ZA200605670B - Sulfonamide derivatives for the treatment of diseases - Google Patents

Info

Publication number

ZA200605670B

ZA200605670B ZA200605670A ZA200605670A ZA200605670B ZA 200605670 B ZA200605670 B ZA 200605670B ZA 200605670 A ZA200605670 A ZA 200605670A ZA 200605670 A ZA200605670 A ZA 200605670A ZA 200605670 B ZA200605670 B ZA 200605670B

Authority

ZA

South Africa

Prior art keywords

hydroxy

amino

phenyl

ethyl

formula

Prior art date

2004-01-22

Links

• Espacenet
• Global Dossier
• Discuss

• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 18
• 201000010099 disease Diseases 0.000 title claims description 15
• 238000011282 treatment Methods 0.000 title claims description 13
• 229940124530 sulfonamide Drugs 0.000 title description 5
• 150000003456 sulfonamides Chemical class 0.000 title description 5
• 150000001875 compounds Chemical class 0.000 claims description 108
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 73
• -1 4'-Hydroxybiphenyl-4-yl Chemical group 0.000 claims description 55
• 238000000034 method Methods 0.000 claims description 37
• 125000000217 alkyl group Chemical group 0.000 claims description 35
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 32
• 150000003839 salts Chemical class 0.000 claims description 31
• 150000001412 amines Chemical class 0.000 claims description 26
• 239000002904 solvent Substances 0.000 claims description 26
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 24
• 239000002253 acid Substances 0.000 claims description 22
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
• 239000000556 agonist Substances 0.000 claims description 21
• 208000006673 asthma Diseases 0.000 claims description 21
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 17
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
• 229910052739 hydrogen Inorganic materials 0.000 claims description 14
• 239000000203 mixture Substances 0.000 claims description 14
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
• 230000008569 process Effects 0.000 claims description 11
• FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 11
• 239000003814 drug Substances 0.000 claims description 10
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
• 102000005962 receptors Human genes 0.000 claims description 9
• 108020003175 receptors Proteins 0.000 claims description 9
• 239000003054 catalyst Substances 0.000 claims description 8
• 229940079593 drug Drugs 0.000 claims description 8
• 230000001404 mediated effect Effects 0.000 claims description 8
• 238000002360 preparation method Methods 0.000 claims description 8
• 239000011734 sodium Substances 0.000 claims description 8
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 7
• 229910052799 carbon Inorganic materials 0.000 claims description 7
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
• 229910052708 sodium Inorganic materials 0.000 claims description 7
• 239000012453 solvate Substances 0.000 claims description 7
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 6
• 125000002947 alkylene group Chemical group 0.000 claims description 6
• KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 6
• 230000008878 coupling Effects 0.000 claims description 6
• 238000010168 coupling process Methods 0.000 claims description 6
• 238000005859 coupling reaction Methods 0.000 claims description 6
• 229910052700 potassium Inorganic materials 0.000 claims description 6
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
• 239000005557 antagonist Substances 0.000 claims description 5
• 230000000694 effects Effects 0.000 claims description 5
• 229910052744 lithium Inorganic materials 0.000 claims description 5
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
• 230000002757 inflammatory effect Effects 0.000 claims description 4
• 229910052751 metal Inorganic materials 0.000 claims description 4
• 239000002184 metal Substances 0.000 claims description 4
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
• ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 claims description 4
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
• 206010006482 Bronchospasm Diseases 0.000 claims description 3
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
• 239000000654 additive Substances 0.000 claims description 3
• 230000007885 bronchoconstriction Effects 0.000 claims description 3
• 239000003795 chemical substances by application Substances 0.000 claims description 3
• 239000007822 coupling agent Substances 0.000 claims description 3
• 238000005984 hydrogenation reaction Methods 0.000 claims description 3
• YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 claims description 3
• 239000011736 potassium bicarbonate Substances 0.000 claims description 3
• 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
• 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
• TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
• 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 3
• 229940121786 Beta 2 adrenoreceptor agonist Drugs 0.000 claims description 2
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
• 229910019567 Re Re Inorganic materials 0.000 claims description 2
• 230000000996 additive effect Effects 0.000 claims description 2
• 239000013566 allergen Substances 0.000 claims description 2
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
• 239000000812 cholinergic antagonist Substances 0.000 claims description 2
• 239000012351 deprotecting agent Substances 0.000 claims description 2
• IKGLACJFEHSFNN-UHFFFAOYSA-N hydron;triethylazanium;trifluoride Chemical compound F.F.F.CCN(CC)CC IKGLACJFEHSFNN-UHFFFAOYSA-N 0.000 claims description 2
• 230000000155 isotopic effect Effects 0.000 claims description 2
• NWKYZYGOSPOKDY-UHFFFAOYSA-N n,n-dimethylformamide;pyridine Chemical compound CN(C)C=O.C1=CC=NC=C1 NWKYZYGOSPOKDY-UHFFFAOYSA-N 0.000 claims description 2
• 150000007530 organic bases Chemical class 0.000 claims description 2
• NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 2
• 125000004076 pyridyl group Chemical group 0.000 claims description 2
• 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
• 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
• 229960000278 theophylline Drugs 0.000 claims description 2
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
• 206010006451 bronchitis Diseases 0.000 claims 14
• 201000009267 bronchiectasis Diseases 0.000 claims 9
• 239000003112 inhibitor Substances 0.000 claims 6
• 125000001475 halogen functional group Chemical group 0.000 claims 4
• 201000010659 intrinsic asthma Diseases 0.000 claims 4
• 230000008506 pathogenesis Effects 0.000 claims 4
• 208000035475 disorder Diseases 0.000 claims 3
• HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims 3
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims 2
• 102000001381 Arachidonate 5-Lipoxygenase Human genes 0.000 claims 2
• 108010093579 Arachidonate 5-lipoxygenase Proteins 0.000 claims 2
• 206010006458 Bronchitis chronic Diseases 0.000 claims 2
• 206010014561 Emphysema Diseases 0.000 claims 2
• 208000027771 Obstructive airways disease Diseases 0.000 claims 2
• 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims 2
• 230000001154 acute effect Effects 0.000 claims 2
• 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims 2
• 201000000028 adult respiratory distress syndrome Diseases 0.000 claims 2
• 208000007451 chronic bronchitis Diseases 0.000 claims 2
• 230000001684 chronic effect Effects 0.000 claims 2
• 208000024711 extrinsic asthma Diseases 0.000 claims 2
• 239000003199 leukotriene receptor blocking agent Substances 0.000 claims 2
• 238000004519 manufacturing process Methods 0.000 claims 2
• 230000000414 obstructive effect Effects 0.000 claims 2
• 229940044551 receptor antagonist Drugs 0.000 claims 2
• 239000002464 receptor antagonist Substances 0.000 claims 2
• 102000004023 5-Lipoxygenase-Activating Proteins Human genes 0.000 claims 1
• 108090000411 5-Lipoxygenase-Activating Proteins Proteins 0.000 claims 1
• OIRDTQYFTABQOQ-CRKDRTNXSA-N 9-α-D-ribofuranosyl-9H-Purin-6-amine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-CRKDRTNXSA-N 0.000 claims 1
• 206010003557 Asthma exercise induced Diseases 0.000 claims 1
• 206010003645 Atopy Diseases 0.000 claims 1
• 208000035143 Bacterial infection Diseases 0.000 claims 1
• 229940124638 COX inhibitor Drugs 0.000 claims 1
• 102000004127 Cytokines Human genes 0.000 claims 1
• 108090000695 Cytokines Proteins 0.000 claims 1
• 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 claims 1
• 101100135868 Dictyostelium discoideum pde3 gene Proteins 0.000 claims 1
• 102000015554 Dopamine receptor Human genes 0.000 claims 1
• 108050004812 Dopamine receptor Proteins 0.000 claims 1
• 208000000059 Dyspnea Diseases 0.000 claims 1
• 206010013975 Dyspnoeas Diseases 0.000 claims 1
• 208000004657 Exercise-Induced Asthma Diseases 0.000 claims 1
• 206010017533 Fungal infection Diseases 0.000 claims 1
• 229940122236 Histamine receptor antagonist Drugs 0.000 claims 1
• 239000003458 I kappa b kinase inhibitor Substances 0.000 claims 1
• 108010008212 Integrin alpha4beta1 Proteins 0.000 claims 1
• 102000042838 JAK family Human genes 0.000 claims 1
• 108091082332 JAK family Proteins 0.000 claims 1
• 102000005741 Metalloproteases Human genes 0.000 claims 1
• 108010006035 Metalloproteases Proteins 0.000 claims 1
• 229940122694 Muscarinic M3 receptor antagonist Drugs 0.000 claims 1
• 229940121948 Muscarinic receptor antagonist Drugs 0.000 claims 1
• 208000031888 Mycoses Diseases 0.000 claims 1
• 101150085511 PEDS1 gene Proteins 0.000 claims 1
• 102100037592 Plasmanylethanolamine desaturase Human genes 0.000 claims 1
• 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 claims 1
• 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 claims 1
• 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 claims 1
• 241000191940 Staphylococcus Species 0.000 claims 1
• 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 claims 1
• 102000000551 Syk Kinase Human genes 0.000 claims 1
• 108010016672 Syk Kinase Proteins 0.000 claims 1
• 239000000150 Sympathomimetic Substances 0.000 claims 1
• 102000003141 Tachykinin Human genes 0.000 claims 1
• 206010054094 Tumour necrosis Diseases 0.000 claims 1
• 102000003990 Urokinase-type plasminogen activator Human genes 0.000 claims 1
• 108090000435 Urokinase-type plasminogen activator Proteins 0.000 claims 1
• 208000036142 Viral infection Diseases 0.000 claims 1
• 206010047924 Wheezing Diseases 0.000 claims 1
• 206010069351 acute lung injury Diseases 0.000 claims 1
• 239000002465 adenosine A2a receptor agonist Substances 0.000 claims 1
• 239000003470 adrenal cortex hormone Substances 0.000 claims 1
• 239000000048 adrenergic agonist Substances 0.000 claims 1
• 201000009961 allergic asthma Diseases 0.000 claims 1
• 230000000954 anitussive effect Effects 0.000 claims 1
• 239000003242 anti bacterial agent Substances 0.000 claims 1
• 230000000259 anti-tumor effect Effects 0.000 claims 1
• 229940088710 antibiotic agent Drugs 0.000 claims 1
• 229940124584 antitussives Drugs 0.000 claims 1
• 230000001580 bacterial effect Effects 0.000 claims 1
• 208000022362 bacterial infectious disease Diseases 0.000 claims 1
• 229940111134 coxibs Drugs 0.000 claims 1
• 229960000265 cromoglicic acid Drugs 0.000 claims 1
• 239000003260 cyclooxygenase 1 inhibitor Substances 0.000 claims 1
• 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 claims 1
• 239000000850 decongestant Substances 0.000 claims 1
• PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 claims 1
• VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 claims 1
• 238000002651 drug therapy Methods 0.000 claims 1
• 239000003602 elastase inhibitor Substances 0.000 claims 1
• 230000007613 environmental effect Effects 0.000 claims 1
• 201000009580 eosinophilic pneumonia Diseases 0.000 claims 1
• 230000005713 exacerbation Effects 0.000 claims 1
• 208000024695 exercise-induced bronchoconstriction Diseases 0.000 claims 1
• 239000003172 expectorant agent Substances 0.000 claims 1
• 230000003325 follicular Effects 0.000 claims 1
• 230000002538 fungal effect Effects 0.000 claims 1
• 230000035874 hyperreactivity Effects 0.000 claims 1
• 239000003018 immunosuppressive agent Substances 0.000 claims 1
• 229940125721 immunosuppressive agent Drugs 0.000 claims 1
• 208000015181 infectious disease Diseases 0.000 claims 1
• 230000002458 infectious effect Effects 0.000 claims 1
• 230000001524 infective effect Effects 0.000 claims 1
• 208000030603 inherited susceptibility to asthma Diseases 0.000 claims 1
• 230000002427 irreversible effect Effects 0.000 claims 1
• 229940043355 kinase inhibitor Drugs 0.000 claims 1
• VNYSSYRCGWBHLG-AMOLWHMGSA-N leukotriene B4 Chemical compound CCCCC\C=C/C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)CCCC(O)=O VNYSSYRCGWBHLG-AMOLWHMGSA-N 0.000 claims 1
• 239000011159 matrix material Substances 0.000 claims 1
• 230000000510 mucolytic effect Effects 0.000 claims 1
• 229940066491 mucolytics Drugs 0.000 claims 1
• 239000003681 muscarinic M3 receptor antagonist Substances 0.000 claims 1
• SMZMQFAPMPRASR-SANMLTNESA-N n-[(2-chloro-4-hydroxyphenyl)methyl]-2-[3-[2-[[(2r)-2-hydroxy-2-[4-hydroxy-3-(methanesulfonamido)phenyl]ethyl]amino]-2-methylpropyl]phenyl]acetamide Chemical compound C([C@H](O)C=1C=C(NS(C)(=O)=O)C(O)=CC=1)NC(C)(C)CC(C=1)=CC=CC=1CC(=O)NCC1=CC=C(O)C=C1Cl SMZMQFAPMPRASR-SANMLTNESA-N 0.000 claims 1
• 125000001624 naphthyl group Chemical group 0.000 claims 1
• 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims 1
• 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims 1
• 208000007892 occupational asthma Diseases 0.000 claims 1
• 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 claims 1
• 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 claims 1
• 230000001991 pathophysiological effect Effects 0.000 claims 1
• 230000037361 pathway Effects 0.000 claims 1
• 239000008194 pharmaceutical composition Substances 0.000 claims 1
• 239000000546 pharmaceutical excipient Substances 0.000 claims 1
• 239000003757 phosphotransferase inhibitor Substances 0.000 claims 1
• 229920003199 poly(diethylsiloxane) Polymers 0.000 claims 1
• 230000000750 progressive effect Effects 0.000 claims 1
• 208000028172 protozoa infectious disease Diseases 0.000 claims 1
• 201000009732 pulmonary eosinophilia Diseases 0.000 claims 1
• 208000002815 pulmonary hypertension Diseases 0.000 claims 1
• 230000019491 signal transduction Effects 0.000 claims 1
• 229940127230 sympathomimetic drug Drugs 0.000 claims 1
• 208000011580 syndromic disease Diseases 0.000 claims 1
• 108060008037 tachykinin Proteins 0.000 claims 1
• 229960005356 urokinase Drugs 0.000 claims 1
• 239000005526 vasoconstrictor agent Substances 0.000 claims 1
• 230000009385 viral infection Effects 0.000 claims 1
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
• 150000002148 esters Chemical class 0.000 description 11
• 238000006243 chemical reaction Methods 0.000 description 10
• 229940002612 prodrug Drugs 0.000 description 10
• 239000000651 prodrug Substances 0.000 description 10
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 8
• 239000001257 hydrogen Substances 0.000 description 8
• 229910052763 palladium Inorganic materials 0.000 description 8
• 125000005843 halogen group Chemical group 0.000 description 7
• 108060003345 Adrenergic Receptor Proteins 0.000 description 6
• 102000017910 Adrenergic receptor Human genes 0.000 description 6
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
• 229910052757 nitrogen Inorganic materials 0.000 description 6
• 230000000172 allergic effect Effects 0.000 description 5
• 208000010668 atopic eczema Diseases 0.000 description 5
• 150000002576 ketones Chemical class 0.000 description 5
• 239000002243 precursor Substances 0.000 description 5
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
• 150000001336 alkenes Chemical class 0.000 description 4
• FNXLCIKXHOPCKH-UHFFFAOYSA-N bromamine Chemical compound BrN FNXLCIKXHOPCKH-UHFFFAOYSA-N 0.000 description 4
• 239000011575 calcium Substances 0.000 description 4
• 238000004587 chromatography analysis Methods 0.000 description 4
• 238000007796 conventional method Methods 0.000 description 4
• 125000006239 protecting group Chemical group 0.000 description 4
• 230000002829 reductive effect Effects 0.000 description 4
• 125000001424 substituent group Chemical group 0.000 description 4
• 150000003509 tertiary alcohols Chemical class 0.000 description 4
• 210000001519 tissue Anatomy 0.000 description 4
• NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 3
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
• JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 3
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
• 150000001502 aryl halides Chemical class 0.000 description 3
• 239000012298 atmosphere Substances 0.000 description 3
• 230000015572 biosynthetic process Effects 0.000 description 3
• 230000007883 bronchodilation Effects 0.000 description 3
• 150000001732 carboxylic acid derivatives Chemical group 0.000 description 3
• 238000004128 high performance liquid chromatography Methods 0.000 description 3
• 150000002431 hydrogen Chemical class 0.000 description 3
• XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
• HNQIVZYLYMDVSB-NJFSPNSNSA-N methanesulfonamide Chemical compound [14CH3]S(N)(=O)=O HNQIVZYLYMDVSB-NJFSPNSNSA-N 0.000 description 3
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
• 239000012038 nucleophile Substances 0.000 description 3
• 230000000144 pharmacologic effect Effects 0.000 description 3
• 230000009467 reduction Effects 0.000 description 3
• 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 3
• 238000003419 tautomerization reaction Methods 0.000 description 3
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
• VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
• UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 2
• RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 2
• FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
• ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
• NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
• BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
• 150000007513 acids Chemical class 0.000 description 2
• 230000009471 action Effects 0.000 description 2
• 150000003973 alkyl amines Chemical class 0.000 description 2
• 150000001408 amides Chemical class 0.000 description 2
• ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
• 125000004429 atom Chemical group 0.000 description 2
• 230000008901 benefit Effects 0.000 description 2
• WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
• 125000001246 bromo group Chemical group Br* 0.000 description 2
• 239000004044 bronchoconstricting agent Substances 0.000 description 2
• 230000003435 bronchoconstrictive effect Effects 0.000 description 2
• 125000004432 carbon atom Chemical group C* 0.000 description 2
• 229910002091 carbon monoxide Inorganic materials 0.000 description 2
• 239000003638 chemical reducing agent Substances 0.000 description 2
• 239000000460 chlorine Substances 0.000 description 2
• 125000001309 chloro group Chemical group Cl* 0.000 description 2
• 238000003776 cleavage reaction Methods 0.000 description 2
• 239000013065 commercial product Substances 0.000 description 2
• 125000004122 cyclic group Chemical group 0.000 description 2
• 238000010511 deprotection reaction Methods 0.000 description 2
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
• 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
• 125000001153 fluoro group Chemical group F* 0.000 description 2
• 238000001640 fractional crystallisation Methods 0.000 description 2
• 230000002496 gastric effect Effects 0.000 description 2
• 150000004820 halides Chemical class 0.000 description 2
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
• 238000001727 in vivo Methods 0.000 description 2
• 125000002346 iodo group Chemical group I* 0.000 description 2
• 239000002207 metabolite Substances 0.000 description 2
• 231100000252 nontoxic Toxicity 0.000 description 2
• 230000003000 nontoxic effect Effects 0.000 description 2
• JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
• 210000000056 organ Anatomy 0.000 description 2
• 229910052760 oxygen Inorganic materials 0.000 description 2
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
• 238000012877 positron emission topography Methods 0.000 description 2
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
• 239000000047 product Substances 0.000 description 2
• 150000003254 radicals Chemical class 0.000 description 2
• 230000002285 radioactive effect Effects 0.000 description 2
• 238000012552 review Methods 0.000 description 2
• 230000007017 scission Effects 0.000 description 2
• 208000017520 skin disease Diseases 0.000 description 2
• 239000000126 substance Substances 0.000 description 2
• 238000006467 substitution reaction Methods 0.000 description 2
• 239000000758 substrate Substances 0.000 description 2
• 239000001117 sulphuric acid Substances 0.000 description 2
• 235000011149 sulphuric acid Nutrition 0.000 description 2
• 238000003786 synthesis reaction Methods 0.000 description 2
• 229940095064 tartrate Drugs 0.000 description 2
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
• COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 2
• DAXJNUBSBFUTRP-RTQNCGMRSA-N (8r,9s,10r,13s,14s)-6-(hydroxymethyl)-10,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthrene-3,17-dione Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(CO)C2=C1 DAXJNUBSBFUTRP-RTQNCGMRSA-N 0.000 description 1
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
• FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 1
• PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
• RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
• YGTUPRIZNBMOFV-UHFFFAOYSA-N 2-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(O)C=C1 YGTUPRIZNBMOFV-UHFFFAOYSA-N 0.000 description 1
• HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
• OCUAPVNNQFAQSM-UHFFFAOYSA-N 3-Methyl-3-butenyl acetate Chemical compound CC(=C)CCOC(C)=O OCUAPVNNQFAQSM-UHFFFAOYSA-N 0.000 description 1
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-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
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
• 239000004475 Arginine Substances 0.000 description 1
• IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
• BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
• BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
• 101800004538 Bradykinin Proteins 0.000 description 1
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
• 239000004215 Carbon black (E152) Substances 0.000 description 1
• OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
• BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
• 206010007559 Cardiac failure congestive Diseases 0.000 description 1
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
• KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
• DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
• RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
• AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
• JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 description 1
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
• 102000002045 Endothelin Human genes 0.000 description 1
• 108050009340 Endothelin Proteins 0.000 description 1
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
• BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
• VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
• 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
• 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
• 208000010412 Glaucoma Diseases 0.000 description 1
• 239000004471 Glycine Substances 0.000 description 1
• QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
• 206010019280 Heart failures Diseases 0.000 description 1
• CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-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
• 229930194542 Keto Natural products 0.000 description 1
• 102100035792 Kininogen-1 Human genes 0.000 description 1
• ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
• CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
• KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
• JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
• KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
• 239000004472 Lysine Substances 0.000 description 1
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
• OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
• 241000124008 Mammalia Species 0.000 description 1
• MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
• 229910002651 NO3 Inorganic materials 0.000 description 1
• PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
• NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
• 208000008589 Obesity Diseases 0.000 description 1
• MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
• 229910019142 PO4 Inorganic materials 0.000 description 1
• 206010033557 Palpitations Diseases 0.000 description 1
• 208000008469 Peptic Ulcer Diseases 0.000 description 1
• NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
• OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
• 208000006399 Premature Obstetric Labor Diseases 0.000 description 1
• 206010036600 Premature labour Diseases 0.000 description 1
• 201000004681 Psoriasis Diseases 0.000 description 1
• 208000001431 Psychomotor Agitation Diseases 0.000 description 1
• 206010038743 Restlessness Diseases 0.000 description 1
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
• 239000005864 Sulphur Substances 0.000 description 1
• 208000001871 Tachycardia Diseases 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
• ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
• 206010044565 Tremor Diseases 0.000 description 1
• DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
• YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
• OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
• 229960004373 acetylcholine Drugs 0.000 description 1
• 239000003377 acid catalyst Substances 0.000 description 1
• 230000002378 acidificating effect Effects 0.000 description 1
• 125000005042 acyloxymethyl group Chemical group 0.000 description 1
• 230000001800 adrenalinergic effect Effects 0.000 description 1
• 230000002411 adverse Effects 0.000 description 1
• 230000008484 agonism Effects 0.000 description 1
• 210000005057 airway smooth muscle cell Anatomy 0.000 description 1
• 125000003158 alcohol group Chemical group 0.000 description 1
• 230000001476 alcoholic effect Effects 0.000 description 1
• 125000003342 alkenyl group Chemical group 0.000 description 1
• 125000004450 alkenylene group Chemical group 0.000 description 1
• 125000003545 alkoxy group Chemical group 0.000 description 1
• 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 1
• 230000029936 alkylation Effects 0.000 description 1
• 238000005804 alkylation reaction Methods 0.000 description 1
• 239000004411 aluminium Substances 0.000 description 1
• 229910052782 aluminium Inorganic materials 0.000 description 1
• XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
• 125000003368 amide group Chemical group 0.000 description 1
• 229940024606 amino acid Drugs 0.000 description 1
• 235000001014 amino acid Nutrition 0.000 description 1
• 150000001413 amino acids Chemical class 0.000 description 1
• 229910021529 ammonia Inorganic materials 0.000 description 1
• 150000008064 anhydrides Chemical class 0.000 description 1
• 230000001078 anti-cholinergic effect Effects 0.000 description 1
• 230000002590 anti-leukotriene effect Effects 0.000 description 1
• 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 description 1
• 239000011260 aqueous acid Substances 0.000 description 1
• 229960003121 arginine Drugs 0.000 description 1
• 125000003118 aryl group Chemical group 0.000 description 1
• 229940009098 aspartate Drugs 0.000 description 1
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
• 230000004888 barrier function Effects 0.000 description 1
• JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
• SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
• QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
• 210000000988 bone and bone Anatomy 0.000 description 1
• QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
• 229910052791 calcium Inorganic materials 0.000 description 1
• MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
• 239000000496 cardiotonic agent Substances 0.000 description 1
• 239000000969 carrier Substances 0.000 description 1
• 210000004027 cell Anatomy 0.000 description 1
• 239000003153 chemical reaction reagent Substances 0.000 description 1
• 229910052801 chlorine Inorganic materials 0.000 description 1
• OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
• 229960001231 choline Drugs 0.000 description 1
• 239000013078 crystal Substances 0.000 description 1
• 238000002425 crystallisation Methods 0.000 description 1
• 230000008025 crystallization Effects 0.000 description 1
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
• 239000002274 desiccant Substances 0.000 description 1
• 238000013461 design Methods 0.000 description 1
• 238000001514 detection method Methods 0.000 description 1
• 229910052805 deuterium Inorganic materials 0.000 description 1
• 206010012601 diabetes mellitus Diseases 0.000 description 1
• ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
• NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
• 229950010286 diolamine Drugs 0.000 description 1
• 229940110377 dl- arginine Drugs 0.000 description 1
• 238000009510 drug design Methods 0.000 description 1
• 230000032050 esterification Effects 0.000 description 1
• 238000005886 esterification reaction Methods 0.000 description 1
• CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
• 238000001704 evaporation Methods 0.000 description 1
• 230000008020 evaporation Effects 0.000 description 1
• 230000001747 exhibiting effect Effects 0.000 description 1
• KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
• 238000001914 filtration Methods 0.000 description 1
• 239000011737 fluorine Substances 0.000 description 1
• 229910052731 fluorine Inorganic materials 0.000 description 1
• 229940044170 formate Drugs 0.000 description 1
• 229940050411 fumarate Drugs 0.000 description 1
• 229960001731 gluceptate Drugs 0.000 description 1
• KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
• 229940050410 gluconate Drugs 0.000 description 1
• 229940097042 glucuronate Drugs 0.000 description 1
• 229960002449 glycine Drugs 0.000 description 1
• 210000005003 heart tissue Anatomy 0.000 description 1
• IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
• 229950000177 hibenzate Drugs 0.000 description 1
• 229960001340 histamine Drugs 0.000 description 1
• 210000003630 histaminocyte Anatomy 0.000 description 1
• 229930195733 hydrocarbon Natural products 0.000 description 1
• 150000002430 hydrocarbons Chemical class 0.000 description 1
• 230000003301 hydrolyzing effect Effects 0.000 description 1
• 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
• 125000001841 imino group Chemical group [H]N=* 0.000 description 1
• 238000011065 in-situ storage Methods 0.000 description 1
• 238000010348 incorporation Methods 0.000 description 1
• 230000005764 inhibitory process Effects 0.000 description 1
• 230000000968 intestinal effect Effects 0.000 description 1
• PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
• 238000005342 ion exchange Methods 0.000 description 1
• SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
• XXIKYCPRDXIMQM-UHFFFAOYSA-N isoprenyl acetate Natural products CC(C)=CCOC(C)=O XXIKYCPRDXIMQM-UHFFFAOYSA-N 0.000 description 1
• 125000000468 ketone group Chemical group 0.000 description 1
• 150000003951 lactams Chemical class 0.000 description 1
• 150000002596 lactones Chemical class 0.000 description 1
• 239000012731 long-acting form Substances 0.000 description 1
• 229960003646 lysine Drugs 0.000 description 1
• 239000011777 magnesium Substances 0.000 description 1
• 229910052749 magnesium Inorganic materials 0.000 description 1
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
• 235000019341 magnesium sulphate Nutrition 0.000 description 1
• 229940091250 magnesium supplement Drugs 0.000 description 1
• 238000009115 maintenance therapy Methods 0.000 description 1
• 229940049920 malate Drugs 0.000 description 1
• VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
• BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
• 239000000463 material Substances 0.000 description 1
• 229960003194 meglumine Drugs 0.000 description 1
• 230000002503 metabolic effect Effects 0.000 description 1
• NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
• JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
• 239000002808 molecular sieve Substances 0.000 description 1
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
• 125000005487 naphthalate group Chemical group 0.000 description 1
• 210000000653 nervous system Anatomy 0.000 description 1
• 239000002547 new drug Substances 0.000 description 1
• 235000001968 nicotinic acid Nutrition 0.000 description 1
• 239000011664 nicotinic acid Substances 0.000 description 1
• 239000012454 non-polar solvent Substances 0.000 description 1
• 235000020824 obesity Nutrition 0.000 description 1
• QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
• 229950004864 olamine Drugs 0.000 description 1
• 230000003287 optical effect Effects 0.000 description 1
• PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 1
• 230000003647 oxidation Effects 0.000 description 1
• 238000007254 oxidation reaction Methods 0.000 description 1
• 125000003544 oxime group Chemical group 0.000 description 1
• 239000001301 oxygen Substances 0.000 description 1
• 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
• 230000007310 pathophysiology Effects 0.000 description 1
• 235000019371 penicillin G benzathine Nutrition 0.000 description 1
• 150000002989 phenols Chemical class 0.000 description 1
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
• 239000010452 phosphate Substances 0.000 description 1
• 229910052698 phosphorus Inorganic materials 0.000 description 1
• 239000011574 phosphorus Substances 0.000 description 1
• 239000011591 potassium Substances 0.000 description 1
• 229960003975 potassium Drugs 0.000 description 1
• 229910000027 potassium carbonate Inorganic materials 0.000 description 1
• 235000011181 potassium carbonates Nutrition 0.000 description 1
• 239000002244 precipitate Substances 0.000 description 1
• 208000026440 premature labor Diseases 0.000 description 1
• 150000003138 primary alcohols Chemical class 0.000 description 1
• 150000003141 primary amines Chemical class 0.000 description 1
• 230000002062 proliferating effect Effects 0.000 description 1
• 150000003180 prostaglandins Chemical class 0.000 description 1
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
• 238000006722 reduction reaction Methods 0.000 description 1
• 229920005989 resin Polymers 0.000 description 1
• 239000011347 resin Substances 0.000 description 1
• 208000023504 respiratory system disease Diseases 0.000 description 1
• 230000002441 reversible effect Effects 0.000 description 1
• 238000007142 ring opening reaction Methods 0.000 description 1
• 229910052701 rubidium Inorganic materials 0.000 description 1
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
• 210000002460 smooth muscle Anatomy 0.000 description 1
• 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
• 229940083542 sodium Drugs 0.000 description 1
• URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
• 239000012279 sodium borohydride Substances 0.000 description 1
• 229910000033 sodium borohydride Inorganic materials 0.000 description 1
• BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
• 239000007858 starting material Substances 0.000 description 1
• KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
• 229910021653 sulphate ion Inorganic materials 0.000 description 1
• 230000002459 sustained effect Effects 0.000 description 1
• 230000016978 synaptic transmission, cholinergic Effects 0.000 description 1
• 230000009885 systemic effect Effects 0.000 description 1
• 230000006794 tachycardia Effects 0.000 description 1
• 239000011975 tartaric acid Substances 0.000 description 1
• 235000002906 tartaric acid Nutrition 0.000 description 1
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• 150000003512 tertiary amines Chemical class 0.000 description 1
• 125000001302 tertiary amino group Chemical group 0.000 description 1
• 230000001225 therapeutic effect Effects 0.000 description 1
• 229910052723 transition metal Inorganic materials 0.000 description 1
• 150000003624 transition metals Chemical class 0.000 description 1
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
• 229910052722 tritium Inorganic materials 0.000 description 1
• 229960000281 trometamol Drugs 0.000 description 1
• 230000002792 vascular Effects 0.000 description 1
• 229920001567 vinyl ester resin Polymers 0.000 description 1
• 229950000339 xinafoate Drugs 0.000 description 1
• 150000003751 zinc Chemical class 0.000 description 1