | 2017-03-21 | 2017-06-20 | 苏州汉德创宏生化科技有限公司 | 2‑(1‑哌啶基)‑5‑溴噻唑的合成方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997028128A1 (fr) * | 1996-02-02 | 1997-08-07 | Zeneca Limited | Composes heterocycliques utiles en tant qu'agents pharmaceutiques |
CN103562202A (zh) * | 2011-01-25 | 2014-02-05 | 密执安大学评议会 | Bcl-2/bcl-xl抑制剂和使用它们的治疗方法 |
US20140235646A1 (en) * | 2007-02-02 | 2014-08-21 | Motonari Uesugi | Methods and Compositions for the Treatment of Body Weight Related Disorders |
-
2015
- 2015-12-31 WO PCT/CN2015/100201 patent/WO2016107603A1/fr active Application Filing
- 2015-12-31 CN CN201511026661.2A patent/CN105753814A/zh active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997028128A1 (fr) * | 1996-02-02 | 1997-08-07 | Zeneca Limited | Composes heterocycliques utiles en tant qu'agents pharmaceutiques |
US20140235646A1 (en) * | 2007-02-02 | 2014-08-21 | Motonari Uesugi | Methods and Compositions for the Treatment of Body Weight Related Disorders |
CN103562202A (zh) * | 2011-01-25 | 2014-02-05 | 密执安大学评议会 | Bcl-2/bcl-xl抑制剂和使用它们的治疗方法 |
Non-Patent Citations (1)
Title |
---|
ZHOU, HAIBIN ET AL.: "Design of Bcl-2 and Bcl-xL Inhibitors with Subnanomolar Binding Affinities Based upon a New Scaffold", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 10, 26 March 2012 (2012-03-26), pages 4664 - 4682, XP002725242, DOI: doi:10.1021/jm300178u * |
Cited By (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9732080B2 (en) | 2006-11-03 | 2017-08-15 | Vertex Pharmaceuticals Incorporated | Azaindole derivatives as CFTR modulators |
US10081621B2 (en) | 2010-03-25 | 2018-09-25 | Vertex Pharmaceuticals Incorporated | Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide |
US10071979B2 (en) | 2010-04-22 | 2018-09-11 | Vertex Pharmaceuticals Incorporated | Process of producing cycloalkylcarboxamido-indole compounds |
US10206877B2 (en) | 2014-04-15 | 2019-02-19 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases |
US10821106B2 (en) | 2015-08-21 | 2020-11-03 | Srx Cardio, Llc | Composition and methods of use of novel phenylalanine small organic compounds to directly modulate PCSK9 protein activity |
US10568882B2 (en) | 2015-08-21 | 2020-02-25 | Srx Cardio, Llc | Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use |
US11944619B2 (en) | 2015-08-21 | 2024-04-02 | Srx Cardio, Llc | Phenylalanine small organic compounds to directly modulate PCSK9 protein activity |
US10980801B2 (en) | 2015-08-21 | 2021-04-20 | Srx Cardio, Llc | Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use |
US11945782B2 (en) | 2015-08-21 | 2024-04-02 | Srx Cardio, Llc | Composition and methods of use of tetrahydroisoquinoline small molecules to bind and modulate PCSK9 protein activity |
US11925637B2 (en) | 2015-08-21 | 2024-03-12 | Srx Cardio, Llc | Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use |
US11214625B2 (en) | 2015-10-29 | 2022-01-04 | Min Chen | Application of PCSK9 inhibitors in the preparation of drugs for the treatment of inflammatory immune diseases |
US11891369B2 (en) | 2016-02-23 | 2024-02-06 | Srx Cardio, Llc | Compounds for binding proprotein convertase subtilisin/kexin type 9 |
US11970486B2 (en) | 2016-10-24 | 2024-04-30 | Janssen Pharmaceutica Nv | Compounds and uses thereof |
EP3609882A4 (fr) * | 2017-03-17 | 2020-10-28 | Cardio Therapeutics Pty Ltd | Inhibiteurs hétérocycliques de pcsk9 |
WO2018165718A1 (fr) | 2017-03-17 | 2018-09-20 | Cardio Therapeutics Pty Ltd | Inhibiteurs hétérocycliques de pcsk9 |
US11091466B2 (en) | 2017-03-17 | 2021-08-17 | Cardio Therapeutics Pty Ltd | Heterocyclic inhibitors of PCSK9 |
US11897868B2 (en) | 2017-03-17 | 2024-02-13 | Cardio Therapeutics Pty Ltd | Heterocyclic inhibitors of PCSK9 |
US10918728B2 (en) | 2017-06-20 | 2021-02-16 | Imbria Pharmaceuticals, Inc. | Compositions and methods for increasing efficiency of cardiac metabolism |
US11376330B2 (en) | 2017-06-20 | 2022-07-05 | Imbria Pharmaceuticals, Inc. | Compositions and methods for increasing efficiency of cardiac metabolism |
US10953102B2 (en) | 2017-06-20 | 2021-03-23 | Imbria Pharmaceuticals, Inc. | Compositions and methods for increasing efficiency of cardiac metabolism |
US10556013B2 (en) | 2017-06-20 | 2020-02-11 | Imbria Pharmaceuticals, Inc. | Compositions and methods for increasing efficiency of cardiac metabolism |
US11844840B2 (en) | 2017-06-20 | 2023-12-19 | Imbria Pharmaceuticals, Inc. | Compositions and methods for increasing efficiency of cardiac metabolism |
US11285153B2 (en) | 2017-09-29 | 2022-03-29 | Sunshine Lake Pharma Co., Ltd. | Substituted pyrimidine piperazine compound and use thereof |
US11873298B2 (en) | 2017-10-24 | 2024-01-16 | Janssen Pharmaceutica Nv | Compounds and uses thereof |
CN109776509B (zh) * | 2018-01-30 | 2023-07-07 | 成都麻沸散医药科技有限公司 | 一种n-取代咪唑甲酸酯类衍生物及其用途 |
US11034669B2 (en) | 2018-11-30 | 2021-06-15 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
US12098146B2 (en) | 2020-01-24 | 2024-09-24 | Janssen Pharmaceutica Nv | Compounds and uses thereof |
US11780811B2 (en) | 2020-06-30 | 2023-10-10 | Imbria Pharmaceuticals, Inc. | Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate |
US11530184B2 (en) | 2020-06-30 | 2022-12-20 | Imbria Pharmaceuticals, Inc. | Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate |
US12065410B2 (en) | 2020-06-30 | 2024-08-20 | Imbria Pharmaceuticals, Inc. | Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate |
US11746090B2 (en) | 2020-06-30 | 2023-09-05 | Imbria Pharmaceuticals, Inc. | Crystal forms of 2-[4-[(2,3,4- trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate |
US11883396B2 (en) | 2021-05-03 | 2024-01-30 | Imbria Pharmaceuticals, Inc. | Methods of treating kidney conditions using modified forms of trimetazidine |
US11802128B2 (en) | 2021-10-01 | 2023-10-31 | Xinthera, Inc. | Azetidine and pyrrolidine PARP1 inhibitors and uses thereof |
US11939329B2 (en) | 2022-01-21 | 2024-03-26 | Xinthera, Inc. | PARP1 inhibitors and uses thereof |
US12006322B2 (en) | 2022-04-28 | 2024-06-11 | Xin Thera, Inc. | Substituted pyridines as PARP1 inhibitors |
US11795173B1 (en) | 2022-04-28 | 2023-10-24 | Xinthera, Inc. | Substituted pyridines as PARP1 inhibitors |
CN116283819A (zh) * | 2023-03-22 | 2023-06-23 | 中国科学院长春应用化学研究所 | 一种异噻唑-5(2h)-亚胺类化合物的制备方法及其应用 |
Also Published As
Publication number | Publication date |
---|---|
CN105753814A (zh) | 2016-07-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2016107603A1 (fr) | Dérivés hétérocycliques contenant de l'azote substitué et leurs applications | |
WO2016107602A1 (fr) | Dérivés hétérocycliques d'azote substitués et leur utilisation | |
CN101006065B (zh) | 抑制bcl蛋白与结合伴侣的相互作用的化合物和方法 | |
CN102485721B (zh) | 取代的2,3-二氮杂萘酮化合物及其用途 | |
EP1820515A1 (fr) | Compose a base de cycles accoles azotes et ses utilisation | |
JP2005521698A (ja) | 新規な三環式化合物 | |
EA010656B1 (ru) | Тетрагидрохинолиноны и их применение в качестве антагонистов метаботропных глутаматных рецепторов | |
JPS62103065A (ja) | ピリジン誘導体 | |
OA12631A (fr) | Amides d'acide anthranilique avec une chaîne latérale hétéroarylsulfonyle, procédé our leur préparation, leur utilisation comme médeicament ou comme agent de diagnostic et préparations pharmaceutiquescontenant lesdits composés. | |
EP1985297A1 (fr) | Acide carboxylique et applications | |
JP4805166B2 (ja) | アロイルフランおよびアロイルチオフェン | |
WO2024008129A1 (fr) | Composé utilisé en tant qu'inhibiteur de kat6 | |
WO1996020190A1 (fr) | Derives de la piperizine-2,5-dione comme modulateurs de la resistance multi-medicament | |
CN110386927A (zh) | 组蛋白乙酰转移酶(hat)抑制剂及其用途 | |
WO2016041515A1 (fr) | Dérivés de la tétrahydropalmatine et leur application | |
WO2020221006A1 (fr) | Inhibiteur de bet, son procédé de préparation et son utilisation | |
JP2012504588A (ja) | ピリミド誘導体およびその製薬学的用途 | |
KR102537615B1 (ko) | 히스톤 탈아세틸화효소 6 억제제로서의 1,3,4-옥사다이아졸 유도체 화합물 및 이를 포함하는 약제학적 조성물 | |
CN101314584A (zh) | HGF/c-Met信号通道抑制剂及其制备方法和用途 | |
CN106604918B (zh) | 多环hERG激活剂 | |
CA2787860C (fr) | 2-imidazolidones substitues et analogues et leur utilisation contre le cancer | |
CN101243074A (zh) | 杂环化合物 | |
CA2844783A1 (fr) | 2-imidazolidinones et 2-imidazolones substituees et leur utilisation dans le traitement du cancer | |
WO2005090320A2 (fr) | Derives de triazole et leur methode d'utilisation pour traiter les infections par le vih | |
CN101717364A (zh) | 作为hiv逆转录酶抑制剂的吡啶类化合物及其制备方法和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15875279 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 15875279 Country of ref document: EP Kind code of ref document: A1 |