JP5634263B2 - キナゾリンジオンキマーゼ阻害剤 - Google Patents
キナゾリンジオンキマーゼ阻害剤 Download PDFInfo
- Publication number
- JP5634263B2 JP5634263B2 JP2010521115A JP2010521115A JP5634263B2 JP 5634263 B2 JP5634263 B2 JP 5634263B2 JP 2010521115 A JP2010521115 A JP 2010521115A JP 2010521115 A JP2010521115 A JP 2010521115A JP 5634263 B2 JP5634263 B2 JP 5634263B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- carbon atoms
- mmol
- dimethyl
- ylmethyl
- 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
- 239000003601 chymase inhibitor Substances 0.000 title description 8
- 229940119334 Chymase inhibitor Drugs 0.000 title description 6
- SDQJTWBNWQABLE-UHFFFAOYSA-N 1h-quinazoline-2,4-dione Chemical compound C1=CC=C2C(=O)NC(=O)NC2=C1 SDQJTWBNWQABLE-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 113
- 125000004432 carbon atom Chemical group C* 0.000 claims description 67
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 125000005843 halogen group Chemical group 0.000 claims description 26
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 10
- 239000002671 adjuvant Substances 0.000 claims description 9
- 125000003277 amino group Chemical group 0.000 claims description 9
- 150000001721 carbon Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 208000020832 chronic kidney disease Diseases 0.000 claims description 4
- 230000000302 ischemic effect Effects 0.000 claims description 4
- 206010007558 Cardiac failure chronic Diseases 0.000 claims description 3
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 3
- 230000009787 cardiac fibrosis Effects 0.000 claims description 3
- 210000004351 coronary vessel Anatomy 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 3
- 208000037803 restenosis Diseases 0.000 claims description 3
- 206010002329 Aneurysm Diseases 0.000 claims description 2
- 206010002388 Angina unstable Diseases 0.000 claims description 2
- 206010003658 Atrial Fibrillation Diseases 0.000 claims description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 2
- 208000003037 Diastolic Heart Failure Diseases 0.000 claims description 2
- 206010049694 Left Ventricular Dysfunction Diseases 0.000 claims description 2
- 208000025584 Pericardial disease Diseases 0.000 claims description 2
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 2
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims description 2
- 206010063837 Reperfusion injury Diseases 0.000 claims description 2
- 208000007718 Stable Angina Diseases 0.000 claims description 2
- 206010042957 Systolic hypertension Diseases 0.000 claims description 2
- 208000007814 Unstable Angina Diseases 0.000 claims description 2
- 206010000891 acute myocardial infarction Diseases 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 208000029078 coronary artery disease Diseases 0.000 claims description 2
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 208000028208 end stage renal disease Diseases 0.000 claims description 2
- 201000000523 end stage renal failure Diseases 0.000 claims description 2
- 208000018578 heart valve disease Diseases 0.000 claims description 2
- 206010020871 hypertrophic cardiomyopathy Diseases 0.000 claims description 2
- 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 2
- 238000013146 percutaneous coronary intervention Methods 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
- 208000015658 resistant hypertension Diseases 0.000 claims description 2
- 238000001356 surgical procedure Methods 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims 1
- 206010047281 Ventricular arrhythmia Diseases 0.000 claims 1
- 208000002815 pulmonary hypertension Diseases 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 108
- 239000000243 solution Substances 0.000 description 86
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 71
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 70
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 70
- 235000019439 ethyl acetate Nutrition 0.000 description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- -1 benzoimidazolyl group Chemical group 0.000 description 41
- 239000011541 reaction mixture Substances 0.000 description 37
- 238000000034 method Methods 0.000 description 32
- 239000000203 mixture Substances 0.000 description 32
- 239000012044 organic layer Substances 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 238000003818 flash chromatography Methods 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 239000003480 eluent Substances 0.000 description 20
- 229910052938 sodium sulfate Inorganic materials 0.000 description 20
- 235000011152 sodium sulphate Nutrition 0.000 description 20
- 239000011259 mixed solution Substances 0.000 description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 102100024539 Chymase Human genes 0.000 description 14
- 108090000227 Chymases Proteins 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 125000002252 acyl group Chemical group 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 8
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 7
- 125000001072 heteroaryl group Chemical group 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 5
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 239000012131 assay buffer Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 5
- ZBZANMKPESOHLJ-UHFFFAOYSA-N 3-(bromomethyl)-4,6-dimethyl-1,2-benzothiazole Chemical compound CC1=CC(C)=C2C(CBr)=NSC2=C1 ZBZANMKPESOHLJ-UHFFFAOYSA-N 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 238000002405 diagnostic procedure Methods 0.000 description 4
- 125000001041 indolyl group Chemical group 0.000 description 4
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical class NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 4
- NUKZAGXMHTUAFE-UHFFFAOYSA-N methyl hexanoate Chemical compound CCCCCC(=O)OC NUKZAGXMHTUAFE-UHFFFAOYSA-N 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 125000000962 organic group Chemical group 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- CUKWUWBLQQDQAC-VEQWQPCFSA-N (3s)-3-amino-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-carboxyethyl]carbamoyl]pyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-ox Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 CUKWUWBLQQDQAC-VEQWQPCFSA-N 0.000 description 3
- BWWHTIHDQBHTHP-UHFFFAOYSA-N 2-nitrobenzoyl chloride Chemical class [O-][N+](=O)C1=CC=CC=C1C(Cl)=O BWWHTIHDQBHTHP-UHFFFAOYSA-N 0.000 description 3
- ICPNHSUPOJFFCD-UHFFFAOYSA-N 4,6-dimethyl-1,2-benzothiazole-3-carboxylic acid Chemical compound CC1=CC(C)=C2C(C(O)=O)=NSC2=C1 ICPNHSUPOJFFCD-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102400000345 Angiotensin-2 Human genes 0.000 description 3
- 101800000733 Angiotensin-2 Proteins 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- 201000004624 Dermatitis Diseases 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 229950006323 angiotensin ii Drugs 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 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
- 238000001816 cooling Methods 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 210000004392 genitalia Anatomy 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 210000003630 histaminocyte Anatomy 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 125000002950 monocyclic group Chemical class 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000004951 trihalomethoxy group Chemical group 0.000 description 3
- IZFRDGQDJQWARS-UHFFFAOYSA-M (1,4-dimethylindol-3-yl)methyl-trimethylazanium;iodide Chemical compound [I-].CC1=CC=CC2=C1C(C[N+](C)(C)C)=CN2C IZFRDGQDJQWARS-UHFFFAOYSA-M 0.000 description 2
- SDZKUKIQXMXPJW-HXUWFJFHSA-N (2r)-2-[2,4-dioxo-1-[(1,4,6-trimethylindol-3-yl)methyl]quinazolin-3-yl]pentanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@@H](C(O)=O)CCC)C(=O)N1CC1=CN(C)C2=CC(C)=CC(C)=C12 SDZKUKIQXMXPJW-HXUWFJFHSA-N 0.000 description 2
- DJMWHGHSHOEXCI-UHFFFAOYSA-N 1,4,6-trimethylindole Chemical compound CC1=CC(C)=C2C=CN(C)C2=C1 DJMWHGHSHOEXCI-UHFFFAOYSA-N 0.000 description 2
- VKFRBJZPULCELH-UHFFFAOYSA-N 1,4,6-trimethylindole-3-carbaldehyde Chemical compound CC1=CC(C)=C2C(C=O)=CN(C)C2=C1 VKFRBJZPULCELH-UHFFFAOYSA-N 0.000 description 2
- JJGZLBMKQXISRV-UHFFFAOYSA-N 1-(1,2,4,5,6,7-hexamethylindol-3-yl)-N-iodomethanamine Chemical compound CC=1C(=C(C(=C2C(=C(N(C12)C)C)CNI)C)C)C JJGZLBMKQXISRV-UHFFFAOYSA-N 0.000 description 2
- VSVKADGXAMKKMQ-UHFFFAOYSA-N 2-amino-n-[1-(4-chlorophenyl)ethyl]benzamide Chemical compound C=1C=C(Cl)C=CC=1C(C)NC(=O)C1=CC=CC=C1N VSVKADGXAMKKMQ-UHFFFAOYSA-N 0.000 description 2
- TYZPEIDQFWDPMR-UHFFFAOYSA-N 3-[1-(4-chlorophenyl)ethyl]-1h-quinazoline-2,4-dione Chemical compound O=C1NC2=CC=CC=C2C(=O)N1C(C)C1=CC=C(Cl)C=C1 TYZPEIDQFWDPMR-UHFFFAOYSA-N 0.000 description 2
- QEUUNWQNJZZRTR-UHFFFAOYSA-N 4,6-dimethyl-1,2-benzothiazole-3-carboxamide Chemical compound CC1=CC(C)=C2C(C(N)=O)=NSC2=C1 QEUUNWQNJZZRTR-UHFFFAOYSA-N 0.000 description 2
- HDQLFGCRKRAPSG-UHFFFAOYSA-N 4,6-dimethyl-1-benzothiophene-2,3-dione Chemical compound CC1=CC(C)=CC2=C1C(=O)C(=O)S2 HDQLFGCRKRAPSG-UHFFFAOYSA-N 0.000 description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 2
- 102400000344 Angiotensin-1 Human genes 0.000 description 2
- 101800000734 Angiotensin-1 Proteins 0.000 description 2
- 208000031229 Cardiomyopathies Diseases 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-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
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000004442 acylamino group Chemical group 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000002619 bicyclic group Chemical class 0.000 description 2
- 230000008512 biological response Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- MQQJJFBIGFIHTN-UGKGYDQZSA-N ethyl (3s)-3-[benzyl-[(1s)-1-phenylethyl]amino]hexanoate Chemical compound CCOC(=O)C[C@H](CCC)N([C@@H](C)C=1C=CC=CC=1)CC1=CC=CC=C1 MQQJJFBIGFIHTN-UGKGYDQZSA-N 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 210000005003 heart tissue Anatomy 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 206010073096 invasive lobular breast carcinoma Diseases 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- CXRVMKSBTCJUJJ-CQSZACIVSA-N methyl (2r)-2-[(2-aminobenzoyl)amino]-2-cyclohexylacetate Chemical compound N([C@@H](C(=O)OC)C1CCCCC1)C(=O)C1=CC=CC=C1N CXRVMKSBTCJUJJ-CQSZACIVSA-N 0.000 description 2
- ORJOGDRCFDWIIJ-DDWIOCJRSA-N methyl (2r)-2-amino-2-cyclohexylacetate;hydrochloride Chemical compound Cl.COC(=O)[C@H](N)C1CCCCC1 ORJOGDRCFDWIIJ-DDWIOCJRSA-N 0.000 description 2
- KPYDGGXPQUVZGM-RUZDIDTESA-N methyl (2r)-2-cyclohexyl-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]acetate Chemical compound C1([C@H](C(=O)OC)N2C(C3=CC=CC=C3N(CC=3C4=C(C)C=CC=C4N(C)C=3)C2=O)=O)CCCCC1 KPYDGGXPQUVZGM-RUZDIDTESA-N 0.000 description 2
- YDVJUKJSODSLLM-AWEZNQCLSA-N methyl (2s)-2-(2,4-dioxo-1h-quinazolin-3-yl)-2-phenylacetate Chemical compound C1([C@@H](C(=O)OC)N2C(C3=CC=CC=C3NC2=O)=O)=CC=CC=C1 YDVJUKJSODSLLM-AWEZNQCLSA-N 0.000 description 2
- QQCWXNLMDGIIGS-ZDUSSCGKSA-N methyl (2s)-2-(6-methoxy-2,4-dioxo-1h-quinazolin-3-yl)hexanoate Chemical compound C1=C(OC)C=C2C(=O)N([C@H](C(=O)OC)CCCC)C(=O)NC2=C1 QQCWXNLMDGIIGS-ZDUSSCGKSA-N 0.000 description 2
- GLGLMZGEYDGGCF-ZDUSSCGKSA-N methyl (2s)-2-(7-methoxy-2,4-dioxo-1h-quinazolin-3-yl)hexanoate Chemical compound COC1=CC=C2C(=O)N([C@H](C(=O)OC)CCCC)C(=O)NC2=C1 GLGLMZGEYDGGCF-ZDUSSCGKSA-N 0.000 description 2
- MJUOQRWOZRUORP-ZDUSSCGKSA-N methyl (2s)-2-[(2-amino-4-methoxybenzoyl)amino]hexanoate Chemical compound CCCC[C@@H](C(=O)OC)NC(=O)C1=CC=C(OC)C=C1N MJUOQRWOZRUORP-ZDUSSCGKSA-N 0.000 description 2
- WHHZGIWONLTJKJ-ZDUSSCGKSA-N methyl (2s)-2-[(2-amino-5-methoxybenzoyl)amino]hexanoate Chemical compound CCCC[C@@H](C(=O)OC)NC(=O)C1=CC(OC)=CC=C1N WHHZGIWONLTJKJ-ZDUSSCGKSA-N 0.000 description 2
- AHBSCMUDGOGERK-AWEZNQCLSA-N methyl (2s)-2-[(2-aminobenzoyl)amino]-2-phenylacetate Chemical compound N([C@H](C(=O)OC)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1N AHBSCMUDGOGERK-AWEZNQCLSA-N 0.000 description 2
- LGDZJHLYOLPHRG-VWLOTQADSA-N methyl (2s)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]-2-phenylacetate Chemical compound C1([C@@H](C(=O)OC)N2C(C3=CC=CC=C3N(CC=3C4=C(C)C=CC=C4N(C)C=3)C2=O)=O)=CC=CC=C1 LGDZJHLYOLPHRG-VWLOTQADSA-N 0.000 description 2
- FMMOVZRXLNVNBI-RGMNGODLSA-N methyl (2s)-2-aminohexanoate;hydrochloride Chemical compound Cl.CCCC[C@H](N)C(=O)OC FMMOVZRXLNVNBI-RGMNGODLSA-N 0.000 description 2
- ROAADFVJPNIJBA-UHFFFAOYSA-N methyl 2-(2,4-dioxo-1h-quinazolin-3-yl)pentanoate Chemical compound C1=CC=C2C(=O)N(C(C(=O)OC)CCC)C(=O)NC2=C1 ROAADFVJPNIJBA-UHFFFAOYSA-N 0.000 description 2
- ZJYHMGZPIKXYOU-UHFFFAOYSA-N methyl 2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]pentanoate Chemical compound C12=CC=CC=C2C(=O)N(C(C(=O)OC)CCC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 ZJYHMGZPIKXYOU-UHFFFAOYSA-N 0.000 description 2
- JZHYRNXRYLFNSK-UHFFFAOYSA-N methyl 2-[1-[(2,4-dioxo-1h-quinazolin-3-yl)methyl]cyclohexyl]acetate Chemical compound O=C1NC2=CC=CC=C2C(=O)N1CC1(CC(=O)OC)CCCCC1 JZHYRNXRYLFNSK-UHFFFAOYSA-N 0.000 description 2
- JGEJAFLJAWJAGY-UHFFFAOYSA-N methyl 2-[1-[[(2-aminobenzoyl)amino]methyl]cyclohexyl]acetate Chemical compound C=1C=CC=C(N)C=1C(=O)NCC1(CC(=O)OC)CCCCC1 JGEJAFLJAWJAGY-UHFFFAOYSA-N 0.000 description 2
- GHIBEUTYQSEESV-UHFFFAOYSA-N methyl 2-[1-[[(2-nitrobenzoyl)amino]methyl]cyclohexyl]acetate Chemical compound C=1C=CC=C([N+]([O-])=O)C=1C(=O)NCC1(CC(=O)OC)CCCCC1 GHIBEUTYQSEESV-UHFFFAOYSA-N 0.000 description 2
- VXGRMCZTYDXKQW-UHFFFAOYSA-N methyl 2-aminopentanoate Chemical compound CCCC(N)C(=O)OC VXGRMCZTYDXKQW-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 210000004789 organ system Anatomy 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- ZYZHMSJNPCYUTB-ZDUSSCGKSA-N (1s)-n-benzyl-1-phenylethanamine Chemical compound N([C@@H](C)C=1C=CC=CC=1)CC1=CC=CC=C1 ZYZHMSJNPCYUTB-ZDUSSCGKSA-N 0.000 description 1
- PITIKRNWJIOREK-HSZRJFAPSA-N (2r)-2-(4-chlorophenyl)-2-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]acetic acid Chemical compound C1([C@H](C(O)=O)N2C(=O)C3=CC=CC=C3N(C2=O)CC=2C3=C(C)C=C(C=C3SN=2)C)=CC=C(Cl)C=C1 PITIKRNWJIOREK-HSZRJFAPSA-N 0.000 description 1
- QWLZWAZGMFTFKF-XMMPIXPASA-N (2r)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]-2-phenylacetic acid Chemical compound C1([C@H](C(O)=O)N2C(=O)C3=CC=CC=C3N(C2=O)CC2=CN(C)C=3C=CC=C(C2=3)C)=CC=CC=C1 QWLZWAZGMFTFKF-XMMPIXPASA-N 0.000 description 1
- YVKUIEYCLLXTQJ-QGZVFWFLSA-N (2r)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]butanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@@H](C(O)=O)CC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 YVKUIEYCLLXTQJ-QGZVFWFLSA-N 0.000 description 1
- NNBONEROOZVHEW-OAQYLSRUSA-N (2r)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]hexanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@@H](C(O)=O)CCCC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 NNBONEROOZVHEW-OAQYLSRUSA-N 0.000 description 1
- BMPDZYSQAHKCKA-HXUWFJFHSA-N (2r)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]pentanamide Chemical compound C12=CC=CC=C2C(=O)N([C@@H](C(N)=O)CCC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 BMPDZYSQAHKCKA-HXUWFJFHSA-N 0.000 description 1
- ZUNBVJJNUMHMCO-HXUWFJFHSA-N (2r)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]pentanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@@H](C(O)=O)CCC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 ZUNBVJJNUMHMCO-HXUWFJFHSA-N 0.000 description 1
- KIFZOHFMVUNDIE-CQSZACIVSA-N (2r)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]propanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@@H](C(O)=O)C)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 KIFZOHFMVUNDIE-CQSZACIVSA-N 0.000 description 1
- DBDQFOZBZBNOHW-JOCHJYFZSA-N (2r)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-6-methoxy-2,4-dioxoquinazolin-3-yl]hexanoic acid Chemical compound C12=CC=C(OC)C=C2C(=O)N([C@@H](C(O)=O)CCCC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 DBDQFOZBZBNOHW-JOCHJYFZSA-N 0.000 description 1
- NEWJGZVTFOFOTC-HSZRJFAPSA-N (2r)-2-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]-2-phenylacetic acid Chemical compound C1([C@H](C(O)=O)N2C(=O)C3=CC=CC=C3N(C2=O)CC=2C3=C(C)C=C(C=C3SN=2)C)=CC=CC=C1 NEWJGZVTFOFOTC-HSZRJFAPSA-N 0.000 description 1
- RCESAMLAFWBAPA-MRXNPFEDSA-N (2r)-2-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]butanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@@H](C(O)=O)CC)C(=O)N1CC1=NSC2=CC(C)=CC(C)=C12 RCESAMLAFWBAPA-MRXNPFEDSA-N 0.000 description 1
- WCTNOCXIKIBRKC-LJQANCHMSA-N (2r)-2-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]hexanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@@H](C(O)=O)CCCC)C(=O)N1CC1=NSC2=CC(C)=CC(C)=C12 WCTNOCXIKIBRKC-LJQANCHMSA-N 0.000 description 1
- UKCGMKFKOAZNQD-OAQYLSRUSA-N (2r)-2-[2,4-dioxo-1-[(1,4,6-trimethylindol-3-yl)methyl]quinazolin-3-yl]hexanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@@H](C(O)=O)CCCC)C(=O)N1CC1=CN(C)C2=CC(C)=CC(C)=C12 UKCGMKFKOAZNQD-OAQYLSRUSA-N 0.000 description 1
- QMUIOFNZAZPFFT-OGFXRTJISA-N (2r)-2-amino-2-cyclohexylacetic acid;hydrochloride Chemical compound Cl.OC(=O)[C@H](N)C1CCCCC1 QMUIOFNZAZPFFT-OGFXRTJISA-N 0.000 description 1
- GZNIFTWRXMFPAQ-XMMPIXPASA-N (2r)-2-cyclohexyl-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]acetic acid Chemical compound C1([C@@H](N2C(=O)C3=CC=CC=C3N(C2=O)CC2=CN(C)C=3C=CC=C(C2=3)C)C(O)=O)CCCCC1 GZNIFTWRXMFPAQ-XMMPIXPASA-N 0.000 description 1
- WKFVDAVKZWKSQH-OAQYLSRUSA-N (2r)-2-cyclopropyl-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]acetic acid Chemical compound C1([C@@H](N2C(=O)C3=CC=CC=C3N(C2=O)CC2=CN(C)C=3C=CC=C(C2=3)C)C(O)=O)CC1 WKFVDAVKZWKSQH-OAQYLSRUSA-N 0.000 description 1
- BKGGFYANBUDDFN-HXUWFJFHSA-N (2r)-2-cyclopropyl-2-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]acetic acid Chemical compound C1([C@@H](N2C(=O)C3=CC=CC=C3N(C2=O)CC=2C3=C(C)C=C(C=C3SN=2)C)C(O)=O)CC1 BKGGFYANBUDDFN-HXUWFJFHSA-N 0.000 description 1
- PITIKRNWJIOREK-QHCPKHFHSA-N (2s)-2-(4-chlorophenyl)-2-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]acetic acid Chemical compound C1([C@@H](C(O)=O)N2C(=O)C3=CC=CC=C3N(C2=O)CC=2C3=C(C)C=C(C=C3SN=2)C)=CC=C(Cl)C=C1 PITIKRNWJIOREK-QHCPKHFHSA-N 0.000 description 1
- QWLZWAZGMFTFKF-DEOSSOPVSA-N (2s)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]-2-phenylacetic acid Chemical compound C1([C@@H](C(O)=O)N2C(=O)C3=CC=CC=C3N(C2=O)CC2=CN(C)C=3C=CC=C(C2=3)C)=CC=CC=C1 QWLZWAZGMFTFKF-DEOSSOPVSA-N 0.000 description 1
- YVKUIEYCLLXTQJ-KRWDZBQOSA-N (2s)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]butanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@H](C(O)=O)CC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 YVKUIEYCLLXTQJ-KRWDZBQOSA-N 0.000 description 1
- NNBONEROOZVHEW-NRFANRHFSA-N (2s)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]hexanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@H](C(O)=O)CCCC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 NNBONEROOZVHEW-NRFANRHFSA-N 0.000 description 1
- ZUNBVJJNUMHMCO-FQEVSTJZSA-N (2s)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]pentanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@H](C(O)=O)CCC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 ZUNBVJJNUMHMCO-FQEVSTJZSA-N 0.000 description 1
- KIFZOHFMVUNDIE-AWEZNQCLSA-N (2s)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]propanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@H](C(O)=O)C)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 KIFZOHFMVUNDIE-AWEZNQCLSA-N 0.000 description 1
- SONHMZYYQJWDJO-FQEVSTJZSA-N (2s)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-6,7-dimethoxy-2,4-dioxoquinazolin-3-yl]hexanoic acid Chemical compound C12=CC(OC)=C(OC)C=C2C(=O)N([C@H](C(O)=O)CCCC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 SONHMZYYQJWDJO-FQEVSTJZSA-N 0.000 description 1
- DBDQFOZBZBNOHW-QFIPXVFZSA-N (2s)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-6-methoxy-2,4-dioxoquinazolin-3-yl]hexanoic acid Chemical compound C12=CC=C(OC)C=C2C(=O)N([C@H](C(O)=O)CCCC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 DBDQFOZBZBNOHW-QFIPXVFZSA-N 0.000 description 1
- RUVCLPJBRMBSHB-NRFANRHFSA-N (2s)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-7-methoxy-2,4-dioxoquinazolin-3-yl]hexanoic acid Chemical compound C12=CC(OC)=CC=C2C(=O)N([C@H](C(O)=O)CCCC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 RUVCLPJBRMBSHB-NRFANRHFSA-N 0.000 description 1
- NEWJGZVTFOFOTC-QHCPKHFHSA-N (2s)-2-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]-2-phenylacetic acid Chemical compound C1([C@@H](C(O)=O)N2C(=O)C3=CC=CC=C3N(C2=O)CC=2C3=C(C)C=C(C=C3SN=2)C)=CC=CC=C1 NEWJGZVTFOFOTC-QHCPKHFHSA-N 0.000 description 1
- RCESAMLAFWBAPA-INIZCTEOSA-N (2s)-2-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]butanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@H](C(O)=O)CC)C(=O)N1CC1=NSC2=CC(C)=CC(C)=C12 RCESAMLAFWBAPA-INIZCTEOSA-N 0.000 description 1
- WCTNOCXIKIBRKC-IBGZPJMESA-N (2s)-2-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]hexanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@H](C(O)=O)CCCC)C(=O)N1CC1=NSC2=CC(C)=CC(C)=C12 WCTNOCXIKIBRKC-IBGZPJMESA-N 0.000 description 1
- AENPAAWMCPERPQ-ZDUSSCGKSA-N (2s)-2-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]propanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@H](C(O)=O)C)C(=O)N1CC1=NSC2=CC(C)=CC(C)=C12 AENPAAWMCPERPQ-ZDUSSCGKSA-N 0.000 description 1
- NAFYXJGBTNASFN-FQEVSTJZSA-N (2s)-2-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-6-methoxy-2,4-dioxoquinazolin-3-yl]hexanoic acid Chemical compound C12=CC=C(OC)C=C2C(=O)N([C@H](C(O)=O)CCCC)C(=O)N1CC1=NSC2=CC(C)=CC(C)=C12 NAFYXJGBTNASFN-FQEVSTJZSA-N 0.000 description 1
- GZNIFTWRXMFPAQ-DEOSSOPVSA-N (2s)-2-cyclohexyl-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]acetic acid Chemical compound C1([C@H](N2C(=O)C3=CC=CC=C3N(C2=O)CC2=CN(C)C=3C=CC=C(C2=3)C)C(O)=O)CCCCC1 GZNIFTWRXMFPAQ-DEOSSOPVSA-N 0.000 description 1
- WKFVDAVKZWKSQH-NRFANRHFSA-N (2s)-2-cyclopropyl-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]acetic acid Chemical compound C1([C@H](N2C(=O)C3=CC=CC=C3N(C2=O)CC2=CN(C)C=3C=CC=C(C2=3)C)C(O)=O)CC1 WKFVDAVKZWKSQH-NRFANRHFSA-N 0.000 description 1
- BKGGFYANBUDDFN-FQEVSTJZSA-N (2s)-2-cyclopropyl-2-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]acetic acid Chemical compound C1([C@H](N2C(=O)C3=CC=CC=C3N(C2=O)CC=2C3=C(C)C=C(C=C3SN=2)C)C(O)=O)CC1 BKGGFYANBUDDFN-FQEVSTJZSA-N 0.000 description 1
- WIBGNMCELRFOLS-XMMPIXPASA-N (3r)-3-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]-3-phenylpropanoic acid Chemical compound C1([C@@H](CC(O)=O)N2C(=O)C3=CC=CC=C3N(C2=O)CC2=CN(C)C=3C=CC=C(C2=3)C)=CC=CC=C1 WIBGNMCELRFOLS-XMMPIXPASA-N 0.000 description 1
- WEDASWMLQAPLSD-QGZVFWFLSA-N (3r)-3-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]pentanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@@H](CC(O)=O)CC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 WEDASWMLQAPLSD-QGZVFWFLSA-N 0.000 description 1
- BLHNAEGZRAUCQF-CQSZACIVSA-N (3r)-3-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]butanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@@H](CC(O)=O)C)C(=O)N1CC1=NSC2=CC(C)=CC(C)=C12 BLHNAEGZRAUCQF-CQSZACIVSA-N 0.000 description 1
- WIBGNMCELRFOLS-DEOSSOPVSA-N (3s)-3-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]-3-phenylpropanoic acid Chemical compound C1([C@H](CC(O)=O)N2C(=O)C3=CC=CC=C3N(C2=O)CC2=CN(C)C=3C=CC=C(C2=3)C)=CC=CC=C1 WIBGNMCELRFOLS-DEOSSOPVSA-N 0.000 description 1
- OPSKZKOOZNVHNT-SFHVURJKSA-N (3s)-3-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]hexanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@H](CC(O)=O)CCC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 OPSKZKOOZNVHNT-SFHVURJKSA-N 0.000 description 1
- WEDASWMLQAPLSD-KRWDZBQOSA-N (3s)-3-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]pentanoic acid Chemical compound C12=CC=CC=C2C(=O)N([C@H](CC(O)=O)CC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 WEDASWMLQAPLSD-KRWDZBQOSA-N 0.000 description 1
- BCZCWCKZRCDFLC-UHFFFAOYSA-N (4,6-dimethyl-1,2-benzothiazol-3-yl)methanol Chemical compound CC1=CC(C)=C2C(CO)=NSC2=C1 BCZCWCKZRCDFLC-UHFFFAOYSA-N 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 1
- PINPOEWMCLFRRB-UHFFFAOYSA-N 1-(4-chlorophenyl)ethanamine Chemical compound CC(N)C1=CC=C(Cl)C=C1 PINPOEWMCLFRRB-UHFFFAOYSA-N 0.000 description 1
- WCDQIPBCOHSMTE-UHFFFAOYSA-N 1-[(1,4-dimethylindol-3-yl)methyl]-3-(1-methoxypropan-2-yl)quinazoline-2,4-dione Chemical compound C12=CC=CC=C2C(=O)N(C(C)COC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 WCDQIPBCOHSMTE-UHFFFAOYSA-N 0.000 description 1
- KULPHANKNJAGFF-UHFFFAOYSA-N 1-[(1,4-dimethylindol-3-yl)methyl]-3-(2-morpholin-4-ylethyl)quinazoline-2,4-dione Chemical compound C1=2C(C)=CC=CC=2N(C)C=C1CN(C1=O)C2=CC=CC=C2C(=O)N1CCN1CCOCC1 KULPHANKNJAGFF-UHFFFAOYSA-N 0.000 description 1
- PZEKGSYMRFFMFB-UHFFFAOYSA-N 1-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]cyclohexane-1-carboxylic acid Chemical compound C1=2C(C)=CC=CC=2N(C)C=C1CN(C1=O)C2=CC=CC=C2C(=O)N1C1(C(O)=O)CCCCC1 PZEKGSYMRFFMFB-UHFFFAOYSA-N 0.000 description 1
- PZGFYAGAECEPIY-UHFFFAOYSA-N 1-[[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]methyl]cyclohexane-1-carboxylic acid Chemical compound C1=2C(C)=CC=CC=2N(C)C=C1CN(C1=O)C2=CC=CC=C2C(=O)N1CC1(C(O)=O)CCCCC1 PZGFYAGAECEPIY-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
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- JNGRENQDBKMCCR-UHFFFAOYSA-N 2-(3-amino-6-iminoxanthen-9-yl)benzoic acid;hydrochloride Chemical compound [Cl-].C=12C=CC(=[NH2+])C=C2OC2=CC(N)=CC=C2C=1C1=CC=CC=C1C(O)=O JNGRENQDBKMCCR-UHFFFAOYSA-N 0.000 description 1
- YZWGVEFDYYLKLA-UHFFFAOYSA-N 2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]-2-methylbutanoic acid Chemical compound C12=CC=CC=C2C(=O)N(C(C)(C(O)=O)CC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 YZWGVEFDYYLKLA-UHFFFAOYSA-N 0.000 description 1
- GZECJTOXOGDARI-UHFFFAOYSA-N 2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]-2-methylpropanoic acid Chemical compound C12=CC=CC=C2C(=O)N(C(C)(C)C(O)=O)C(=O)N1CC1=CN(C)C2=C1C(C)=CC=C2 GZECJTOXOGDARI-UHFFFAOYSA-N 0.000 description 1
- YVKUIEYCLLXTQJ-UHFFFAOYSA-N 2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]butanoic acid Chemical compound C12=CC=CC=C2C(=O)N(C(C(O)=O)CC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 YVKUIEYCLLXTQJ-UHFFFAOYSA-N 0.000 description 1
- NNBONEROOZVHEW-UHFFFAOYSA-N 2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]hexanoic acid Chemical compound C12=CC=CC=C2C(=O)N(C(C(O)=O)CCCC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 NNBONEROOZVHEW-UHFFFAOYSA-N 0.000 description 1
- ZUNBVJJNUMHMCO-UHFFFAOYSA-N 2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]pentanoic acid Chemical compound C12=CC=CC=C2C(=O)N(C(C(O)=O)CCC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 ZUNBVJJNUMHMCO-UHFFFAOYSA-N 0.000 description 1
- AMTMORYJHZODLD-UHFFFAOYSA-N 2-[1-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]cyclohexyl]acetic acid Chemical compound C1=2C(C)=CC=CC=2N(C)C=C1CN(C1=O)C2=CC=CC=C2C(=O)N1C1(CC(O)=O)CCCCC1 AMTMORYJHZODLD-UHFFFAOYSA-N 0.000 description 1
- MUQPTJPFUVZHQM-UHFFFAOYSA-N 2-[1-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]cyclohexyl]acetic acid Chemical compound N=1SC2=CC(C)=CC(C)=C2C=1CN(C1=O)C2=CC=CC=C2C(=O)N1C1(CC(O)=O)CCCCC1 MUQPTJPFUVZHQM-UHFFFAOYSA-N 0.000 description 1
- DOFFYOGIGKSQIE-UHFFFAOYSA-N 2-[1-[[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]methyl]cyclohexyl]acetic acid Chemical compound C1=2C(C)=CC=CC=2N(C)C=C1CN(C1=O)C2=CC=CC=C2C(=O)N1CC1(CC(O)=O)CCCCC1 DOFFYOGIGKSQIE-UHFFFAOYSA-N 0.000 description 1
- NZWJHICJQRAJBE-UHFFFAOYSA-N 2-[4-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]oxan-4-yl]acetic acid Chemical compound C1=2C(C)=CC=CC=2N(C)C=C1CN(C1=O)C2=CC=CC=C2C(=O)N1C1(CC(O)=O)CCOCC1 NZWJHICJQRAJBE-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- HHNWXQCVWVVVQZ-UHFFFAOYSA-N 2-amino-4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C(N)=C1 HHNWXQCVWVVVQZ-UHFFFAOYSA-N 0.000 description 1
- IXXIIAPIURLROR-UHFFFAOYSA-N 2-aminopentanoic acid;hydrochloride Chemical compound Cl.CCCC(N)C(O)=O IXXIIAPIURLROR-UHFFFAOYSA-N 0.000 description 1
- CESBAYSBPMVAEI-UHFFFAOYSA-N 3,5-dimethylbenzenethiol Chemical compound CC1=CC(C)=CC(S)=C1 CESBAYSBPMVAEI-UHFFFAOYSA-N 0.000 description 1
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 1
- VBQPHKVRAUIRSX-UHFFFAOYSA-N 3-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]-4-phenylbutanoic acid Chemical compound C1=2C(C)=CC=CC=2N(C)C=C1CN(C1=O)C2=CC=CC=C2C(=O)N1C(CC(O)=O)CC1=CC=CC=C1 VBQPHKVRAUIRSX-UHFFFAOYSA-N 0.000 description 1
- DDZWOOZVAJGJLD-UHFFFAOYSA-N 3-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]butanoic acid Chemical compound C12=CC=CC=C2C(=O)N(C(CC(O)=O)C)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 DDZWOOZVAJGJLD-UHFFFAOYSA-N 0.000 description 1
- KQYMSWBJQOPLNT-UHFFFAOYSA-N 3-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]heptanoic acid Chemical compound C12=CC=CC=C2C(=O)N(C(CC(O)=O)CCCC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 KQYMSWBJQOPLNT-UHFFFAOYSA-N 0.000 description 1
- WEDASWMLQAPLSD-UHFFFAOYSA-N 3-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]pentanoic acid Chemical compound C12=CC=CC=C2C(=O)N(C(CC(O)=O)CC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 WEDASWMLQAPLSD-UHFFFAOYSA-N 0.000 description 1
- WMWZSAWFTFQNRN-UHFFFAOYSA-N 3-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]pentanoic acid Chemical compound C12=CC=CC=C2C(=O)N(C(CC(O)=O)CC)C(=O)N1CC1=NSC2=CC(C)=CC(C)=C12 WMWZSAWFTFQNRN-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
- JUNVXAOGQUENAB-UHFFFAOYSA-N 3-cyclopropyl-3-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]propanoic acid Chemical compound C1=2C(C)=CC=CC=2N(C)C=C1CN(C1=O)C2=CC=CC=C2C(=O)N1C(CC(O)=O)C1CC1 JUNVXAOGQUENAB-UHFFFAOYSA-N 0.000 description 1
- VDUBSIDZONBFPU-UHFFFAOYSA-N 3-cyclopropyl-3-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]propanoic acid Chemical compound N=1SC2=CC(C)=CC(C)=C2C=1CN(C1=O)C2=CC=CC=C2C(=O)N1C(CC(O)=O)C1CC1 VDUBSIDZONBFPU-UHFFFAOYSA-N 0.000 description 1
- WUCQJZHJZJSFLU-UHFFFAOYSA-N 4,6-dimethyl-1h-indole Chemical compound CC1=CC(C)=C2C=CNC2=C1 WUCQJZHJZJSFLU-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- FONFKIOKLLSURP-UHFFFAOYSA-N 4-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]-3-phenylbutanoic acid Chemical compound C1=2C(C)=CC=CC=2N(C)C=C1CN(C1=O)C2=CC=CC=C2C(=O)N1CC(CC(O)=O)C1=CC=CC=C1 FONFKIOKLLSURP-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- JFAFNQOODJCVGT-UHFFFAOYSA-N 6-methoxy-1h-3,1-benzoxazine-2,4-dione Chemical compound N1C(=O)OC(=O)C2=CC(OC)=CC=C21 JFAFNQOODJCVGT-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 206010001197 Adenocarcinoma of the cervix Diseases 0.000 description 1
- 208000034246 Adenocarcinoma of the cervix uteri Diseases 0.000 description 1
- 102000009346 Adenosine receptors Human genes 0.000 description 1
- 108050000203 Adenosine receptors Proteins 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 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
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006143 Brain stem glioma Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZTQLEUUMFVZGSZ-UHFFFAOYSA-N C(C)(=O)OCC1(CCCCC1)CN Chemical compound C(C)(=O)OCC1(CCCCC1)CN ZTQLEUUMFVZGSZ-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- ZZTLLIDJZUVBHI-CYBMUJFWSA-N C1(CCCCC1)[C@H](C(=O)O)NC(C1=C(C=CC=C1)[N+](=O)[O-])=O Chemical compound C1(CCCCC1)[C@H](C(=O)O)NC(C1=C(C=CC=C1)[N+](=O)[O-])=O ZZTLLIDJZUVBHI-CYBMUJFWSA-N 0.000 description 1
- SNDPXSYFESPGGJ-UHFFFAOYSA-N CCCC(C(O)=O)N Chemical compound CCCC(C(O)=O)N SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 1
- QJIRZHCWTCCOEQ-QGZVFWFLSA-N CN1C=C(C2=C(C=CC=C12)C)CN1C(N(C(C2=CC=CC=C12)=O)[C@H](C)CCC)=O Chemical compound CN1C=C(C2=C(C=CC=C12)C)CN1C(N(C(C2=CC=CC=C12)=O)[C@H](C)CCC)=O QJIRZHCWTCCOEQ-QGZVFWFLSA-N 0.000 description 1
- UUSVVDQFPGXFTQ-MRVPVSSYSA-N COC([C@@H](C1CCCCC1)N)=O Chemical compound COC([C@@H](C1CCCCC1)N)=O UUSVVDQFPGXFTQ-MRVPVSSYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 206010007275 Carcinoid tumour Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- IARNFTPGTBHTCE-HSZRJFAPSA-N ClCCCCCC[C@H](C(=O)O)N1C(N(C2=CC=CC=C2C1=O)CC1=CN(C2=CC=CC(=C12)C)C)=O Chemical compound ClCCCCCC[C@H](C(=O)O)N1C(N(C2=CC=CC=C2C1=O)CC1=CN(C2=CC=CC(=C12)C)C)=O IARNFTPGTBHTCE-HSZRJFAPSA-N 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 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
- 229940123900 Direct thrombin inhibitor Drugs 0.000 description 1
- 229940097420 Diuretic Drugs 0.000 description 1
- 102000010180 Endothelin receptor Human genes 0.000 description 1
- 108050001739 Endothelin receptor Proteins 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 206010018366 Glomerulonephritis acute Diseases 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 1
- 101000856199 Homo sapiens Chymotrypsin-like protease CTRL-1 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 206010073094 Intraductal proliferative breast lesion Diseases 0.000 description 1
- JGFBQFKZKSSODQ-UHFFFAOYSA-N Isothiocyanatocyclopropane Chemical compound S=C=NC1CC1 JGFBQFKZKSSODQ-UHFFFAOYSA-N 0.000 description 1
- QWCKQJZIFLGMSD-VKHMYHEASA-N L-alpha-aminobutyric acid Chemical compound CC[C@H](N)C(O)=O QWCKQJZIFLGMSD-VKHMYHEASA-N 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 208000000265 Lobular Carcinoma Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229940127308 Microsomal Triglyceride Transfer Protein Inhibitors Drugs 0.000 description 1
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- WAMWSIDTKSNDCU-SSDOTTSWSA-N N[C@H](C1CCCCC1)C(O)=O Chemical compound N[C@H](C1CCCCC1)C(O)=O WAMWSIDTKSNDCU-SSDOTTSWSA-N 0.000 description 1
- 108020001621 Natriuretic Peptide Proteins 0.000 description 1
- 102000004571 Natriuretic peptide Human genes 0.000 description 1
- 206010051606 Necrotising colitis Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010073338 Optic glioma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 108010014865 PLIalpha Proteins 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 229940123898 Phospholipase A2 inhibitor Drugs 0.000 description 1
- 201000008199 Pleuropulmonary blastoma Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010037448 Pulmonary valve incompetence Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 102000001494 Sterol O-Acyltransferase Human genes 0.000 description 1
- 108010054082 Sterol O-acyltransferase Proteins 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
- 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
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 206010044248 Toxic shock syndrome Diseases 0.000 description 1
- 231100000650 Toxic shock syndrome Toxicity 0.000 description 1
- 206010048873 Traumatic arthritis Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000002223 abdominal aortic aneurysm Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 231100000851 acute glomerulonephritis Toxicity 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 239000002404 acyltransferase inhibitor Substances 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 1
- 208000007128 adrenocortical carcinoma Diseases 0.000 description 1
- 239000002170 aldosterone antagonist Substances 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 201000010105 allergic rhinitis Diseases 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
- 230000033115 angiogenesis Effects 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 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
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 208000019664 bone resorption disease Diseases 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 201000003714 breast lobular carcinoma Diseases 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 201000002143 bronchus adenoma Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 208000002458 carcinoid tumor Diseases 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000002368 cardiac glycoside Substances 0.000 description 1
- 229940097217 cardiac glycoside Drugs 0.000 description 1
- 230000001756 cardiomyopathic effect Effects 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000002659 cell therapy Methods 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 201000007335 cerebellar astrocytoma Diseases 0.000 description 1
- 208000030239 cerebral astrocytoma Diseases 0.000 description 1
- 210000004720 cerebrum Anatomy 0.000 description 1
- 201000006662 cervical adenocarcinoma Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000001906 cholesterol absorption Effects 0.000 description 1
- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000005046 dihydronaphthyl group Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- CNTIXUGILVWVHR-UHFFFAOYSA-N diphosphoryl chloride Chemical compound ClP(Cl)(=O)OP(Cl)(Cl)=O CNTIXUGILVWVHR-UHFFFAOYSA-N 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 201000003908 endometrial adenocarcinoma Diseases 0.000 description 1
- 208000029382 endometrium adenocarcinoma Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- DOVHCCGSGQCCNV-HNNXBMFYSA-N ethyl (2s)-2-(4-chlorophenyl)-2-(2,4-dioxo-1h-quinazolin-3-yl)acetate Chemical compound C1([C@@H](C(=O)OCC)N2C(C3=CC=CC=C3NC2=O)=O)=CC=C(Cl)C=C1 DOVHCCGSGQCCNV-HNNXBMFYSA-N 0.000 description 1
- FJAZKEFQZOZJJO-ZETCQYMHSA-N ethyl (3s)-3-aminohexanoate Chemical compound CCC[C@H](N)CC(=O)OCC FJAZKEFQZOZJJO-ZETCQYMHSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 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
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229940125672 glycoprotein IIb/IIIa inhibitor Drugs 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 238000011553 hamster model Methods 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 206010073095 invasive ductal breast carcinoma Diseases 0.000 description 1
- 201000010985 invasive ductal carcinoma Diseases 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 201000006370 kidney failure Diseases 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
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 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
- 239000000463 material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- ROAADFVJPNIJBA-LLVKDONJSA-N methyl (2r)-2-(2,4-dioxo-1h-quinazolin-3-yl)pentanoate Chemical compound C1=CC=C2C(=O)N([C@@H](C(=O)OC)CCC)C(=O)NC2=C1 ROAADFVJPNIJBA-LLVKDONJSA-N 0.000 description 1
- VZTHSNCTTRCPEI-GOSISDBHSA-N methyl (2r)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]butanoate Chemical compound C12=CC=CC=C2C(=O)N([C@@H](C(=O)OC)CC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 VZTHSNCTTRCPEI-GOSISDBHSA-N 0.000 description 1
- AQWLVAZATIAGEU-OAHLLOKOSA-N methyl (2r)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]propanoate Chemical compound C12=CC=CC=C2C(=O)N([C@H](C)C(=O)OC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 AQWLVAZATIAGEU-OAHLLOKOSA-N 0.000 description 1
- CSUGSSHFDGRNJD-QGZVFWFLSA-N methyl (2r)-2-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]butanoate Chemical compound C12=CC=CC=C2C(=O)N([C@@H](C(=O)OC)CC)C(=O)N1CC1=NSC2=CC(C)=CC(C)=C12 CSUGSSHFDGRNJD-QGZVFWFLSA-N 0.000 description 1
- OQZOEAOMDXLNBO-CQSZACIVSA-N methyl (2r)-2-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]propanoate Chemical compound C12=CC=CC=C2C(=O)N([C@H](C)C(=O)OC)C(=O)N1CC1=NSC2=CC(C)=CC(C)=C12 OQZOEAOMDXLNBO-CQSZACIVSA-N 0.000 description 1
- YLOFLJXLZOOJJS-CQSZACIVSA-N methyl (2r)-2-cyclohexyl-2-(2,4-dioxo-1h-quinazolin-3-yl)acetate Chemical compound C1([C@H](C(=O)OC)N2C(C3=CC=CC=C3NC2=O)=O)CCCCC1 YLOFLJXLZOOJJS-CQSZACIVSA-N 0.000 description 1
- WROGRGNXESITKL-CQSZACIVSA-N methyl (2r)-2-cyclohexyl-2-[(2-nitrobenzoyl)amino]acetate Chemical compound N([C@@H](C(=O)OC)C1CCCCC1)C(=O)C1=CC=CC=C1[N+]([O-])=O WROGRGNXESITKL-CQSZACIVSA-N 0.000 description 1
- VZTHSNCTTRCPEI-SFHVURJKSA-N methyl (2s)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]butanoate Chemical compound C12=CC=CC=C2C(=O)N([C@H](C(=O)OC)CC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 VZTHSNCTTRCPEI-SFHVURJKSA-N 0.000 description 1
- AQWLVAZATIAGEU-HNNXBMFYSA-N methyl (2s)-2-[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]propanoate Chemical compound C12=CC=CC=C2C(=O)N([C@@H](C)C(=O)OC)C(=O)N1CC1=CN(C)C2=CC=CC(C)=C12 AQWLVAZATIAGEU-HNNXBMFYSA-N 0.000 description 1
- CSUGSSHFDGRNJD-KRWDZBQOSA-N methyl (2s)-2-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]butanoate Chemical compound C12=CC=CC=C2C(=O)N([C@H](C(=O)OC)CC)C(=O)N1CC1=NSC2=CC(C)=CC(C)=C12 CSUGSSHFDGRNJD-KRWDZBQOSA-N 0.000 description 1
- OQZOEAOMDXLNBO-AWEZNQCLSA-N methyl (2s)-2-[1-[(4,6-dimethyl-1,2-benzothiazol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]propanoate Chemical compound C12=CC=CC=C2C(=O)N([C@@H](C)C(=O)OC)C(=O)N1CC1=NSC2=CC(C)=CC(C)=C12 OQZOEAOMDXLNBO-AWEZNQCLSA-N 0.000 description 1
- ZZWPOYPWQTUZDY-BYPYZUCNSA-N methyl (2s)-2-aminobutanoate Chemical compound CC[C@H](N)C(=O)OC ZZWPOYPWQTUZDY-BYPYZUCNSA-N 0.000 description 1
- AHAJIVSHVURORT-MRVPVSSYSA-N methyl (3r)-3-(2,4-dioxo-1h-quinazolin-3-yl)butanoate Chemical compound C1=CC=C2C(=O)N([C@H](C)CC(=O)OC)C(=O)NC2=C1 AHAJIVSHVURORT-MRVPVSSYSA-N 0.000 description 1
- XZVGAKJLGCHGMP-UHFFFAOYSA-N methyl 2-(1-aminocyclohexyl)acetate;methyl 2-amino-2-methylbutanoate;methyl 3-amino-4-phenylbutanoate;trihydrochloride Chemical compound Cl.Cl.Cl.CCC(C)(N)C(=O)OC.COC(=O)CC1(N)CCCCC1.COC(=O)CC(N)CC1=CC=CC=C1 XZVGAKJLGCHGMP-UHFFFAOYSA-N 0.000 description 1
- ILQAHNDSOBFFJA-UHFFFAOYSA-N methyl 2-[(2-aminobenzoyl)amino]pentanoate Chemical compound CCCC(C(=O)OC)NC(=O)C1=CC=CC=C1N ILQAHNDSOBFFJA-UHFFFAOYSA-N 0.000 description 1
- FSSAJVQFSGOGCP-UHFFFAOYSA-N methyl 2-[1-(aminomethyl)cyclohexyl]acetate;hydrochloride Chemical compound Cl.COC(=O)CC1(CN)CCCCC1 FSSAJVQFSGOGCP-UHFFFAOYSA-N 0.000 description 1
- KRZBSMVCELQOMO-UHFFFAOYSA-N methyl 2-[1-[[1-[(1,4-dimethylindol-3-yl)methyl]-2,4-dioxoquinazolin-3-yl]methyl]cyclohexyl]acetate Chemical compound O=C1N(CC=2C3=C(C)C=CC=C3N(C)C=2)C2=CC=CC=C2C(=O)N1CC1(CC(=O)OC)CCCCC1 KRZBSMVCELQOMO-UHFFFAOYSA-N 0.000 description 1
- DTHMTBUWTGVEFG-UHFFFAOYSA-N methyl 2-amino-2-phenylacetate;hydrochloride Chemical compound [Cl-].COC(=O)C([NH3+])C1=CC=CC=C1 DTHMTBUWTGVEFG-UHFFFAOYSA-N 0.000 description 1
- IODNYRVZHKRFIW-UHFFFAOYSA-N methyl 2-aminopentanoate;hydrochloride Chemical compound Cl.CCCC(N)C(=O)OC IODNYRVZHKRFIW-UHFFFAOYSA-N 0.000 description 1
- PPIHXYOKURAYBS-UHFFFAOYSA-N methyl 3-(2,4-dioxo-1h-quinazolin-3-yl)pentanoate Chemical compound C1=CC=C2C(=O)N(C(CC(=O)OC)CC)C(=O)NC2=C1 PPIHXYOKURAYBS-UHFFFAOYSA-N 0.000 description 1
- ODZHFODFMGMOPB-UHFFFAOYSA-N methyl 3-aminoheptanoate;hydrochloride Chemical compound Cl.CCCCC(N)CC(=O)OC ODZHFODFMGMOPB-UHFFFAOYSA-N 0.000 description 1
- ANNPFWLPOJPNRM-UHFFFAOYSA-N methyl 4,6-dimethyl-1,2-benzothiazole-3-carboxylate Chemical compound CC1=CC(C)=C2C(C(=O)OC)=NSC2=C1 ANNPFWLPOJPNRM-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- YDZMEYJHWSTMGR-UHFFFAOYSA-N n,n-dimethyl-1-(1,4,6-trimethylindol-3-yl)methanamine Chemical compound CC1=CC(C)=C2C(CN(C)C)=CN(C)C2=C1 YDZMEYJHWSTMGR-UHFFFAOYSA-N 0.000 description 1
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 1
- 239000000692 natriuretic peptide Substances 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 208000004995 necrotizing enterocolitis Diseases 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 208000023833 nerve sheath neoplasm Diseases 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002826 nitrites Chemical class 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 208000008511 optic nerve glioma Diseases 0.000 description 1
- 229940127216 oral anticoagulant drug Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- PXBFMLJZNCDSMP-UHFFFAOYSA-N ortho-aminobenzoylamine Natural products NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- 201000006195 perinatal necrotizing enterocolitis Diseases 0.000 description 1
- 201000005528 peripheral nervous system neoplasm Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 239000003358 phospholipase A2 inhibitor Substances 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 201000010298 pulmonary valve insufficiency Diseases 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 239000002461 renin inhibitor Substances 0.000 description 1
- 229940086526 renin-inhibitors Drugs 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000003590 rho kinase inhibitor Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000004739 secretory vesicle Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229930002534 steroid glycoside Natural products 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- ISXOBTBCNRIIQO-UHFFFAOYSA-N tetrahydrothiophene 1-oxide Chemical compound O=S1CCCC1 ISXOBTBCNRIIQO-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical compound O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 description 1
- NNLBRYQGMOYARS-UHFFFAOYSA-N thiane 1-oxide Chemical compound O=S1CCCCC1 NNLBRYQGMOYARS-UHFFFAOYSA-N 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- WCNFFKHKJLERFM-UHFFFAOYSA-N thiomorpholinyl sulfone group Chemical group N1(CCSCC1)S(=O)(=O)N1CCSCC1 WCNFFKHKJLERFM-UHFFFAOYSA-N 0.000 description 1
- ZCAGUOCUDGWENZ-UHFFFAOYSA-N thiomorpholinyl sulfoxide group Chemical group N1(CCSCC1)S(=O)N1CCSCC1 ZCAGUOCUDGWENZ-UHFFFAOYSA-N 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- CURCMGVZNYCRNY-UHFFFAOYSA-N trimethylazanium;iodide Chemical compound I.CN(C)C CURCMGVZNYCRNY-UHFFFAOYSA-N 0.000 description 1
- YFHICDDUDORKJB-UHFFFAOYSA-N trimethylene carbonate Chemical compound O=C1OCCCO1 YFHICDDUDORKJB-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- C07D403/06—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 carbon chain containing only aliphatic carbon atoms
-
- 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
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
本願は、2007年8月16日に米国に出願された米国仮出願番号60/956,189に基づき優先権を主張する。
また、本発明は、前記キマーゼ阻害剤を用いてこれに関連する様々な疾患や症状を治療する方法を提供することを目的とする。
さらに、本発明は、前記キマーゼ阻害剤を製造する方法を提供することを目的とする。
R1はハロゲン原子、トリハロメチル基、シアノ基、アミノ基、ヒドロキシル基、炭素数1〜4のアルキル基、炭素数1〜4のアルコキシ基、COR6、COOR6、CONR6R7又はNR6R7であり;
R2及びR3はそれぞれ独立して水素原子、ハロゲン原子、トリハロメチル基、シアノ基、アミノ基、ヒドロキシル基、炭素数1〜4のアルキル基、ハロゲン原子若しくは炭素数1〜4のアルキル基で置換されていてもよい炭素環、炭素数1〜4のアルコキシ基、COR6、COOR6、CONR6R7又はNR6R7であり、R2及びR3が同時に水素原子であることはなく;
あるいは、R2及びR3は共にR2及びR3が結合している炭素原子と環化して、1以上のハロゲン原子若しくは炭素数1〜4のアルキル基で置換されてもよい炭素環若しくはヘテロ環、炭素数1〜4のアルコキシ基、トリハロメチル基、シアノ基、アミノ基、ヒドロキシル基、COR6、COOR6、CONR6R7又はNR6R7を形成してもよく;
R4及びR5はそれぞれ独立して水素原子、ハロゲン原子、トリハロメチル基、シアノ基、アミノ基、ヒドロキシル基、炭素数1〜4のアルキル基、炭素数1〜4のアルコキシ基、COR6、COOR6、CONR6R7又はNR6R7であり;
Arは、7〜10の炭素原子を有し、且つ、環中に酸素原子、窒素原子及び硫黄原子からなる群から選択される1以上のヘテロ原子を有する、モノ−若しくはポリ−置換又は非置換の縮合ヘテロ芳香族基であり;前記芳香族基若しくはヘテロ芳香族基上の各置換基はハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、炭素数1〜6の直鎖若しくは分岐鎖状のアルキル基、炭素数1〜6の直鎖若しくは分岐鎖状のアルコキシ基(2つの隣接する基がアセタール結合を形成する場合を含む)、炭素数1〜6の直鎖若しくは分岐鎖状のアルキルチオ基、炭素数1〜6の直鎖若しくは分岐鎖状のアルキルスルホニル基、フェニルスルホニル基、炭素数1〜6の直鎖若しくは分岐鎖状のアシル基、炭素数1〜6の直鎖若しくは分岐鎖状のアシルアミノ基、トリハロメチル基、トリハロメトキシ基、フェニル基、オキソ基、COOR6、CONR6R7、SO2NR6R7、NR6R7、及び1以上のハロゲン原子で置換されてもよいフェノキシ基の中から選択され;
R6及びR7はそれぞれ独立して水素原子又は炭素数1〜6の直鎖若しくは分岐鎖状のアルキル基を表し、又は、R6及びR7は共に−CH2−CH2−、−CH2−CH2−CH2−若しくは−CH2−CH2−CH2を表し、R6及びR7が結合しているN原子と共に環化して1以上の炭素数1〜4のアルキル基で置換されてもよいヘテロ環を形成してもよい。
Arはインドリル基、アザインドリル基、イソインドリル基、ベンゾオキサゾリル基、ベンゾチアゾリル基、ベンゾイミダゾリル基、イソキノリニル基、キノリニル基、ベンゾフラニル基、ベンゾジオキソリル基又はインダゾリル基であって、それぞれハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、炭素数1〜6の直鎖若しくは分岐鎖状のアルキル基、炭素数1〜6の直鎖若しくは分岐鎖状のアルコキシ基(2つの隣接する基がアセタール結合を形成する場合を含む)、炭素数1〜6の直鎖若しくは分岐鎖状のアルキルチオ基、炭素数1〜6の直鎖若しくは分岐鎖状のアルキルスルホニル基、フェニルスルホニル基、炭素数1〜6の直鎖若しくは分岐鎖状のアシル基、炭素数1〜6の直鎖若しくは分岐鎖状のアシルアミノ基、トリハロメチル基、トリハロメトキシ基、フェニル基、オキソ基、COOR6、CONR6R7、SO2NR6R7、NR6R7、及び1以上のハロゲン原子で置換されていてもよいフェノキシ基の中から選択される基で置換されていてもよく;
R1は炭素数1〜4のアルコキシ基、COR6、COOR6又はCONR6R7であり;
R2及びR3はそれぞれ独立してハロゲン原子、炭素数1〜4のアルキル基、炭素数3〜6のシクロアルキル基又はフェニル基であって、各々の環は水素原子若しくは炭素数1〜4のアルキル基で置換されていてもよく、R2及びR3が同時に水素原子であることはなく;
あるいは、R2及びR3は共にR2及びR3が結合している炭素原子と環化して、1以上のハロゲン原子若しくは炭素数1〜4のアルキル基で置換されてもよい炭素数3〜6のシクロアルキル基又は炭素数3〜6のヘテロ環を形成してもよく;
R4及びR5はそれぞれ独立して水素原子、炭素数1〜4のアルキル基又は炭素数1〜4のアルコキシ基であることを特徴とする化合物が提供される。
Arは、インドリル基又はベンゾイソチアゾリル基であって、それぞれハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、炭素数1〜6の直鎖若しくは分岐鎖状のアルキル基、炭素数1〜6の直鎖若しくは分岐鎖状のアルコキシ基、炭素数1〜6の直鎖若しくは分岐鎖状のアルキルチオ基、炭素数1〜6の直鎖若しくは分岐鎖状のアルキルスルホニル基、炭素数1〜6の直鎖若しくは分岐鎖状のアシル基、炭素数1〜6の直鎖若しくは分岐鎖状のアシルアミノ基、トリハロメチル基、及びトリハロメトキシ基から選択される基で置換されていてもよく;
R1はCOR6、COOR6又はCONR6R7であり;
R2及びR3はそれぞれ独立してハロゲン原子、メチル基、エチル基、プロピル基、ブチル基、シクロプロピル基、シクロヘキシル基又はフェニル基であって、各々の環は水素原子若しくは炭素数1〜4のアルキル基で置換されていてもよく、R2及びR3が同時に水素原子であることはなく;
あるいは、R2及びR3は共にR2及びR3が結合している炭素原子と環化して、1以上のハロゲン原子若しくは炭素数1〜4のアルキル基で置換されてもよいシクロヘキシル基又はテトラヒドロピラニル基を形成してもよいことを特徴とする化合物が提供される。
Arは、炭素数1〜6の直鎖若しくは分岐鎖状のアルキル基で置換されていてもよいインドリル基又はベンゾイソチアゾリル基であることを特徴とする化合物が提供される。
本明細書において用いられているように、「窒素原子」及び「硫黄原子」はあらゆる酸化型の窒素原子及び硫黄原子、並びに、四級型のあらゆる塩基性窒素原子を含む。開放鎖又は環式基における全てのヘテロ原子は、全ての酸化型を含む。
本発明は、式(I)の化合物の製造方法をも提供する。当該スキームにおいて、別段の指定がない限り、下記式中のR1、R2、R3、R4、R5、Ar、m及びnは、上記本発明の式(I)におけるR1、R2、R3、R4、R5、Ar、m及びnの意味を有するものとする。
適切な溶媒の中で、置換されていてもよい2−ニトロベンゾイルクロリドとアミンとを反応させることにより、式(III)の2−ニトロベンズアミド化合物が得られる。標準的な手法を用いて、当該ニトロ基をアミノ基に還元し、対応する式(IV)の2−アミノベンズアミド化合物を得る。ホスゲン、ジホスゲン、CDI又はクロロギ酸トリクロロメチルなどの適した試薬を用いて式(IV)の化合物を環化し、式(V)のキナゾリンジオン化合物を得る。式(V)の化合物とAr−CH2−X(ここで、Xはハロゲン原子又は第四級アンモニウム塩である)とを反応させて、式(I)の化合物を得る。
(S)−2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−酪酸。LCMS(ESMS):m/z 406(M+H+)。
(R)−2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−酪酸。LCMS(ESMS):m/z 406(M+H+)。
{1−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−シクロヘキシル}−酢酸。LCMS(ESMS):m/z 446.19(M+H+)。
2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−2−メチル−酪酸。LCMS(ESMS):m/z 419.99(M+H+)。
3−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−酪酸。LCMS(ESMS):m/z 406.07(M+H+)。
(R)−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−フェニル−酢酸。LCMS(ESMS):m/z 454.16(M+H+)。
{4−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−テトラヒドロ−ピラン−4−イル}−酢酸。LCMS(ESMS):m/z 462.13(M+H+)。
(S)−シクロヘキシル−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−酢酸。LCMS(ESMS):m/z 460.87(M+H+)。
(R)−シクロヘキシル−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−酢酸。LCMS(ESMS):m/z 460.86(M+H+)。
(S)−2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−酪酸メチルエステル。LCMS(ESMS):m/z 420(M+H+)。
(R)−2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−酪酸メチルエステル。LCMS(ESMS):m/z 420(M+H+)。
3−シクロプロピル−3−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−プロピオン酸。LCMS(ESMS):m/z 432(M+H+)。
(R)−シクロプロピル−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−酢酸。LCMS(ESMS):m/z 418(M+H+)。
(S)−シクロプロピル−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−酢酸。LCMS(ESMS):m/z 418(M+H+)。
3−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ペンタン酸。LCMS(ESMS):m/z 420.21(M+H+)。
2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ヘキサン酸。LCMS(ESMS):m/z 434.23(M+H+)。
2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−酪酸。LCMS(ESMS):m/z 406.20(M+H+)。
3−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ヘプタン酸。LCMS(ESMS):m/z 448.24(M+H+)。
1−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イルメチル]−シクロヘキサンカルボン酸。LCMS(ESMS):m/z 460.18(M+H+)。
4−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−3−フェニル−酪酸。LCMS(ESMS):m/z 482.15(M+H+)。
(R)−3−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ペンタン酸。LCMS(ESMS):m/z 420.2(M+H+)。
(S)−3−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ペンタン酸。LCMS(ESMS):m/z 420.1(M+H+)。
(R)−2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−プロピオン酸。LCMS(ESMS):m/z 392(M+H+)。
(S)−2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−プロピオン酸。LCMS(ESMS):m/z 392(M+H+)。
(S)−3−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ヘキサン酸。LCMS(ESMS):m/z 434.12(M+H+)。
2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−2−メチル−プロピオン酸。LCMS(ESMS):m/z 406.23(M+H+)。
(R)−3−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−3−フェニル−プロピオン酸。LCMS(ESMS):m/z 468.27(M+H+)。
(S)−3−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−3−フェニル−プロピオン酸。LCMS(ESMS):m/z 468.22(M+H+)。
1−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−シクロヘキサンカルボン酸。LCMS(ESMS):m/z 446.19(M+H+)。
(S)−2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ヘキサン酸。LCMS(ESMS):m/z 434.15(M+H+)。
(R)−2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ヘキサン酸。LCMS(ESMS):m/z 434.15(M+H+)。
(S)−2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ペンタン酸。LCMS(ESMS):m/z 420.13(M+H+)。
(R)−2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ペンタン酸。LCMS(ESMS):m/z 420.11(M+H+)。
(R)−2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−プロピオン酸メチルエステル。LCMS(ESMS):m/z 406(M+H+)。
(S)−2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−プロピオン酸メチルエステル。LCMS(ESMS):m/z 406(M+H+)。
(R)−シクロプロピル−[1−(4,6−ジメチル−1,2−ベンゾイソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−酢酸。LCMS(ESMS):m/z 436(M+H+)。
(S)−シクロプロピル−[1−(4,6−ジメチル−1,2−ベンゾイソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−酢酸。LCMS(ESMS):m/z 436(M+H+)。
3−シクロプロピル−3−[1−(4,6−ジメチル−1,2−ベンゾイソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−プロピオン酸。LCMS(ESMS):m/z 450(M+H+)。
(S)−[1−(4,6−ジメチル−1,2−ベンゾイソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−フェニル−酢酸。LCMS(ESMS):m/z 472.75(M+H+)。
(R)−(4−クロロ−フェニル)−[1−(4,6−ジメチル−1,2−ベンゾイソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−酢酸。LCMS(ESMS):m/z 506.15(M+H+)。
{1−[1−(4,6−ジメチル−1,2−ベンゾイソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−シクロヘキシル}−酢酸。LCMS(ESMS):m/z 478.16(M+H+)。
(R)−3−[1−(4,6−ジメチル−ベンゾ[d]イソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ペンタン酸。LCMS(ESMS):m/z 438.2(M+H+)。
(S)−3−[1−(4,6−ジメチル−ベンゾ[d]イソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ペンタン酸。LCMS(ESMS):m/z 438.2(M+H+)。
(S)−2−[1−(4,6−ジメチル−1,2−ベンゾイソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−酪酸。LCMS(ESMS):m/z 424.0(M+H+)。
(R)−2−[1−(4,6−ジメチル−1,2−ベンゾイソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−酪酸。LCMS(ESMS):m/z 424(M+H+)。
(R)−[1−(4,6−ジメチル−1,2−ベンゾイソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−フェニル−酢酸。LCMS(ESMS):m/z 472.75(M+H+)。
(R)−2−[1−(4,6−ジメチル−1,2−ベンゾイソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−酪酸メチルエステル。LCMS(ESMS):m/z 438(M+H+)。
(S)−2−[1−(4,6−ジメチル−1,2−ベンゾイソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−酪酸メチルエステル。LCMS(ESMS):m/z 438(M+H+)。
(S)−2−[1−(4,6−ジメチル−1,2−ベンゾイソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−プロピオン酸。LCMS(ESMS):m/z 410(M+H+)。
(S)−2−[1−(4,6−ジメチル−1,2−ベンゾイソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ヘキサン酸。LCMS(ESMS):m/z 452.74(M+H+)。
(R)−2−[1−(4,6−ジメチル−1,2−ベンゾイソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ヘキサン酸。LCMS(ESMS):m/z 452.74(M+H+)。
(S)−2−[1−(4,6−ジメチル−1,2−ベンゾイソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−プロピオン酸メチルエステル。LCMS(ESMS):m/z 424(M+H+)。
(R)−2−[1−(4,6−ジメチル−1,2−ベンゾイソチアゾール−3−イルメチル)−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−プロピオン酸メチルエステル。LCMS(ESMS):m/z 424(M+H+)。
(R)−2−[2,4−ジオキソ−1−(1,4,6−トリメチル−1H−インドール−3−イルメチル)−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ヘキサン酸。LCMS(ESMS):m/z 448.91(M+H+)。
(S)−2−[1−(4,6−ジメチル−1,2−ベンゾイソチアゾール−3−イルメチル)−6−メトキシ−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ヘキサン酸。LCMS(ESMS):m/z 482.90(M+H+)。
(R)−2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−6−メトキシ−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ヘキサン酸。LCMS(ESMS):m/z 464.87(M+H+)。
(S)−2−[1−(1,4−ジメチル−1H−インドール−3−イルメチル)−6,7−ジメトキシ−2,4−ジオキソ−1,4−ジヒドロ−2H−キナゾリン−3−イル]−ヘキサン酸。LCMS(ESMS):m/z 494.92(M+H+)。
1−(1,4−ジメチル−1H−インドール−3−イルメチル)−3−(2−メトキシ−1−メチル−エチル)−1H−キナゾリン−2,4−ジオン。LCMS(ESMS):m/z 392.11(M+H+)。
[実施例A] (R)−アミノ−シクロヘキシル−酢酸メチルエステル塩酸塩
(1−アミノ−シクロヘキシル)−酢酸メチルエステル塩酸塩
3−アミノ−4−フェニル−酪酸メチルエステル塩酸塩
2−アミノ−2−メチル−酪酸メチルエステル塩酸塩
(1−アミノメチル−シクロヘキシル)−酢酸メチルエステル塩酸塩
4−アミノ−3−フェニル−酪酸メチルエステル塩酸塩
(R)−2−アミノ−ヘキサン酸メチルエステル;塩酸塩
3−アミノ−ヘプタン酸メチルエステル塩酸塩
2−アミノ−2−メチル−プロピオン酸メチルエステル塩酸塩
3−アミノ−ペンタン酸メチルエステル塩酸塩
2−アミノ−酪酸メチルエステル塩酸塩
1−アミノ−シクロヘキサンカルボン酸メチルエステル塩酸塩
本発明によれば、本明細書に記載した化合物及び製薬学的に許容されるその化合物の誘導体の使用方法が提供される。本発明で用いられる化合物はキマーゼを阻害する。キマーゼはアンギオテンシンIをアンギオテンシンIIに変換することが知られており、TGF−β、マトリックスプロテアーゼ及びサイトカインの活性化に寄与し得るため、キマーゼの阻害は様々な疾患や症状を防止、治療するための魅力的手段である。例として、慢性心不全(非虚血性)、心筋梗塞後心不全(虚血性)、急性心筋梗塞、再灌流障害、左心室機能障害、心臓線維症、拡張期心不全及び肥大型心筋症を含む心不全;肺高血圧症、収縮期高血圧症及び抵抗性高血圧症を含む高血圧症;冠動脈疾患、末梢動脈閉塞性疾患、動脈瘤、安定/不安定狭心症、再狭窄、糖尿病性腎症、心房細動/心室性不整脈、心臓弁膜症、心膜疾患、腎不全(慢性腎疾患、末期腎疾患)及び脳卒中が挙げられる。本発明の化合物は以下の治療(手術)に対して有益であってもよい:冠動脈バイパス術、経皮冠動脈インターベンション及びステント留置術。
(i)特に患者が遺伝的に又はその他の理由で当該病態になりやすいが未だその病態を有していると診断されていない場合に、患者がその病態になるのを防ぐこと;
(ii)患者の当該病態を抑制又は改善すること、つまり、病態の進展を止め又は遅らせること;又は
(iii)患者の当該病態を軽減すること、つまり、当該病態を軽減又は治すこと。
Claims (7)
- 式(I)の化合物又は当該化合物の製薬学的に許容される塩:
R1はハロゲン原子、トリハロメチル基、シアノ基、アミノ基、ヒドロキシル基、炭素数1〜4のアルキル基、炭素数1〜4のアルコキシ基、COR6、COOR6、CONR6R7又はNR6R7であり;
R2及びR3はそれぞれ独立して水素原子、ハロゲン原子、トリハロメチル基、シアノ基、アミノ基、ヒドロキシル基、炭素数1〜4のアルキル基、ハロゲン原子若しくは炭素数1〜4のアルキル基で置換されていてもよい炭素環、炭素数1〜4のアルコキシ基、COR6、COOR6、CONR6R7又はNR6R7であり、R2及びR3が同時に水素原子であることはなく;
あるいは、R2及びR3は共にR2及びR3が結合している炭素原子と環化して、1以上のハロゲン原子、炭素数1〜4のアルキル基、炭素数1〜4のアルコキシ基、トリハロメチル基、シアノ基、アミノ基、ヒドロキシル基、COR6、COOR6、CONR6R7又はNR6R7で置換されていてもよい炭素環若しくはヘテロ環を形成してもよく;
R4及びR5はそれぞれ独立して水素原子、ハロゲン原子、トリハロメチル基、シアノ基、アミノ基、ヒドロキシル基、炭素数1〜4のアルキル基、炭素数1〜4のアルコキシ基、COR6、COOR6、CONR6R7又はNR6R7であり;
Arは、下記に示すいずれかの基であり:
- R1が炭素数1〜4のアルコキシ基、COR6、COOR6又はCONR6R7であり;
R2及びR3がそれぞれ独立してハロゲン原子、炭素数1〜4のアルキル基、炭素数3〜6のシクロアルキル基又はフェニル基であって、各々の環は水素原子若しくは炭素数1〜4のアルキル基で置換されていてもよく、R2及びR3が同時に水素原子であることはなく;
あるいは、R2及びR3が共にR2及びR3が結合している炭素原子と環化して、1以上のハロゲン原子若しくは炭素数1〜4のアルキル基で置換されてもよい炭素数3〜6のシクロアルキル基又は炭素数3〜6のヘテロ環を形成してもよく;
R4及びR5がそれぞれ独立して水素原子、炭素数1〜4のアルキル基又は炭素数1〜4のアルコキシ基であることを特徴とする、請求項1に記載の化合物。 - R1がCOR6、COOR6又はCONR6R7であり;
R2及びR3がそれぞれ独立してハロゲン原子、メチル基、エチル基、プロピル基、ブチル基、シクロプロピル基、シクロヘキシル基又はフェニル基であって、各々の環は水素原子若しくは炭素数1〜4のアルキル基で置換されていてもよく、R2及びR3が同時に水素原子であることはなく;
あるいは、R2及びR3が共にR2及びR3が結合している炭素原子と環化して、1以上のハロゲン原子若しくは炭素数1〜4のアルキル基で置換されてもよいシクロヘキシル基又はテトラヒドロピラニル基を形成してもよいことを特徴とする、請求項2に記載の化合物。 - 治療上有効な量の請求項1に記載の化合物と、1以上の製薬学的に許容される担体及び/又は補助剤とを有する医薬組成物。
- 慢性心不全(非虚血性)、心筋梗塞後心不全(虚血性)、急性心筋梗塞、再灌流障害、左心室機能障害、心臓線維症、拡張期心不全、肥大型心筋症、肺高血圧症、収縮期高血圧症、抵抗性高血圧症、冠動脈疾患、末梢動脈閉塞性疾患、動脈瘤、安定/不安定狭心症、再狭窄、糖尿病性腎症、心房細動/心室性不整脈、心臓弁膜症、心膜疾患、慢性腎疾患、末期腎疾患及び脳卒中の中から選択される疾患又は症状を治療するための医薬組成物であって、請求項1に記載の化合物を含む、前記医薬組成物。
- 冠動脈バイパス術、経皮冠動脈インターベンション及びステント留置術から選択される医学的手術を必要とする疾患又は症状を治療するための医薬組成物であって、請求項1に記載の化合物を含む、前記医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US95618907P | 2007-08-16 | 2007-08-16 | |
US60/956,189 | 2007-08-16 | ||
PCT/US2008/072849 WO2009023655A1 (en) | 2007-08-16 | 2008-08-12 | Quinazolinedione chymase inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2010536768A JP2010536768A (ja) | 2010-12-02 |
JP5634263B2 true JP5634263B2 (ja) | 2014-12-03 |
Family
ID=39865478
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2010521115A Active JP5634263B2 (ja) | 2007-08-16 | 2008-08-12 | キナゾリンジオンキマーゼ阻害剤 |
Country Status (5)
Country | Link |
---|---|
US (1) | US8377949B2 (ja) |
EP (1) | EP2188277B1 (ja) |
JP (1) | JP5634263B2 (ja) |
CA (1) | CA2696430C (ja) |
WO (1) | WO2009023655A1 (ja) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2364313B1 (en) * | 2008-09-09 | 2014-01-08 | Boehringer Ingelheim International GmbH | Aza-benzimidazolone chymase inhibitors |
JP5587914B2 (ja) * | 2009-01-30 | 2014-09-10 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | キマーゼ阻害剤として有用なアザキナゾリンジオン |
NZ600748A (en) | 2009-12-25 | 2014-06-27 | Daiichi Sankyo Co Ltd | Seven-membered ring compound and pharmaceutical use therefor |
WO2013177349A2 (en) * | 2012-05-25 | 2013-11-28 | Glaxosmithkline Llc | Quinazolinediones as tankyrase inhibitors |
US9428460B2 (en) | 2012-06-26 | 2016-08-30 | Bayer Pharma Aktiengesellschaft | N-[4-(quinolin-4-yloxy)cyclohexyl(methyl)](hetero)arylcarboxamides as androgen receptor antagonists, production and use thereof as medicinal products |
EP3762379A1 (en) | 2018-03-07 | 2021-01-13 | Bayer Aktiengesellschaft | Identification and use of erk5 inhibitors |
WO2020234103A1 (en) | 2019-05-21 | 2020-11-26 | Bayer Aktiengesellschaft | Identification and use of kras inhibitors |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0747582B2 (ja) * | 1989-12-11 | 1995-05-24 | 杏林製薬株式会社 | キナゾリン―3―アルカン酸誘導体とその塩およびその製造法 |
DE4341665A1 (de) * | 1993-12-07 | 1995-06-08 | Basf Ag | Bicyclen-Derivate, ihre Herstellung und Verwendung |
FR2733233B1 (fr) * | 1995-04-20 | 1997-05-30 | Roussel Uclaf | Nouveaux derives de quinoleine, leur procede de preparation, les nouveaux intermediaires obtenus, leur application a titre de medicaments et les compositions pharmaceutiques les renfermant |
DE19528418A1 (de) * | 1995-08-02 | 1997-02-06 | Merck Patent Gmbh | Endothelin-Rezeptor-Antagonisten |
DE69622148T2 (de) * | 1995-09-28 | 2002-10-31 | Suntory Ltd Osaka | Chinazozin derivate und deren verwendung |
JP2007119478A (ja) * | 1998-07-15 | 2007-05-17 | Teijin Ltd | チオベンズイミダゾール誘導体 |
US20040010004A1 (en) | 2000-01-17 | 2004-01-15 | Naoki Tsuchiya | Benzimidazole derivatives |
FR2784379B1 (fr) | 1998-10-07 | 2000-11-17 | Synthelabo | Derives de quinazolinedione, leurs preparations et leurs applications en therapeutique |
WO2001032621A1 (fr) * | 1999-10-29 | 2001-05-10 | Wakunaga Pharmaceutical Co., Ltd. | Nouveaux derives d'indole, et medicaments contenant lesdits derives comme principe actif |
US6774134B2 (en) * | 2000-12-20 | 2004-08-10 | Bristol-Myers Squibb Company | Heterocyclic substituted 2-methyl-benzimidazole antiviral agents |
US6919331B2 (en) * | 2001-12-10 | 2005-07-19 | Bristol-Myers Squibb Company | Substituted 2-methyl-benzimidazole respiratory syncytial virus antiviral agents |
FR2837201A1 (fr) * | 2002-03-18 | 2003-09-19 | Servier Lab | Nouveaux composes derives de la quinazoline, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
JP2007137818A (ja) * | 2005-11-17 | 2007-06-07 | Taisho Pharmaceut Co Ltd | 8−ヒドロキシ−2,4(1h,3h)−キナゾリンジオン誘導体 |
-
2008
- 2008-08-12 WO PCT/US2008/072849 patent/WO2009023655A1/en active Application Filing
- 2008-08-12 JP JP2010521115A patent/JP5634263B2/ja active Active
- 2008-08-12 EP EP08797662A patent/EP2188277B1/en active Active
- 2008-08-12 CA CA2696430A patent/CA2696430C/en active Active
- 2008-08-12 US US12/673,103 patent/US8377949B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
CA2696430A1 (en) | 2009-02-19 |
WO2009023655A1 (en) | 2009-02-19 |
EP2188277A1 (en) | 2010-05-26 |
US20120122863A1 (en) | 2012-05-17 |
JP2010536768A (ja) | 2010-12-02 |
EP2188277B1 (en) | 2012-11-21 |
CA2696430C (en) | 2015-10-06 |
US8377949B2 (en) | 2013-02-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5268120B2 (ja) | ベンゾイミダゾロンキマーゼ阻害薬 | |
JP5634263B2 (ja) | キナゾリンジオンキマーゼ阻害剤 | |
JP5258790B2 (ja) | Rhoキナーゼインヒビター | |
US8193214B2 (en) | Chymase inhibitors | |
US9062056B2 (en) | Aza-benzimidazolone Chymase inhibitors | |
JP5587914B2 (ja) | キマーゼ阻害剤として有用なアザキナゾリンジオン | |
EP2323991B1 (en) | Chymase inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20110811 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130731 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20131030 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140421 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140612 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20141006 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20141014 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5634263 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |