CN109790151B - 杂环爱帕琳肽受体(apj)激动剂及其用途 - Google Patents
杂环爱帕琳肽受体(apj)激动剂及其用途 Download PDFInfo
- Publication number
- CN109790151B CN109790151B CN201780061192.9A CN201780061192A CN109790151B CN 109790151 B CN109790151 B CN 109790151B CN 201780061192 A CN201780061192 A CN 201780061192A CN 109790151 B CN109790151 B CN 109790151B
- Authority
- CN
- China
- Prior art keywords
- alkyl
- compound
- apj
- disorder
- disease
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 102100030949 Apelin receptor Human genes 0.000 title abstract description 30
- 108091008803 APLNR Proteins 0.000 title abstract description 16
- 239000000556 agonist Substances 0.000 title abstract description 7
- 125000000623 heterocyclic group Chemical group 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 131
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 70
- -1 hydroxy Chemical group 0.000 claims description 60
- 239000003814 drug Substances 0.000 claims description 42
- 208000035475 disorder Diseases 0.000 claims description 41
- 239000008194 pharmaceutical composition Substances 0.000 claims description 30
- 108010052412 Apelin Proteins 0.000 claims description 26
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 25
- 238000011282 treatment Methods 0.000 claims description 25
- 208000019423 liver disease Diseases 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 23
- 125000005842 heteroatom Chemical group 0.000 claims description 22
- 102000018746 Apelin Human genes 0.000 claims description 20
- 230000004770 neurodegeneration Effects 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 206010020772 Hypertension Diseases 0.000 claims description 16
- BWVPHIKGXQBZPV-QKFDDRBGSA-N apelin Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N1[C@H](C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2NC=NC=2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=2NC=NC=2)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCSC)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(O)=O)CCC1 BWVPHIKGXQBZPV-QKFDDRBGSA-N 0.000 claims description 15
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 13
- 229940125364 angiotensin receptor blocker Drugs 0.000 claims description 12
- 108010011903 peptide receptors Proteins 0.000 claims description 12
- 201000002282 venous insufficiency Diseases 0.000 claims description 12
- 102000014187 peptide receptors Human genes 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 208000008589 Obesity Diseases 0.000 claims description 10
- 206010012601 diabetes mellitus Diseases 0.000 claims description 10
- 235000020824 obesity Nutrition 0.000 claims description 10
- 210000003462 vein Anatomy 0.000 claims description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 201000011461 pre-eclampsia Diseases 0.000 claims description 9
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 8
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 8
- 206010061218 Inflammation Diseases 0.000 claims description 8
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 8
- 208000006673 asthma Diseases 0.000 claims description 8
- 230000004054 inflammatory process Effects 0.000 claims description 8
- 208000030159 metabolic disease Diseases 0.000 claims description 8
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 8
- 230000008085 renal dysfunction Effects 0.000 claims description 8
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 7
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 7
- 239000002876 beta blocker Substances 0.000 claims description 7
- 229940097320 beta blocking agent Drugs 0.000 claims description 7
- 239000000480 calcium channel blocker Substances 0.000 claims description 7
- 206010047249 Venous thrombosis Diseases 0.000 claims description 6
- 239000002160 alpha blocker Substances 0.000 claims description 6
- 239000002934 diuretic Substances 0.000 claims description 6
- 201000011066 hemangioma Diseases 0.000 claims description 6
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 6
- 208000022309 Alcoholic Liver disease Diseases 0.000 claims description 5
- 241000700605 Viruses Species 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 208000030761 polycystic kidney disease Diseases 0.000 claims description 5
- 231100000167 toxic agent Toxicity 0.000 claims description 5
- 239000003440 toxic substance Substances 0.000 claims description 5
- 230000001882 diuretic effect Effects 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229940097420 Diuretic Drugs 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 208000017169 kidney disease Diseases 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 239000012190 activator Substances 0.000 abstract 1
- 150000003254 radicals Chemical class 0.000 description 76
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 66
- 229910002092 carbon dioxide Inorganic materials 0.000 description 60
- 125000001072 heteroaryl group Chemical group 0.000 description 54
- 125000003118 aryl group Chemical group 0.000 description 53
- 239000000203 mixture Substances 0.000 description 53
- 239000000243 solution Substances 0.000 description 45
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000003480 eluent Substances 0.000 description 35
- 238000000034 method Methods 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 229940124597 therapeutic agent Drugs 0.000 description 30
- 201000010099 disease Diseases 0.000 description 29
- 235000002639 sodium chloride Nutrition 0.000 description 29
- 239000007864 aqueous solution Substances 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 19
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 229940002612 prodrug Drugs 0.000 description 16
- 239000000651 prodrug Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 229910052799 carbon Inorganic materials 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 125000000217 alkyl group Chemical group 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 239000002552 dosage form Substances 0.000 description 12
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 229910052736 halogen Inorganic materials 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 102000016555 Apelin receptors Human genes 0.000 description 8
- 239000007821 HATU Substances 0.000 description 8
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 8
- 235000001014 amino acid Nutrition 0.000 description 8
- 229940024606 amino acid Drugs 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 238000000576 coating method Methods 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 230000000155 isotopic effect Effects 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 150000003568 thioethers Chemical class 0.000 description 8
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 7
- 206010019280 Heart failures Diseases 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 6
- 229910052805 deuterium Inorganic materials 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 208000031886 HIV Infections Diseases 0.000 description 5
- 208000037357 HIV infectious disease Diseases 0.000 description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 5
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 239000002671 adjuvant Substances 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 230000036772 blood pressure Effects 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 238000012377 drug delivery Methods 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 5
- 230000000670 limiting effect Effects 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 230000000699 topical effect Effects 0.000 description 5
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 4
- 201000001320 Atherosclerosis Diseases 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 206010007556 Cardiac failure acute Diseases 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 4
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 4
- 239000013553 cell monolayer Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 4
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(I) nitrate Inorganic materials [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
- NAKYQDGOQWIGHR-NSHDSACASA-N tert-butyl (3S)-3-amino-5-(3,3-difluoropiperidin-1-yl)pentanoate Chemical compound N[C@H](CC(=O)OC(C)(C)C)CCN1CC(CCC1)(F)F NAKYQDGOQWIGHR-NSHDSACASA-N 0.000 description 4
- 238000011287 therapeutic dose Methods 0.000 description 4
- 229930192474 thiophene Natural products 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 150000003852 triazoles Chemical class 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 3
- 239000005541 ACE inhibitor Substances 0.000 description 3
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010007559 Cardiac failure congestive Diseases 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 3
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 3
- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 102000003729 Neprilysin Human genes 0.000 description 3
- 108090000028 Neprilysin Proteins 0.000 description 3
- 235000019502 Orange oil Nutrition 0.000 description 3
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 208000032109 Transient ischaemic attack Diseases 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 239000001099 ammonium carbonate Substances 0.000 description 3
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 3
- 239000007900 aqueous suspension Substances 0.000 description 3
- 239000012131 assay buffer Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 125000005518 carboxamido group Chemical group 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- NDTCXABJQNJPCF-UHFFFAOYSA-N chlorocyclopentane Chemical compound ClC1CCCC1 NDTCXABJQNJPCF-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000011260 co-administration Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000000302 ischemic effect Effects 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000010502 orange oil Substances 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 238000009097 single-agent therapy Methods 0.000 description 3
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Substances [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 3
- 210000000130 stem cell Anatomy 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 3
- 201000010875 transient cerebral ischemia Diseases 0.000 description 3
- 230000032258 transport Effects 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- VEVRNHHLCPGNDU-MUGJNUQGSA-N (2s)-2-amino-5-[1-[(5s)-5-amino-5-carboxypentyl]-3,5-bis[(3s)-3-amino-3-carboxypropyl]pyridin-1-ium-4-yl]pentanoate Chemical compound OC(=O)[C@@H](N)CCCC[N+]1=CC(CC[C@H](N)C(O)=O)=C(CCC[C@H](N)C([O-])=O)C(CC[C@H](N)C(O)=O)=C1 VEVRNHHLCPGNDU-MUGJNUQGSA-N 0.000 description 2
- OCPBTKNQPKOWHR-HNNXBMFYSA-N (3S)-3-[[1-cyclopentyl-5-[3-(trifluoromethyl)pyridin-2-yl]-1,2,4-triazole-3-carbonyl]amino]-5-(3,3-difluoropiperidin-1-yl)pentanoic acid Chemical compound OC(=O)C[C@H](CCN1CCCC(F)(F)C1)NC(=O)C1=NN(C2CCCC2)C(=N1)C1=NC=CC=C1C(F)(F)F OCPBTKNQPKOWHR-HNNXBMFYSA-N 0.000 description 2
- JILGSCARHWMWET-FERBBOLQSA-N (3S)-3-[[2-cyclopentyl-1-[2-(trifluoromethyl)phenyl]imidazole-4-carbonyl]amino]-5-(3,3-difluoropiperidin-1-yl)pentanoic acid hydrochloride Chemical compound Cl.C1(CCCC1)C=1N(C=C(N=1)C(=O)N[C@H](CC(=O)O)CCN1CC(CCC1)(F)F)C1=C(C=CC=C1)C(F)(F)F JILGSCARHWMWET-FERBBOLQSA-N 0.000 description 2
- SVJMLYUFVDMUHP-XIFFEERXSA-N (4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-[3-(4,4-diphenyl-1-piperidinyl)propyl] ester O3-methyl ester Chemical compound C1([C@@H]2C(=C(C)NC(C)=C2C(=O)OC)C(=O)OCCCN2CCC(CC2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=CC=CC([N+]([O-])=O)=C1 SVJMLYUFVDMUHP-XIFFEERXSA-N 0.000 description 2
- LOZWAPSEEHRYPG-UHFFFAOYSA-N 1,4-dithiane Chemical compound C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- PRBLVOJMRAVDHY-UHFFFAOYSA-N 1-cyclopentyl-5-[3-(trifluoromethyl)pyridin-2-yl]-1,2,4-triazole-3-carboxylic acid Chemical compound OC(=O)C1=NN(C2CCCC2)C(=N1)C1=NC=CC=C1C(F)(F)F PRBLVOJMRAVDHY-UHFFFAOYSA-N 0.000 description 2
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 2
- AAQTWLBJPNLKHT-UHFFFAOYSA-N 1H-perimidine Chemical compound N1C=NC2=CC=CC3=CC=CC1=C32 AAQTWLBJPNLKHT-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- OSQVYKAPWCJDSP-UHFFFAOYSA-N 2-cyclopentyl-1-[2-(trifluoromethyl)phenyl]imidazole-4-carbonyl chloride Chemical compound C1(CCCC1)C=1N(C=C(N=1)C(=O)Cl)C1=C(C=CC=C1)C(F)(F)F OSQVYKAPWCJDSP-UHFFFAOYSA-N 0.000 description 2
- YNTQAWKDFNKEBF-UHFFFAOYSA-N 2-cyclopentyl-1-[2-(trifluoromethyl)phenyl]imidazole-4-carboxylic acid Chemical compound C1(CCCC1)C=1N(C=C(N=1)C(=O)O)C1=C(C=CC=C1)C(F)(F)F YNTQAWKDFNKEBF-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- DMWLBOPLZYJGPT-UHFFFAOYSA-N 3-(trifluoromethyl)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=C1C(F)(F)F DMWLBOPLZYJGPT-UHFFFAOYSA-N 0.000 description 2
- GGSVKJQWIMQIKT-UHFFFAOYSA-N 5-cyclopentyl-1-[2-(trifluoromethyl)pyridin-3-yl]-1,2,4-triazole-3-carboxylic acid Chemical compound OC(=O)C1=NN(C(=N1)C1CCCC1)C1=CC=CN=C1C(F)(F)F GGSVKJQWIMQIKT-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 229940123338 Aldosterone synthase inhibitor Drugs 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 2
- 102400000252 Apelin-13 Human genes 0.000 description 2
- 206010003658 Atrial Fibrillation Diseases 0.000 description 2
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 description 2
- 206010059027 Brugada syndrome Diseases 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 206010007558 Cardiac failure chronic Diseases 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- 108010061435 Enalapril Proteins 0.000 description 2
- 206010016807 Fluid retention Diseases 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 125000003338 L-glutaminyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C(=O)N([H])[H] 0.000 description 2
- UCUNFLYVYCGDHP-BYPYZUCNSA-N L-methionine sulfone Chemical compound CS(=O)(=O)CC[C@H](N)C(O)=O UCUNFLYVYCGDHP-BYPYZUCNSA-N 0.000 description 2
- 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 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 229910013596 LiOH—H2O Inorganic materials 0.000 description 2
- 108010007859 Lisinopril Proteins 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 description 2
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- KBIPBIPQAZBYEU-QFIPXVFZSA-N N-[(3S)-1-(cyclobutylamino)-5-(3,3-difluoropiperidin-1-yl)-1-oxopentan-3-yl]-2-cyclopentyl-1-[2-(trifluoromethyl)phenyl]imidazole-4-carboxamide Chemical compound FC(F)(F)C1=C(C=CC=C1)N1C=C(N=C1C1CCCC1)C(=O)N[C@@H](CCN1CCCC(F)(F)C1)CC(=O)NC1CCC1 KBIPBIPQAZBYEU-QFIPXVFZSA-N 0.000 description 2
- NTLAUOQOLUCKGT-UHFFFAOYSA-N N-cyclopentyl-3-(trifluoromethyl)pyridine-2-carbohydrazide Chemical compound C1(CCCC1)N(N)C(C1=NC=CC=C1C(F)(F)F)=O NTLAUOQOLUCKGT-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 239000005480 Olmesartan Substances 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 206010033645 Pancreatitis Diseases 0.000 description 2
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 2
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 208000006011 Stroke Diseases 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
- 206010042496 Sunburn Diseases 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 208000030886 Traumatic Brain injury Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- 229960002122 acebutolol Drugs 0.000 description 2
- GOEMGAFJFRBGGG-UHFFFAOYSA-N acebutolol Chemical compound CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 GOEMGAFJFRBGGG-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 229940124308 alpha-adrenoreceptor antagonist Drugs 0.000 description 2
- 150000001412 amines Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 2
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 229960002932 anastrozole Drugs 0.000 description 2
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- XXCCRHIAIBQDPX-PEWBXTNBSA-N apelin-13 Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(N)=O)C1=CN=CN1 XXCCRHIAIBQDPX-PEWBXTNBSA-N 0.000 description 2
- 108010040480 apelin-13 peptide Proteins 0.000 description 2
- 206010003119 arrhythmia Diseases 0.000 description 2
- 230000006793 arrhythmia Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- MOTJMGVDPWRKOC-QPVYNBJUSA-N atrasentan Chemical compound C1([C@H]2[C@@H]([C@H](CN2CC(=O)N(CCCC)CCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1 MOTJMGVDPWRKOC-QPVYNBJUSA-N 0.000 description 2
- 229950010993 atrasentan Drugs 0.000 description 2
- 229960004530 benazepril Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- KKBIUAUSZKGNOA-HNAYVOBHSA-N benzyl (2s)-2-[[(2s)-2-(acetylsulfanylmethyl)-3-(1,3-benzodioxol-5-yl)propanoyl]amino]propanoate Chemical compound O=C([C@@H](NC(=O)[C@@H](CSC(C)=O)CC=1C=C2OCOC2=CC=1)C)OCC1=CC=CC=C1 KKBIUAUSZKGNOA-HNAYVOBHSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 230000009787 cardiac fibrosis Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- KZZKOVLJUKWSKX-UHFFFAOYSA-N cyclobutanamine Chemical compound NC1CCC1 KZZKOVLJUKWSKX-UHFFFAOYSA-N 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 2
- 229960004166 diltiazem Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical group C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 description 2
- 229940030606 diuretics Drugs 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 229960000873 enalapril Drugs 0.000 description 2
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 2
- 229960001208 eplerenone Drugs 0.000 description 2
- JUKPWJGBANNWMW-VWBFHTRKSA-N eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-N 0.000 description 2
- GDCVVOWHQFOPFT-UHFFFAOYSA-N ethyl 1-[2-(trifluoromethyl)phenyl]imidazole-4-carboxylate Chemical compound CCOC(=O)c1cn(cn1)-c1ccccc1C(F)(F)F GDCVVOWHQFOPFT-UHFFFAOYSA-N 0.000 description 2
- OLDSMVUVWJKSGB-UHFFFAOYSA-N ethyl 1-cyclopentyl-5-[3-(trifluoromethyl)pyridin-2-yl]-1,2,4-triazole-3-carboxylate Chemical compound CCOC(=O)c1nc(-c2ncccc2C(F)(F)F)n(n1)C1CCCC1 OLDSMVUVWJKSGB-UHFFFAOYSA-N 0.000 description 2
- RDULEYWUGKOCMR-UHFFFAOYSA-N ethyl 2-chloro-3-oxobutanoate Chemical compound CCOC(=O)C(Cl)C(C)=O RDULEYWUGKOCMR-UHFFFAOYSA-N 0.000 description 2
- FOHFDAJQLBTGMN-UHFFFAOYSA-N ethyl 2-cyclopentyl-1-[2-(trifluoromethyl)phenyl]imidazole-4-carboxylate Chemical compound C1(CCCC1)C=1N(C=C(N=1)C(=O)OCC)C1=C(C=CC=C1)C(F)(F)F FOHFDAJQLBTGMN-UHFFFAOYSA-N 0.000 description 2
- GMIYJMHAFIUQPK-UHFFFAOYSA-N ethyl 5-cyclopentyl-1-[2-(trifluoromethyl)pyridin-3-yl]-1,2,4-triazole-3-carboxylate Chemical compound CCOC(=O)C1=NN(C(=N1)C1CCCC1)C1=CC=CN=C1C(F)(F)F GMIYJMHAFIUQPK-UHFFFAOYSA-N 0.000 description 2
- 229950005203 fasidotril Drugs 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 208000004104 gestational diabetes Diseases 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 208000019622 heart disease Diseases 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 230000036737 immune function Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 229960002394 lisinopril Drugs 0.000 description 2
- RLAWWYSOJDYHDC-BZSNNMDCSA-N lisinopril Chemical compound C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 RLAWWYSOJDYHDC-BZSNNMDCSA-N 0.000 description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 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
- 208000037819 metastatic cancer Diseases 0.000 description 2
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 2
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- TUYWTLTWNJOZNY-UHFFFAOYSA-N n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(2h-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]-5-propan-2-ylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C2=NNN=N2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 TUYWTLTWNJOZNY-UHFFFAOYSA-N 0.000 description 2
- 239000002833 natriuretic agent Substances 0.000 description 2
- 229960001597 nifedipine Drugs 0.000 description 2
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 2
- 229950010800 niguldipine Drugs 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 2
- 229960005117 olmesartan Drugs 0.000 description 2
- LVRLSYPNFFBYCZ-VGWMRTNUSA-N omapatrilat Chemical compound C([C@H](S)C(=O)N[C@H]1CCS[C@H]2CCC[C@H](N2C1=O)C(=O)O)C1=CC=CC=C1 LVRLSYPNFFBYCZ-VGWMRTNUSA-N 0.000 description 2
- 229950000973 omapatrilat Drugs 0.000 description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 2
- 150000002916 oxazoles Chemical class 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- 235000010603 pastilles Nutrition 0.000 description 2
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical compound C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 229920001184 polypeptide Chemical group 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 125000006238 prop-1-en-1-yl group Chemical group [H]\C(*)=C(/[H])C([H])([H])[H] 0.000 description 2
- 150000003217 pyrazoles Chemical class 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003233 pyrroles Chemical class 0.000 description 2
- 229960003401 ramipril Drugs 0.000 description 2
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- PHWXUGHIIBDVKD-UHFFFAOYSA-N sitaxentan Chemical compound CC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)CC=2C(=CC=3OCOC=3C=2)C)=C1Cl PHWXUGHIIBDVKD-UHFFFAOYSA-N 0.000 description 2
- 229960002578 sitaxentan Drugs 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 2
- 150000003536 tetrazoles Chemical class 0.000 description 2
- 229950000584 tezosentan Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 150000003557 thiazoles Chemical class 0.000 description 2
- 150000003577 thiophenes Chemical class 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000009529 traumatic brain injury Effects 0.000 description 2
- 229910052722 tritium Inorganic materials 0.000 description 2
- 208000019553 vascular disease Diseases 0.000 description 2
- 206010047302 ventricular tachycardia Diseases 0.000 description 2
- 235000012431 wafers Nutrition 0.000 description 2
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical compound N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 description 2
- HMJIYCCIJYRONP-UHFFFAOYSA-N (+-)-Isradipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC2=NON=C12 HMJIYCCIJYRONP-UHFFFAOYSA-N 0.000 description 1
- CEMAWMOMDPGJMB-UHFFFAOYSA-N (+-)-Oxprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1OCC=C CEMAWMOMDPGJMB-UHFFFAOYSA-N 0.000 description 1
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- NXWGWUVGUSFQJC-GFCCVEGCSA-N (2r)-1-[(2-methyl-1h-indol-4-yl)oxy]-3-(propan-2-ylamino)propan-2-ol Chemical compound CC(C)NC[C@@H](O)COC1=CC=CC2=C1C=C(C)N2 NXWGWUVGUSFQJC-GFCCVEGCSA-N 0.000 description 1
- YKFCISHFRZHKHY-NGQGLHOPSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;trihydrate Chemical compound O.O.O.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 YKFCISHFRZHKHY-NGQGLHOPSA-N 0.000 description 1
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 1
- DAEYHJNLHCLZTP-INIZCTEOSA-N (3S)-3-[[5-cyclopentyl-1-[2-(trifluoromethyl)pyridin-3-yl]-1,2,4-triazole-3-carbonyl]amino]-5-(3,3-difluoropiperidin-1-yl)pentanoic acid Chemical compound C1(CCCC1)C1=NC(=NN1C=1C(=NC=CC=1)C(F)(F)F)C(=O)N[C@H](CC(=O)O)CCN1CC(CCC1)(F)F DAEYHJNLHCLZTP-INIZCTEOSA-N 0.000 description 1
- KRZJRNZICWNMOA-GXSJLCMTSA-N (3s,4r)-4,8-dihydroxy-3-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1=CC=C2[C@@H](O)[C@@H](OC)CC(=O)C2=C1O KRZJRNZICWNMOA-GXSJLCMTSA-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
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 1
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- LORRLQMLLQLPSJ-UHFFFAOYSA-N 1,3,5-trithiane Chemical compound C1SCSCS1 LORRLQMLLQLPSJ-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- YIKWKLYQRFRGPM-UHFFFAOYSA-N 1-dodecylguanidine acetate Chemical compound CC(O)=O.CCCCCCCCCCCCN=C(N)N YIKWKLYQRFRGPM-UHFFFAOYSA-N 0.000 description 1
- BGVGHYOIWIALFF-UHFFFAOYSA-N 1-fluoro-2-(trifluoromethyl)benzene Chemical compound FC1=CC=CC=C1C(F)(F)F BGVGHYOIWIALFF-UHFFFAOYSA-N 0.000 description 1
- 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 1
- BSZXAFXFTLXUFV-UHFFFAOYSA-N 1-phenylethylbenzene Chemical compound C=1C=CC=CC=1C(C)C1=CC=CC=C1 BSZXAFXFTLXUFV-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- MFJCPDOGFAYSTF-UHFFFAOYSA-N 1H-isochromene Chemical compound C1=CC=C2COC=CC2=C1 MFJCPDOGFAYSTF-UHFFFAOYSA-N 0.000 description 1
- ODMMNALOCMNQJZ-UHFFFAOYSA-N 1H-pyrrolizine Chemical compound C1=CC=C2CC=CN21 ODMMNALOCMNQJZ-UHFFFAOYSA-N 0.000 description 1
- XIZCDQOKKYYCRH-UHFFFAOYSA-N 1h-benzimidazole-2-carboxamide Chemical class C1=CC=C2NC(C(=O)N)=NC2=C1 XIZCDQOKKYYCRH-UHFFFAOYSA-N 0.000 description 1
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- XZKZVCLLDKWOKM-UHFFFAOYSA-N 2-(trifluoromethyl)pyridin-3-amine Chemical compound NC1=CC=CN=C1C(F)(F)F XZKZVCLLDKWOKM-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical compound C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 description 1
- JIVPVXMEBJLZRO-CQSZACIVSA-N 2-chloro-5-[(1r)-1-hydroxy-3-oxo-2h-isoindol-1-yl]benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC([C@@]2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-CQSZACIVSA-N 0.000 description 1
- GDHXJNRAJRCGMX-UHFFFAOYSA-N 2-fluorobenzonitrile Chemical compound FC1=CC=CC=C1C#N GDHXJNRAJRCGMX-UHFFFAOYSA-N 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- UOGQPXQDNUHUIB-UHFFFAOYSA-N 3,3-difluoropiperidine Chemical compound FC1(F)CCCNC1 UOGQPXQDNUHUIB-UHFFFAOYSA-N 0.000 description 1
- NMKSAYKQLCHXDK-UHFFFAOYSA-N 3,3-diphenyl-N-(1-phenylethyl)-1-propanamine Chemical compound C=1C=CC=CC=1C(C)NCCC(C=1C=CC=CC=1)C1=CC=CC=C1 NMKSAYKQLCHXDK-UHFFFAOYSA-N 0.000 description 1
- XLZYKTYMLBOINK-UHFFFAOYSA-N 3-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C(=O)C=2C=CC(O)=CC=2)=C1 XLZYKTYMLBOINK-UHFFFAOYSA-N 0.000 description 1
- BRMWTNUJHUMWMS-UHFFFAOYSA-N 3-Methylhistidine Natural products CN1C=NC(CC(N)C(O)=O)=C1 BRMWTNUJHUMWMS-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- SKMUADUXCABNRO-UHFFFAOYSA-N 3-methyl-2h-1,3-thiazole Chemical compound CN1CSC=C1 SKMUADUXCABNRO-UHFFFAOYSA-N 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- MJOUJKDTBGXKIU-UHFFFAOYSA-N 4,4-difluoropiperidine Chemical compound FC1(F)CCNCC1 MJOUJKDTBGXKIU-UHFFFAOYSA-N 0.000 description 1
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 1
- GDRVFDDBLLKWRI-UHFFFAOYSA-N 4H-quinolizine Chemical compound C1=CC=CN2CC=CC=C21 GDRVFDDBLLKWRI-UHFFFAOYSA-N 0.000 description 1
- 125000001054 5 membered carbocyclic group Chemical group 0.000 description 1
- RHIVYFPWRDZADG-KRWDZBQOSA-N 5-cyclopentyl-N-[(2S)-4-(3,3-difluoropiperidin-1-yl)-1-(2H-tetrazol-5-yl)butan-2-yl]-1-[2-(trifluoromethyl)phenyl]-1,2,4-triazole-3-carboxamide Chemical compound FC(F)(F)C1=C(C=CC=C1)N1N=C(N=C1C1CCCC1)C(=O)N[C@@H](CCN1CCCC(F)(F)C1)CC1=NN=NN1 RHIVYFPWRDZADG-KRWDZBQOSA-N 0.000 description 1
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 description 1
- 125000004008 6 membered carbocyclic group Chemical group 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
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- FHHHOYXPRDYHEZ-COXVUDFISA-N Alacepril Chemical compound CC(=O)SC[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FHHHOYXPRDYHEZ-COXVUDFISA-N 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010053026 Apelin receptors Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 239000002080 C09CA02 - Eprosartan Substances 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 1
- 239000002081 C09CA05 - Tasosartan Substances 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 1
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- JOATXPAWOHTVSZ-UHFFFAOYSA-N Celiprolol Chemical compound CCN(CC)C(=O)NC1=CC=C(OCC(O)CNC(C)(C)C)C(C(C)=O)=C1 JOATXPAWOHTVSZ-UHFFFAOYSA-N 0.000 description 1
- IFYLTXNCFVRALQ-OALUTQOASA-N Ceronapril Chemical compound O([C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)P(O)(=O)CCCCC1=CC=CC=C1 IFYLTXNCFVRALQ-OALUTQOASA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 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
- 108010016626 Dipeptides Proteins 0.000 description 1
- 108010066671 Enalaprilat Proteins 0.000 description 1
- 108050009340 Endothelin Proteins 0.000 description 1
- 102000002045 Endothelin Human genes 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- XQLWNAFCTODIRK-UHFFFAOYSA-N Gallopamil Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC(OC)=C(OC)C(OC)=C1 XQLWNAFCTODIRK-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 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 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- WDZVGELJXXEGPV-YIXHJXPBSA-N Guanabenz Chemical compound NC(N)=N\N=C\C1=C(Cl)C=CC=C1Cl WDZVGELJXXEGPV-YIXHJXPBSA-N 0.000 description 1
- INJOMKTZOLKMBF-UHFFFAOYSA-N Guanfacine Chemical compound NC(=N)NC(=O)CC1=C(Cl)C=CC=C1Cl INJOMKTZOLKMBF-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101100323464 Homo sapiens APLNR gene Proteins 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- LCWXJXMHJVIJFK-UHFFFAOYSA-N Hydroxylysine Natural products NCC(O)CC(N)CC(O)=O LCWXJXMHJVIJFK-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- OWYWGLHRNBIFJP-UHFFFAOYSA-N Ipazine Chemical compound CCN(CC)C1=NC(Cl)=NC(NC(C)C)=N1 OWYWGLHRNBIFJP-UHFFFAOYSA-N 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 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
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 125000003412 L-alanyl group Chemical group [H]N([H])[C@@](C([H])([H])[H])(C(=O)[*])[H] 0.000 description 1
- 125000000570 L-alpha-aspartyl group Chemical group [H]OC(=O)C([H])([H])[C@]([H])(N([H])[H])C(*)=O 0.000 description 1
- 125000002059 L-arginyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])C(=N[H])N([H])[H] 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- 125000000010 L-asparaginyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(=O)N([H])[H] 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
- 125000000415 L-cysteinyl group Chemical group O=C([*])[C@@](N([H])[H])([H])C([H])([H])S[H] 0.000 description 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- 125000002061 L-isoleucyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](C([H])([H])[H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- 125000003440 L-leucyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 1
- 125000001176 L-lysyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C([H])([H])C([H])([H])C(N([H])[H])([H])[H] 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 125000002435 L-phenylalanyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 1
- 125000002842 L-seryl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])O[H] 0.000 description 1
- 125000000769 L-threonyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](O[H])(C([H])([H])[H])[H] 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 125000002707 L-tryptophyl group Chemical group [H]C1=C([H])C([H])=C2C(C([C@](N([H])[H])(C(=O)[*])[H])([H])[H])=C([H])N([H])C2=C1[H] 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 125000003798 L-tyrosyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 125000003580 L-valyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(C([H])([H])[H])(C([H])([H])[H])[H] 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 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
- 229930195725 Mannitol Natural products 0.000 description 1
- CESYKOGBSMNBPD-UHFFFAOYSA-N Methyclothiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CCl)NC2=C1 CESYKOGBSMNBPD-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- HBNPJJILLOYFJU-VMPREFPWSA-N Mibefradil Chemical compound C1CC2=CC(F)=CC=C2[C@H](C(C)C)[C@@]1(OC(=O)COC)CCN(C)CCCC1=NC2=CC=CC=C2N1 HBNPJJILLOYFJU-VMPREFPWSA-N 0.000 description 1
- UWWDHYUMIORJTA-HSQYWUDLSA-N Moexipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC(OC)=C(OC)C=C2C1)C(O)=O)CC1=CC=CC=C1 UWWDHYUMIORJTA-HSQYWUDLSA-N 0.000 description 1
- JDHILDINMRGULE-LURJTMIESA-N N(pros)-methyl-L-histidine Chemical compound CN1C=NC=C1C[C@H](N)C(O)=O JDHILDINMRGULE-LURJTMIESA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- FAIIFDPAEUKBEP-UHFFFAOYSA-N Nilvadipine Chemical compound COC(=O)C1=C(C#N)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 FAIIFDPAEUKBEP-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 238000006008 O'Donnell synthesis reaction Methods 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
- 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
- 229940122985 Peptide agonist Drugs 0.000 description 1
- 108010043958 Peptoids Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- IFFPICMESYHZPQ-UHFFFAOYSA-N Prenylamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)CCNC(C)CC1=CC=CC=C1 IFFPICMESYHZPQ-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-ZSJDYOACSA-N Sulfuric acid-d2 Chemical compound [2H]OS(=O)(=O)O[2H] QAOWNCQODCNURD-ZSJDYOACSA-N 0.000 description 1
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-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
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- ZROUQTNYPCANTN-UHFFFAOYSA-N Tiapamil Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC1(C=2C=C(OC)C(OC)=CC=2)S(=O)(=O)CCCS1(=O)=O ZROUQTNYPCANTN-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- VXFJYXUZANRPDJ-WTNASJBWSA-N Trandopril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@H]2CCCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 VXFJYXUZANRPDJ-WTNASJBWSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000012382 advanced drug delivery Methods 0.000 description 1
- 229950007884 alacepril Drugs 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- 239000002170 aldosterone antagonist Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 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
- 229910052782 aluminium Inorganic materials 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 1
- 229960002576 amiloride Drugs 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
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 1
- PHFDAOXXIZOUIX-UHFFFAOYSA-N anipamil Chemical compound C=1C=CC(OC)=CC=1C(CCCCCCCCCCCC)(C#N)CCCN(C)CCC1=CC=CC(OC)=C1 PHFDAOXXIZOUIX-UHFFFAOYSA-N 0.000 description 1
- 229950011530 anipamil Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- BVUSIQTYUVWOSX-UHFFFAOYSA-N arsindole Chemical compound C1=CC=C2[As]C=CC2=C1 BVUSIQTYUVWOSX-UHFFFAOYSA-N 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960002274 atenolol Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000003305 autocrine Effects 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 229960004067 benazeprilat Drugs 0.000 description 1
- MADRIHWFJGRSBP-ROUUACIJSA-N benazeprilat Chemical compound C([C@H](N[C@H]1CCC2=CC=CC=C2N(C1=O)CC(=O)O)C(O)=O)CC1=CC=CC=C1 MADRIHWFJGRSBP-ROUUACIJSA-N 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- GPRLTFBKWDERLU-UHFFFAOYSA-N bicyclo[2.2.2]octane Chemical compound C1CC2CCC1CC2 GPRLTFBKWDERLU-UHFFFAOYSA-N 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 229960002781 bisoprolol Drugs 0.000 description 1
- VHYCDWMUTMEGQY-UHFFFAOYSA-N bisoprolol Chemical compound CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VHYCDWMUTMEGQY-UHFFFAOYSA-N 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 description 1
- 229960003065 bosentan Drugs 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000005510 but-1-en-2-yl group Chemical group 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000011111 cardboard Substances 0.000 description 1
- LWAFSWPYPHEXKX-UHFFFAOYSA-N carteolol Chemical compound N1C(=O)CCC2=C1C=CC=C2OCC(O)CNC(C)(C)C LWAFSWPYPHEXKX-UHFFFAOYSA-N 0.000 description 1
- 229960001222 carteolol Drugs 0.000 description 1
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 description 1
- 229960004195 carvedilol Drugs 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229960002320 celiprolol Drugs 0.000 description 1
- 230000030570 cellular localization Effects 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229940083181 centrally acting adntiadrenergic agent methyldopa Drugs 0.000 description 1
- 229950005749 ceronapril Drugs 0.000 description 1
- 229940081733 cetearyl alcohol Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960002155 chlorothiazide Drugs 0.000 description 1
- 229960001523 chlortalidone Drugs 0.000 description 1
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 1
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 229960005025 cilazapril Drugs 0.000 description 1
- HHHKFGXWKKUNCY-FHWLQOOXSA-N cilazapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N2[C@@H](CCCN2CCC1)C(O)=O)=O)CC1=CC=CC=C1 HHHKFGXWKKUNCY-FHWLQOOXSA-N 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 239000008199 coating composition Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 229960005227 delapril Drugs 0.000 description 1
- WOUOLAUOZXOLJQ-MBSDFSHPSA-N delapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N(CC(O)=O)C1CC2=CC=CC=C2C1)CC1=CC=CC=C1 WOUOLAUOZXOLJQ-MBSDFSHPSA-N 0.000 description 1
- YSMODUONRAFBET-UHFFFAOYSA-N delta-DL-hydroxylysine Natural products NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- PSHRANCNVXNITH-UHFFFAOYSA-N dimethylamino acetate Chemical compound CN(C)OC(C)=O PSHRANCNVXNITH-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- RUZYUOTYCVRMRZ-UHFFFAOYSA-N doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 description 1
- 229960001389 doxazosin Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000008387 emulsifying waxe Substances 0.000 description 1
- 229960002680 enalaprilat Drugs 0.000 description 1
- LZFZMUMEGBBDTC-QEJZJMRPSA-N enalaprilat (anhydrous) Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 LZFZMUMEGBBDTC-QEJZJMRPSA-N 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 description 1
- 229960004563 eprosartan Drugs 0.000 description 1
- YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 description 1
- AQNDDEOPVVGCPG-UHFFFAOYSA-N esmolol Chemical compound COC(=O)CCC1=CC=C(OCC(O)CNC(C)C)C=C1 AQNDDEOPVVGCPG-UHFFFAOYSA-N 0.000 description 1
- 229960003745 esmolol Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- KLWYPRNPRNPORS-UHFFFAOYSA-N ethyl 1h-imidazole-5-carboxylate Chemical compound CCOC(=O)C1=CN=CN1 KLWYPRNPRNPORS-UHFFFAOYSA-N 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229950011548 fadrozole Drugs 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 229960003580 felodipine Drugs 0.000 description 1
- 229960002602 fendiline Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- SMANXXCATUTDDT-QPJJXVBHSA-N flunarizine Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)N1CCN(C\C=C\C=2C=CC=CC=2)CC1 SMANXXCATUTDDT-QPJJXVBHSA-N 0.000 description 1
- 229960000326 flunarizine Drugs 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 229960002490 fosinopril Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 229960000457 gallopamil Drugs 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 229960004553 guanabenz Drugs 0.000 description 1
- 229960002048 guanfacine Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- QJHBJHUKURJDLG-UHFFFAOYSA-N hydroxy-L-lysine Natural products NCCCCC(NO)C(O)=O QJHBJHUKURJDLG-UHFFFAOYSA-N 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960002198 irbesartan Drugs 0.000 description 1
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 1
- RGXCTRIQQODGIZ-UHFFFAOYSA-O isodesmosine Chemical compound OC(=O)C(N)CCCC[N+]1=CC(CCC(N)C(O)=O)=CC(CCC(N)C(O)=O)=C1CCCC(N)C(O)=O RGXCTRIQQODGIZ-UHFFFAOYSA-O 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 229960004427 isradipine Drugs 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 229960004340 lacidipine Drugs 0.000 description 1
- GKQPCPXONLDCMU-CCEZHUSRSA-N lacidipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C1=CC=CC=C1\C=C\C(=O)OC(C)(C)C GKQPCPXONLDCMU-CCEZHUSRSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 239000002171 loop diuretic Substances 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 235000019793 magnesium trisilicate 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
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960003134 mepindolol Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 description 1
- 150000005217 methyl ethers Chemical class 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 229960002237 metoprolol Drugs 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 229960004438 mibefradil Drugs 0.000 description 1
- 229940042472 mineral oil Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960005170 moexipril Drugs 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- OWIUPIRUAQMTTK-UHFFFAOYSA-M n-aminocarbamate Chemical compound NNC([O-])=O OWIUPIRUAQMTTK-UHFFFAOYSA-M 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 229960004255 nadolol Drugs 0.000 description 1
- VWPOSFSPZNDTMJ-UCWKZMIHSA-N nadolol Chemical compound C1[C@@H](O)[C@@H](O)CC2=C1C=CC=C2OCC(O)CNC(C)(C)C VWPOSFSPZNDTMJ-UCWKZMIHSA-N 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000001452 natriuretic effect Effects 0.000 description 1
- 229960001783 nicardipine Drugs 0.000 description 1
- 229960005366 nilvadipine Drugs 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 229960000227 nisoldipine Drugs 0.000 description 1
- 229960005425 nitrendipine Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910000069 nitrogen hydride 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
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 108091008880 orphan GPCRs Proteins 0.000 description 1
- 238000007827 osmolarity assay Methods 0.000 description 1
- 229960004570 oxprenolol Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000011087 paperboard Substances 0.000 description 1
- 230000003076 paracrine Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000004963 pathophysiological condition Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229960002035 penbutolol Drugs 0.000 description 1
- KQXKVJAGOJTNJS-HNNXBMFYSA-N penbutolol Chemical compound CC(C)(C)NC[C@H](O)COC1=CC=CC=C1C1CCCC1 KQXKVJAGOJTNJS-HNNXBMFYSA-N 0.000 description 1
- AEABQBMUYZBBCW-UHFFFAOYSA-N pentanamide Chemical compound CC[CH]CC(N)=O AEABQBMUYZBBCW-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002263 peptidergic effect Effects 0.000 description 1
- 229960002582 perindopril Drugs 0.000 description 1
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 229960001289 prazosin Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 229960001989 prenylamine Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 229960001455 quinapril Drugs 0.000 description 1
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 1
- 229960001007 quinaprilat Drugs 0.000 description 1
- FLSLEGPOVLMJMN-YSSFQJQWSA-N quinaprilat Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)C(O)=O)CC1=CC=CC=C1 FLSLEGPOVLMJMN-YSSFQJQWSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 229960002231 ramiprilat Drugs 0.000 description 1
- KEDYTOTWMPBSLG-HILJTLORSA-N ramiprilat Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)C(O)=O)CC1=CC=CC=C1 KEDYTOTWMPBSLG-HILJTLORSA-N 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000000894 saliuretic effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 229960002909 spirapril Drugs 0.000 description 1
- HRWCVUIFMSZDJS-SZMVWBNQSA-N spirapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2(C1)SCCS2)C(O)=O)CC1=CC=CC=C1 HRWCVUIFMSZDJS-SZMVWBNQSA-N 0.000 description 1
- 108700035424 spirapril Proteins 0.000 description 1
- CTDQAGUNKPRERK-UHFFFAOYSA-N spirodecane Chemical compound C1CCCC21CCCCC2 CTDQAGUNKPRERK-UHFFFAOYSA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013269 sustained drug release Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229960002613 tamsulosin Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960000651 tasosartan Drugs 0.000 description 1
- ADXGNEYLLLSOAR-UHFFFAOYSA-N tasosartan Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ADXGNEYLLLSOAR-UHFFFAOYSA-N 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 229960004084 temocapril Drugs 0.000 description 1
- FIQOFIRCTOWDOW-BJLQDIEVSA-N temocapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C[C@H](SC1)C=1SC=CC=1)=O)CC1=CC=CC=C1 FIQOFIRCTOWDOW-BJLQDIEVSA-N 0.000 description 1
- 230000028016 temperature homeostasis Effects 0.000 description 1
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 1
- 229960001693 terazosin Drugs 0.000 description 1
- IKEJTVFYONIBIP-SFHVURJKSA-N tert-butyl (3S)-3-[[1-cyclopentyl-5-[3-(trifluoromethyl)pyridin-2-yl]-1,2,4-triazole-3-carbonyl]amino]-5-(3,3-difluoropiperidin-1-yl)pentanoate Chemical compound CC(C)(C)OC(=O)C[C@H](CCN1CCCC(F)(F)C1)NC(=O)c1nc(-c2ncccc2C(F)(F)F)n(n1)C1CCCC1 IKEJTVFYONIBIP-SFHVURJKSA-N 0.000 description 1
- QZDSRISEIRZLNS-NRFANRHFSA-N tert-butyl (3S)-3-[[2-cyclopentyl-1-[2-(trifluoromethyl)phenyl]imidazole-4-carbonyl]amino]-5-(3,3-difluoropiperidin-1-yl)pentanoate Chemical compound CC(C)(C)OC(=O)C[C@H](CCN1CCCC(F)(F)C1)NC(=O)c1cn(c(n1)C1CCCC1)-c1ccccc1C(F)(F)F QZDSRISEIRZLNS-NRFANRHFSA-N 0.000 description 1
- NLINDCBXKNQSPJ-IBGZPJMESA-N tert-butyl (3S)-3-[[5-cyclopentyl-1-[2-(trifluoromethyl)pyridin-3-yl]-1,2,4-triazole-3-carbonyl]amino]-5-(3,3-difluoropiperidin-1-yl)pentanoate Chemical compound CC(C)(C)OC(=O)C[C@H](CCN1CCCC(F)(F)C1)NC(=O)c1nc(C2CCCC2)n(n1)-c1cccnc1C(F)(F)F NLINDCBXKNQSPJ-IBGZPJMESA-N 0.000 description 1
- JQQJGTQKMJCMGT-UHFFFAOYSA-N tert-butyl n-(cyclopentylamino)carbamate Chemical compound CC(C)(C)OC(=O)NNC1CCCC1 JQQJGTQKMJCMGT-UHFFFAOYSA-N 0.000 description 1
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 150000004897 thiazines Chemical class 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229950003137 tiapamil Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229960002051 trandolapril Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000005167 vascular cell Anatomy 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229960002769 zofenopril Drugs 0.000 description 1
- IAIDUHCBNLFXEF-MNEFBYGVSA-N zofenopril Chemical compound C([C@@H](C)C(=O)N1[C@@H](C[C@@H](C1)SC=1C=CC=CC=1)C(O)=O)SC(=O)C1=CC=CC=C1 IAIDUHCBNLFXEF-MNEFBYGVSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
- C07D233/66—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 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
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- 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
- C07D403/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pulmonology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Gastroenterology & Hepatology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Child & Adolescent Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本申请内容涉及具有杂环核的爱帕琳肽受体(APJ)激活剂和这种激动剂的用途。
Description
相关申请的交叉引用
本申请要求2016年10月12日提交的美国临时专利申请号62/407,206的权益,其全部内容通过引用并入本文。
1.领域
本公开内容大体上涉及爱帕琳肽受体(apelin receptor,APJ)激动剂和这种激动剂的用途。
2.背景
2.1引言:爱帕琳肽和爱帕琳肽受体(APJ)
爱帕琳肽受体(APJ)在1993年作为孤儿G蛋白偶联受体(GPCR)被克隆出来。人类APJ基因位于染色体11的长臂上,并且编码377氨基酸的G蛋白偶联受体。由于两种受体之间的序列相似性,APJ的基因被命名为血管紧张素受体样1(AGTRL1)。Carpene等人,J PhysiolBiochem.2007;63(4):359–373。然而,血管紧张素受体的已知肽能配体(包括血管紧张素)均不激活APJ。直到1998年,APJ仍然是孤儿GPCR,这一年肽即爱帕琳肽被鉴定为其内源性配体。Lee等人,J Neurochem.2000;74(1):34–41;Habata等人,Biochim Biophys Acta.1999;1452(1):25-35。
多年来,爱帕琳肽和APJ已成为各种生理过程的重要调节剂。爱帕琳肽和APJ两者均在中枢神经系统(CNS)中表达,并在许多组织中在外周表达。APJ的表达已经在某些器官的脉管系统中被注意到,并且是相关过程的有效调节剂,该相关过程包括血管生成和血管收缩。Cobellis等人报道了在先兆子痫并发的妊娠中爱帕琳肽和APJ受体两者的表达水平增加。Cobellis等人,Histol Histopathol.2007;22(1):1-8。APJ还在心脏、肝脏和CNS的非血管细胞类型中表达,其中APJ的主要作用目前正在研究中。Medhurst等人,JNeurochem.2003;84(5):1162–1172。爱帕琳肽和APJ通常共同定位于同一器官内,这表明该受体通过其配体的自分泌调节。然而,爱帕琳肽已经在血液中被检测到,这表明该受体的并行旁分泌调节也是可能的。爱帕琳肽-APJ系统已被认为是各种生理功能的调节剂,并且被认为在体温调节、免疫、葡萄糖代谢、血管生成、体液平衡(fluid homeostasis)、心脏功能、肝功能和肾功能中起重要作用。Ladeiras-Lopes等人,Arq Bras Cardiol.2008;90(5):343–349。在HIV感染期间,APJ还充当共受体。O’Donnell等人,J Neurochem.2007;102(6):1905–1917;Zou等人,FEBS Lett.2000;473(1):15–18。
爱帕琳肽和APJ的表达在各种病理生理病症中上调或下调。具体地,APJ是治疗心血管衰竭、肝纤维化、癌症、血管病、胰腺炎以及预防HIV感染的新兴靶标。具体地,APJ表现为是用于治疗心血管衰竭、肝纤维化、癌症、血管病、胰腺炎以及作为预防HIV感染的新兴靶。在2011年,Andersen等人的综述中将爱帕琳肽和APJ认定为具有肺性高血压和肺动脉高血压(PAH)治疗用途的可能。Andersen等人Pulm.Circ.2011;1(3)334-346。
遗憾地是,缺乏具有合适药理学性质的APJ的小分子配体。迄今为止,鲜有非肽配体系统的报道。Iturrioz等人报告含有多环荧光团的化合物如丽丝胺(lissamine),这使得它们不适合用于制药用途。Iturrioz等人,FASEB J.2010;24:1506-1517;EP 1903052(Llorens-Cortes等人)。美国公开专利申请2014/0094450(Hachtel等人)公开了苯并咪唑-羧酸酰胺衍生物作为APJ受体调节剂。
因此,需要APJ的小分子激动剂。
3.发明概述
在具体的非限制性实施方案中,本公开提供了由式I表示的化合物、或药学上可接受的盐、前药或前药的盐,式I为:
其中环A为5元杂芳环;每个G1独立地选自C或N;每个G2独立地选自CH或N;每两个G1或G2之间的键为单键或双键,以使环A成为芳香杂环,其中环中至少一个G1或G2为N,并且环中G1或G2中的最多三个同时为N;条件是如果环A中有两个N,且连接至R2的G1为N,则相邻的G2不是N;R1由下式表示:
其中是单环的芳基或杂芳基基团;每个A独立地为C1-8烷基、C1-8烷基(芳基)、C1-8烷氧基、C1-8烷氧基芳基、C2-8烯基、C3-8炔基、C3-8环烷基、-CF3、-(CH2)xNR7R8、-CN、-CONR7R8、-COR7、-CO2(CH2)xNR7R8、-CO2R7、卤素、羟基、-N3、-NHCOR7、-NHSO2C1-8烷基、-NHCO2C1-8烷基、-NO2、-NR7R8、-O(CH2)xNR7R8、-O(CH2)xCO2R7、-OCOC1-8烷基、-OCO(CH2)xNR7R8、-SO2NR7R8、-SO(1-3)R7或-SR7;
R7和R8独立地为C1-8烷氧基、芳基、C1-8烷基、C1-8烷基醇、C1-8烷基氨基、C1-8烷基酰氨基、C1-8烷基(芳基)、C1-8烷基(C3-8环烷基)、C1-8烷基胍基、C1-8烷基杂芳基、C1-8烷基硫醚、C1-8烷基硫醇、C2-8烯基、C3-8炔基、C3-8环烷基、-(CH2)xCONHR9、-(CH2)xCOR9、-(CH2)xCO2R9、H或杂芳基;或者R7和R8一起形成可含有一个或更多个杂原子的3-9元环;或者R7和R8一起形成具有一个或更多个羰基基团的5-8元含氮环;n是1、2、3、4或5;R2是任选取代的C3-8烷基或任选取代的C0-8烷基-R10,其中R10是3-至8-元环,其任选地含有一个或多个选自N、O或S的杂原子并任选地具有一个或多个不饱和度;R3是H;R4和R5独立地为金刚烷基、芳基、C1-8烷基、C1-8烷基醇、C1-8烷基氨基、C1-8烷基酰氨基、C2-8烷基(芳基)、C1-8烷基(C3-8环烷基)、C1-8烷基(C3-8环烷基)-CO2R7、C1-8烷基胍基、C1-8烷基杂芳基、C2-4烷基杂环烷基、C1-8烷基硫醚、C1-8烷基硫醇、C2-8烯基、C2-8烯基(芳基)、C2-8烯基(杂芳基)、C3-8炔基、C3-8环烷基、C3-8环烷基-CO2R7、-(CH2)xNR7R8、-(CH2)xOR7、-(CH2)xNR9COR7、-(CH2)xNR9SO2R7、-(CH2)xNR9CO2R7、-(CH2)xNHCOR7、-(CH2)xNHSO2R7、-(CH2)xNHCO2R7、-(CH2)xCONR7R8、-(CH2)xCONR7(CH2)yCO2R9、-(CH2)xCONR7(CH2)yCONR7R8、-(CH2)xCONR7(CH2)yR9、-(CH2)xCO7、-(CH2)xCO2R7、-(CH2)xSO2NR7(CH2)yR9、-CHR7COR9、-CHR7CONHCHR8COR9、-CONR7R8、-CONR7(CH2)xCO2R8、-CONR7CHR8CO2R9、-CO2R9、H或-NHCO2R7;-(CH2)xSO2NR7R8;或者R4和R5一起形成可以被一个或更多个杂原子取代的4-8元环;或者R4和R5一起形成具有一个或更多个羰基基团的5-8元含氮环;R9是芳基、C1-8烷氧基、C1-8烷基、C1-8烷基(芳基)、C3-8环烷基、H、杂芳基或羟基;每个x独立地为0-8;并且每个y独立地为1-8。
式II代表的化合物、或药学上可接受的盐、前药或前药的盐:
其中环A是5元杂芳环;每个G1独立地选自C或N;每个G2或G3独立地选自CH、N、O或S;其中至少一个G2或G3为O或S;如果G2为O或S,则G3为CH或N;如果G3为O或S,则G2为CH或N;G1、G2或G3每两个之间的键是单键或双键,以使环A成为芳香杂环,并且环中G1、G2或G3的最多两个同时为N;R1由下式表示:
其中是单环的芳基或杂芳基基团;每个A独立地为C1-8烷基、C1-8烷基(芳基)、C1-8烷氧基、C1-8烷氧基芳基、C2-8烯基、C3-8炔基、C3-8环烷基、-CF3、-(CH2)xNR7R8、-CN、-CONR7R8、-COR7、-CO2(CH2)xNR7R8、-CO2R7、卤素、羟基、-N3、-NHCOR7、-NHSO2C1-8烷基、-NHCO2C1-8烷基、-NO2、-NR7R8、-O(CH2)xNR7R8、-O(CH2)xCO2R7、-OCOC1-8烷基、-OCO(CH2)xNR7R8、-SO2NR7R8、-SO(1-3)R7或-SR7;
R7和R8独立地为C1-8烷氧基、芳基、C1-8烷基、C1-8烷基醇、C1-8烷基氨基、C1-8烷基酰氨基、C1-8烷基(芳基)、C1-8烷基(C3-8环烷基)、C1-8烷基胍基、C1-8烷基杂芳基、C1-8烷基硫醚、C1-8烷基硫醇、C2-8烯基、C3-8炔基、C3-8环烷基、-(CH2)xCONHR9、-(CH2)xCOR9、-(CH2)xCO2R9、H或杂芳基;或者R7和R8一起形成可含有一个或更多个杂原子的3-9元环;或者R7和R8一起形成具有一个或更多个羰基基团的5-8元含氮环;n是1、2、3、4或5;R2是任选取代的C3-8烷基或任选取代的C0-8烷基-R10,其中R10是3-至8-元环,其任选地含有一个或多个选自N、O或S的杂原子并任选地具有一个或多个不饱和度;R3是H;R4和R5独立地为金刚烷基、芳基、C1-8烷基、C1-8烷基醇、C1-8烷基氨基、C1-8烷基酰氨基、C2-8烷基(芳基)、C1-8烷基(C3-8环烷基)、C1-8烷基(C3-8环烷基)-CO2R7、C1-8烷基胍基、C1-8烷基杂芳基、C2-4烷基杂环烷基、C1-8烷基硫醚、C1-8烷基硫醇、C2-8烯基、C2-8烯基(芳基)、C2-8烯基(杂芳基)、C3-8炔基、C3-8环烷基、C3-8环烷基-CO2R7、-(CH2)xNR7R8、-(CH2)xOR7、-(CH2)xNR9COR7、-(CH2)xNR9SO2R7、-(CH2)xNR9CO2R7、-(CH2)xNHCOR7、-(CH2)xNHSO2R7、-(CH2)xNHCO2R7、-(CH2)xCONR7R8、-(CH2)xCONR7(CH2)yCO2R9、-(CH2)xCONR7(CH2)yCONR7R8、-(CH2)xCONR7(CH2)yR9、-(CH2)xCOR7、-(CH2)xCO2R7、-(CH2)xSO2NR7(CH2)yR9、-CHR7COR9、-CHR7CONHCHR8COR9、-CONR7R8、-CONR7(CH2)xCO2R8、-CONR7CHR8CO2R9、-CO2R9、H或-NHCO2R7;-(CH2)xSO2NR7R8;或者R4和R5一起形成可以被一个或更多个杂原子取代的4-8元环;或者R4和R5一起形成具有一个或更多个羰基基团的5-8元含氮环;R9是芳基、C1-8烷氧基、C1-8烷基、C1-8烷基(芳基)、C3-8环烷基、H、杂芳基或羟基;每个x独立地为0-8;并且每个y独立地为1-8。
“发明概述”第1段落中所述的化合物,其由式III表示:
“发明概述”第1段落中所述的化合物,其由式IV表示:
“发明概述”第1段落中所述的化合物,其由式V表示:
上数第1-5个段落中任一段所述的化合物,其中是单环的芳基基团;其中n是1或2;每个A独立地为C1-4烷氧基、C1-4烷氧基芳基或卤素;R2为取代的芳基、取代的杂芳基、未取代的杂芳基、C2-8烷基或C3-8环烷基;R4为C1-8烷基、C2-8烷基(芳基)、C1-8烷基(C3-8环烷基)或-CO2R9;R5为-(CH2)xCNHCOR7、-(CH2)xCNHCO2R7、-(CH2)xCONR7R8、-(CH2)xCONR7(CH2)yCO2R9、-(CH2)xCONR7(CH2)yCONR7R8、-(CH2)xCONR7(CH2)yR9、-(CH2)xCOR7、-(CH2)xCO2R7、-CHR7COR9、-CHR7CONHCHR8COR9、-CONR7R8、-CONR7(CH2)xCO2R8或-CO2R9;R6为H;R9为C1-8烷基、H或杂芳基,该杂芳基为噁唑;
x为1-4;y为1-3;且Z为=O。
上数第1-6个段落中任一段所述的化合物,其中n是1或2;每个A独立地为C1烷氧基、C1烷氧基芳基或卤素;R2为取代的芳基、未取代的杂芳基、取代的杂芳基、C4烷基或C6环烷基;R4为C1-8烷基、C2-8烷基(芳基)、C1-8烷基(C3-8环烷基)或-CO2R9;R5为-(CH2)xCNHCOR7、-(CH2)xCNHCO2R7、-(CH2)xCONR7R8、-(CH2)xCONR7(CH2)yCO2R9、-(CH2)xCONR7(CH2)yCONR7R8、-(CH2)xCONR7(CH2)yR9、-(CH2)xCOR7、-(CH2)xCO2R7、-CHR7COR9、-CHR7CONHCHR8COR9、-CONR7R8、-CONR7(CH2)xCO2R8或-CO2R9;R6为H;R8为C1-4烷基或H;R9为C1-8烷基、H或杂芳基,该杂芳基为噁唑;x为1-4;y为1-3;且Z为=O。
上数第1-7个段落中任一段所述的化合物,其中每个A独立地为C1–C3烷氧基、C1-C3烷基、氯或氟。
上一段落中所述的化合物,其中每个A独立地为氟取代的C1–C3烷氧基或氟取代的C1-C3烷基。
上数第1-9个段落中任一段所述的化合物,其中R2为任选取代的5或6元杂芳基环、-C4H9、-C5H11、-cC4H8或-cC5H10。
上数第1-10个段落中任一段所述的化合物,其中R4为C1-8烷基(芳基)、C1-8烷基杂芳基、C2-8烯基(芳基)或C2-8烯基(杂芳基)。
上一段落中所述的化合物,其中R4为C1-8烷基(二氟芳基)、C1-8烷基二氟杂芳基、C2-8烯基(二氟芳基)或C2-8烯基(二氟杂芳基)。
上数第1-12段落中任一段所述的化合物,其中R8为杂芳基。
上一段落中所述的化合物,其中R8为噁二唑、噁唑、n-甲基噻唑、四唑、噻唑或三唑。
“发明概述”第1个段落中所述的化合物,其中所述化合物为(3S)-N-环丁基-3-({5-环戊基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲酰氨基)-5-(哌啶-1-基)戊酰胺、(3S)-N-环丁基-3-({1-环戊基-5-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲酰氨基)-5-(哌啶-1-基)戊酰胺、(3S)-N-环丁基-3-({1-环戊基-5-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酰胺、(3S)-N-环丁基-3-({5-环戊基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酰胺、(3S)-3-({5-环戊基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲酰氨基)-5-(3,3-二氟哌啶-1-基)-N-甲基-N-(1,3-噻唑-2-基)戊酰胺、(3S)-3-({1-环戊基-5-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲酰氨基)-5-(3,3-二氟哌啶-1-基)-N-甲基-N-(1,3-噻唑-2-基)戊酰胺、(3S)-3-({5-环戊基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酸、(3S)-3-({1-环戊基-5-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酸、(3S)-N-环丁基-3-({2-环戊基-1-[2-(三氟甲基)苯基]-1H-咪唑-4-基}甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酰胺、(3S)-3-({2-环戊基-1-[2-(三氟甲基)苯基]-1H-咪唑-4-基}甲酰氨基)-5-(3,3-二氟哌啶-1-基)-N-甲基-N-(1,3-噻唑-2-基)戊酰胺、(3S)-3-(1-{5-环戊基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}-N-甲基甲酰氨基)-5-(3,3-二氟哌啶-1-基)-N-甲基-N-(1,3-噻唑-2-基)戊酰胺、(3S)-3-{[4-(2-氯苯基)-1-甲基-5-(2-甲基丙基)-1H-咪唑-2-基]甲酰氨基}-5-(3,3-二氟哌啶-1-基)戊酸、(3S)-3-{[4-(2-氯苯基)-1-甲基-5-(2-甲基丙基)-1H-咪唑-2-基]甲酰氨基}-5-(3,3-二氟哌啶-1-基)-N-甲基-N-(1,3-噻唑-2-基)戊酰胺、(3S)-3-{[4-(2-氯苯基)-1-甲基-5-(2-甲基丙基)-1H-咪唑-2-基]甲酰氨基}-N-环丁基-5-(3,3-二氟哌啶-1-基)戊酰胺、(3S)-3-({1-环戊基-5-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酸、(3S)-3-({5-环戊基-1-[2-(三氟甲基)吡啶-3-基]-1H-1,2,4-三唑-3-基}甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酸、(3S)-N-环丁基-3-({1-环戊基-5-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酰胺、(3S)-N-环丁基-3-({5-环戊基-1-[2-(三氟甲基)吡啶-3-基]-1H-1,2,4-三唑-3-基}甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酰胺、(3S)-N-环丁基-3-({1-环戊基-5-[2-(三氟甲基)吡啶-3-基]-1H-1,2,4-三唑-3-基}甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酰胺、(2S)-2-({5-环戊基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲酰氨基)-N-(2-甲氧基乙基)-N-甲基-4-苯基丁酰胺、(2S)-2-({1-环戊基-5-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲酰氨基)-N-(2-甲氧基乙基)-N-甲基-4-苯基丁酰胺、(3S)-3-({5-环戊基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲酰氨基)-5-(3,3-二氟吡咯烷-1-基)戊酸、5-环戊基-N-[(2S)-4-(3,3-二氟哌啶-1-基)-1-(1H-1,2,3,4-四唑-5-基)丁-2-基]-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-甲酰胺或(3S)-3-({2-环戊基-1-[2-(三氟甲基)苯基]-1H-咪唑-4-基}甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酸。
药物组合物,所述药物组合物包含至少一种药学上可接受的赋形剂和治疗有效量的“发明概述”第1-15段落中任一段所述的化合物。
上一段落的药物组合物,其中所述治疗有效量是有效降低血压的量。
上数第2个段落中所述的药物组合物,其中所述治疗有效量是有效治疗以下疾病的量:哮喘、心肌病、糖尿病、血脂异常、高血压、炎症、肝病、代谢紊乱、神经退行性疾病、肥胖症、先兆子痫或肾功能障碍。
上一段落的药物组合物,其中所述高血压是肺动脉高血压。
上数第2个段落的药物组合物,其中所述肝病是酒精性肝病、毒物诱导的肝病或病毒诱导的肝病。
上数第3个段落的药物组合物,其中所述肾功能障碍是多囊性肾病。
上数第6个段落的药物组合物,其中所述治疗有效量是有效治疗静脉相关的病症的量。
上数第7个段落的药物组合物,其中所述治疗有效量是有效治疗血管瘤、静脉功能不全、淤滞或血栓症的量。
上数第8个段落的药物组合物,其中所述治疗有效量是有效减少HIV相关的神经退行的可能性的量。
式II代表的化合物、或药学上可接受的盐、前药或前药的盐在治疗爱帕琳肽受体(APJ)相关的病症中的用途:
其中环A是5元杂芳环;每个G1独立地选自C或N;每个G2或G3独立地选自CH、N、O或S;其中至少一个G2或G3为O或S;如果G2为O或S,则G3为CH或N;如果G3为O或S,则G2为CH或N;G1、G2或G3每两个之间的键是单键或双键,以使环A成为芳香杂环,并且环中G1、G2或G3的最多两个同时为N;R1由下式表示:
其中是单环的芳基或杂芳基基团;每个A独立地为C1-8烷基、C1-8烷基(芳基)、C1-8烷氧基、C1-8烷氧基芳基、C2-8烯基、C3-8炔基、C3-8环烷基、-CF3、-(CH2)xNR7R8、-CN、-CONR7R8、-COR7、-CO2(CH2)xNR7R8、-CO2R7、卤素、羟基、-N3、-NHCOR7、-NHSO2C1-8烷基、-NHCO2C1-8烷基、-NO2、-NR7R8、-O(CH2)xNR7R8、-O(CH2)xCO2R7、-OCOC1-8烷基、-OCO(CH2)xNR7R8、-SO2NR7R8、-SO(1-3)R7或-SR7;R7和R8独立地为C1-8烷氧基、芳基、C1-8烷基、C1-8烷基醇、C1-8烷基氨基、C1-8烷基酰氨基、C1-8烷基(芳基)、C1-8烷基(C3-8环烷基)、C1-8烷基胍基、C1-8烷基杂芳基、C1-8烷基硫醚、C1-8烷基硫醇、C2-8烯基、C3-8炔基、C3-8环烷基、-(CH2)xCONHR9、-(CH2)xCOR9、-(CH2)xCO2R9、H或杂芳基;或者R7和R8一起形成可含有一个或更多个杂原子的3-9元环;或者R7和R8一起形成具有一个或更多个羰基基团的5-8元含氮环;n是1、2、3、4或5;R2是任选取代的C3-8烷基或任选取代的C0-8烷基-R10,其中R10是3-至8-元环,其任选地含有一个或多个选自N、O或S的杂原子并任选地具有一个或多个不饱和度;R3为H;R4和R5独立地为金刚烷基、芳基、C1-8烷基、C1-8烷基醇、C1-8烷基氨基、C1-8烷基酰氨基、C2-8烷基(芳基)、C1-8烷基(C3-8环烷基)、C1-8烷基(C3-8环烷基)CO2R7、C1-8烷基胍基、C1-8烷基杂芳基、C2-4烷基杂环烷基、C1-8烷基硫醚、C1-8烷基硫醇、C2-8烯基、C2-8烯基(芳基)、C2-8烯基(杂芳基)、C3-8炔基、C3-8环烷基、C3-8环烷基-CO2R7、-(CH2)xNR7R8、-(CH2)xOR7、-(CH2)xNR9COR7、-(CH2)xNR9SO2R7、-(CH2)xNR9CO2R7、-(CH2)xNHCOR7、-(CH2)xNHSO2R7、-(CH2)xNHCO2R7、-(CH2)xCONR7R8、-(CH2)xCONR7(CH2)yCO2R9、-(CH2)xCONR7(CH2)yCONR7R8、-(CH2)xCONR7(CH2)yR9、-(CH2)xCOR7、-(CH2)xCO2R7、-(CH2)xSO2NR7(CH2)yR9、-CHR7COR9、-CHR7CONHCHR8COR9、-CONR7R8、-CONR7(CH2)xCO2R8、-CONR7CHR8CO2R9、-CO2R9、H或-NHCO2R7;-(CH2)xSO2NR7R8,或者R4和R5一起形成可以被一个或更多个杂原子取代的4-8元环;或者R4和R5一起形成具有一个或更多个羰基基团的5-8元含氮环;R9是芳基、C1-8烷氧基、C1-8烷基、C1-8烷基(芳基)、C3-8环烷基、H、杂芳基或羟基;每个x独立地为0-8;并且每个y独立地为1-8。
式II代表的化合物、或药学上可接受的盐、前药或前药的盐在治疗爱帕琳肽受体(APJ)相关的病症中的用途:
其中环A是5元杂芳环;每个G1独立地选自C或N;每个G2或G3独立地选自CH、N、O或S;其中至少一个G2或G3为O或S;如果G2为O或S,则G3为CH或N;如果G3为O或S,则G2为CH或N;G1、G2或G3每两个之间的键是单键或双键,以使环A成为芳香杂环,并且环中G1、G2或G3的最多两个同时为N;
R1由下式表示:
其中是单环的芳基或杂芳基基团;每个A独立地为C1-8烷基、C1-8烷基(芳基)、C1-8烷氧基、C1-8烷氧基芳基、C2-8烯基、C3-8炔基、C3-8环烷基、-CF3、-(CH2)xNR7R8、-CN、-CONR7R8、-COR7、-CO2(CH2)xNR7R8、-CO2R7、卤素、羟基、-N3、-NHCOR7、-NHSO2C1-8烷基、-NHCO2C1-8烷基、-NO2、-NR7R8、-O(CH2)xNR7R8、-O(CH2)xCO2R7、-OCOC1-8烷基、-OCO(CH2)xNR7R8、-SO2NR7R8、-SO(1-3)R7或-SR7;R7和R8独立地为C1-8烷氧基、芳基、C1-8烷基、C1-8烷基醇、C1-8烷基氨基、C1-8烷基酰氨基、C1-8烷基(芳基)、C1-8烷基(C3-8环烷基)、C1-8烷基胍基、C1-8烷基杂芳基、C1-8烷基硫醚、C1-8烷基硫醇、C2-8烯基、C3-8炔基、C3-8环烷基、-(CH2)xCONHR9、-(CH2)xCOR9、-(CH2)xCO2R9、H或杂芳基;或者R7和R8一起形成可含有一个或更多个杂原子的3-9元环;或者R7和R8一起形成具有一个或更多个羰基基团的5-8元含氮环;n是1、2、3、4或5;R2是任选取代的C3-8烷基或任选取代的C0-8烷基-R10,其中R10是3-至8-元环,其任选地含有一个或多个选自N、O或S的杂原子并任选地具有一个或多个不饱和度;R3为H;R4和R5独立地为金刚烷基、芳基、C1-8烷基、C1-8烷基醇、C1-8烷基氨基、C1-8烷基酰氨基、C2-8烷基(芳基)、C1-8烷基(C3-8环烷基)、C1-8烷基(C3-8环烷基)-CO2R7、C1-8烷基胍基、C1-8烷基杂芳基、C2-4烷基杂环烷基、C1-8烷基硫醚、C1-8烷基硫醇、C2-8烯基、C2-8烯基(芳基)、C2-8烯基(杂芳基)、C3-8炔基、C3-8环烷基、C3-8环烷基-CO2R7、-(CH2)xNR7R8、-(CH2)xOR7、-(CH2)xNR9COR7、-(CH2)xNR9SO2R7、-(CH2)xNR9CO2R7、-(CH2)xNHCOR7、-(CH2)xNHSO2R7、-(CH2)xNHCO2R7、-(CH2)xCONR7R8、-(CH2)xCONR7(CH2)yCO2R9、-(CH2)xCONR7(CH2)yCONR7R8、-(CH2)xCONR7(CH2)yR9、-(CH2)xCOR7、-(CH2)xCO2R7、-(CH2)xSO2NR7(CH2)yR9、-CHR7COR9、-CHR7CONHCHR8COR9、-CONR7R8、-CONR7(CH2)xCO2R8、-CONR7CHR8CO2R9、-CO2R9、H或-NHCO2R7、-(CH2)xSO2NR7R8;或者R4和R5一起形成可以被一个或更多个杂原子取代的4-8元环;或者R4和R5一起形成具有一个或更多个羰基基团的5-8元含氮环;R9是芳基、C1-8烷氧基、C1-8烷基、C1-8烷基(芳基)、C3-8环烷基、H、杂芳基或羟基;每个x独立地为0-8;并且每个y独立地为1-8。
上面两个段落中任一段的用途,其中该化合物具有如上所限定的式I、III、IV或V。
上面3个段落中任一段的用途,其中所述爱帕琳肽受体(APJ)相关的病症是哮喘、心肌病、糖尿病、血脂异常、高血压、炎症、肝病、代谢紊乱、神经退行性疾病、肥胖症、先兆子痫或肾功能障碍。
上一段落的用途,其中所述高血压是肺动脉高血压。
上数第2个段落的用途,其中所述肝病是酒精性肝病、毒物诱导的肝病或病毒诱导的肝病。
上数第3个段落的用途,其中所述肾功能障碍是多囊性肾病。
上数第4个段落的用途,还包括用于治疗所述爱帕琳肽受体(APJ)相关的病症的α-阻断剂、血管紧张素转化酶(ACE)抑制剂、血管紧张素受体阻断剂(ARB)、β-阻断剂、钙通道阻断剂或利尿剂。
“发明概述”第1-15段落中任一段所述的化合物,其用于治疗静脉相关的病症。
上一段落的用途,其中所述静脉相关的病症是血管瘤、静脉功能不全、淤滞或血栓症。
“发明概述”第1-15段落中任一段所述的化合物,其用于治疗以减少HIV相关的神经退行的可能性。
4.公开内容的详述
4.1定义
“烯基”指的是通过从母体烯烃的单个碳原子中除去一个氢原子衍生的具有至少一个碳-碳双键的不饱和的支链、直链或环状的烷基基团。该基团围绕双键可以呈Z型和E型(或顺式构象或反式构象)。典型的烯基基团包括但不限于乙烯基;丙烯基例如丙-1-烯-1-基、丙-1-烯-2-基、丙-2-烯-1-基(烯丙基)、丙-2-烯-2-基、环丙-1-烯-1-基;环丙-2-烯-1-基;丁烯基例如丁-1-烯-1-基、丁-1-烯-2-基、2-甲基-丙-1-烯-1-基、丁-2-烯-1-基、丁-2-烯-1-基、丁-2-烯-2-基、丁-1,3-二烯-1-基、丁-1,3-二烯-2-基、环丁-1-烯-1-基、环丁-1-烯-3-基、环丁-1,3-二烯-1-基;及类似基团。烯基基团可以是取代的或未取代的。在某些实施方案中,烯基基团具有2至20个碳原子,并且在其他实施方案中具有2至8个碳原子。
“烷氧基”指基团-OR,其中R表示如本文定义的烷基、烷基、环烷基、芳基或杂芳基基团。代表性实例包括但不限于:甲氧基、乙氧基、丙氧基、丁氧基、环己氧基等。该烷氧基可以是取代的或未取代的。
“烷基”指的是通过从母体烷烃的单个碳原子中除去一个氢原子衍生的饱和的支链或直链的单价烃基团。典型的烷基基团包括但不限于甲基;乙基;丙基例如丙-1-基、丙-2-基和环丙-1-基;丁基例如丁-1-基、丁-2-基、2-甲基-丙-1-基、2-甲基-丙-2-基、环丁-1-基、叔丁基;及类似基团。该烷基基团可以是取代的或未取代的;例如被卤素例如二氟或三氟取代。在某些实施方案中,烷基基团包含1至20个碳原子。可选择地,烷基基团可以包含1至8个碳原子。
“烷基(芳基)”指的是其中与碳原子(典型地为末端碳原子或sp3碳原子)结合的氢原子中的一个被芳基基团取代的非环状烷基基团。典型的烷基(芳基)基团包括但不限于苄基、2-苯基乙-1-基、2-苯基乙烯-1-基、萘基甲基、2-萘基乙-1-基、2-萘基乙烯-1-基、萘并苄基(naphthobenzyl)、2-萘并苯基乙-1-基等。在某些实施方案中,烷基(芳基)基团可以是(C6-20)烷基(芳基),例如烷基基团可以是(C1-10),并且芳基部分可以是(C5-10)。该烷基(芳基)基团可以是取代的或未取代的。
“炔基”指的是通过从母体炔烃的单个碳原子中除去一个氢原子衍生的具有至少一个碳-碳叁键的不饱和的支链或直链烷基基团。典型的炔基基团包括但不限于乙炔基、丙炔基、丁炔基、2-戊炔基、3-戊炔基、2-己炔基、3-己炔基等。炔基基团可以是取代的或未取代的。在某些实施方案中,炔基基团具有3至20个碳原子,并且在其他实施方案中具有3至8个碳原子。
“芳基”指的是通过从母体芳香族环体系的单个碳原子中除去一个氢原子衍生的单价芳香族烃基团。芳基涵盖5元和6元碳环芳香族环,例如苯或环戊二烯;双环体系,其中至少一个环是碳环的和芳香族的,例如萘、茚满;或两个芳香族环体系,例如苄基苯基、联苯基、二苯基乙烷、二苯基甲烷。该芳基基团可以是取代的或未取代的,例如被卤素例如氟取代的。
“环烷基”指的是饱和的或不饱和的环状烷基基团。当意指具体水平的饱和度时,使用命名“环烷基”或“环烯基”。典型的环烷基基团包括但不限于衍生自以下的基团:环丙烷、环丁烷、环戊烷、环己烷等。环烷基基团可以是取代的或未取代的。在某些实施方案中,环烷基基团可以是C3-10环烷基,诸如例如C6环烷基或cC6H12。环烷基基团还可以是桥接的双环环烷基基团、稠合的环烷基基团或螺环烷基基团。桥接的双环环烷基基团的非限制性实例是双环[2.2.1]庚烷、双环[2.2.1]己烷、双环[2.2.2]辛烷。稠合的环烷基基团的实例是双环[4.4.0]癸烷或十氢萘。螺环烷基基团的非限制性实例是螺[3.3]庚烷、螺[4.3]辛烷或螺[5.4]癸烷。
“疾病”指的是任何疾病、病症、状况、症状或适应症。
“卤素”指的是氟基团、氯基团、溴基团或碘基团。
“杂芳基”指的是通过从母体杂芳香族环体系的单个原子中除去一个氢原子衍生的单价杂芳香族基团。杂芳基涵盖:包含一个或更多个,例如1至4个或在某些实施方案中1至3个杂原子的5元至7元芳香族单环,所述杂原子选自N、O和S,且剩余的环原子是碳;和包含一个或更多个,例如1至4个或在某些实施方案中1至3个杂原子的多环杂环烷基环,所述杂原子选自N、O和S,且剩余的环原子是碳并且其中至少一个杂原子存在于芳香族环中。该杂芳基基团可以是取代的或未取代的。
例如,杂芳基包括稠合至5元至7元环烷基环的5元至7元杂芳香族环和稠合至5元至7元杂环烷基环的5元至7元杂芳香族环。对于其中仅一个环包含一个或更多个杂原子的这样的稠合的、双环杂芳基环体系,连接的点可以在杂芳香族环或环烷基环处。当杂芳基基团中的S原子和O原子的总数超过1时,那些杂原子不是彼此邻近的。在某些实施方案中,杂芳基基团中的S原子和O原子的总数不大于2。在某些实施方案中,芳香族杂环中的S原子和O原子的总数不大于1。典型的杂芳基基团包括但不限于衍生自以下的基团:吖啶、砷杂茚(arsindole)、咔唑、β-咔啉、色满、色烯、噌啉、呋喃、咪唑、吲唑、吲哚、二氢吲哚、吲嗪、异苯并呋喃、异色烯、异吲哚、异二氢吲哚、异喹啉、异噻唑、异噁唑、萘啶、噁二唑、噁唑、呸啶(perimidine)、菲啶、菲咯啉、吩嗪、酞嗪、哌啶、蝶啶、嘌呤、吡喃、吡嗪、吡唑、哒嗪、吡啶、嘧啶、吡咯、吡咯嗪(pyrrolizine)、喹唑啉、喹啉、喹嗪、喹喔啉、四唑、噻二唑、噻唑、噻吩、三唑、呫吨等。在某些实施方案中,该杂芳基基团可以是5元至20元杂芳基,诸如例如5元至10元杂芳基。在某些实施方案中,该杂芳基基团可以是衍生自以下的杂芳基基团:噻吩、吡咯、苯并噻吩、苯并呋喃、吲哚、吡啶、喹啉、咪唑、噁唑和吡嗪。
“杂环烷基”指的是具有一个或更多个杂原子的非芳香族单环或稠合的非芳香族多环,所述杂原子独立地选自N、S和O,且剩余的环原子是碳并且其中至少一个杂原子存在于每个非芳香族环中。杂环基团可以是三元环、四元环、五元环、六元环或七元环。在某些实施方案中,杂环烷基基团是1,4-二噁烷、1,3-二氧戊环、1,4-二噻烷、咪唑烷、吗啉、哌啶、哌啶酮、哌嗪、吡咯烷酮、吡咯烷或1,3,5-三噻烷。杂环烷基基团可以包括酰亚胺。该杂环烷基基团可以是双环的,例如杂螺化合物,例如杂螺[3.3]庚基、杂螺[3.4]辛基或杂螺[5.5]十一烷基。该杂环烷基基团可以是取代的或未取代的。因此,杂环烷基基团涵盖被一个或更多个卤素取代的杂环烷基基团,例如3,3-二氟哌啶或4,4-二氟哌啶。此外,该杂环烷基基团可以被C1-C4烷基或C1-C4卤代烷基基团例如-CF3基团取代。
“药学上可接受的”指通常被认可在动物,并且更具体地在人类中使用。
“药学上可接受的盐”指化合物的药学上可接受的盐,且其具有期望的母体化合物的药学活性。此类盐包括:(1)酸加成盐,所述酸加成盐是与无机酸诸如盐酸、氢溴酸、硫酸、硝酸、磷酸等形成的;或是与有机酸诸如乙酸、丙酸、己酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸等形成的;或(2)当存在于母体化合物中的酸性质子被金属离子(例如碱金属离子、碱土金属离子或铝离子)替换时形成的盐;或与有机碱(诸如乙醇胺、二乙醇胺、三乙醇胺、N-甲基葡萄糖胺、二环己基胺等)配位形成的盐。
“药学上可接受的赋形剂”、“药学上可接受的载体”或“药学上可接受的佐剂”分别指与本公开的至少一种化合物一起给药的赋形剂、载体或佐剂。“药学上可接受的媒介物”指与本公开的至少一种化合物一起给药的稀释剂、佐剂、赋形剂或载体中的任何一种。
“前药”指的是药物活性物质的前体或衍生物形式,其与母体药物相比生物活性较小,并且能够被酶促地活化或被转化成更有活性的母体形式。本文描述的化合物的前药形式可以被设计成改进生物利用度或稳定性或降低毒性。例如,具有游离的氨基、酰氨基、羧基、羟基或硫醇基团的本发明化合物可以被转化成前药。参见Rautio等人,2008 Nat RevDrug Dis 7 255-270。例如,游离的羧基基团可以被衍生化为酰胺、氨基甲酸酯、酯或N-曼尼希碱。可以使用以下基团来衍生化游离的羟基基团,所述基团包括但不限于碳酸酯、二甲基氨基乙酸酯、醚、半琥珀酸酯、磷酸酯以及磷酰基氧基甲氧基羰基,如在Fleisher等人,1996 Advanced Drug Delivery Reviews 19,115-130中概述的。还包括羟基和氨基基团的氨基甲酸酯前药,以及羟基基团的碳酸酯前药、磺酸酯和硫酸酯。还涵盖将羟基基团衍生化为(酰基氧基)甲基醚和(酰基氧基)乙基醚,其中酰基基团可以是烷基酯,所述烷基酯任选地被包括但不限于醚官能团、胺官能团和羧酸官能团的基团取代,或者其中酰基基团是如上文描述的氨基酸酯。此类型的前药在Robinson等人,1996 J Med Chem 39 10-18中描述。游离的胺也可以被衍生化为酰胺、氨基甲酸酯、亚胺、N-曼尼希碱、肟、磷酰胺或磺酰胺。羰基可以被衍生化成亚胺或肟前药。硫醇可以被衍生化为酯或醚。前药还可以包括其中氨基酸残基或两个或更多个(例如两个、三个或四个)氨基酸残基的多肽链通过酰胺键或酯键被共价地连接至本发明化合物的游离氨基、羟基或羧酸基团的化合物。该氨基酸残基包括但不限于通常由三个字母符号表示的20种天然存在的氨基酸,并且还包括β-丙氨酸、瓜氨酸、锁链素(demosine)、γ-氨基丁酸、高半胱氨酸、高丝氨酸、4-羟基脯氨酸、羟基赖氨酸、异锁链素(isodemosine)、3-甲基组氨酸、正缬氨酸(norvalin)、甲硫氨酸砜(methioninesulfone)和鸟氨酸。
“立体异构体”指的是在空间中组成原子的排列不同的异构体。彼此为镜像且是光学活性的立体异构体被称为“对映异构体”,彼此不是镜像且是光学活性的立体异构体被称为“非对映异构体”。
“受试者”包括哺乳动物和人类。术语“人类”和“受试者”在本文中可互换地使用。
“取代的”指的是其中一个或更多个氢原子各自独立地被相同或不同的取代基取代的基团。典型的取代基包括但不限于CO2H、氰基、二氟、卤素、羟基、-N3、-NH2、-SO(1-3)H、-SH或三氟。
“治疗有效量”指的是当给药至受试者用于治疗疾病,或者疾病或病症的临床症状中的至少一种时,足以影响该疾病、病症或症状的治疗的化合物的量。取决于化合物,疾病、病症和/或疾病或病症的症状,疾病、病症和/或疾病或病症的症状的严重程度,待被治疗的受试者的年龄和/或待被治疗的受试者的体重,“治疗有效量”可以变化。在任何给定的情况下,合适的量对于本领域技术人员可以是明显的,或通过常规实验能够确定。
任何疾病或病症的“治疗(treating)”或“治疗(treatment)”指的是阻止或减轻疾病、病症、或者疾病或病症的至少一种临床症状,降低获得疾病、病症、或疾病或病症的至少一种临床症状的风险,降低疾病、病症、或疾病或病症的至少一种临床症状的发展,或者降低发展成疾病、病症、或疾病或病症的至少一种临床症状的风险。“治疗(treating)”或“治疗(treatment)”还指的是在身体上(例如稳定可观察到的症状)、生理学上(例如物理参数的稳定性)或两者上抑制疾病或病症,或者抑制可能对于受试者不可辨别的至少一个物理参数。另外,“治疗(treating)”或“治疗(treatment)”指的是在可能被暴露于或易患疾病或病症的受试者中延迟疾病或病症或至少其症状的发作,即使该受试者尚未经历或显示疾病或病症的症状。
本文定义的官能团对可以以化学上合理的方式组合。例如,C1-C8烷基氨基意指官能团C1-C8烷基(例如-nC5H11)与官能团氨基(例如-NH2)组合,从而在此实例中形成-nC5H10NH2。类似地,C1-C8烷氧基芳基意指官能团C1-C8烷氧基例如-CH2CH2OCH2CH3或-OCH2CH3与芳基基团例如-C6H5F组合以分别形成-CH2CH2OCH2CH2-C6H5F或-OCH2CH3-C6H5F。
如本文使用的,取代基R4、R5、R6、R7或R8可独立地为单个的α、β、γ、δ氨基酸或其对应的侧链,例如二十种天然存在的氨基酸,例如丙氨酸(Ala/A);精氨酸(Arg/R);天冬酰胺(Asn/N);天冬氨酸(Asp/D);半胱氨酸(Cys/C);谷氨酸(Glu/E);谷氨酰胺(Gln/Q);甘氨酸(Gly/G);组氨酸(His/H);异亮氨酸(Ile/I);亮氨酸(Leu/L);赖氨酸(Lys/K);甲硫氨酸(Met/M);苯丙氨酸(Phe/F);脯氨酸(Pro/P);丝氨酸(Ser/S);苏氨酸(Thr/T);色氨酸(Trp/W);酪氨酸(Tyr/Y);和缬氨酸(Val/V)。单独的氨基酸可以具有R手性或S手性。可选择地,R4、R5、R6、R7或R8可以独立地是通过肽键连接的两个或三个氨基酸。R4、R5、R6、R7或R8可以独立地是二肽或三肽(Hobbs等人,Proc Nat Acad Sci USA.1993,90,6909-6913);美国专利号6,075,121(Bartlett等人)类肽类(peptoids);或插烯多肽类(vinylogouspolypeptides)(Hagihara等人,J Amer Chem Soc.1992,114,6568),这些参考文献的内容通过引用整体并入本文。R4、R5、R6、R7或R8可以独立地是扩展的非天然氨基酸的一部分,例如Xie和Schultz,Nat Rev Mol Cell Biol.2006,7(10):775-82或Wang等人,ChemBiol.2009,16(3):323-36,这些参考文献的内容通过引用整体并入本文。
4.2氘代同位素变体和其他同位素变体
本发明还包括本发明化合物的所有合适的同位素变体(variation)。本发明化合物的同位素变体被定义为其中至少一个原子被具有相同原子数但原子质量不同于通常或主要在自然界中发现的原子质量的原子替代的变体。可以并入到本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘的同位素,例如分别地2H(氘)、3H(氚)、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、129I和131I。本发明化合物的某些同位素变体,例如,其中并入了一种或更多种放射性同位素例如3H或14C的那些同位素变体,可用于药物和/或底物组织分布研究。氚化同位素和碳-14(即14C)同位素由于它们易于制备和易检测性是特别优选的。用正电子发射同位素(例如11C、18F、15O和13N)取代,可以用于正电子发射断层扫描(PET)研究中。
此外,用同位素例如氘取代可以提供由更高的代谢稳定性产生的某些治疗优点,例如增加的体内半衰期或降低的剂量需求,并且因此在某些情况下可以是优选的。本发明化合物的同位素变体通常可以通过本领域技术人员已知的常规方法来制备,例如使用合适试剂的适当同位素变体,通过示例性方法或通过下文实施例中描述的制备方法。在另一个实施方案中,同位素标记的化合物包括氘(2H)同位素、氚(3H)同位素或14C同位素。本发明的同位素标记的化合物可以通过本领域普通技术人员熟知的一般方法来制备。
这种同位素标记的化合物可以通过用易于获得的同位素标记的试剂代替未标记的试剂,通过进行本文公开的实施例和方案中公开的方法方便地制备。在一些情况下,化合物可以用同位素标记的试剂处理以用其同位素交换正常原子,例如,用于氘的氢可以通过含氘酸(deuteric acid)如D2SO4/D2O的作用进行交换。可选择地,氘还可以使用例如通过使用如LiAlD4或NaBD3的还原、使用合适的氘代试剂例如氘化物、D2和D2O的催化氢化或酸性同位素交换或碱性同位素交换的方法被并入到化合物中。除了上文之外,还有PCT公开WO2014/169280;WO2015/058067;美国专利号8,354,557;8,704,001和美国专利申请公开号2010/0331540;2014/0081019;2014/0341994;2015/0299166,这些方法在此引入作为参考。
4.3杂环核的合成方案
本文描述的化合物可以通过本领域技术人员已知的许多方法制备。具体的合成方案可以在实验部分找到。参见5.1部分中的方案1-3。合成呋喃类、咪唑类、噁唑类、吡唑类、吡咯类、噻唑类、噻吩类和三唑类的非限制性方法如下所示。
4.3.1吡咯类
4.3.2呋喃类
4.3.3噻吩类
4.3.4吡唑类
4.3.5咪唑类
4.3.6噁唑类
4.3.7噻唑类
4.3.8三唑类
4.4药物组合物
本公开内容还提供了药物组合物,所述药物组合物包含有效量的式I(例如,本文公开的任何式和/或结构)的化合物,或所述化合物的药学上可接受的盐;和药学上可接受的载体。
可以用于本公开的药物组合物中的药学上可接受的载体、佐剂和媒介物包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白例如人血清白蛋白、缓冲剂物质例如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇和羊毛脂。如有必要,在药物组合物中的本公开的化合物的溶解度和生物利用度可以通过本领域熟知的方法来提高。一种方法包括在制剂中使用脂质赋形剂。参见“Oral Lipid-Based Formulations:Enhancing the Bioavailability of PoorlyWater-Soluble Drugs(Drugs and the Pharmaceutical Sciences)”,David J.Hauss,编辑,Informa Healthcare,2007;和“Role of Lipid Excipients in Modifying Oral andParenteral Drug Delivery:Basic Principles and Biological Examples”,KishorM.Wasan编辑,Wiley-Interscience,2006。
提高生物利用度的另一种已知方法是使用本公开的化合物的无定形形式,该无定形形式任选地用泊洛沙姆例如LUTROLTM和PLURONICTM(BASF Corporation)或环氧乙烷和环氧丙烷的嵌段共聚物来配制。参见美国专利号7,014,866(Infeld等人);和美国专利公开号20060094744(Maryanoff等人)和20060079502(Lang)。
本公开的药物组合物包括适合于口服、直肠、经鼻、局部(包括含服和舌下)、肺部、阴道或肠胃外(包括皮下、肌内、静脉内和皮内)给药的那些药物组合物。在某些实施方案中,本文中的通式化合物被透皮给药(例如,使用透皮贴剂或离子电渗技术)。其他制剂可以方便地以单位剂型例如片剂、缓释胶囊以及以脂质体来提供,并且可以通过药学领域熟知的任何方法制备。参见例如Remington's Pharmaceutical Sciences,Mack PublishingCompany,Philadelphia,PA(第17版,1985)。
这样的制备方法包括使成分例如构成一种或更多种辅助成分的载体与待被给药的分子结合(association)的步骤。通常,通过如下来制备组合物:使活性成分与液体载体、脂质体或精细分开的固体载体或两者均匀且紧密地结合,并且然后如果有必要,使产品成形。在某些实施方案中,化合物被口服给药。适合于口服给药的本公开的组合物可以作为离散单元,例如胶囊、小袋(sachet)或片剂存在,它们各自包含预定量的活性成分;粉末或颗粒;它们为在含水液体或非含水液体中的溶液或悬浮液;水包油液体乳剂;油包水液体乳剂;包装在脂质体中;或作为推注剂(bolus)等。软明胶胶囊可用于容纳这种悬浮液,这可以有益地增加化合物吸收速率。
在口服片剂的情况下,常用的载体包括乳糖和玉米淀粉。通常还添加润滑剂,例如硬脂酸镁。对于胶囊形式的口服给药,有用的稀释剂包括乳糖和干玉米淀粉。当口服给予含水悬浮液时,将活性成分与乳化剂和悬浮剂混合。如果需要,可以加入某些甜味剂和/或调味剂和/或着色剂。
适于口服给药的组合物包括含有调味基础成分(通常是蔗糖和阿拉伯胶或黄蓍胶)的锭剂;和软锭剂(pastille),其包含于惰性基质(例如明胶和甘油,或蔗糖和阿拉伯胶)中的活性成分。
适于胃肠外给药的组合物包括含水和非含水的无菌注射溶液,其可含有抗氧化剂、缓冲剂、抑菌剂和溶质,所述溶质使制剂与预期接受者的血液等渗;和含水和非含水的无菌悬浮液,其可包含悬浮剂和增稠剂。制剂可以在单位剂量或多剂量容器例如密封的安瓿(ampule)和小瓶中存在,并且可以储存在冷冻干燥的(冻干的)条件中,仅需要在立即使用之前添加无菌液体载体例如注射用水。即时(extemporaneous)注射溶液和悬浮液可以由无菌粉末、颗粒和片剂来制备。
所述注射溶液可以呈例如无菌的可注射的含水悬浮液或油质(oleaginous)悬浮液的形式。此悬浮液可以根据本领域已知的技术使用合适的分散剂或湿润剂(比如例如吐温80)和悬浮剂来配制。无菌的可注射的制剂还可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌的可注射的溶液或悬浮液,例如作为在1,3-丁二醇中的溶液。可以使用的可接受的媒介物和溶剂包括甘露醇、水、林格氏溶液和等渗氯化钠溶液。此外,无菌的不挥发性油通常用作溶剂或悬浮介质。为了此目的,可以使用任何无刺激性的不挥发性油,包括合成的单甘油酯或二甘油酯。脂肪酸,诸如油酸及其甘油酯衍生物可用于制备可注射剂,以及天然的药学上可接受的油诸如橄榄油或蓖麻油,尤其以其聚氧乙烯化的形式。这些油溶液或悬浮液还可以含有长链醇稀释剂或分散剂。
本公开的药物组合物可以以栓剂的形式用于直肠给药。这些组合物可以通过将本公开的化合物与合适的非刺激性赋形剂混合来制备,所述非刺激性赋形剂在室温是固体,但在直肠温度是液体,并因此将在直肠中融化以释放活性组分。这样的材料包括但不限于可可脂、蜂蜡和聚乙二醇。
本公开的药物组合物可以通过鼻气雾剂或吸入给药。这样的组合物根据药物制剂领域中熟知的技术来制备,并且可以使用苄醇或其他合适的防腐剂、提高生物利用度的吸收促进剂、碳氟化合物和/或本领域已知的其他增溶剂或分散剂制备成在盐水中的溶液。参见例如美国专利号6,803,031(Rabinowitz&Zaffaroni)。
当所需治疗涉及通过局部应用易于接近的区域或器官时,本公开的药物组合物的局部给药特别有用。对于局部施用于皮肤的局部应用,药物组合物应该用合适的软膏配制,该软膏含有悬浮或溶解在载体中的活性成分。用于局部给药本公开化合物的载体包括但不限于矿物油、液体石油、白石油(white petroleum)、丙二醇、聚氧乙烯或聚氧丙烯化合物、乳化蜡和水。或者,药物组合物可以用合适的洗剂或乳膏配制,该洗剂或乳膏含有悬浮或溶解在载体中的活性化合物。合适的载体包括但不限于矿物油、脱水山梨糖醇单硬脂酸酯、聚山梨醇酯60、十六烷基酯蜡、鲸蜡硬脂醇(cetearyl alcohol)、2-辛基十二烷醇、苯甲醇和水。本公开的药物组合物也可以通过直肠栓剂制剂或以合适的灌肠制剂局部施用于下肠道(lower intestinal tract)。局部透皮贴剂和离子电渗疗法给药也包括在本公开中。
治疗剂的应用可以是局部的,以便在感兴趣的部位施用。可以使用各种技术在感兴趣的部位提供该组合物,例如注射、使用导管、套管针、射弹剂(projectile)、普兰尼克(pluronic)凝胶、支架、持续药物释放聚合物或提供内部通路的其他装置。因此,根据另一个实施方案,本发明的化合物可以并入到用于涂覆可植入医疗装置(例如假体、人造瓣膜、血管移植物、支架或导管)的组合物中。合适的涂层和经涂覆的可植入装置的一般制备是本领域已知的,并且在美国专利号4,522,569(Ding&Helmus);5,886,026(Hunter等人);和5,304,121(Sahatjian)中有举例说明。涂层典型地是生物相容的聚合物材料,例如水凝胶聚合物、聚甲基二硅氧烷、聚己内酯、聚乙二醇、聚乳酸、乙烯乙酸乙烯酯及其混合物。涂层可任选地进一步被合适的氟硅氧烷、多糖、聚乙二醇、磷脂或其组合的外涂层(topcoat)覆盖,以赋予组合物控释特性。用于侵入性装置(invasive device)的涂层也包括在药学上可接受的载体、佐剂或媒介物(如本文所用的那些术语)的定义中。
根据另一个实施方案,本发明提供了涂覆可植入医疗装置的方法,所述方法包括使所述装置与上述涂层组合物接触的步骤。对于本领域技术人员显而易见的是,对装置进行涂层在植入哺乳动物之前发生。
根据另一个实施方案,本公开内容提供了浸渍可植入药物释放装置的方法,所述方法包括使所述药物释放装置与本公开的化合物或组合物接触的步骤。可植入的药物释放装置包括但不限于可生物降解的聚合物胶囊或弹丸(bullet)、不可降解的可扩散的聚合物胶囊和可生物降解的聚合物华夫片(wafer)。
根据另一个实施方案,本公开内容提供了涂覆有本公开的化合物或涂覆有包含本公开的化合物的组合物的可植入医疗装置,使得所述化合物具有治疗活性。
根据另一个实施方案,本公开内容提供了可植入的药物释放装置,所述可植入的药物释放装置浸渍有或含有本公开的化合物或包含本公开的化合物的组合物,使得所述化合物从所述装置释放并具有治疗活性。在器官或组织由于从受试者移除而可接近的情况下,这样的器官或组织可以被浸泡(bathe)在包含本公开的组合物的介质中,本公开的组合物可以被涂在器官上,或者本公开的组合物可以以任何其他方便的方式来应用。
在一个实施方案中,本公开内容提供了包含式I化合物或本文公开的更具体的化合物的组合物,以治疗或预防哮喘、动脉粥样硬化、癌症、心肌病、糖尿病、血脂异常、HIV神经退行、高血压、炎症、肝病、代谢紊乱、神经退行性疾病、肥胖症或先兆子痫。在另一个实施方案中,本公开内容提供了包含式I化合物或本文公开的更具体的化合物的组合物,以治疗或预防癌症、细胞增殖、糖尿病、体液平衡、心脏病(例如高血压和心力衰竭,例如充血性心力衰竭)、HIV感染、免疫功能、肥胖症、干细胞运输(stem cell trafficking)、转移性癌症或静脉相关的病症例如血管瘤、静脉功能不全、淤滞或血栓症。
在另一个实施方案中,本公开的组合物还包含第二治疗剂。在一个实施方案中,该第二治疗剂是本公开的一种或更多种另外的化合物。在另一个实施方案中,当将具有与式I的APJ受体化合物具有相同的作用机理的化合物给药时,该第二治疗剂可以选自已知具有或经证实具有有利性质的任何化合物或治疗剂。
在特定的实施方案中,该第二治疗剂是可用于治疗或预防选自以下的疾病或状况的药剂:急性失代偿性心力衰竭(ADHF)、肌萎缩侧索硬化、心律失常、哮喘、动脉粥样硬化、动脉粥样硬化、心房颤动、Brugada综合征、烧伤(包括晒伤)、癌症、心脏纤维化、心肌病、脑血管意外、慢性心力衰竭、糖尿病(包括妊娠糖尿病)、血脂异常、HIV神经退行、高血压、炎症、缺血性心血管病、肝病、代谢紊乱、神经退行性疾病、肥胖症、外周动脉疾病、先兆子痫、肺性高血压、再狭窄、短暂性缺血发作(transient ischemic attack)、创伤性脑损伤、室性心动过速或水潴留(water retention)。在另一个实施方案中,该第二治疗剂是可用于治疗或预防选自以下的疾病或状况的药剂:癌症、细胞增殖、糖尿病、体液平衡、心脏病(例如高血压和心力衰竭,例如充血性心力衰竭)、HIV感染、免疫功能、肥胖症、干细胞运输或转移性癌症。
例如,当疾病或状况是充血性心力衰竭时,该第二治疗剂可以选自:ACE抑制剂、β阻断剂、血管扩张剂、钙通道阻断剂、髓袢利尿剂(loop diuretics)、醛固酮拮抗剂和血管紧张素受体阻断剂。
当被治疗的疾病或状况是高血压时,该第二治疗剂可以选自:α-阻断剂、β-阻断剂、钙通道阻断剂、利尿剂、促尿钠排泄剂(natriuretics)、促尿盐排泄药(saluretics)、中枢作用的抗高血压药、血管紧张素转化酶(ACE)抑制剂、ACE和中性内肽酶(NEP)双重抑制剂、血管紧张素受体阻断剂(ARB)、醛固酮合酶抑制剂、醛固酮受体拮抗剂或内皮素受体拮抗剂。
α-阻断剂的非限制性实例包括多沙唑嗪、哌唑嗪、坦洛新和特拉唑嗪。
用于组合疗法的β-阻断剂的非限制性实例选自醋丁洛尔(acebutolol)、醋丁洛尔(acetutolol)、阿替洛尔、比索洛尔、布拉洛尔、卡替洛尔、卡维地洛、塞利洛尔、艾司洛尔、甲吲洛尔、美托洛尔、纳多洛尔、氧烯洛尔、喷布洛尔、吲哚洛尔、普萘洛尔(propanolol)、他林洛尔(taliprolol)、及其药学上可接受的盐。
钙通道阻断剂的非限制性实例包括二氢吡啶(DHP)和非DHP。优选的DHP选自:氨氯地平、非洛地平、伊拉地平、拉西地平、尼卡地平、硝苯地平(nifedipine)、尼古地平(nigulpidine)、尼鲁地平、尼莫地平、尼索地平、尼群地平、尼伐地平、瑞西丁(ryosidine)及其药学上可接受的盐。非DHP选自:阿尼帕米、地尔硫卓(diltiazem)、芬地林、氟桂利嗪、戈洛帕米、咪拉地尔(mibefradil)、普尼拉明、噻帕米和维拉帕米(verampimil)及其药学上可接受的盐。
利尿剂是例如选自阿米洛利、氯噻酮(chlorothalidon)、氯噻嗪、氢氯噻嗪和甲基氯噻嗪的噻嗪衍生物。
中枢作用抗高血压药的非限制性实例包括可乐定、胍那苄、胍法辛和甲基多巴。
ACE抑制剂的非限制性实例包括阿拉普利、贝那普利、贝那普利拉、卡托普利、西罗普利、西拉普利、地拉普利、依那普利、依那普利拉、福辛普利、赖诺普利、莫西普利、莫维普利、培哚普利、喹那普利、喹那普利拉、雷米普利、雷米普利拉、螺普利、替莫普利、群多普利和佐芬普利。优选的ACE抑制剂是贝那普利、依那普利、赖诺普利和雷米普利。
ACE/NEP双重抑制剂的非限制性实例是例如奥马曲拉(omapatrilat)、法西多曲(fasidotril)和法西多曲拉(fasidotrilat)。
优选的ARB的非限制性实例包括坎地沙坦、依普沙坦、伊贝沙坦、氯沙坦、奥美沙坦(olmesartan)、他索沙坦、替米沙坦和缬沙坦。
优选的醛固酮合酶抑制剂的非限制性实例是阿那曲唑(anastrozole)、法倔唑和依西美坦。
优选的醛固酮受体拮抗剂的非限制性实例是螺内酯和依普利酮(eplerenone)。
优选的内皮素拮抗剂的非限制性实例为例如波生坦、恩拉生坦(enrasentan)、阿曲生坦(atrasentan)、达卢生坦(darusentan)、西他生坦(sitaxentan)和替唑生坦(tezosentan)及其药学上可接受的盐。.
在一个实施方案中,本公开内容提供了本公开化合物和任何上述第二治疗剂中的一种或多种的单独剂型,其中所述化合物与第二治疗剂彼此组合。如本文使用的术语“彼此组合”是指将单独的剂型包装在一起或以其他方式彼此结合,使得显而易见地是单独的剂型旨在一起出售和施用(在彼此小于24小时内,连续地或同时地施用)。
在本公开的药物组合物中,本公开的化合物以有效量存在。如本文所用术语“有效量”是指当以适当的给药方案给药时足以治疗(治疗或预防)目标病症的量。例如,有效量足以减轻或改善所治疗病症的严重性、持续时间或进展,防止所治疗病症的进展,引起所治疗病症的消退,或增强或改善另一种疗法的预防或治疗效果。优选地,该化合物在组合物中的存在量为0.1至50重量%,更优选1至30重量%,最优选5至20重量%。
用于动物和人的剂量(基于每平方米的体表面积的毫克数)的相互关系描述在Freireich等人,(1966)Cancer Chemother.Rep50:219中。体表面积可以由受试者的身高和体重大致确定。参见例如Scientific Tables,Geigy Pharmaceuticals,Ardsley,N.Y.,1970,537。
对于包含第二治疗剂的药物组合物,第二治疗剂的有效量是仅使用该药剂的单一疗法方案中常规使用的剂量的约20%至100%。优选地,有效量为常规单一疗法剂量的约70%至100%。这些第二治疗剂的常规单一疗法剂量是本领域熟知的。参见例如Wells等人,eds.,Pharmacotherapy Handbook,2nd Edition,Appleton and Lange,Stamford,Conn.(2000);PDR Pharmacopoeia,Tarascon Pocket Pharmacopoeia2000,Deluxe Edition,Tarascon Publishing,Loma Linda,Calif.(2000),每篇参考文献都通过引用整体并入本文。
用于本公开方法的化合物可以配制成单位剂型。术语“单位剂型”是指适合作为接受治疗的受试者的单位剂量的物理上离散的单位,其中每个单位含有经计算可产生所需的治疗效果的预定量的活性物质,任选地与合适的药物载体组合。单位剂型可以是单个日治疗剂量或多个日治疗剂量(例如,每天约1至4次或更多次)之一。当使用多个日治疗剂量时,对于每个剂量,单位剂型可以相同或不同。
4.5治疗方法
本公开内容还包括治疗受益于APJ受体调节的疾病、病症或病理状况的方法,所述方法包括向有此需要的受试者给药有效量的本公开的APJ受体化合物。可受益于APJ受体调节(抑制或激活)的疾病和病症包括但不限于:急性失代偿性心力衰竭(ADHF)、肌萎缩侧索硬化、心律失常、哮喘、动脉粥样硬化、动脉粥样硬化、心房颤动、Brugada综合征、烧伤(包括晒伤)、癌症、心脏纤维化、心肌病、脑血管意外、慢性心力衰竭、糖尿病(包括妊娠糖尿病)、血脂异常、HIV神经退行、高血压、炎症、缺血性心血管病、肝病、代谢紊乱、神经退行性疾病、肥胖症、外周动脉疾病、先兆子痫、肺性高血压、再狭窄、短暂性缺血发作、创伤性脑损伤、室性心动过速或水潴留。更具体地,该高血压可以是肺动脉高血压。该肝病可以是酒精性肝病、毒物诱导的肝病或病毒诱导的肝病,并且该肾功能障碍可以是多囊性肾病。该爱帕琳肽受体系统涉及静脉相关的病症。参见例如Lathen等人,“ERG-APLNR Axis ControlsPulmonary Venule Endothelial Proliferation in Pulmonary Veno-OcclusiveDisease”2014 Circulation130:1179-1191。爱帕琳肽受体系统也已经被认为与心力衰竭有关。参见例如Sheikh等人,“In vivo genetic profiling and cellular localizationof apelin reveals a hypoxia-sensitive,endothelial-centered pathway activatedin ischemic heart failure”2007 Am J Physiol Heart Circ Physiol294:H88-H98。Lathen等人和Sheikh等人的内容通过引用整体并入本公开。
在一个非限制性实施方案中,本公开提供了治疗受试者中的爱帕琳肽受体(APJ)相关的病症的方法,所述方法包括向受试者给药实施方案1的化合物。该爱帕琳肽受体(APJ)相关的病症可以是哮喘、动脉粥样硬化、癌症、心肌病、糖尿病、血脂异常、高血压、炎症、肝病、代谢紊乱、神经退行性疾病、肥胖症或先兆子痫。本公开内容提供了进一步包括用α-阻断剂、血管紧张素转化酶(ACE)抑制剂、血管紧张素受体阻断剂(ARB)、β-阻断剂、钙通道阻断剂或利尿剂治疗受试者的方法。或者,本公开内容提供了治疗或预防静脉相关的病症例如血管瘤、静脉功能不全、淤滞或血栓症的方法。
此外,本公开内容提供了预防受试者中HIV神经退行的方法,所述方法包括向受试者给药实施方案1的化合物。
在一个实施方案中,本公开化合物的有效量可以为每次治疗约0.005mg至约5000mg。在更具体的实施方案中,该范围为约0.05mg至约1000mg,或约0.5mg至约500mg,或约5mg至约50mg。治疗可以每天给药一次或多次(例如每天一次、每天两次、每天三次、每天四次、每天五次等)。当使用多次治疗时,量可以相同或不同。可以理解,可以每天、每隔一天、每2天、每3天、每4天、每5天等进行治疗。例如,在每隔一天给药的情况下,治疗剂量可以在周一开始,周三进行第一次后续治疗,周五进行第二次后续治疗等。治疗通常每天施用一至两次。如本领域技术人员公知的,根据所治疗的疾病、疾病的严重程度、给药途径、受试者的性别、年龄和一般健康状况、赋形剂的使用、与其他治疗疗法(如使用其他药物)共用的可能性、以及治疗医师的判断,有效剂量也将变化。
或者,本公开化合物的有效量为约0.01mg/kg/天至约1000mg/kg/天,约0.1mg/kg/天至约100mg/kg/天,约0.5mg/kg/天至约50mg/kg/天,或约1mg/kg/天至10mg/kg/天。
在另一个实施方案中,任何上述治疗方法包括向所述受试者共同给药一种或多种第二治疗剂的另外的步骤。第二治疗剂的选择可以从已知可用于与调节APJ受体的化合物共同给药的任何第二治疗剂中进行。第二治疗剂的选择还取决于待治疗的特定疾病或病症。可以在本公开的方法中使用的第二治疗剂的实例是上述用于包含本公开化合物和第二治疗剂的联用组合物中的那些。
如本文所用的术语“共同给药”是指第二治疗剂可以与本公开的化合物一起作为单一剂型的一部分(例如包含本公开的化合物和如上所述的第二种治疗剂的本公开的组合物)或作为单独的多剂型进行给药。或者,可以在给药本公开化合物的之前施用、与本公开化合物的给药依次施用或在本公开化合物的给药之后施用。在这种组合疗法治疗中,本公开的化合物和第二治疗剂均通过常规方法给药。向受试者给药包含本公开化合物和第二治疗剂的本公开组合物并不排除在治疗过程期间的另一时间,将相同治疗剂、任何其他第二治疗剂或任何本公开化合物单独给药于所述受试者。
在本公开的一个实施方案中,在将第二治疗剂给药于受试者时,本公开化合物的有效量小于其在不给药第二治疗剂的情况下的有效量。在另一个实施方案中,该第二治疗剂的有效量小于其在不给药本公开化合物的情况下的有效量。以这种方式,可以使与高剂量的任一种药剂相关的不期望的副作用最小化。其他潜在的优点(包括但不限于改进的给药方案和/或降低的药物成本)对于本领域技术人员而言是显而易见的。
4.6试剂盒
本公开还提供了用于治疗目标疾病、病症或状况的试剂盒。这些试剂盒包括(a)药物组合物,所述药物组合物包含式I化合物或其盐,其中所述药物组合物在容器中;和(b)描述使用药物组合物治疗目标疾病、病症或状况的方法的说明书。
该容器可以是可容纳所述药物组合物的任何器皿或其他密封的或可密封的设备。实例包括瓶子、安瓿、分开的或多室的容纳瓶(其中每个分区或室包含单剂量的所述组合物)、分开的箔包(其中每个分区包含单剂量的所述组合物)或分配单剂量所述组合物的分配器。该容器可以呈如本领域已知的任何常规的形状或形式,其由药学上可接受的材料制成,例如纸或纸板箱、玻璃或塑料瓶或罐、可再密封的袋(例如,以保持片剂的“再填充”用于放置到不同的容器中)或单独剂量的泡罩包装,该泡罩包装根据治疗方案将所述剂量压出包装。使用的容器可取决于所涉及的确切剂型,例如通常不使用常规纸板箱来容纳液体悬浮液。可行的是,可以在单个包装中一起使用多于一个容器以销售单一剂型。例如,片剂可以包含在瓶子中,该瓶子又装在盒子中。在一个实施方案中,该容器是泡罩包装。
本公开的试剂盒还可以包含施用或测量出单位剂量的药物组合物的装置。如果所述组合物是可吸入组合物,则这种装置可包括吸入器;如果所述组合物是可注射组合物,则这种装置可以包括注射器和针头;如果所述组合物是口服液体组合物,则这种装置可以包括具有或不具有体积标记的注射器、匙、泵或器皿;或者这种装置可以包括任何其他适合于试剂盒中存在的组合物的剂量制剂(dosage formulation)的测量或递送装置。
在某些实施方案中,本公开的试剂盒可以在容器的单独器皿中包含药物组合物,所述药物组合物包含第二治疗剂,例如上文列出的用于与本公开的化合物共同给药的那些。
除非另外定义,否则本文使用的所有技术术语和科学术语具有与本公开内容所属领域的普通技术人员通常理解的含义相同的含义。冠词“一(a)”和“一个(an)”在本文中用于指一个或多于一个(即至少一个)该冠词的语法对象(grammatical object)。举例来说,“要素(an element)”表示一个或多个要素。
在整个说明书中,词语“包括(comprising)”或变型例如“包含(comprises)”或“含有(comprising)”,将被理解为意味着包括所陈述的要素、整数或步骤,或者要素组、整数组或步骤组但不排除任何其他的要素、整数或步骤,或者要素组、整数组或步骤组。本公开内容可以合适地“包括”权利要求中描述的步骤、要素和/或试剂、“由权利要求中描述的步骤、要素和/或试剂组成”或者“基本上由权利要求中描述的步骤、要素和/或试剂组成”。
还应注意,可以修改权利要求以排除任何可选要素。因此,此陈述旨在作为使用“唯一地(solely)”、“仅”等与权利要求要素的叙述相关的这种排他性术语或使用“否定”限制的修改依据。
在提供值的范围的情况下,应当理解,除非上下文另外明确指明,否则在该范围的上限和下限之间的每一个中间值至下限单位的十分之一也被具体地公开。在所陈述的范围内的任何陈述的值或中间值和在该陈述的范围内的任何其他陈述的值或中间值之间的每个较小的范围被涵盖在本公开内容中。这些较小的范围的上限和下限可以独立地被包括在该范围内或排除在该范围之外,并且其中任一极限、两个极限都不或者两个极限都被包括在较小范围内的每个范围也被涵盖在本公开内容中,受限于陈述的范围内的任何特定排除的极限。在陈述的范围包括所述极限中的一个或两个的情况下,排除那些所包括的极限中的任一个或两个的范围也被包括在本公开内容中。
以下实施例进一步说明了本发明,并不意图限制本发明的范围。特别地,应该理解本公开不限于所描述的特定实施例,因此当然可以改变。还应理解,本文使用的术语仅用于描述特定实施方案的目的,并不旨在限制,因为本公开的范围仅受所附权利要求的限制。
5.实施例
5.1方法和代表性化合物的制备
方案1:(S)-3-(5-环戊基-1-(2-(三氟甲基)吡啶-3-基)-1H-1,2,4-三唑-3-甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酸的制备
试剂和条件:(a)6N HCl水溶液,NaNO2,EtOH,0℃,2-氯乙酰乙酸乙酯,1小时;(b)0.5M NH3的二噁烷溶液,0℃至室温,18小时;(c)环戊甲酰氯,甲苯,0-110℃持续3天;(d)1NNaOH,THF:MeOH(1:1),室温,18小时;(e)(S)-3-氨基-5-(3,3-二氟哌啶-1-基)戊酸叔丁酯,HATU,i-PrNEt2,DMF,0℃至室温,18h;(f)4M HCl的二噁烷溶液,室温,18小时
(Z)-2-氯-2-(2-(2-(三氟甲基)吡啶-3-基)肼叉基)乙酸乙酯:在室温下,将6N的HCl水溶液(5.9mL)加入到2-(三氟甲基)吡啶-3-胺(1.00g,6.17mmol,1.00当量)中。将反应混合物冷却至0℃,滴加亚硝酸钠(426mg,6.17mmol,1.00当量)的水(1.2mL)溶液。将反应混合物在0℃下搅拌30分钟。在相同温度下,使用推注器在1小时内加入2-氯乙酰乙酸乙酯(1.02g,6.21mmol,1.00当量)的乙醇(2.3mL)溶液。将反应混合物在0℃下搅拌30分钟,加入乙酸钠(1.52g,18.5mmol,3.00当量)的水(4.7mL)溶液。将反应混合物在室温下搅拌18小时。过滤浅橙色沉淀,用水洗涤并真空干燥,得到1.39g(76%)标题化合物,为橙色固体。m/z(M+H)+=296.0;RT=1.73min;纯度=98.2%。HPLC条件:柱:XBridge C18,3.5μm,4.6x30mm;梯度:5B 0.2min,5B-100B 1.8min,100B 1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。1H NMR(500MHz,DMSO)δ1.30(t,J=7.1 Hz,3H),4.32(q,J=7.1 Hz,2H),7.76(dd,J=8.5,4.5 Hz,1H),8.04(d,J=8.5 Hz,1H),8.46(dd,J=4.4,0.8 Hz,1H),9.52(s,1H).
(Z)-2-氨基-2-(2-(2-(三氟甲基)吡啶-3-基)肼叉基)乙酸乙酯:在0℃下,将(Z)-2-氯-2-(2-(2-(三氟甲基)吡啶-3-基)肼叉基)乙酸乙酯(1.39g,4.70mmol,1.00当量)的THF(3mL)溶液加入到0.5M氨的二噁烷溶液(28.2mL,14.1mmol,3.00当量)中。将反应混合物搅拌18小时。减压蒸发溶剂,并加入氯仿(50mL)。过滤不溶的氯化铵,蒸发滤液,得到1.30g(定量产率)标题化合物,为粘稠的橙色油状物。m/z(M+H)+=277.0;RT=1.34min;纯度=99%。HPLC条件:柱:XBridge C18,3.5μm,4.6x30mm;梯度:5B0.2min,5B-100B 1.8min,100B1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。1H NMR(500MHz,DMSO)δ1.28(t,J=7.1Hz,3H),4.25(q,J=7.1Hz,2H),6.56(s,2H),7.57(dd,J=8.6,4.3Hz,1H),8.02(dd,J=8.6,0.9Hz,1H),8.05(s,1H),8.10(dd,J=4.4,1.2Hz,1H).
5-环戊基-1-(2-(三氟甲基)吡啶-3-基)-1H-1,2,4-三唑-3-甲酸乙酯
在0℃下,将环戊甲酰氯(96mg,0.73mmol,2.5当量)的甲苯(0.15mL)溶液加入到(Z)-2-氨基-2-(2-(2-(三氟甲基)吡啶-3-基)肼叉基)乙酸乙酯(100mg,0.362mmol,1.00当量)的甲苯(0.20mL)溶液中。将反应混合物在室温下搅拌1.5小时,并加入另一部分环戊甲酰氯(72mg,0.54mmol,1.5当量)。将反应混合物在110℃加热3天。蒸发溶剂,将粗产物在硅胶柱上经快速色谱法纯化,用乙酸乙酯的己烷溶液(10-60%)洗脱,得到83mg(65%)标题化合物,为浅橙色固体。m/z(M+H)+=355.2;RT=1.62min;纯度=86%。HPLC条件:柱:XBridgeC18,3.5μm,4.6x30mm;梯度:5B 0.2min,5B-100B 1.8min,100B 1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。1H NMR(500MHz,DMSO)δ1.31(t,J=7.1Hz,3H),1.58–1.47(m,2H),1.88–1.69(m,6H),2.92(五重峰,J=7.9Hz,1H),4.35(q,J=7.1Hz,2H),8.05(dd,J=8.1,4.7Hz,1H),8.43(d,J=8.1Hz,1H),9.03(d,J=4.7Hz,1H).
5-环戊基-1-(2-(三氟甲基)吡啶-3-基)-1H-1,2,4-三唑-3-甲酸:将1N氢氧化钠溶液(0.47mL,0.47mmol,2.0当量)加入到5-环戊基-1-(2-(三氟甲基)吡啶-3-基)-1H-1,2,4-三唑-3-甲酸乙酯(83mg,0.23mmol,1.00当量)的THF:MeOH(1:1,1.2mL)溶液中。将反应混合物在室温下搅拌18小时。加入1H HCl直至pH=1,并将混合物用乙酸乙酯萃取2次。将合并的有机层用硫酸钠干燥,过滤并蒸发,得到61mg(80%)标题化合物,为浅褐色固体。m/z(M+H)+=327.1;RT=1.13min;纯度=>99%。HPLC条件:柱:XBridge C18,3.5μm,4.6x30mm;梯度:5B 0.2min,5B-100B 1.8min,100B 1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。
(S)-3-(5-环戊基-1-(2-(三氟甲基)吡啶-3-基)-1H-1,2,4-三唑-3-甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酸叔丁酯:在0℃下,将HATU(39mg,0.10mmol,1.1当量)加入到(S)-3-氨基-5-(3,3-二氟哌啶-1-基)戊酸叔丁酯(27mg,0.092mmol,1.0当量)、5-环戊基-1-(2-(三氟甲基)吡啶-3-基)-1H-1,2,4-三唑-3-甲酸(30mg,0.092mmol,1.0当量)和二异丙基乙胺(48μL,0.28mmol,3.0当量)的DMF(0.37mL)溶液中。将反应混合物在室温下搅拌18小时。加入水,然后加入乙酸乙酯。分离各相,将有机层用饱和碳酸氢钠水溶液(3x)洗涤,用硫酸钠干燥,过滤并蒸发。使用MeOH的DCM溶液(0至5%),经硅胶快速色谱法纯化粗产物,得到48.7mg(88%)标题化合物,为浅橙色油状物。使用MeCN的水溶液(含有10mM甲酸铵,pH=3.8)(10-70%),在C-18柱上通过反相色谱法进一步纯化该化合物。合并级分并蒸发。将残余物与乙酸乙酯和饱和NaHCO3水溶液混合。分离各相,有机层用硫酸钠干燥,过滤并蒸发,得到28.6mg(52%),为浅黄色油状物。m/z(M+H)+=601.3;RT=1.72min;纯度=>95%。HPLC条件:柱:XBridge C18,3.5μm,4.6x30mm;梯度:5B 0.2min,5B-100B 1.8min,100B 1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。
(S)-3-(5-环戊基-1-(2-(三氟甲基)吡啶-3-基)-1H-1,2,4-三唑-3-甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酸:将4M HCl的二噁烷溶液(0.24mL,0.95mmol,20当量)加入到(S)-3-(5-环戊基-1-(2-(三氟甲基)吡啶-3-基)-1H-1,2,4-三唑-3-甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酸叔丁酯(29mg,0.048mmol,1.0当量)中。将反应混合物在室温下搅拌18小时,蒸发溶剂。将粗产物使用MeCN的水溶液(含有10mM碳酸氢铵,pH=10)(5至50%,205nM检测),在C-18柱上通过反相色谱法纯化。将纯级分冻干,得到15.8mg(61%)标题化合物,为白色固体。m/z(M+H)+=545.2;RT=1.25min;纯度=99.5%。HPLC条件:柱:XBridge C18,3.5μm,4.6x30mm;梯度:5B 0.2min,5B-100B 1.8min,100B 1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。1H NMR(500MHz,DMSO)δ1.58–1.48(m,2H),1.68–1.59(m,2H),1.88–1.69(m,10H),2.45–2.30(m,4H),2.52-2.46(m,1H),2.66–2.53(m,3H),2.89(五重峰,J=8.1Hz,1H),4.35–4.26(m,1H),8.04(dd,J=8.2,4.7Hz,1H),8.41(d,J=8.2Hz,1H),8.48(s,1H),9.02(d,J=4.7Hz,1H).
方案2:(S)-3-(1-环戊基-5-(3-(三氟甲基)吡啶-2-基)-1H-1,2,4-三唑-3-甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酸的制备
试剂和条件:(a)3-(三氟甲基)吡啶-2-甲酸,HATU,i-PrNEt2,DMF,0℃至室温,18小时;(b)4M HCl的二噁烷溶液,室温,18小时;(c)2-氨基-2-硫代乙酸乙酯,甲苯,CH3COOH,110℃,3天;(d)NaOH,THF:MeOH(1:1),室温,18小时;(e)(S)-3-氨基-5-(3,3-二氟哌啶-1-基)戊酸叔丁酯,HATU,HOAt,i-PrNEt2,DMF,0℃至室温,18小时;(f)4M HCl的二噁烷溶液,室温,18小时
2-环戊基-2-(3-(三氟甲基)吡啶-2-甲酰基)肼甲酸叔丁酯:在0℃下,将HATU(4.18g,11.0mmol,1.10当量)加入到2-环戊基肼甲酸叔丁酯(2.00g,10.0mmol,1.00当量)、3-(三氟甲基)吡啶-2-甲酸(2.10g,11.0mmol,1.10当量)和二异丙基乙胺(5.22mL,30.0mmol,3.00当量)在DMF(40mL)中的溶液中。将反应混合物在室温下搅拌18小时。将混合物溶解在EtOAc中,将溶液用盐水洗涤(4x),用硫酸钠干燥,过滤并蒸发。使用乙酸乙酯的己烷溶液(20至60%),通过硅胶快速色谱法纯化粗产物,得到2.94g(74%)标题化合物,为白色固体。m/z(M+H)+=374.2;RT=1.67min;纯度=98.7%。HPLC条件:柱:XBridge C18,3.5μm,4.6x30mm;梯度:5B0.2min,5B-100B 1.8min,100B 1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。
N-环戊基-3-(三氟甲基)吡啶-2-甲酰肼:将4M HCl的二噁烷溶液(20mL,79mmol,10当量)加入到2-环戊基-2-(3-三氟甲基)吡啶-2-甲酰基)肼甲酸叔丁酯(2.94g,7.87mmol,1.00当量)中。将反应在室温下搅拌18小时。缓慢加入饱和的NaHCO3水溶液(100mL),然后加入6N NaOH直至pH=10。将混合物用THF的DCM溶液(1:3)萃取4次,将合并的有机层用硫酸钠干燥,过滤并蒸发,得到2.19g(定量收率)标题化合物,为浅黄色油状物。m/z(M+H)+=274.1;RT=1.25-1.35min(信号很宽,具有两个峰);纯度=92.6%。HPLC条件:柱:XBridge C18,3.5μm,4.6x30mm;梯度:5B 0.2min,5B-100B 1.8min,100B 1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。
1-环戊基-5-(3-(三氟甲基)吡啶-2-基)-1H-1,2,4-三唑-3-甲酸乙酯:将2-氨基-2-硫代乙酸乙酯(586mg,4.39mmol,3.00当量)加入到N-环戊基-3-(三氟甲基)吡啶-2-甲酰肼(400mg,1.46mmol,1.00当量)的甲苯(2.4mL)溶液中。加入乙酸(0.24mL),将反应混合物在110℃加热3天。蒸发溶剂,使用乙酸乙酯的己烷溶液(30-50%),经硅胶快速色谱法纯化粗产物,得到216mg(42%)标题化合物,为褐色油状物。m/z(M+H)+=355.2;RT=1.68min;纯度=86%。HPLC条件:柱:XBridge C18,3.5μm,4.6x30mm;梯度:5B 0.2min,5B-100B1.8min,100B 1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。1H NMR(500MHz,DMSO)δ1.32(t,J=7.1Hz,3H),1.62–1.50(m,2H),1.95–1.78(m,4H),2.05–1.96(m,2H),4.36(q,J=7.1Hz,2H),4.71–4.63(m,1H),7.92(ddd,J=8.1,4.9,0.7Hz,1H),8.50(dd,J=8.2,1.2Hz,1H),9.06(dd,J=4.8,0.9Hz,1H).
1-环戊基-5-(3-(三氟甲基)吡啶-2-基)-1H-1,2,4-三唑-3-甲酸:将1N NaOH(1.2mL,1.2mmol,2.0当量)加入到1-环戊基-5-(3-(三氟甲基)吡啶-2-基)-1H-1,2,4-三唑-3-甲酸乙酯在THF:MeOH(1:1,3.1mL)中的溶液中。将反应混合物在室温下搅拌18小时。加入1H HCl以酸化该混合物。将混合物搅拌2分钟,形成沉淀,然后过滤并真空干燥,得到86mg(43%)标题化合物,为米色固体。m/z(M+H)+=327.1;RT=1.13min;纯度=98.5%。HPLC条件:柱:XBridge C18,3.5μm,4.6x30mm;梯度:5B 0.2min,5B-100B 1.8min,100B 1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。
(S)-3-(1-环戊基-5-(3-(三氟甲基)吡啶-2-基)-1H-1,2,4-三唑-3-甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酸叔丁酯:在0℃下,将HATU(39mg,0.10mmol,1.1当量)加入到(S)-3-氨基-5-(3,3-二氟哌啶-1-基)戊酸叔丁酯(27mg,0.092mmol,1.0当量)、1-环戊基-5-(3-(三氟甲基)吡啶-2-基)-1H-1,2,4-三唑-3-甲酸(30mg,0.092mmol,1.0当量)和二异丙基乙胺(48μL,0.28mmol,3.0当量)在DMF(0.37mL)中的溶液中。将反应混合物在室温下搅拌18小时。加入水,然后加入乙酸乙酯。分离各相,有机层用饱和碳酸氢钠水溶液洗涤(3x),用硫酸钠干燥,过滤并蒸发。使用MeOH的DCM溶液(0至10%),通过硅胶快速色谱法纯化粗产物,得到35.5mg(64%)标题化合物,为浅橙色油状物。m/z(M+H)+=601.3;RT=1.74min;纯度=96.8%。HPLC条件:柱:XBridge C18,3.5μm,4.6x30mm;梯度:5B 0.2min,5B-100B1.8min,100B 1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。1H NMR(500MHz,CDCl3)δ1.43(s,9H),1.79–1.70(m,2H),1.63–1.53(m,2H),1.91–1.80(m,4H),2.04–1.92(m,4H),2.23–2.12(m,2H),2.48–2.40(m,2H),2.68–2.50(m,6H),4.52–4.45(m,1H),4.56(五重峰,J=7.6Hz,1H),7.65–7.59(m,1H),7.75(d,J=9.1Hz,1H),8.19(dd,J=8.1,1.3Hz,1H),8.93(dd,J=4.8,1.1Hz,1H).
(S)-3-(1-环戊基-5-(3-(三氟甲基)吡啶-2-基)-1H-1,2,4-三唑-3-甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酸:将4M HCl的二噁烷溶液(0.30mL,1.2mmol,20当量)加入到(S)-3-(1-环戊基-5-(3-(三氟甲基)吡啶-2-基)-1H-1,2,4-三唑-3-甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酸叔丁酯(36mg,0.059mmol,1.0当量)中。将反应混合物在室温下搅拌3小时,蒸发溶剂。使用MeCN的水溶液(含有10mM碳酸氢铵,pH=10)(5至50%,205nM检测),在C-18柱上通过反相色谱法纯化粗产物。将纯级分冻干,得到17.3mg(54%)标题化合物,为白色固体。m/z(M+H)+=545.3;RT=1.28min;纯度=>99%。HPLC条件:柱:XBridge C18,3.5μm,4.6x30mm;梯度:5B 0.2min,5B-100B 1.8min,100B 1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。1H NMR(500MHz,DMSO)δ1.66–1.53(m,4H),1.77–1.68(m,2H),2.03–1.77(m,8H),2.44–2.31(m,4H),2.54-2.44 9m,2H),2.63–2.55(m,2H),4.34–4.24(m,1H),4.60(五重峰,J=7.0Hz,1H),7.91(dd,J=7.8,5.1Hz,1H),8.46(s,1H),8.51(d,J=7.8Hz,1H),9.06(d,J=3.9Hz,1H).
方案3:(S)-N-(1-(环丁基氨基)-5-(3,3-二氟哌啶-1-基)-1-氧代戊-3-基)-2-环戊基-1-(2-(三氟甲基)苯基)-1H-咪唑-4-甲酰胺的制备
试剂和条件:(a)1-氟-2-(三氟甲基)苯,K2CO3,DMSO,微波,150℃;(b)环戊甲酸,AgNO3,10%的H2SO4水溶液,90℃,1h;(c)LiOH-H2O,THF,H2O,MeOH,50℃,16小时;(d)SOCl2,60℃,4h;(e)(S)-3-氨基-5-(3,3-二氟哌啶-1-基)戊酸叔丁酯,i-PrNEt2,DCM,0℃至室温,18小时;(f)4M HCl的二噁烷溶液,室温,18小时;(g)环丁基胺,HATU,DIPEA,DMF,18小时
1-(2-(三氟甲基)苯基)-1H-咪唑-4-甲酸乙酯:在微波瓶中加入1H-咪唑-4-甲酸乙酯(500mg,3.57mmol,1当量)、2-氟苄腈(1.17g,906μL,7.14mmol,2当量)、K2CO3(987mg,7.14mmol,2当量)和DMSO(10mL)。将小瓶密封并将混合物在150℃下照射30分钟,冷却至室温,倒入250mL水中。将产物用3×75mL DCM萃取,合并有机萃取物,用3×250mL水、3×100mL饱和的NaCl水溶液洗涤,干燥(MgSO4),过滤,蒸发滤液。将琥珀色油状物在高真空下干燥1小时。几分钟后产物开始结晶,得到962mg(95%)标题化合物,为琥珀色结晶固体。m/z(M+H)+=285.3;RT=1.41min;纯度=96.3%。HPLC条件:柱:XBridge C18,3.5μm,4.6x30mm;梯度:5B 0.2min,5B-100B 1.8min,100B 1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。1H NMR(500MHz,DMSO)δ1.29(t,J=7.1Hz,3H),4.27(q,J=7.1Hz,2H),7.69(d,J=7.8Hz,1H),7.83-7.72(m,1H),7.89(td,J=7.7,0.9Hz,1H),8.02-7.96(m,3H),8.13(d,J=0.6Hz,1H).
2-环戊基-1-(2-(三氟甲基)苯基)-1H-咪唑-4-甲酸乙酯:将1-(2-(三氟甲基)苯基)-1H-咪唑-4-甲酸乙酯(500mg,1.76mmol,1当量)加入到硝酸银(179mg,1.06mmol,0.6当量)和环戊甲酸(602mg,572μL,5.28mmol,3当量)在10%H2SO4水溶液(6mL)中的混合物中,将反应混合物在90℃下加热。在约20分钟内逐滴加入新制备的过硫酸铵(1.21g,5.28mmol,3当量)的水(6mL)溶液。然后除去加热源,随着二氧化碳的释放进行反应。1小时后,通过将其倒入到冰/水(约100ml)中终止该反应。用30%NH4OH溶液使所得混合物呈碱性,并用乙酸乙酯(2×50mL)萃取。将合并的萃取液用饱和NaCl水溶液(2X50mL)洗涤,干燥(MgSO4)并过滤。将滤液真空蒸发,将残余物通过Combi-Flash,40g硅胶柱,用DCM等浓度洗脱2分钟,然后用15%甲醇/DCM洗脱15分钟来纯化。合并最纯的级分,蒸发溶剂。将残余物在高真空下干燥过夜,得到125mg(20%)标题化合物,为无定形琥珀色固体。m/z(M+H)+=353.3;RT=1.71min;纯度=89.2%。HPLC条件:柱:XBridge C18,3.5μm,4.6x30mm;梯度:5B 0.2min,5B-100B1.8min,100B 1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。1H NMR(500MHz,DMSO)δ1.27(t,J=7.1Hz,3H),1.48-1.38(m,2H),1.77-1.58(m,5H),1.86-1.78(m,1H),2.59(q,J=8.1Hz,1H),4.30–4.17(m,2H),7.67(d,J=7.8Hz,1H),7.81(t,J=7.7Hz,1H),7.89(td,J=7.7,1.0Hz,1H),7.93(d,J=0.7Hz,1H),7.99(dd,J=7.8,1.1Hz,1H).
2-环戊基-1-(2-(三氟甲基)苯基)-1H-咪唑-4-甲酸:向搅拌下的2-环戊基-1-(2-(三氟甲基)苯基)-1H-咪唑-4-甲酸乙酯(123mg,0.35mmol,1当量)的THF(6ml)溶液中加入LiOH-H2O(17.6mg,0.42mmol,1.2当量),随后加入甲醇(3ml)和水(3ml)。LiOH不完全溶解,加入更多的水(约1.5ml),并将溶液加热至50℃过夜。使其冷却至室温,蒸发有机溶剂,将水溶液用10ml水稀释,加入1N HCl水溶液(420μL,1.2当量),产物用2×10ml乙酸乙酯萃取。合并有机萃取物,用10ml饱和NaCl水溶液洗涤,干燥(MgSO4),过滤,蒸发滤液,在高真空下干燥残余物。得到115mg(101%)标题化合物,为无定形固体。m/z(M+H)+=325.3;RT=1.37min;纯度=82.2%。HPLC条件:柱:XBridge C18,3.5μm,4.6x30mm;梯度:5B 0.2min,5B-100B1.8min,100B 1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。1H NMR(500 MHz,DMSO)δ1.50-1.35(m,2H),1.80-1.55(m,6H),2.62-2.54(m,1H),7.86-7.72(m,2H),7.89(td,J=7.7,1.0Hz,1H),8.01-7.97(m,1H),13.2-11.2(s,宽的,1H)。
2-环戊基-1-(2-(三氟甲基)苯基)-1H-咪唑-4-甲酰氯:将2-环戊基-1-(2-(三氟甲基)苯基)-1H-咪唑-4-甲酸(67mg,0.19mmol)溶于氯化亚砜(1.5mL)中。将溶液在氮气下搅拌并加热至60℃,保持4小时。冷却至室温,蒸发挥发物,将残余物溶于10ml二噁烷中,将该溶液蒸发至干,将残余物在高真空下干燥1小时。得到68mg(105%)标题化合物,为琥珀色油状物。将粗产物原样用于下一次转化。
(S)-3-(2-环戊基-1-(2-(三氟甲基)苯基)-1H-咪唑-4-甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酸叔丁酯:在氮气下,向搅拌下的冰冷却的(S)-3-氨基-5-(3,3-二氟哌啶-1-基)戊酸叔丁酯(56mg,0.19mmol,1当量)的DCM(4mL)溶液中加入二异丙基乙胺(49mg,66μL,0.38mmol,2当量),随后滴加2-环戊基-1-(2-(三氟甲基)苯基)-1H-咪唑-4-甲酰氯(65mg,0.19mmol,1当量)的DCM(1ml)溶液。将混合物在冷却下搅拌30分钟,使其温热至室温,搅拌过夜。用30ml DCM稀释,用2×10ml饱和的NaHCO3水溶液、10ml饱和的NaCl水溶液洗涤。干燥(MgSO4),过滤,蒸发滤液。将残余物通过Combi-Flash,12g柱,用DCM等浓度洗脱2分钟,然后用10%MeOH/DCM洗脱10分钟来纯化,合并最纯的级分,蒸发溶剂。将残余物在高真空下干燥,得到37mg(32%)标题化合物,为无定形固体。m/z(M+H)+=599.5;RT=1.88min;纯度=97.6%。HPLC条件:柱:XBridge C18,3.5μm,4.6x30mm;梯度:5B 0.2min,5B-100B 1.8min,100B 1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。1H NMR(500MHz,DMSO)δ1.40-1.33(旋转异构体,2s,9H),1.50-1.41(m,2H),1.93-1.55(m,11H),2.72-2.28(m,10H),4.35-4.23(m,1H),7.67-7.59(m,2H),7.76-7.68(m,1H),7.80(t,J=7.7Hz,1H),7.89(t,J=7.7Hz,1H),7.98(d,J=7.9Hz,1H).
(S)-3-(2-环戊基-1-(2-(三氟甲基)苯基)-1H-咪唑-4-甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酸盐酸盐:在氮气下,向搅拌下的(S)-3-(2-环戊基-1-(2-(三氟甲基)苯基)-1H-咪唑-4-甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酸叔丁酯(33mg,0.055mmol,1当量)的二噁烷(500μL)溶液中加入1ml的4N HCl/二噁烷溶液。将生成的溶液在室温下搅拌4小时。蒸发溶剂,得到琥珀色油状物,加入t-BuOMe(10mL),将混合物超声处理10分钟,蒸发溶剂,得到34mg(107%)标题化合物,为褐色固体。m/z(M+H)+=543.3;RT=1.42min;纯度=97.1%。HPLC条件:柱:XBridge C18,3.5μm,4.6x30mm;梯度:5B 0.2min,5B-100B 1.8min,100B1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。
(S)-N-(1-(环丁基氨基)-5-(3,3-二氟哌啶-1-基)-1-氧代戊-3-基)-2-环戊基-1-(2-(三氟甲基)苯基)-1H-咪唑-4-甲酰胺:在氮气下,向搅拌下的(S)-3-(2-环戊基-1-(2-(三氟甲基)苯基)-1H-咪唑-4-甲酰氨基)-5-(3,3-二氟哌啶-1-基)戊酸盐酸盐(10mg,0.018mmol,1当量)的DMF(500μL)溶液中加入HATU(8.6mg,0.023mmol,1.25当量)、HOAt(3.1mg,0.023mmol,1.25当量)、DIPEA(9.3mg,0.072mmol,12.5μL,4当量)和环丁基胺(1.95mg,0.027mmol,2.34μL,1.5当量)。将溶液搅拌过夜(16小时),然后将其用乙酸乙酯(约30ml)稀释,用3×20ml饱和的NaHCO3水溶液、20ml饱和的NaCl水溶液洗涤,干燥(MgSO4),过滤,蒸发滤液。将残余物通过Combi-Flash,反相12g C18柱,用10mM碳酸铵等浓度洗脱2分钟,然后用100%乙腈洗脱15分钟来纯化。合并最纯的级分,蒸发乙腈,将剩余的含水悬浮液转移到称量瓶(tared vial)中,将烧瓶用2×1ml乙腈冲洗,将洗涤液与含水悬浮液(得到澄清溶液)合并。将溶液冷冻并冻干,得到6.2mg(58%)标题化合物,为白色固体。m/z(M+H)+=596.2;RT=1.56min;纯度=99.0%。HPLC条件:柱:XBridge C18,3.5μm,4.6x30mm;梯度:5B0.2min,5B-100B 1.8min,100B 1min;3mL/min。洗脱液A:pH3.8 10mM甲酸铵的水溶液;洗脱液B:乙腈。1H NMR(500 MHz,DMSO)δ1.50-1.40(m,2H),1.78-1.55(m,10H),1.92-1.79(m,4H),2.18-2.05(m,2H),2.45-2.25(m,6H),2.75-2.48(m,5H),4.30-4.12(m,2H),7.67-7.60(m,2H),7.80(t,J=7.7Hz,1H),7.88(t,J=7.7Hz,1H),8.00-7.93(m,2H),8.20-8.14(m,1H).
化合物的爱帕琳肽激动剂活性的表征
使用由Giddings等人描述的方法,研究上述化合物作为爱帕琳肽激动剂的体外活性。Giddings等人,2010 Int J High Thro Screen.1:39-47,其内容通过引用整体并入本文。如所述使用Giddings等人中描述的方法,并且爱帕琳肽-13作为阳性对照。
表1.
表2
1.1.细胞摄取测定
Caco-2细胞(克隆C2BBe1)获自美国模式培养物保藏中心(American TypeCulture Collection)(Manassas,VA)。使细胞单层在12孔Costar Transwell板中的胶原包被的微孔聚碳酸酯膜上生长至汇合。板及其认证的详细信息如下所示。渗透性测定缓冲液是Hanks平衡盐溶液(HBSS),其含有10mM HEPES和15mM葡萄糖,pH为7.4。接收室(receiverchamber)中的缓冲液还含有1%牛血清白蛋白。对于测定缓冲液中的每种测试物品,给药溶液浓度为5μM。将细胞单层给药于顶侧(A至B)或基底外侧(B至A),并在湿润培养箱中在37℃、5%CO2下培养。在120分钟时从供体室和接收室中取样。每次测定一式两份进行。实验后,从插入物(insert)中除去所有测定缓冲液。将细胞单层在A至B侧上以空白500μM荧光黄给药,并在B至A侧上以空白HBSS给药,并在37℃培养。在60分钟时从B至A侧取样。测量每个单层的荧光黄的通量,以确保在通量期间没有对细胞单层造成损害。使用电喷雾电离通过LC-MS/MS分析所有样品。表观渗透率(P表观)和回收百分比根据如下计算:
P表观=(dCr/dt)×Vr/(A×CA) (1)
回收百分比=100×((Vr×Cr 最终)+(Vd×Cd 最终))/(Vd×CN) (2)
其中dCr/dt是接收室中累积浓度相对于时间的斜率,单位为μM s-1;
Vr是接收室的体积,单位为cm3;
Vd是供体室的体积,单位为cm3;
A是插入物的面积(对于12孔Transwell为1.13cm2);
CA是标称给药浓度和测量的120分钟供体浓度的平均值,单位为μM;
CN是给药溶液的标称浓度,单位为μM;
Cr 最终是培养期结束时的累积接收浓度,单位为μM;
Cd 最终是培养期结束时的供体的浓度,单位为μM。
流出比率(ER)定义为P表观(B-至-A)/P表观(A-至-B)。
吸收电位(Absorption Potential)分类:
P表观(A-至-B)<1.0×10-6cm/s:低
P表观(A-至-B)≥1.0×10-6cm/s:高
明显的流出定义为:ER≥2.0并且Papp(B-至-A)≥1.0×10-6cm/s
化合物的体内血压降低活性
还使用C57BL/6小鼠和Tatemoto等人描述的方法测定了相关化合物的血压活性。新型肽-爱帕琳肽通过一氧化氮依赖性机制降低血压。Regul Pept.2001;99:87-92。合成该化合物,并使用上文描述的体外测定来表征该化合物。已经公开一些研究,其中提到给药爱帕琳肽后发生血压下降。爱帕琳肽-13被用作阳性对照。参见WO 2015/188073(ResearchTriangle Inst.),其内容通过引用并入本文。
应理解,虽然已经结合其详述描述了本公开内容,但前述描述意欲举例说明本公开内容,并非限制本公开内容的范围。本公开的其他方面、优点和修改在下面阐述的权利要求的范围内。本说明书中引用的所有出版物、专利和专利申请均通过引用并入到本文中,如同每个单独的出版物或专利申请被具体和单独地指明通过引用并入。
Claims (21)
1.由式I表示的化合物、或其药学上可接受的盐:
其中环A为咪唑;与R1相连的G1为N;与R2相连的G1为C;与酰胺相连的G1为C;
R1由下式表示:
A为―CF3;
R7和R8独立地为甲基、乙基、丙基或丁基、C3-8环烷基、H、具有1至4个选自N、O和S的杂原子的5-6元杂芳基或者R7和R8一起形成5-6元含氮环;
n是1;
R2是任选氟取代的C3-8烷基或任选氟或羟基取代的C0烷基-R10,其中R10是3至8元环,其任选地含有一个选自N、O或S的杂原子并任选地具有一个或多个不饱和度;
R3是H;
R4和R5独立地为C1-8烷基-5至6元杂芳基、-(CH2)xNR7R8、-(CH2)xCONR7R8和-(CH2)xxCO2R7,所述5至6元杂芳基具有1至4个选自N、O和S的杂原子;
每个x独立地为0-8;并且
每个xx独立地为1-8。
2.权利要求1的化合物,
R2是C3-8环烷基;
R5为-(CH2)xCONR7R8或者-(CH2)xxCO2R7
x为1-4;且
xx为1-4。
3.权利要求1的化合物,
R2是C6环烷基;
R5为-(CH2)xCONR7R8或-(CH2)xxCO2R7;
R3为H;
R8为C1-4烷基或H;
x为1-4;且
xx为1-4。
5.药物组合物,所述药物组合物包含至少一种药学上可接受的赋形剂和治疗有效量的权利要求1-4中任一项的化合物。
6.权利要求1-3中任一项的化合物在制备用于治疗爱帕琳肽受体(APJ)相关的病症的药物中的用途。
7.权利要求6的用途,其中所述爱帕琳肽受体(APJ)相关的病症选自哮喘、心肌病、糖尿病、血脂异常、高血压、炎症、肝病、代谢紊乱、神经退行性疾病、肥胖症、先兆子痫、肾功能障碍、静脉相关的病症和HIV相关的神经退行。
8.权利要求6的用途,其中所述高血压是肺动脉高血压。
9.权利要求6的用途,其中所述肝病是酒精性肝病、毒物诱导的肝病或病毒诱导的肝病。
10.权利要求6的用途,其中所述肾功能障碍是多囊性肾病。
11.权利要求6的用途,其中所述静脉相关的病症是血管瘤、静脉功能不全、淤滞或血栓症。
12.权利要求6的用途,其中所述爱帕琳肽受体(APJ)相关的病症是HIV相关的神经退行。
13.权利要求6的用途,其中所述药物进一步包括α-阻断剂、血管紧张素转化酶(ACE)抑制剂、血管紧张素受体阻断剂(ARB)、β-阻断剂、钙通道阻断剂或利尿剂。
14.权利要求4的化合物在制备用于治疗爱帕琳肽受体(APJ)相关的病症的药物中的用途。
15.权利要求14的用途,其中所述爱帕琳肽受体(APJ)相关的病症选自哮喘、心肌病、糖尿病、血脂异常、高血压、炎症、肝病、代谢紊乱、神经退行性疾病、肥胖症、先兆子痫、肾功能障碍、静脉相关的病症和HIV相关的神经退行。
16.权利要求14的用途,其中所述高血压是肺动脉高血压。
17.权利要求14的用途,其中所述肝病是酒精性肝病、毒物诱导的肝病或病毒诱导的肝病。
18.权利要求14的用途,其中所述肾功能障碍是多囊性肾病。
19.权利要求14的用途,其中所述静脉相关的病症是血管瘤、静脉功能不全、淤滞或血栓症。
20.权利要求14的用途,其中所述爱帕琳肽受体(APJ)相关的病症是HIV相关的神经退行。
21.权利要求14的用途,其中所述药物进一步包括α-阻断剂、血管紧张素转化酶(ACE)抑制剂、血管紧张素受体阻断剂(ARB)、β-阻断剂、钙通道阻断剂或利尿剂。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210236504.8A CN114507217A (zh) | 2016-10-12 | 2017-10-11 | 杂环爱帕琳肽受体(apj)激动剂及其用途 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662407206P | 2016-10-12 | 2016-10-12 | |
US62/407,206 | 2016-10-12 | ||
PCT/US2017/056117 WO2018071526A1 (en) | 2016-10-12 | 2017-10-11 | Heterocyclic apelin receptor (apj) agonists and uses thereof |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210236504.8A Division CN114507217A (zh) | 2016-10-12 | 2017-10-11 | 杂环爱帕琳肽受体(apj)激动剂及其用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109790151A CN109790151A (zh) | 2019-05-21 |
CN109790151B true CN109790151B (zh) | 2022-03-29 |
Family
ID=61905967
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210236504.8A Pending CN114507217A (zh) | 2016-10-12 | 2017-10-11 | 杂环爱帕琳肽受体(apj)激动剂及其用途 |
CN201780061192.9A Active CN109790151B (zh) | 2016-10-12 | 2017-10-11 | 杂环爱帕琳肽受体(apj)激动剂及其用途 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210236504.8A Pending CN114507217A (zh) | 2016-10-12 | 2017-10-11 | 杂环爱帕琳肽受体(apj)激动剂及其用途 |
Country Status (15)
Country | Link |
---|---|
US (1) | US11926612B2 (zh) |
EP (1) | EP3526209A4 (zh) |
JP (1) | JP7104690B2 (zh) |
KR (1) | KR102541080B1 (zh) |
CN (2) | CN114507217A (zh) |
AU (1) | AU2017343638B2 (zh) |
BR (1) | BR112019003420A2 (zh) |
CA (1) | CA3033913A1 (zh) |
CO (1) | CO2019003590A2 (zh) |
IL (1) | IL265414A (zh) |
MA (1) | MA46540A (zh) |
MX (1) | MX2019004214A (zh) |
PE (1) | PE20190806A1 (zh) |
RU (1) | RU2764039C2 (zh) |
WO (1) | WO2018071526A1 (zh) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2015269247B2 (en) | 2014-06-06 | 2019-10-24 | Research Triangle Institute | Apelin receptor (APJ) agonists and uses thereof |
JP2019501899A (ja) | 2015-12-09 | 2019-01-24 | リサーチ トライアングル インスティテュート | 改良アペリンレセプター(apj)アゴニストおよびその使用 |
RU2764039C2 (ru) | 2016-10-12 | 2022-01-14 | Рисерч Трайэнгл Инститьют | Гетероциклические агонисты рецептора апелина (apj) и их применение |
EP3541805B1 (en) | 2016-11-16 | 2020-10-14 | Amgen Inc. | Heteroaryl-substituted triazoles as apj receptor agonists |
WO2018093577A1 (en) | 2016-11-16 | 2018-05-24 | Amgen Inc. | Cycloalkyl substituted triazole compounds as agonists of the apj receptor |
WO2018097944A1 (en) | 2016-11-16 | 2018-05-31 | Amgen Inc. | Triazole furan compounds as agonists of the apj receptor |
WO2018093579A1 (en) | 2016-11-16 | 2018-05-24 | Amgen Inc. | Triazole phenyl compounds as agonists of the apj receptor |
WO2018093576A1 (en) | 2016-11-16 | 2018-05-24 | Amgen Inc. | Alkyl substituted triazole compounds as agonists of the apj receptor |
EP3704122B1 (en) | 2017-11-03 | 2021-09-01 | Amgen Inc. | Fused triazole agonists of the apj receptor |
EP3788037A1 (en) | 2018-05-01 | 2021-03-10 | Amgen Inc. | Substituted pyrimidinones as agonists of the apj receptor |
EP4021447A4 (en) * | 2019-08-29 | 2023-10-11 | Research Triangle Institute | METHODS AND USES FOR APELIN RECEPTOR AGONISTS |
US20240174638A1 (en) * | 2021-02-25 | 2024-05-30 | Research Triangle Institute | Heteroaryl derivatives as apelin receptor agonists |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1556703A (zh) * | 2001-09-21 | 2004-12-22 | ������ҩ������˾ | 具有cb1激动活性,cb1部分激动活性或cb1拮抗活性的1h-咪唑衍生物 |
WO2005099705A2 (en) * | 2004-03-24 | 2005-10-27 | Bayer Pharmaceuticals Corporation | Preparation of imidazole derivatives and methods of use |
Family Cites Families (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS58194866A (ja) | 1982-05-07 | 1983-11-12 | Kureha Chem Ind Co Ltd | トリアゾ−ル誘導体及び該誘導体を含有する除草剤 |
DE3316300A1 (de) * | 1982-05-07 | 1983-11-24 | Kureha Kagaku Kogyo K.K., Tokyo | Heribizide zusammensetzung mit einem gehalt an einem derivat des 1,2,4-triazols als wirkstoff |
JPS5998004A (ja) | 1982-11-25 | 1984-06-06 | Kureha Chem Ind Co Ltd | 1,2,4―トリアゾール誘導体及び除草剤 |
JP3003148B2 (ja) * | 1989-01-05 | 2000-01-24 | 藤沢薬品工業株式会社 | チアゾール化合物、その製造法およびそれを含有する医薬組成物 |
US5571810A (en) * | 1990-06-11 | 1996-11-05 | Fujisawa Pharmaceutical Co., Ltd. | Thiophene derivatives |
FR2692575B1 (fr) | 1992-06-23 | 1995-06-30 | Sanofi Elf | Nouveaux derives du pyrazole, procede pour leur preparation et compositions pharmaceutiques les contenant. |
US7109216B2 (en) * | 2001-09-21 | 2006-09-19 | Solvay Pharmaceuticals B.V. | 1H-imidazole derivatives having CB1 agonistic, CB1 partial agonistic or CB1-antagonistic activity |
PE20030547A1 (es) | 2001-09-24 | 2003-08-18 | Bayer Corp | Derivados de imidazol para el tratamiento de la obesidad |
US7319110B2 (en) | 2002-09-19 | 2008-01-15 | Solvay Pharmaceuticals B.V. | 1H-1,2,4-triazole-3-carboxamide derivatives having cannabinoid-CB1 receptor agonistic, partial agonistic, inverse agonistic or antagonistic activity |
FR2860792B1 (fr) * | 2003-10-10 | 2006-02-24 | Sanofi Synthelabo | Derives de thiophene-2-carboxamide, leur preparation et leur application en therapeutique |
ZA200703562B (en) * | 2004-10-19 | 2008-08-27 | Daiichi Seiyaku Co | 1,5-diheterocycle-1H-triazole derivative |
AU2007226673A1 (en) | 2006-03-10 | 2007-09-20 | Jenrin Discovery | Cannabinoid receptor antagonists/inverse agonists useful for treating obesity |
EP1903052A3 (en) | 2006-07-28 | 2008-04-02 | Faust Pharmaceuticals SA | APJ receptor ligands and uses thereof |
US20100256357A1 (en) | 2006-08-09 | 2010-10-07 | Agouron Pharmaceuticals, Inc. | Heterocycles useful as inhibitors of carbonic anhydrase |
UY30892A1 (es) * | 2007-02-07 | 2008-09-02 | Smithkline Beckman Corp | Inhibidores de la actividad akt |
JP5464395B2 (ja) | 2008-02-01 | 2014-04-09 | 大陽日酸株式会社 | 重水素化された芳香環又は複素環を有する化合物の製造方法 |
WO2009154754A2 (en) | 2008-06-17 | 2009-12-23 | Concert Pharmaceuticals, Inc. | Synthesis of deuterated morpholine derivatives |
WO2010033511A1 (en) | 2008-09-16 | 2010-03-25 | Concert Pharmaceuticals, Inc. | Deuterated 2-amino-3-hydroxypropanoic acid derivatives |
CN101519430A (zh) | 2009-03-20 | 2009-09-02 | 中国农业大学 | 一类新型保幼激素合成抑制剂-苯丙-甘-亮三肽酰胺类似物 |
KR101386679B1 (ko) | 2009-07-10 | 2014-04-17 | 주식회사 녹십자 | 신규한 아릴피페라진-함유 이미다졸 4-카복사마이드 유도체 및 이를 포함하는 약학 조성물 |
WO2011156557A2 (en) | 2010-06-11 | 2011-12-15 | Thomas James B | Compounds active at the neurotensin receptor |
JP5925301B2 (ja) | 2011-05-23 | 2016-05-25 | サノフイ | N−アルキル基を含有するジュウテリウム化化合物の製造方法 |
CN103827097B (zh) | 2011-07-26 | 2016-03-16 | 赛诺菲 | 3-杂芳酰基氨基-丙酸衍生物及其作为药物的用途 |
CN104603118B (zh) | 2012-05-31 | 2017-10-03 | 菲尼克斯药品股份公司 | 作为孤儿核受体RORγ调节物的经甲酰胺或磺酰胺取代的噻唑及相关衍生物 |
JO3215B1 (ar) | 2012-08-09 | 2018-03-08 | Phenex Pharmaceuticals Ag | حلقات غير متجانسة بها 5 ذرات تحتوي على النيتروجين بها استبدال بكربوكساميد أو سلفوناميد كمعدلات لمستقبل نووي غير محمي RORy |
CA2883641C (en) | 2012-09-18 | 2021-09-14 | Auspex Pharmaceuticals, Inc. | Formulations pharmacokinetics of deuterated benzoquinoline inhibitors of vesicular monoamine transporter 2 |
DK2897939T3 (en) | 2012-09-21 | 2017-05-08 | Sanofi Sa | BENZOIMIDAZOLCARBOXYL ACID AMIDE DERIVATIVES FOR THE TREATMENT OF METABOLIC OR CARDIOVASCULAR DISEASES |
WO2014053533A1 (en) | 2012-10-05 | 2014-04-10 | Sanofi | Use of substituted 3-heteroaroylamino-propionic acid derivatives as pharmaceuticals for prevention/treatment of atrial fibrillation |
WO2014100431A1 (en) | 2012-12-20 | 2014-06-26 | Concert Pharmaceuticals, Inc. | Deuterated alk inhibitors |
WO2014169280A2 (en) | 2013-04-12 | 2014-10-16 | Achillion Pharmaceuticals, Inc. | Deuterated nucleoside prodrugs useful for treating hcv |
EP3057953B1 (en) | 2013-10-17 | 2018-08-15 | Vertex Pharmaceuticals Incorporated | Co-crystals of (s)-n-methyl-8-(1-((2'-methyl-[4,5'-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide and deuterated derivatives thereof as dna-pk inhibitors |
WO2015184011A2 (en) | 2014-05-28 | 2015-12-03 | Sanford-Burnham Medical Research Institute | Agonists of the apelin receptor and methods of use thereof |
AU2015269247B2 (en) | 2014-06-06 | 2019-10-24 | Research Triangle Institute | Apelin receptor (APJ) agonists and uses thereof |
JP2019501899A (ja) | 2015-12-09 | 2019-01-24 | リサーチ トライアングル インスティテュート | 改良アペリンレセプター(apj)アゴニストおよびその使用 |
RU2764039C2 (ru) | 2016-10-12 | 2022-01-14 | Рисерч Трайэнгл Инститьют | Гетероциклические агонисты рецептора апелина (apj) и их применение |
-
2017
- 2017-10-11 RU RU2019103873A patent/RU2764039C2/ru active
- 2017-10-11 CA CA3033913A patent/CA3033913A1/en active Pending
- 2017-10-11 WO PCT/US2017/056117 patent/WO2018071526A1/en unknown
- 2017-10-11 BR BR112019003420-0A patent/BR112019003420A2/pt unknown
- 2017-10-11 AU AU2017343638A patent/AU2017343638B2/en active Active
- 2017-10-11 EP EP17860899.8A patent/EP3526209A4/en active Pending
- 2017-10-11 MX MX2019004214A patent/MX2019004214A/es unknown
- 2017-10-11 CN CN202210236504.8A patent/CN114507217A/zh active Pending
- 2017-10-11 JP JP2019508240A patent/JP7104690B2/ja active Active
- 2017-10-11 US US16/341,597 patent/US11926612B2/en active Active
- 2017-10-11 PE PE2019000806A patent/PE20190806A1/es unknown
- 2017-10-11 CN CN201780061192.9A patent/CN109790151B/zh active Active
- 2017-10-11 KR KR1020197013143A patent/KR102541080B1/ko active IP Right Grant
- 2017-10-11 MA MA046540A patent/MA46540A/fr unknown
-
2019
- 2019-03-17 IL IL265414A patent/IL265414A/en unknown
- 2019-04-11 CO CONC2019/0003590A patent/CO2019003590A2/es unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1556703A (zh) * | 2001-09-21 | 2004-12-22 | ������ҩ������˾ | 具有cb1激动活性,cb1部分激动活性或cb1拮抗活性的1h-咪唑衍生物 |
WO2005099705A2 (en) * | 2004-03-24 | 2005-10-27 | Bayer Pharmaceuticals Corporation | Preparation of imidazole derivatives and methods of use |
Also Published As
Publication number | Publication date |
---|---|
CO2019003590A2 (es) | 2019-04-30 |
KR20190055251A (ko) | 2019-05-22 |
MX2019004214A (es) | 2019-06-10 |
MA46540A (fr) | 2019-08-21 |
CA3033913A1 (en) | 2018-04-19 |
RU2019103873A (ru) | 2020-11-17 |
JP7104690B2 (ja) | 2022-07-21 |
PE20190806A1 (es) | 2019-06-10 |
BR112019003420A2 (pt) | 2019-05-21 |
WO2018071526A1 (en) | 2018-04-19 |
JP2019534848A (ja) | 2019-12-05 |
CN114507217A (zh) | 2022-05-17 |
US20190322644A1 (en) | 2019-10-24 |
AU2017343638A1 (en) | 2019-02-28 |
RU2764039C2 (ru) | 2022-01-14 |
RU2019103873A3 (zh) | 2021-02-04 |
KR102541080B1 (ko) | 2023-06-08 |
EP3526209A4 (en) | 2020-08-19 |
IL265414A (en) | 2019-05-30 |
EP3526209A1 (en) | 2019-08-21 |
US11926612B2 (en) | 2024-03-12 |
CN109790151A (zh) | 2019-05-21 |
AU2017343638B2 (en) | 2021-12-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN109790151B (zh) | 杂环爱帕琳肽受体(apj)激动剂及其用途 | |
USRE49594E1 (en) | Apelin receptor (APJ) agonists and uses thereof | |
US11401244B2 (en) | Apelin receptor (APJ) agonists and uses thereof | |
US20240174638A1 (en) | Heteroaryl derivatives as apelin receptor agonists |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |