AU2007265454B2 - Human protein tyrosine phosphatase inhibitors and methods of use - Google Patents

Info

Publication number

AU2007265454B2

AU2007265454B2 AU2007265454A AU2007265454A AU2007265454B2 AU 2007265454 B2 AU2007265454 B2 AU 2007265454B2 AU 2007265454 A AU2007265454 A AU 2007265454A AU 2007265454 A AU2007265454 A AU 2007265454A AU 2007265454 B2 AU2007265454 B2 AU 2007265454B2

Authority

AU

Australia

Prior art keywords

ethyl

phenyl

substituted

thiazol

methyl

Prior art date

2006-06-27

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.)

Ceased

Links

• Espacenet
• Global Dossier
• Discuss

• 238000000034 method Methods 0.000 title claims abstract description 76
• 239000003806 protein tyrosine phosphatase inhibitor Substances 0.000 title description 2
• 102000003839 Human Proteins Human genes 0.000 title 1
• 108090000144 Human Proteins Proteins 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 156
• 239000000203 mixture Substances 0.000 claims abstract description 85
• 230000033115 angiogenesis Effects 0.000 claims abstract description 80
• 230000001105 regulatory effect Effects 0.000 claims abstract description 34
• -1 1,2,3,4 tetrazol-1-yl ,1,2,3,4-tetrazol-5-yl Chemical group 0.000 claims description 603
• 229910052739 hydrogen Inorganic materials 0.000 claims description 246
• 239000001257 hydrogen Substances 0.000 claims description 237
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 163
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 128
• 125000001072 heteroaryl group Chemical group 0.000 claims description 97
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 89
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 85
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 77
• BEHLMOQXOSLGHN-UHFFFAOYSA-N benzenamine sulfate Chemical compound OS(=O)(=O)NC1=CC=CC=C1 BEHLMOQXOSLGHN-UHFFFAOYSA-N 0.000 claims description 52
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 44
• 210000001519 tissue Anatomy 0.000 claims description 44
• 125000005842 heteroatom Chemical group 0.000 claims description 41
• 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 40
• 201000010099 disease Diseases 0.000 claims description 35
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 35
• 125000000217 alkyl group Chemical group 0.000 claims description 31
• 229910052736 halogen Inorganic materials 0.000 claims description 31
• 150000002367 halogens Chemical class 0.000 claims description 31
• 239000011734 sodium Substances 0.000 claims description 28
• 238000006467 substitution reaction Methods 0.000 claims description 27
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 26
• 150000002431 hydrogen Chemical class 0.000 claims description 25
• 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 25
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
• 229910052757 nitrogen Inorganic materials 0.000 claims description 24
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 23
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 23
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 23
• 229910052760 oxygen Inorganic materials 0.000 claims description 23
• 239000001301 oxygen Substances 0.000 claims description 23
• 125000006413 ring segment Chemical group 0.000 claims description 23
• 150000003839 salts Chemical class 0.000 claims description 23
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 23
• 239000007787 solid Substances 0.000 claims description 23
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 22
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 22
• 229910052717 sulfur Inorganic materials 0.000 claims description 22
• 239000011593 sulfur Substances 0.000 claims description 22
• 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 22
• 125000000623 heterocyclic group Chemical group 0.000 claims description 20
• 125000003118 aryl group Chemical group 0.000 claims description 19
• 125000003145 oxazol-4-yl group Chemical group O1C=NC(=C1)* 0.000 claims description 19
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
• 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 claims description 18
• 230000017423 tissue regeneration Effects 0.000 claims description 18
• 206010028980 Neoplasm Diseases 0.000 claims description 17
• 239000003814 drug Substances 0.000 claims description 17
• 239000002253 acid Substances 0.000 claims description 16
• 230000012010 growth Effects 0.000 claims description 16
• 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 claims description 16
• 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 16
• 125000004429 atom Chemical group 0.000 claims description 15
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 14
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 14
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 14
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 13
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 12
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 12
• 125000003545 alkoxy group Chemical group 0.000 claims description 12
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 12
• 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 11
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 11
• 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 11
• 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims description 11
• 208000031953 Hereditary hemorrhagic telangiectasia Diseases 0.000 claims description 10
• 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 10
• 230000001737 promoting effect Effects 0.000 claims description 10
• 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
• 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 9
• 230000001684 chronic effect Effects 0.000 claims description 9
• 208000029078 coronary artery disease Diseases 0.000 claims description 9
• 230000000302 ischemic effect Effects 0.000 claims description 9
• 125000001793 isothiazol-3-yl group Chemical group [H]C1=C([H])C(*)=NS1 0.000 claims description 9
• 125000004500 isothiazol-4-yl group Chemical group S1N=CC(=C1)* 0.000 claims description 9
• 125000004501 isothiazol-5-yl group Chemical group S1N=CC=C1* 0.000 claims description 9
• 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 claims description 9
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
• 201000000306 sarcoidosis Diseases 0.000 claims description 9
• 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
• 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 8
• 206010046851 Uveitis Diseases 0.000 claims description 8
• 208000014674 injury Diseases 0.000 claims description 8
• 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 claims description 8
• 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 7
• 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 7
• 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
• 210000001367 artery Anatomy 0.000 claims description 7
• 239000008280 blood Substances 0.000 claims description 7
• 210000004369 blood Anatomy 0.000 claims description 7
• 229920006395 saturated elastomer Polymers 0.000 claims description 7
• 125000001617 2,3-dimethoxy phenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 6
• 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 6
• 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 6
• LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims description 6
• 210000002027 skeletal muscle Anatomy 0.000 claims description 6
• 230000008733 trauma Effects 0.000 claims description 6
• 208000030507 AIDS Diseases 0.000 claims description 5
• 206010009900 Colitis ulcerative Diseases 0.000 claims description 5
• 208000011231 Crohn disease Diseases 0.000 claims description 5
• 208000018262 Peripheral vascular disease Diseases 0.000 claims description 5
• 201000004681 Psoriasis Diseases 0.000 claims description 5
• 208000006011 Stroke Diseases 0.000 claims description 5
• 201000006704 Ulcerative Colitis Diseases 0.000 claims description 5
• RGFRRSOWKXIOLI-AMVUTOCUSA-N [4-[(2s)-2-(2,3-diphenylpropanoylamino)-2-(4-ethyl-1,3-thiazol-2-yl)ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)C(CC=2C=CC=CC=2)C=2C=CC=CC=2)=N1 RGFRRSOWKXIOLI-AMVUTOCUSA-N 0.000 claims description 5
• JRSUKSWTUCRNEX-IBGZPJMESA-N [4-[(2s)-2-(benzylcarbamoylamino)-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound C1=CC(NS(=O)(=O)O)=CC=C1C[C@@H](C=1N=C(SC=1)C=1SC=CC=1)NC(=O)NCC1=CC=CC=C1 JRSUKSWTUCRNEX-IBGZPJMESA-N 0.000 claims description 5
• VIYUQCGNYBLDBS-IBGZPJMESA-N [4-[(2s)-2-(benzylcarbamoylamino)-2-(4-ethyl-1,3-thiazol-2-yl)ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)NCC=2C=CC=CC=2)=N1 VIYUQCGNYBLDBS-IBGZPJMESA-N 0.000 claims description 5
• 201000011510 cancer Diseases 0.000 claims description 5
• 201000011066 hemangioma Diseases 0.000 claims description 5
• 208000015181 infectious disease Diseases 0.000 claims description 5
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
• 208000011580 syndromic disease Diseases 0.000 claims description 5
• 125000000335 thiazolyl group Chemical group 0.000 claims description 5
• 102100028187 ATP-binding cassette sub-family C member 6 Human genes 0.000 claims description 4
• 208000009137 Behcet syndrome Diseases 0.000 claims description 4
• 208000002691 Choroiditis Diseases 0.000 claims description 4
• 206010012689 Diabetic retinopathy Diseases 0.000 claims description 4
• 208000016974 Eales' disease Diseases 0.000 claims description 4
• 201000002563 Histoplasmosis Diseases 0.000 claims description 4
• 206010051151 Hyperviscosity syndrome Diseases 0.000 claims description 4
• 208000016604 Lyme disease Diseases 0.000 claims description 4
• 206010025412 Macular dystrophy congenital Diseases 0.000 claims description 4
• 206010062207 Mycobacterial infection Diseases 0.000 claims description 4
• 208000010191 Osteitis Deformans Diseases 0.000 claims description 4
• 208000027868 Paget disease Diseases 0.000 claims description 4
• 208000004788 Pars Planitis Diseases 0.000 claims description 4
• 208000003971 Posterior uveitis Diseases 0.000 claims description 4
• 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 claims description 4
• 201000004613 Pseudoxanthoma elasticum Diseases 0.000 claims description 4
• 206010038848 Retinal detachment Diseases 0.000 claims description 4
• 206010038910 Retinitis Diseases 0.000 claims description 4
• 206010038933 Retinopathy of prematurity Diseases 0.000 claims description 4
• 206010038934 Retinopathy proliferative Diseases 0.000 claims description 4
• 208000027073 Stargardt disease Diseases 0.000 claims description 4
• 201000005485 Toxoplasmosis Diseases 0.000 claims description 4
• 206010047663 Vitritis Diseases 0.000 claims description 4
• HDNKEDKQVAHIKV-KRWDZBQOSA-N [4-[(2s)-2-[(4-methoxycarbonyl-1,3-thiazol-5-yl)amino]-2-(2-phenyl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound N1=CSC(N[C@@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)C=2N=C(SC=2)C=2C=CC=CC=2)=C1C(=O)OC HDNKEDKQVAHIKV-KRWDZBQOSA-N 0.000 claims description 4
• 208000013653 hyalitis Diseases 0.000 claims description 4
• 208000002780 macular degeneration Diseases 0.000 claims description 4
• 208000027202 mammary Paget disease Diseases 0.000 claims description 4
• 208000027531 mycobacterial infectious disease Diseases 0.000 claims description 4
• 208000031225 myocardial ischemia Diseases 0.000 claims description 4
• 208000001491 myopia Diseases 0.000 claims description 4
• 230000004379 myopia Effects 0.000 claims description 4
• 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 claims description 4
• 230000000414 obstructive effect Effects 0.000 claims description 4
• 230000006785 proliferative vitreoretinopathy Effects 0.000 claims description 4
• 208000023558 pseudoxanthoma elasticum (inherited or acquired) Diseases 0.000 claims description 4
• 230000004264 retinal detachment Effects 0.000 claims description 4
• 208000007056 sickle cell anemia Diseases 0.000 claims description 4
• 208000006379 syphilis Diseases 0.000 claims description 4
• 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
• 210000003462 vein Anatomy 0.000 claims description 4
• 201000007790 vitelliform macular dystrophy Diseases 0.000 claims description 4
• 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
• INUIUGLCVCUBPQ-FQEVSTJZSA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[3-(2-methoxyphenyl)propanoylamino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CCC=2C(=CC=CC=2)OC)=N1 INUIUGLCVCUBPQ-FQEVSTJZSA-N 0.000 claims description 3
• RCKIITSHDNZSIP-FQEVSTJZSA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[[2-(3-methoxyphenyl)acetyl]amino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CC=2C=C(OC)C=CC=2)=N1 RCKIITSHDNZSIP-FQEVSTJZSA-N 0.000 claims description 3
• DEIJXDZGXQFLLW-KRWDZBQOSA-N [4-[(2s)-2-[[2-(4-ethyl-2,3-dioxopiperazin-1-yl)acetyl]amino]-2-(4-ethyl-1,3-thiazol-2-yl)ethyl]phenyl]sulfamic acid Chemical compound O=C1C(=O)N(CC)CCN1CC(=O)N[C@H](C=1SC=C(CC)N=1)CC1=CC=C(NS(O)(=O)=O)C=C1 DEIJXDZGXQFLLW-KRWDZBQOSA-N 0.000 claims description 3
• 150000001408 amides Chemical group 0.000 claims description 3
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
• 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
• BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
• FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 2
• FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 2
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
• BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
• KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims 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 claims description 2
• BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
• VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
• 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 claims description 2
• JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
• OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 2
• MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
• 229910019142 PO4 Inorganic materials 0.000 claims description 2
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
• XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
• LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 claims description 2
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
• VZXKRKOTZBSHIZ-QFIPXVFZSA-N [4-[(2s)-2-(2-cyclopropyl-1,3-thiazol-4-yl)-2-[[4-[(3-methoxyphenyl)methyl]-1,3-thiazol-2-yl]amino]ethyl]phenyl]sulfamic acid Chemical compound COC1=CC=CC(CC=2N=C(N[C@@H](CC=3C=CC(NS(O)(=O)=O)=CC=3)C=3N=C(SC=3)C3CC3)SC=2)=C1 VZXKRKOTZBSHIZ-QFIPXVFZSA-N 0.000 claims description 2
• RZKKDVFBXQXZTE-SFHVURJKSA-N [4-[(2s)-2-(2-methyl-1,3-thiazol-4-yl)-2-[(5-phenyl-1,3-oxazol-2-yl)amino]ethyl]phenyl]sulfamic acid Chemical compound S1C(C)=NC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC=2OC(=CN=2)C=2C=CC=CC=2)=C1 RZKKDVFBXQXZTE-SFHVURJKSA-N 0.000 claims description 2
• AHCRDMDVIAESCO-ZDUSSCGKSA-N [4-[(2s)-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)-2-(2,2,2-trifluoroethylsulfonylamino)ethyl]phenyl]sulfamic acid Chemical compound C1=CC(NS(=O)(=O)O)=CC=C1C[C@H](NS(=O)(=O)CC(F)(F)F)C1=CSC(C=2SC=CC=2)=N1 AHCRDMDVIAESCO-ZDUSSCGKSA-N 0.000 claims description 2
• CXVLJDZUNHLZTF-FQEVSTJZSA-N [4-[(2s)-2-(3-phenylpropanoylamino)-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound C1=CC(NS(=O)(=O)O)=CC=C1C[C@@H](C=1N=C(SC=1)C=1SC=CC=1)NC(=O)CCC1=CC=CC=C1 CXVLJDZUNHLZTF-FQEVSTJZSA-N 0.000 claims description 2
• RKGUDGLPJMQUOJ-NRFANRHFSA-N [4-[(2s)-2-(3-phenylpropylsulfonylamino)-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound C1=CC(NS(=O)(=O)O)=CC=C1C[C@@H](C=1N=C(SC=1)C=1SC=CC=1)NS(=O)(=O)CCCC1=CC=CC=C1 RKGUDGLPJMQUOJ-NRFANRHFSA-N 0.000 claims description 2
• UIAZWGVZVAATRB-FQEVSTJZSA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-(3-phenylpropanoylamino)ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CCC=2C=CC=CC=2)=N1 UIAZWGVZVAATRB-FQEVSTJZSA-N 0.000 claims description 2
• GBLHRFSKNLGKOI-NRFANRHFSA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[3-(3-methoxyphenyl)propanoylamino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CCC=2C=C(OC)C=CC=2)=N1 GBLHRFSKNLGKOI-NRFANRHFSA-N 0.000 claims description 2
• ZKHCEGCYHCMNNC-NRFANRHFSA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[3-(4-methoxyphenyl)propanoylamino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CCC=2C=CC(OC)=CC=2)=N1 ZKHCEGCYHCMNNC-NRFANRHFSA-N 0.000 claims description 2
• XUJJNTYWZAVJHS-IBGZPJMESA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[[2-(2-fluorophenyl)acetyl]amino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CC=2C(=CC=CC=2)F)=N1 XUJJNTYWZAVJHS-IBGZPJMESA-N 0.000 claims description 2
• FZLZQVMBGLZHJE-IBGZPJMESA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[[2-(2-methoxyphenyl)acetyl]amino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CC=2C(=CC=CC=2)OC)=N1 FZLZQVMBGLZHJE-IBGZPJMESA-N 0.000 claims description 2
• UWXTZGOAPALKPA-GEVKEYJPSA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[[2-(3-methoxyphenyl)-3-phenylpropanoyl]amino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)C(CC=2C=CC=CC=2)C=2C=C(OC)C=CC=2)=N1 UWXTZGOAPALKPA-GEVKEYJPSA-N 0.000 claims description 2
• TYRWQYRBFXZGRH-INIZCTEOSA-N [4-[(2s)-2-[(4-ethoxy-4-oxobutanoyl)amino]-2-(4-ethyl-1,3-thiazol-2-yl)ethyl]phenyl]sulfamic acid Chemical compound C([C@H](NC(=O)CCC(=O)OCC)C=1SC=C(CC)N=1)C1=CC=C(NS(O)(=O)=O)C=C1 TYRWQYRBFXZGRH-INIZCTEOSA-N 0.000 claims description 2
• BVXOVRYBMVNXNO-IBGZPJMESA-N [4-[(2s)-2-[(4-methyl-2,3-dihydro-1,4-benzoxazin-7-yl)sulfonylamino]-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound C([C@H](NS(=O)(=O)C=1C=C2OCCN(C2=CC=1)C)C=1N=C(SC=1)C=1SC=CC=1)C1=CC=C(NS(O)(=O)=O)C=C1 BVXOVRYBMVNXNO-IBGZPJMESA-N 0.000 claims description 2
• ULRGLQXEKCSVMQ-AWEZNQCLSA-N [4-[(2s)-2-[(6-methyl-4-oxo-1h-pyrimidin-2-yl)amino]-2-(2-methyl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound S1C(C)=NC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC=2N=C(O)C=C(C)N=2)=C1 ULRGLQXEKCSVMQ-AWEZNQCLSA-N 0.000 claims description 2
• OYRLZGKRUDDGED-SFHVURJKSA-N [4-[(2s)-2-[[2-(2,3-difluorophenyl)acetyl]amino]-2-(4-ethyl-1,3-thiazol-2-yl)ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CC=2C(=C(F)C=CC=2)F)=N1 OYRLZGKRUDDGED-SFHVURJKSA-N 0.000 claims description 2
• VLWFEBRQUXEKDY-IBGZPJMESA-N [4-[(2s)-2-[[2-(2-chlorophenyl)acetyl]amino]-2-(4-ethyl-1,3-thiazol-2-yl)ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CC=2C(=CC=CC=2)Cl)=N1 VLWFEBRQUXEKDY-IBGZPJMESA-N 0.000 claims description 2
• UMEVMMJAIZFKAX-IBGZPJMESA-N [4-[(2s)-2-[[2-(3,4-dimethoxyphenyl)acetyl]amino]-2-(4-ethyl-1,3-thiazol-2-yl)ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CC=2C=C(OC)C(OC)=CC=2)=N1 UMEVMMJAIZFKAX-IBGZPJMESA-N 0.000 claims description 2
• YHKHPIGWVBNMPO-FQEVSTJZSA-N [4-[(2s)-2-[[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-oxobutanoyl]amino]-2-(4-ethyl-1,3-thiazol-2-yl)ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CCC(=O)C=2C=C3OCCOC3=CC=2)=N1 YHKHPIGWVBNMPO-FQEVSTJZSA-N 0.000 claims description 2
• FFYRKUNZJVNFMA-FQEVSTJZSA-N [4-[(2s)-2-[[4-(2,3-dimethoxyphenyl)-4-oxobutanoyl]amino]-2-(4-ethyl-1,3-thiazol-2-yl)ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CCC(=O)C=2C(=C(OC)C=CC=2)OC)=N1 FFYRKUNZJVNFMA-FQEVSTJZSA-N 0.000 claims description 2
• UYNRTOJKJBTNHR-NRFANRHFSA-N [4-[(2s)-2-[[4-(3,4-dihydro-2h-1,5-benzodioxepin-7-yl)-4-oxobutanoyl]amino]-2-(4-ethyl-1,3-thiazol-2-yl)ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CCC(=O)C=2C=C3OCCCOC3=CC=2)=N1 UYNRTOJKJBTNHR-NRFANRHFSA-N 0.000 claims description 2
• 150000001450 anions Chemical class 0.000 claims description 2
• 229910052797 bismuth Inorganic materials 0.000 claims description 2
• JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 claims description 2
• 239000011575 calcium Substances 0.000 claims description 2
• 229910052791 calcium Inorganic materials 0.000 claims description 2
• 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 2
• 150000001768 cations Chemical class 0.000 claims description 2
• 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 2
• XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
• QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 2
• 229910052744 lithium Inorganic materials 0.000 claims description 2
• 239000011777 magnesium Substances 0.000 claims description 2
• 229910052749 magnesium Inorganic materials 0.000 claims description 2
• VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
• 230000002107 myocardial effect Effects 0.000 claims description 2
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
• 239000010452 phosphate Substances 0.000 claims description 2
• 239000011591 potassium Substances 0.000 claims description 2
• 229910052700 potassium Inorganic materials 0.000 claims description 2
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
• 229910052708 sodium Inorganic materials 0.000 claims description 2
• KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
• 229940095064 tartrate Drugs 0.000 claims description 2
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
• UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims 2
• QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims 1
• OBHMTXKJVROLQU-UHFFFAOYSA-N 4-(4-fluorophenyl)-1,3-thiazole Chemical compound C1=CC(F)=CC=C1C1=CSC=N1 OBHMTXKJVROLQU-UHFFFAOYSA-N 0.000 claims 1
• JDQZZSFRQXEIAN-AWEZNQCLSA-N [4-[(2s)-2-(2-ethyl-1,3-thiazol-4-yl)-2-[(1-methylimidazol-4-yl)sulfonylamino]ethyl]phenyl]sulfamic acid Chemical compound S1C(CC)=NC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NS(=O)(=O)C=2N=CN(C)C=2)=C1 JDQZZSFRQXEIAN-AWEZNQCLSA-N 0.000 claims 1
• HYAQFGBVQLUSJA-IBGZPJMESA-N [4-[(2s)-2-(2-ethyl-1,3-thiazol-4-yl)-2-[(3-methoxyphenyl)methylsulfonylamino]ethyl]phenyl]sulfamic acid Chemical compound S1C(CC)=NC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NS(=O)(=O)CC=2C=C(OC)C=CC=2)=C1 HYAQFGBVQLUSJA-IBGZPJMESA-N 0.000 claims 1
• BZWXLZQQSYELIZ-IBGZPJMESA-N [4-[(2s)-2-(2-ethyl-1,3-thiazol-4-yl)-2-[(4-methoxycarbonylphenyl)methylsulfonylamino]ethyl]phenyl]sulfamic acid Chemical compound S1C(CC)=NC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NS(=O)(=O)CC=2C=CC(=CC=2)C(=O)OC)=C1 BZWXLZQQSYELIZ-IBGZPJMESA-N 0.000 claims 1
• LJYGCZBQGVHPQD-KRWDZBQOSA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[[4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoyl]amino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CCC(=O)OC(C)(C)C)=N1 LJYGCZBQGVHPQD-KRWDZBQOSA-N 0.000 claims 1
• JQRZASYIJJKHSD-KRWDZBQOSA-N [4-[(2s)-2-[(2-methyl-1,3-thiazol-4-yl)methylsulfonylamino]-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound S1C(C)=NC(CS(=O)(=O)N[C@@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)C=2N=C(SC=2)C=2SC=CC=2)=C1 JQRZASYIJJKHSD-KRWDZBQOSA-N 0.000 claims 1
• WRKKLLDUNAVQMR-HNNXBMFYSA-N [4-[(2s)-2-[(4-ethoxycarbonyl-1,3-thiazol-2-yl)amino]-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound CCOC(=O)C1=CSC(N[C@@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)C=2N=C(SC=2)C=2SC=CC=2)=N1 WRKKLLDUNAVQMR-HNNXBMFYSA-N 0.000 claims 1
• OAXJUUOBPQKZHJ-FQEVSTJZSA-N [4-[(2s)-2-[3-(3-chlorophenyl)propanoylamino]-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound C1=CC(NS(=O)(=O)O)=CC=C1C[C@@H](C=1N=C(SC=1)C=1SC=CC=1)NC(=O)CCC1=CC=CC(Cl)=C1 OAXJUUOBPQKZHJ-FQEVSTJZSA-N 0.000 claims 1
• RXNNYAMSKLUJSV-IBGZPJMESA-N [4-[(2s)-2-[[2-(2-chlorophenyl)acetyl]amino]-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound C1=CC(NS(=O)(=O)O)=CC=C1C[C@@H](C=1N=C(SC=1)C=1SC=CC=1)NC(=O)CC1=CC=CC=C1Cl RXNNYAMSKLUJSV-IBGZPJMESA-N 0.000 claims 1
• CFBAFWZBQFEGBW-IBGZPJMESA-N [4-[(2s)-2-[[2-(3-chlorophenyl)acetyl]amino]-2-(4-ethyl-1,3-thiazol-2-yl)ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CC=2C=C(Cl)C=CC=2)=N1 CFBAFWZBQFEGBW-IBGZPJMESA-N 0.000 claims 1
• ZELXXOJGKJXXLO-SFHVURJKSA-N [4-[(2s)-2-[[2-(3-methyl-1,2,4-oxadiazol-5-yl)acetyl]amino]-2-(2-phenyl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound CC1=NOC(CC(=O)N[C@@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)C=2N=C(SC=2)C=2C=CC=CC=2)=N1 ZELXXOJGKJXXLO-SFHVURJKSA-N 0.000 claims 1
• BHCIBKZRDRATNT-QHCPKHFHSA-N [4-[(2s)-2-[[4-(4-methoxycarbonylphenyl)-1,3-thiazol-2-yl]amino]-2-(2-phenyl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound C1=CC(C(=O)OC)=CC=C1C1=CSC(N[C@@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)C=2N=C(SC=2)C=2C=CC=CC=2)=N1 BHCIBKZRDRATNT-QHCPKHFHSA-N 0.000 claims 1
• JJKKEWRFQPAJRH-QFIPXVFZSA-N [4-[(2s)-2-[[5-(2,4-difluorophenyl)-1,3-oxazol-2-yl]amino]-2-(2-phenyl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound C1=CC(NS(=O)(=O)O)=CC=C1C[C@@H](C=1N=C(SC=1)C=1C=CC=CC=1)NC1=NC=C(C=2C(=CC(F)=CC=2)F)O1 JJKKEWRFQPAJRH-QFIPXVFZSA-N 0.000 claims 1
• HEFGADDMNFJTJI-FQEVSTJZSA-N [4-[(2s)-2-[[5-(3-methoxyphenyl)-1,3-oxazol-2-yl]amino]-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound COC1=CC=CC(C=2OC(N[C@@H](CC=3C=CC(NS(O)(=O)=O)=CC=3)C=3N=C(SC=3)C=3SC=CC=3)=NC=2)=C1 HEFGADDMNFJTJI-FQEVSTJZSA-N 0.000 claims 1
• GTCAXTIRRLKXRU-UHFFFAOYSA-N carbamic acid methyl ester Natural products COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 claims 1
• 239000000969 carrier Substances 0.000 claims 1
• 101000738772 Homo sapiens Receptor-type tyrosine-protein phosphatase beta Proteins 0.000 abstract description 31
• 239000003112 inhibitor Substances 0.000 abstract description 18
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
• 238000005481 NMR spectroscopy Methods 0.000 description 70
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 61
• 239000000243 solution Substances 0.000 description 59
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 57
• 238000002360 preparation method Methods 0.000 description 54
• 239000000047 product Substances 0.000 description 53
• 239000003153 chemical reaction reagent Substances 0.000 description 51
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 50
• 208000035475 disorder Diseases 0.000 description 42
• 239000011541 reaction mixture Substances 0.000 description 41
• 230000000670 limiting effect Effects 0.000 description 36
• 239000002904 solvent Substances 0.000 description 31
• 238000006243 chemical reaction Methods 0.000 description 30
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
• 235000019439 ethyl acetate Nutrition 0.000 description 25
• 230000002829 reductive effect Effects 0.000 description 25
• XMAIZXGAIFRSPZ-NSHDSACASA-N tert-butyl n-[(2s)-1-amino-3-(4-nitrophenyl)-1-sulfanylidenepropan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C(N)=S)CC1=CC=C([N+]([O-])=O)C=C1 XMAIZXGAIFRSPZ-NSHDSACASA-N 0.000 description 24
• 239000012267 brine Substances 0.000 description 22
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 19
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 17
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
• 238000010992 reflux Methods 0.000 description 15
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 14
• 150000003863 ammonium salts Chemical class 0.000 description 14
• 239000012298 atmosphere Substances 0.000 description 14
• 238000000746 purification Methods 0.000 description 14
• 238000004366 reverse phase liquid chromatography Methods 0.000 description 14
• 239000000377 silicon dioxide Substances 0.000 description 14
• 239000012043 crude product Substances 0.000 description 13
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 12
• 230000003197 catalytic effect Effects 0.000 description 12
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 12
• 239000010410 layer Substances 0.000 description 12
• CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 11
• 210000004204 blood vessel Anatomy 0.000 description 11
• 239000012044 organic layer Substances 0.000 description 11
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
• 125000001309 chloro group Chemical group Cl* 0.000 description 10
• 239000000725 suspension Substances 0.000 description 10
• 238000003556 assay Methods 0.000 description 9
• 238000001914 filtration Methods 0.000 description 9
• 239000000543 intermediate Substances 0.000 description 9
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
• 239000002244 precipitate Substances 0.000 description 8
• 125000001424 substituent group Chemical group 0.000 description 8
• ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 8
• 125000004432 carbon atom Chemical group C* 0.000 description 7
• 210000004027 cell Anatomy 0.000 description 7
• 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 7
• 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 7
• 150000003254 radicals Chemical class 0.000 description 7
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 6
• LOAOEWUSMWRRDN-IBGZPJMESA-N 2-(3-chlorophenyl)-n-[(1s)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]acetamide Chemical compound C1=CC([N+](=O)[O-])=CC=C1C[C@@H](C=1N=C(SC=1)C=1SC=CC=1)NC(=O)CC1=CC=CC(Cl)=C1 LOAOEWUSMWRRDN-IBGZPJMESA-N 0.000 description 6
• JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 6
• CBBVPEYJGLWZEO-INIZCTEOSA-N 4-[(1s)-1-isothiocyanato-2-(4-nitrophenyl)ethyl]-2-phenyl-1,3-thiazole Chemical compound C1=CC([N+](=O)[O-])=CC=C1C[C@H](N=C=S)C1=CSC(C=2C=CC=CC=2)=N1 CBBVPEYJGLWZEO-INIZCTEOSA-N 0.000 description 6
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
• 208000027418 Wounds and injury Diseases 0.000 description 6
• 125000003342 alkenyl group Chemical group 0.000 description 6
• 125000000304 alkynyl group Chemical group 0.000 description 6
• 150000001412 amines Chemical class 0.000 description 6
• 210000002889 endothelial cell Anatomy 0.000 description 6
• 230000035876 healing Effects 0.000 description 6
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
• 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 6
• 239000012074 organic phase Substances 0.000 description 6
• DTNHUDDLCVNQFM-LBPRGKRZSA-N tert-butyl n-[(2s)-4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)CBr)CC1=CC=C([N+]([O-])=O)C=C1 DTNHUDDLCVNQFM-LBPRGKRZSA-N 0.000 description 6
• YSCKJLZYVJETAF-RSAXXLAASA-N (1s)-2-(4-nitrophenyl)-1-(2-phenyl-1,3-thiazol-4-yl)ethanamine;hydrobromide Chemical compound Br.C([C@H](N)C=1N=C(SC=1)C=1C=CC=CC=1)C1=CC=C([N+]([O-])=O)C=C1 YSCKJLZYVJETAF-RSAXXLAASA-N 0.000 description 5
• 125000004463 2,4-dimethyl-thiazol-5-yl group Chemical group CC=1SC(=C(N1)C)* 0.000 description 5
• DJFATTBHFVEURU-UHFFFAOYSA-N 2-(2-methoxyphenyl)-3-phenylpropanoic acid Chemical compound COC1=CC=CC=C1C(C(O)=O)CC1=CC=CC=C1 DJFATTBHFVEURU-UHFFFAOYSA-N 0.000 description 5
• 206010053648 Vascular occlusion Diseases 0.000 description 5
• 206010052428 Wound Diseases 0.000 description 5
• LJVOECHBYHMFNG-KEKNWZKVSA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[[2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanoyl]amino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)C(CC=2C=CC=CC=2)C=2ON=C(C)N=2)=N1 LJVOECHBYHMFNG-KEKNWZKVSA-N 0.000 description 5
• 230000015572 biosynthetic process Effects 0.000 description 5
• 230000017531 blood circulation Effects 0.000 description 5
• 206010012601 diabetes mellitus Diseases 0.000 description 5
• 239000003102 growth factor Substances 0.000 description 5
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
• 238000004519 manufacturing process Methods 0.000 description 5
• UCNRIVIOUVGFFO-UHFFFAOYSA-N n-[1-(4-ethyl-1,3-thiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-phenylacetamide Chemical compound CCC1=CSC(C(CC=2C=CC(=CC=2)[N+]([O-])=O)NC(=O)CC=2C=CC=CC=2)=N1 UCNRIVIOUVGFFO-UHFFFAOYSA-N 0.000 description 5
• 125000000547 substituted alkyl group Chemical group 0.000 description 5
• 208000021331 vascular occlusion disease Diseases 0.000 description 5
• XSUBWLWHJWYBRZ-YDALLXLXSA-N (1s)-1-(4-ethyl-1,3-thiazol-2-yl)-2-(4-nitrophenyl)ethanamine;hydrobromide Chemical compound Br.CCC1=CSC([C@@H](N)CC=2C=CC(=CC=2)[N+]([O-])=O)=N1 XSUBWLWHJWYBRZ-YDALLXLXSA-N 0.000 description 4
• JSSXJMUARURCER-YDALLXLXSA-N (1s)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethanamine;hydrobromide Chemical compound Br.C([C@H](N)C=1N=C(SC=1)C=1SC=CC=1)C1=CC=C([N+]([O-])=O)C=C1 JSSXJMUARURCER-YDALLXLXSA-N 0.000 description 4
• IJAYMUFRRBWQPU-UHFFFAOYSA-N (2-methyl-1,3-thiazol-4-yl)methanesulfonyl chloride Chemical compound CC1=NC(CS(Cl)(=O)=O)=CS1 IJAYMUFRRBWQPU-UHFFFAOYSA-N 0.000 description 4
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
• 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 4
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
• QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
• HTPBIOVOBBRRHY-FQEVSTJZSA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[(4-oxo-4-phenylbutanoyl)amino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CCC(=O)C=2C=CC=CC=2)=N1 HTPBIOVOBBRRHY-FQEVSTJZSA-N 0.000 description 4
• DTFRRNOJORJJNS-FQEVSTJZSA-N [4-[(2s)-2-[[4-(3-methoxyphenyl)-1,3-thiazol-2-yl]amino]-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound COC1=CC=CC(C=2N=C(N[C@@H](CC=3C=CC(NS(O)(=O)=O)=CC=3)C=3N=C(SC=3)C=3SC=CC=3)SC=2)=C1 DTFRRNOJORJJNS-FQEVSTJZSA-N 0.000 description 4
• UAOKELIWYGBWNB-QHCPKHFHSA-N [4-[(2s)-2-[[5-(3-methoxyphenyl)-1,3-oxazol-2-yl]amino]-2-(2-phenyl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound COC1=CC=CC(C=2OC(N[C@@H](CC=3C=CC(NS(O)(=O)=O)=CC=3)C=3N=C(SC=3)C=3C=CC=CC=3)=NC=2)=C1 UAOKELIWYGBWNB-QHCPKHFHSA-N 0.000 description 4
• MGZHILITYWIJAD-LJQANCHMSA-N [4-[2-[[(2s)-2-(4-ethyl-1,3-oxazol-2-yl)-2-phenylacetyl]amino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=COC([C@@H](C(=O)NCCC=2C=CC(NS(O)(=O)=O)=CC=2)C=2C=CC=CC=2)=N1 MGZHILITYWIJAD-LJQANCHMSA-N 0.000 description 4
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
• 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 4
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
• KFMYBCJKXQBZGI-KEKNWZKVSA-N ethyl 2-benzyl-3-[[(1s)-1-(4-ethyl-1,3-thiazol-2-yl)-2-(4-nitrophenyl)ethyl]amino]-3-oxopropanoate Chemical compound N([C@@H](CC=1C=CC(=CC=1)[N+]([O-])=O)C=1SC=C(CC)N=1)C(=O)C(C(=O)OCC)CC1=CC=CC=C1 KFMYBCJKXQBZGI-KEKNWZKVSA-N 0.000 description 4
• 239000000284 extract Substances 0.000 description 4
• 239000000706 filtrate Substances 0.000 description 4
• 230000001965 increasing effect Effects 0.000 description 4
• YDNLNVZZTACNJX-UHFFFAOYSA-N isocyanatomethylbenzene Chemical compound O=C=NCC1=CC=CC=C1 YDNLNVZZTACNJX-UHFFFAOYSA-N 0.000 description 4
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
• ZDORNXAKFGEHFK-UHFFFAOYSA-N methyl 2-(2-methoxyphenyl)-3-phenylpropanoate Chemical compound C=1C=CC=C(OC)C=1C(C(=O)OC)CC1=CC=CC=C1 ZDORNXAKFGEHFK-UHFFFAOYSA-N 0.000 description 4
• WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 4
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
• 230000008569 process Effects 0.000 description 4
• 238000011069 regeneration method Methods 0.000 description 4
• 230000008439 repair process Effects 0.000 description 4
• DNAWLDKKRJSPPJ-LBPRGKRZSA-N tert-butyl N-[(2S)-4-diazo-1-(4-nitrophenyl)-3-oxobutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)C=[N+]=[N-])CC1=CC=C([N+]([O-])=O)C=C1 DNAWLDKKRJSPPJ-LBPRGKRZSA-N 0.000 description 4
• 230000001225 therapeutic effect Effects 0.000 description 4
• 230000008467 tissue growth Effects 0.000 description 4
• KWUIXSAJBVOAHU-LBPRGKRZSA-N (1s)-1-(4-ethyl-1,3-oxazol-2-yl)-2-(4-nitrophenyl)ethanamine Chemical compound CCC1=COC([C@@H](N)CC=2C=CC(=CC=2)[N+]([O-])=O)=N1 KWUIXSAJBVOAHU-LBPRGKRZSA-N 0.000 description 3
• MHXNSOGZEZWIMY-YDALLXLXSA-N (1s)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl-1,3-oxazol-4-yl)ethanamine;hydrobromide Chemical compound Br.C([C@H](N)C=1N=C(OC=1)C=1SC=CC=1)C1=CC=C([N+]([O-])=O)C=C1 MHXNSOGZEZWIMY-YDALLXLXSA-N 0.000 description 3
• BWFLKAMDZBXOCS-IBGZPJMESA-N 1-benzyl-3-[(1s)-1-(4-ethyl-1,3-thiazol-2-yl)-2-(4-nitrophenyl)ethyl]urea Chemical compound CCC1=CSC([C@H](CC=2C=CC(=CC=2)[N+]([O-])=O)NC(=O)NCC=2C=CC=CC=2)=N1 BWFLKAMDZBXOCS-IBGZPJMESA-N 0.000 description 3
• SSYMXWZMAZRVCC-IBGZPJMESA-N 2-(3-chlorophenyl)-n-[(1s)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl-1,3-oxazol-4-yl)ethyl]acetamide Chemical compound C1=CC([N+](=O)[O-])=CC=C1C[C@@H](C=1N=C(OC=1)C=1SC=CC=1)NC(=O)CC1=CC=CC(Cl)=C1 SSYMXWZMAZRVCC-IBGZPJMESA-N 0.000 description 3
• YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 3
• XBQADBXCNQPHHY-NSHDSACASA-N 33305-77-0 Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C([N+]([O-])=O)C=C1 XBQADBXCNQPHHY-NSHDSACASA-N 0.000 description 3
• KKAUKPMBERGBHC-KRWDZBQOSA-N 5-methyl-n-[(1s)-2-(4-nitrophenyl)-1-(2-phenyl-1,3-thiazol-4-yl)ethyl]-1,3,4-thiadiazol-2-amine Chemical compound S1C(C)=NN=C1N[C@H](C=1N=C(SC=1)C=1C=CC=CC=1)CC1=CC=C([N+]([O-])=O)C=C1 KKAUKPMBERGBHC-KRWDZBQOSA-N 0.000 description 3
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
• VTVASRNEPPSYOY-LBPRGKRZSA-N [(1s)-1-(2-cyclopropyl-1,3-thiazol-4-yl)-2-(4-nitrophenyl)ethyl]thiourea Chemical compound C([C@H](NC(=S)N)C=1N=C(SC=1)C1CC1)C1=CC=C([N+]([O-])=O)C=C1 VTVASRNEPPSYOY-LBPRGKRZSA-N 0.000 description 3
• OCOKWTQISJIFFE-FQEVSTJZSA-N [4-[(2s)-2-(2-cyclopropyl-1,3-thiazol-4-yl)-2-[[4-(3-methoxyphenyl)-1,3-thiazol-2-yl]amino]ethyl]phenyl]sulfamic acid Chemical compound COC1=CC=CC(C=2N=C(N[C@@H](CC=3C=CC(NS(O)(=O)=O)=CC=3)C=3N=C(SC=3)C3CC3)SC=2)=C1 OCOKWTQISJIFFE-FQEVSTJZSA-N 0.000 description 3
• BNMPXZKWADCLTR-KRWDZBQOSA-N [4-[(2s)-2-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]-2-(2-phenyl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound S1C(C)=NN=C1N[C@H](C=1N=C(SC=1)C=1C=CC=CC=1)CC1=CC=C(NS(O)(=O)=O)C=C1 BNMPXZKWADCLTR-KRWDZBQOSA-N 0.000 description 3
• JXRVNQQMLLRAEA-IBGZPJMESA-N [4-[(2s)-2-[[2-(3-chlorophenyl)acetyl]amino]-2-(2-thiophen-2-yl-1,3-oxazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound C1=CC(NS(=O)(=O)O)=CC=C1C[C@@H](C=1N=C(OC=1)C=1SC=CC=1)NC(=O)CC1=CC=CC(Cl)=C1 JXRVNQQMLLRAEA-IBGZPJMESA-N 0.000 description 3
• 230000002491 angiogenic effect Effects 0.000 description 3
• 230000003143 atherosclerotic effect Effects 0.000 description 3
• 230000036770 blood supply Effects 0.000 description 3
• 210000000988 bone and bone Anatomy 0.000 description 3
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
• 229910052799 carbon Inorganic materials 0.000 description 3
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 3
• 230000004663 cell proliferation Effects 0.000 description 3
• 230000004087 circulation Effects 0.000 description 3
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
• 125000004122 cyclic group Chemical group 0.000 description 3
• 230000003247 decreasing effect Effects 0.000 description 3
• 230000000694 effects Effects 0.000 description 3
• 125000001183 hydrocarbyl group Chemical group 0.000 description 3
• 238000000338 in vitro Methods 0.000 description 3
• 238000001727 in vivo Methods 0.000 description 3
• 208000028867 ischemia Diseases 0.000 description 3
• 230000003902 lesion Effects 0.000 description 3
• 125000005647 linker group Chemical group 0.000 description 3
• 238000002595 magnetic resonance imaging Methods 0.000 description 3
• 239000000463 material Substances 0.000 description 3
• 238000012986 modification Methods 0.000 description 3
• 230000004048 modification Effects 0.000 description 3
• NGDQPHPYBDYZNQ-QFIPXVFZSA-N n-[(1s)-1-(2-cyclopropyl-1,3-thiazol-4-yl)-2-(4-nitrophenyl)ethyl]-4-[(3-methoxyphenyl)methyl]-1,3-thiazol-2-amine Chemical compound COC1=CC=CC(CC=2N=C(N[C@@H](CC=3C=CC(=CC=3)[N+]([O-])=O)C=3N=C(SC=3)C3CC3)SC=2)=C1 NGDQPHPYBDYZNQ-QFIPXVFZSA-N 0.000 description 3
• YCOXILGMEFMVKQ-IBGZPJMESA-N n-[(1s)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]-1-phenylmethanesulfonamide Chemical compound C1=CC([N+](=O)[O-])=CC=C1C[C@@H](C=1N=C(SC=1)C=1SC=CC=1)NS(=O)(=O)CC1=CC=CC=C1 YCOXILGMEFMVKQ-IBGZPJMESA-N 0.000 description 3
• 235000015097 nutrients Nutrition 0.000 description 3
• 239000008194 pharmaceutical composition Substances 0.000 description 3
• 230000001023 pro-angiogenic effect Effects 0.000 description 3
• VCKIHAJZSUXHKC-UHFFFAOYSA-M sodium;(2-methyl-1,3-thiazol-4-yl)methanesulfonate Chemical compound [Na+].CC1=NC(CS([O-])(=O)=O)=CS1 VCKIHAJZSUXHKC-UHFFFAOYSA-M 0.000 description 3
• DNAWLDKKRJSPPJ-UHFFFAOYSA-N tert-butyl N-[4-diazo-1-(4-nitrophenyl)-3-oxobutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C(=O)C=[N+]=[N-])CC1=CC=C([N+]([O-])=O)C=C1 DNAWLDKKRJSPPJ-UHFFFAOYSA-N 0.000 description 3
• DTNHUDDLCVNQFM-UHFFFAOYSA-N tert-butyl n-[4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C(=O)CBr)CC1=CC=C([N+]([O-])=O)C=C1 DTNHUDDLCVNQFM-UHFFFAOYSA-N 0.000 description 3
• 238000002560 therapeutic procedure Methods 0.000 description 3
• UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 3
• 230000002792 vascular Effects 0.000 description 3
• LGNGNRKVHLNCIZ-IBGZPJMESA-N 1-benzyl-3-[(1s)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]urea Chemical compound C1=CC([N+](=O)[O-])=CC=C1C[C@@H](C=1N=C(SC=1)C=1SC=CC=1)NC(=O)NCC1=CC=CC=C1 LGNGNRKVHLNCIZ-IBGZPJMESA-N 0.000 description 2
• CCXQVBSQUQCEEO-UHFFFAOYSA-N 1-bromobutan-2-one Chemical compound CCC(=O)CBr CCXQVBSQUQCEEO-UHFFFAOYSA-N 0.000 description 2
• MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 2
• 125000006017 1-propenyl group Chemical group 0.000 description 2
• WFPMUFXQDKMVCO-UHFFFAOYSA-N 2-(3-chlorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Cl)=C1 WFPMUFXQDKMVCO-UHFFFAOYSA-N 0.000 description 2
• ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 description 2
• KDDBSOXJYRJAGU-UHFFFAOYSA-N 2-benzyl-3-ethoxy-3-oxopropanoic acid Chemical compound CCOC(=O)C(C(O)=O)CC1=CC=CC=C1 KDDBSOXJYRJAGU-UHFFFAOYSA-N 0.000 description 2
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
• BZQGAPWJKAYCHR-UHFFFAOYSA-N 3,3-diphenylpropanoic acid Chemical compound C=1C=CC=CC=1C(CC(=O)O)C1=CC=CC=C1 BZQGAPWJKAYCHR-UHFFFAOYSA-N 0.000 description 2
• PPMUNOODEYEXJW-IBGZPJMESA-N 4-(2-methoxyphenyl)-n-[(1s)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]-1,3-thiazol-2-amine Chemical compound COC1=CC=CC=C1C1=CSC(N[C@@H](CC=2C=CC(=CC=2)[N+]([O-])=O)C=2N=C(SC=2)C=2SC=CC=2)=N1 PPMUNOODEYEXJW-IBGZPJMESA-N 0.000 description 2
• KMQLIDDEQAJAGJ-UHFFFAOYSA-N 4-oxo-4-phenylbutyric acid Chemical compound OC(=O)CCC(=O)C1=CC=CC=C1 KMQLIDDEQAJAGJ-UHFFFAOYSA-N 0.000 description 2
• YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
• 201000004569 Blindness Diseases 0.000 description 2
• YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
• 241000282412 Homo Species 0.000 description 2
• 206010020772 Hypertension Diseases 0.000 description 2
• 241001465754 Metazoa Species 0.000 description 2
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
• 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 2
• 206010040943 Skin Ulcer Diseases 0.000 description 2
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
• QIOZLISABUUKJY-UHFFFAOYSA-N Thiobenzamide Chemical compound NC(=S)C1=CC=CC=C1 QIOZLISABUUKJY-UHFFFAOYSA-N 0.000 description 2
• 229910021626 Tin(II) chloride Inorganic materials 0.000 description 2
• 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
• 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
• ZTQSPAZWIDVFAB-KRWDZBQOSA-N [4-[(2s)-2-(1,3-benzodioxole-5-carbonylamino)-2-(4-ethyl-1,3-thiazol-2-yl)ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)C=2C=C3OCOC3=CC=2)=N1 ZTQSPAZWIDVFAB-KRWDZBQOSA-N 0.000 description 2
• OWQRDPCPQKJXGQ-IBGZPJMESA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[[2-(3-fluorophenyl)acetyl]amino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CC=2C=C(F)C=CC=2)=N1 OWQRDPCPQKJXGQ-IBGZPJMESA-N 0.000 description 2
• VUBRJZVWXOODGV-IBGZPJMESA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[[2-(3-hydroxyphenyl)acetyl]amino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CC=2C=C(O)C=CC=2)=N1 VUBRJZVWXOODGV-IBGZPJMESA-N 0.000 description 2
• 230000002378 acidificating effect Effects 0.000 description 2
• 125000005596 alkyl carboxamido group Chemical group 0.000 description 2
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
• 230000001668 ameliorated effect Effects 0.000 description 2
• 229910021529 ammonia Inorganic materials 0.000 description 2
• 206010003246 arthritis Diseases 0.000 description 2
• 230000008901 benefit Effects 0.000 description 2
• 230000033228 biological regulation Effects 0.000 description 2
• 150000001721 carbon Chemical group 0.000 description 2
• 210000000845 cartilage Anatomy 0.000 description 2
• 230000001413 cellular effect Effects 0.000 description 2
• 239000003795 chemical substances by application Substances 0.000 description 2
• 230000006378 damage Effects 0.000 description 2
• 238000013461 design Methods 0.000 description 2
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
• 239000012065 filter cake Substances 0.000 description 2
• 238000004128 high performance liquid chromatography Methods 0.000 description 2
• 238000005984 hydrogenation reaction Methods 0.000 description 2
• 125000002883 imidazolyl group Chemical group 0.000 description 2
• 230000001976 improved effect Effects 0.000 description 2
• 238000010874 in vitro model Methods 0.000 description 2
• 230000001939 inductive effect Effects 0.000 description 2
• 239000004615 ingredient Substances 0.000 description 2
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
• 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 2
• CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 2
• 210000004185 liver Anatomy 0.000 description 2
• VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
• BNQRSYFOIRGRKV-UHFFFAOYSA-N methyl 2-(2-methoxyphenyl)acetate Chemical compound COC(=O)CC1=CC=CC=C1OC BNQRSYFOIRGRKV-UHFFFAOYSA-N 0.000 description 2
• XQYPYNWIXQCCSG-KRWDZBQOSA-N methyl 5-[[(1s)-2-(4-nitrophenyl)-1-(2-phenyl-1,3-thiazol-4-yl)ethyl]amino]-1,3-thiazole-4-carboxylate Chemical compound N1=CSC(N[C@@H](CC=2C=CC(=CC=2)[N+]([O-])=O)C=2N=C(SC=2)C=2C=CC=CC=2)=C1C(=O)OC XQYPYNWIXQCCSG-KRWDZBQOSA-N 0.000 description 2
• 208000010125 myocardial infarction Diseases 0.000 description 2
• AEXITZJSLGALNH-UHFFFAOYSA-N n'-hydroxyethanimidamide Chemical compound CC(N)=NO AEXITZJSLGALNH-UHFFFAOYSA-N 0.000 description 2
• 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
• 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
• 150000002828 nitro derivatives Chemical class 0.000 description 2
• 125000002971 oxazolyl group Chemical group 0.000 description 2
• 230000007170 pathology Effects 0.000 description 2
• 230000002085 persistent effect Effects 0.000 description 2
• 229960003424 phenylacetic acid Drugs 0.000 description 2
• 239000003279 phenylacetic acid Substances 0.000 description 2
• RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
• 238000002600 positron emission tomography Methods 0.000 description 2
• 229910000027 potassium carbonate Inorganic materials 0.000 description 2
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 2
• 230000008929 regeneration Effects 0.000 description 2
• 230000006884 regulation of angiogenesis Effects 0.000 description 2
• 230000004044 response Effects 0.000 description 2
• 239000012047 saturated solution Substances 0.000 description 2
• 238000002603 single-photon emission computed tomography Methods 0.000 description 2
• 231100000019 skin ulcer Toxicity 0.000 description 2
• GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
• 235000011150 stannous chloride Nutrition 0.000 description 2
• 238000003756 stirring Methods 0.000 description 2
• 125000003107 substituted aryl group Chemical group 0.000 description 2
• 238000001356 surgical procedure Methods 0.000 description 2
• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
• HDXYHAPUCGQOBX-UHFFFAOYSA-N thiophene-2-carbothioamide Chemical compound NC(=S)C1=CC=CS1 HDXYHAPUCGQOBX-UHFFFAOYSA-N 0.000 description 2
• AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 2
• 210000004881 tumor cell Anatomy 0.000 description 2
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
• 230000037314 wound repair Effects 0.000 description 2
• FMIVZCBDDMNYJP-LTCKWSDVSA-N (1s)-1-(2-cyclopropyl-1,3-thiazol-4-yl)-2-(4-nitrophenyl)ethanamine;dihydrobromide Chemical compound Br.Br.C([C@H](N)C=1N=C(SC=1)C1CC1)C1=CC=C([N+]([O-])=O)C=C1 FMIVZCBDDMNYJP-LTCKWSDVSA-N 0.000 description 1
• DBBZQDQFYYVTTN-LBPRGKRZSA-N (1s)-1-(4-ethyl-1,3-thiazol-2-yl)-2-(4-nitrophenyl)ethanamine Chemical compound CCC1=CSC([C@@H](N)CC=2C=CC(=CC=2)[N+]([O-])=O)=N1 DBBZQDQFYYVTTN-LBPRGKRZSA-N 0.000 description 1
• PTUSICOEEPWBGO-HNNXBMFYSA-N (1s)-2-(4-nitrophenyl)-1-(2-phenyl-1,3-thiazol-4-yl)ethanamine Chemical compound C([C@H](N)C=1N=C(SC=1)C=1C=CC=CC=1)C1=CC=C([N+]([O-])=O)C=C1 PTUSICOEEPWBGO-HNNXBMFYSA-N 0.000 description 1
• ANAYFLILBXZBKK-PMCHYTPCSA-N (2s)-n-[1-(4-ethyl-1,3-thiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2,3-diphenylpropanamide Chemical compound CCC1=CSC(C(CC=2C=CC(=CC=2)[N+]([O-])=O)NC(=O)[C@@H](CC=2C=CC=CC=2)C=2C=CC=CC=2)=N1 ANAYFLILBXZBKK-PMCHYTPCSA-N 0.000 description 1
• 125000001478 1-chloroethyl group Chemical group [H]C([H])([H])C([H])(Cl)* 0.000 description 1
• 238000004293 19F NMR spectroscopy Methods 0.000 description 1
• 238000005160 1H NMR spectroscopy Methods 0.000 description 1
• 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
• 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
• 125000003070 2-(2-chlorophenyl)ethyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
• GKNCPTLOPRDYMH-UHFFFAOYSA-N 2-bromo-1-(2-methoxyphenyl)ethanone Chemical compound COC1=CC=CC=C1C(=O)CBr GKNCPTLOPRDYMH-UHFFFAOYSA-N 0.000 description 1
• IOOHBIFQNQQUFI-UHFFFAOYSA-N 2-bromo-1-(3-methoxyphenyl)ethanone Chemical compound COC1=CC=CC(C(=O)CBr)=C1 IOOHBIFQNQQUFI-UHFFFAOYSA-N 0.000 description 1
• 125000002856 2-fluorophenylethyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
• WYKHSBAVLOPISI-UHFFFAOYSA-N 2-phenyl-1,3-thiazole Chemical compound C1=CSC(C=2C=CC=CC=2)=N1 WYKHSBAVLOPISI-UHFFFAOYSA-N 0.000 description 1
• 125000004362 3,4,5-trichlorophenyl group Chemical group [H]C1=C(Cl)C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
• LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 1
• 125000003974 3-carbamimidamidopropyl group Chemical group C(N)(=N)NCCC* 0.000 description 1
• 125000000972 4,5-dimethylthiazol-2-yl group Chemical group [H]C([H])([H])C1=C(N=C(*)S1)C([H])([H])[H] 0.000 description 1
• AQBBZYVPKBIILN-UHFFFAOYSA-N 4-(chloromethyl)-2-methyl-1,3-thiazole Chemical compound CC1=NC(CCl)=CS1 AQBBZYVPKBIILN-UHFFFAOYSA-N 0.000 description 1
• KMMCOCMVZYHTDE-ZDUSSCGKSA-N 4-[(1S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]-1,3-thiazol-2-amine Chemical compound [N+](=O)([O-])C1=CC=C(C=C1)C[C@@H](C=1N=C(SC=1)C=1SC=CC=1)C=1N=C(SC=1)N KMMCOCMVZYHTDE-ZDUSSCGKSA-N 0.000 description 1
• GZQWIUWWDSLTDT-NRFANRHFSA-N 4-[(2S)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[3-(3-methoxyphenyl)propanoylamino]ethyl]benzenesulfinic acid Chemical compound C(C)C=1N=C(SC1)[C@H](CC1=CC=C(C=C1)S(=O)O)NC(CCC1=CC(=CC=C1)OC)=O GZQWIUWWDSLTDT-NRFANRHFSA-N 0.000 description 1
• NTKREJUXCBFWFR-KRWDZBQOSA-N 4-[(2s)-2-isothiocyanato-2-(4-nitrophenyl)ethyl]-2-phenyl-1,3-thiazole Chemical compound C1=CC([N+](=O)[O-])=CC=C1[C@@H](N=C=S)CC1=CSC(C=2C=CC=CC=2)=N1 NTKREJUXCBFWFR-KRWDZBQOSA-N 0.000 description 1
• 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 1
• 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 1
• LWYWBZGXZLHFTQ-UHFFFAOYSA-N 5-(3-methoxyphenyl)-n-[2-(4-nitrophenyl)-1-(2-phenyl-1,3-thiazol-4-yl)ethyl]-1,3-oxazol-2-amine Chemical compound COC1=CC=CC(C=2OC(NC(CC=3C=CC(=CC=3)[N+]([O-])=O)C=3N=C(SC=3)C=3C=CC=CC=3)=NC=2)=C1 LWYWBZGXZLHFTQ-UHFFFAOYSA-N 0.000 description 1
• 206010000358 Accelerated hypertension Diseases 0.000 description 1
• 206010002383 Angina Pectoris Diseases 0.000 description 1
• 102000009088 Angiopoietin-1 Human genes 0.000 description 1
• 108010048154 Angiopoietin-1 Proteins 0.000 description 1
• 102000009840 Angiopoietins Human genes 0.000 description 1
• 108010009906 Angiopoietins Proteins 0.000 description 1
• 206010003210 Arteriosclerosis Diseases 0.000 description 1
• 201000001320 Atherosclerosis Diseases 0.000 description 1
• 208000035143 Bacterial infection Diseases 0.000 description 1
• LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
• 208000031229 Cardiomyopathies Diseases 0.000 description 1
• 239000004593 Epoxy Substances 0.000 description 1
• 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
• 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
• 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
• 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
• 102000001554 Hemoglobins Human genes 0.000 description 1
• 108010054147 Hemoglobins Proteins 0.000 description 1
• 208000032843 Hemorrhage Diseases 0.000 description 1
• 101000972485 Homo sapiens Lupus La protein Proteins 0.000 description 1
• 101000606537 Homo sapiens Receptor-type tyrosine-protein phosphatase delta Proteins 0.000 description 1
• 101001087394 Homo sapiens Tyrosine-protein phosphatase non-receptor type 1 Proteins 0.000 description 1
• 206010021143 Hypoxia Diseases 0.000 description 1
• 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
• 102000004877 Insulin Human genes 0.000 description 1
• 108090001061 Insulin Proteins 0.000 description 1
• 206010022562 Intermittent claudication Diseases 0.000 description 1
• 206010022680 Intestinal ischaemia Diseases 0.000 description 1
• 208000035901 Ischaemic ulcer Diseases 0.000 description 1
• 208000034693 Laceration Diseases 0.000 description 1
• 102100022742 Lupus La protein Human genes 0.000 description 1
• 208000004535 Mesenteric Ischemia Diseases 0.000 description 1
• 206010027476 Metastases Diseases 0.000 description 1
• 101100481410 Mus musculus Tek gene Proteins 0.000 description 1
• 208000021908 Myocardial disease Diseases 0.000 description 1
• 206010029113 Neovascularisation Diseases 0.000 description 1
• 208000001132 Osteoporosis Diseases 0.000 description 1
• 208000037273 Pathologic Processes Diseases 0.000 description 1
• 102000035195 Peptidases Human genes 0.000 description 1
• 108091005804 Peptidases Proteins 0.000 description 1
• OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
• ZLMJMSJWJFRBEC-RNFDNDRNSA-N Potassium-43 Chemical compound [43K] ZLMJMSJWJFRBEC-RNFDNDRNSA-N 0.000 description 1
• 239000004365 Protease Substances 0.000 description 1
• 102100039666 Receptor-type tyrosine-protein phosphatase delta Human genes 0.000 description 1
• 208000001647 Renal Insufficiency Diseases 0.000 description 1
• 102100033001 Tyrosine-protein phosphatase non-receptor type 1 Human genes 0.000 description 1
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
• 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
• 206010057469 Vascular stenosis Diseases 0.000 description 1
• 208000036142 Viral infection Diseases 0.000 description 1
• AUZCVNPCJUEPMR-LBPRGKRZSA-N [(1s)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]thiourea Chemical compound C([C@H](NC(=S)N)C=1N=C(SC=1)C=1SC=CC=1)C1=CC=C([N+]([O-])=O)C=C1 AUZCVNPCJUEPMR-LBPRGKRZSA-N 0.000 description 1
• MTPVUXQTHJPPLV-IBGZPJMESA-N [4-[(2s)-2-(2-cyclopropyl-1,3-thiazol-4-yl)-2-[[4-(2,4-difluorophenyl)-1,3-thiazol-2-yl]amino]ethyl]phenyl]sulfamic acid Chemical compound C1=CC(NS(=O)(=O)O)=CC=C1C[C@@H](C=1N=C(SC=1)C1CC1)NC1=NC(C=2C(=CC(F)=CC=2)F)=CS1 MTPVUXQTHJPPLV-IBGZPJMESA-N 0.000 description 1
• KAAQQKVWLKFFHB-IBGZPJMESA-N [4-[(2s)-2-(2-cyclopropyl-1,3-thiazol-4-yl)-2-[[4-(2-methoxyphenyl)-1,3-thiazol-2-yl]amino]ethyl]phenyl]sulfamic acid Chemical compound COC1=CC=CC=C1C1=CSC(N[C@@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)C=2N=C(SC=2)C2CC2)=N1 KAAQQKVWLKFFHB-IBGZPJMESA-N 0.000 description 1
• PGAJAZQWFRIXKK-IBGZPJMESA-N [4-[(2s)-2-(2-cyclopropyl-1,3-thiazol-4-yl)-2-[[4-(4-fluorophenyl)-1,3-thiazol-2-yl]amino]ethyl]phenyl]sulfamic acid Chemical compound C1=CC(NS(=O)(=O)O)=CC=C1C[C@@H](C=1N=C(SC=1)C1CC1)NC1=NC(C=2C=CC(F)=CC=2)=CS1 PGAJAZQWFRIXKK-IBGZPJMESA-N 0.000 description 1
• VFTZUXHVZMPKAG-AWEZNQCLSA-N [4-[(2s)-2-(2-ethyl-1,3-thiazol-4-yl)-2-[(2-methyl-1,3-thiazol-4-yl)sulfonylamino]ethyl]phenyl]sulfamic acid Chemical compound S1C(CC)=NC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NS(=O)(=O)C=2N=C(C)SC=2)=C1 VFTZUXHVZMPKAG-AWEZNQCLSA-N 0.000 description 1
• SDYIWVDHUFVKGU-ZDUSSCGKSA-N [4-[(2s)-2-(2-ethyl-1,3-thiazol-4-yl)-2-[[5-(methoxycarbonylamino)-1-methyl-1,2,4-triazol-3-yl]amino]ethyl]phenyl]sulfamic acid Chemical compound S1C(CC)=NC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC2=NN(C)C(NC(=O)OC)=N2)=C1 SDYIWVDHUFVKGU-ZDUSSCGKSA-N 0.000 description 1
• FTVNMKDJBOHXJD-KRWDZBQOSA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[(5-methyl-4-oxohexanoyl)amino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CCC(=O)C(C)C)=N1 FTVNMKDJBOHXJD-KRWDZBQOSA-N 0.000 description 1
• DPISVJDMXSOTLO-INIZCTEOSA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[3-(1,3-thiazol-2-yl)propanoylamino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CCC=2SC=CN=2)=N1 DPISVJDMXSOTLO-INIZCTEOSA-N 0.000 description 1
• NXOZFOXZLDWPDT-JKGBFCRXSA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[[2-(2-fluorophenyl)-3-phenylpropanoyl]amino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)C(CC=2C=CC=CC=2)C=2C(=CC=CC=2)F)=N1 NXOZFOXZLDWPDT-JKGBFCRXSA-N 0.000 description 1
• CSGSBSHXLABUFG-AMVUTOCUSA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[[2-(2-methoxyphenyl)-3-phenylpropanoyl]amino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)C(CC=2C=CC=CC=2)C=2C(=CC=CC=2)OC)=N1 CSGSBSHXLABUFG-AMVUTOCUSA-N 0.000 description 1
• RYVHXJLQEGKCIJ-KRWDZBQOSA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[[2-(4-ethyl-1,3-thiazol-2-yl)acetyl]amino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC(CC(=O)N[C@@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)C=2SC=C(CC)N=2)=N1 RYVHXJLQEGKCIJ-KRWDZBQOSA-N 0.000 description 1
• IBXJYYUKQGSDAT-INIZCTEOSA-N [4-[(2s)-2-(4-ethyl-1,3-thiazol-2-yl)-2-[[2-(5-methyl-2,4-dioxopyrimidin-1-yl)acetyl]amino]ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CN2C(NC(=O)C(C)=C2)=O)=N1 IBXJYYUKQGSDAT-INIZCTEOSA-N 0.000 description 1
• CBJGFIFTLACKDR-INIZCTEOSA-N [4-[(2s)-2-[(4,6-dimethylpyrimidin-2-yl)amino]-2-(2-methyl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound S1C(C)=NC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC=2N=C(C)C=C(C)N=2)=C1 CBJGFIFTLACKDR-INIZCTEOSA-N 0.000 description 1
• OMRMEYUBCDJARQ-FQEVSTJZSA-N [4-[(2s)-2-[(4-acetamidophenyl)sulfonylamino]-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound C1=CC(NC(=O)C)=CC=C1S(=O)(=O)N[C@H](C=1N=C(SC=1)C=1SC=CC=1)CC1=CC=C(NS(O)(=O)=O)C=C1 OMRMEYUBCDJARQ-FQEVSTJZSA-N 0.000 description 1
• MMYLSMYTNAHPDC-IBGZPJMESA-N [4-[(2s)-2-[(5-benzyl-1,3,4-thiadiazol-2-yl)amino]-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound C1=CC(NS(=O)(=O)O)=CC=C1C[C@@H](C=1N=C(SC=1)C=1SC=CC=1)NC(S1)=NN=C1CC1=CC=CC=C1 MMYLSMYTNAHPDC-IBGZPJMESA-N 0.000 description 1
• NHLYJKHQNOQFLU-NRFANRHFSA-N [4-[(2s)-2-[(5-phenyl-1,3,4-thiadiazol-2-yl)amino]-2-(2-phenyl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound C1=CC(NS(=O)(=O)O)=CC=C1C[C@@H](C=1N=C(SC=1)C=1C=CC=CC=1)NC1=NN=C(C=2C=CC=CC=2)S1 NHLYJKHQNOQFLU-NRFANRHFSA-N 0.000 description 1
• STTNVVHPOLOFHV-FQEVSTJZSA-N [4-[(2s)-2-[3-(3-chlorophenyl)propanoylamino]-2-(4-ethyl-1,3-thiazol-2-yl)ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CCC=2C=C(Cl)C=CC=2)=N1 STTNVVHPOLOFHV-FQEVSTJZSA-N 0.000 description 1
• OMEARSOPYMXZCH-IBGZPJMESA-N [4-[(2s)-2-[[2-(2,3-dimethoxyphenyl)acetyl]amino]-2-(4-ethyl-1,3-thiazol-2-yl)ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CC=2C(=C(OC)C=CC=2)OC)=N1 OMEARSOPYMXZCH-IBGZPJMESA-N 0.000 description 1
• YCSBQALUBMTXON-INIZCTEOSA-N [4-[(2s)-2-[[2-(2,4-dimethyl-1,3-thiazol-5-yl)acetyl]amino]-2-(4-methyl-1,3-thiazol-2-yl)ethyl]phenyl]sulfamic acid Chemical compound CC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CC2=C(N=C(C)S2)C)=N1 YCSBQALUBMTXON-INIZCTEOSA-N 0.000 description 1
• AGKCTKMOEMXUNB-IBGZPJMESA-N [4-[(2s)-2-[[2-(3,4-difluorophenyl)acetyl]amino]-2-(4-ethyl-1,3-thiazol-2-yl)ethyl]phenyl]sulfamic acid Chemical compound CCC1=CSC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC(=O)CC=2C=C(F)C(F)=CC=2)=N1 AGKCTKMOEMXUNB-IBGZPJMESA-N 0.000 description 1
• PEDLPKOPLGMCPC-FQEVSTJZSA-N [4-[(2s)-2-[[2-(3-methoxyphenyl)acetyl]amino]-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound COC1=CC=CC(CC(=O)N[C@@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)C=2N=C(SC=2)C=2SC=CC=2)=C1 PEDLPKOPLGMCPC-FQEVSTJZSA-N 0.000 description 1
• RTAKMRKEPHJWQI-KRWDZBQOSA-N [4-[(2s)-2-[[2-(4-ethyl-2,3-dioxopiperazin-1-yl)acetyl]amino]-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound O=C1C(=O)N(CC)CCN1CC(=O)N[C@H](C=1N=C(SC=1)C=1SC=CC=1)CC1=CC=C(NS(O)(=O)=O)C=C1 RTAKMRKEPHJWQI-KRWDZBQOSA-N 0.000 description 1
• SXEJIWMUFRXLJZ-FQEVSTJZSA-N [4-[(2s)-2-[[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino]-2-(2-phenyl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound CCOC(=O)CC1=CSC(N[C@@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)C=2N=C(SC=2)C=2C=CC=CC=2)=N1 SXEJIWMUFRXLJZ-FQEVSTJZSA-N 0.000 description 1
• FKTZFMQOSAFOBX-AWEZNQCLSA-N [4-[(2s)-2-[[5-(2-methoxy-2-oxoethyl)-1,3,4-thiadiazol-2-yl]amino]-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound S1C(CC(=O)OC)=NN=C1N[C@H](C=1N=C(SC=1)C=1SC=CC=1)CC1=CC=C(NS(O)(=O)=O)C=C1 FKTZFMQOSAFOBX-AWEZNQCLSA-N 0.000 description 1
• JXQKQZIDKIUAQE-SFHVURJKSA-N [4-[(2s)-2-[[5-(2-methoxyphenyl)-1,3-oxazol-2-yl]amino]-2-(2-methyl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound COC1=CC=CC=C1C(O1)=CN=C1N[C@H](C=1N=C(C)SC=1)CC1=CC=C(NS(O)(=O)=O)C=C1 JXQKQZIDKIUAQE-SFHVURJKSA-N 0.000 description 1
• RUBAWUFLFIIMCL-DEOSSOPVSA-N [4-[(2s)-2-[[5-(4-acetamidophenyl)-1,3-oxazol-2-yl]amino]-2-(2-phenyl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound C1=CC(NC(=O)C)=CC=C1C(O1)=CN=C1N[C@H](C=1N=C(SC=1)C=1C=CC=CC=1)CC1=CC=C(NS(O)(=O)=O)C=C1 RUBAWUFLFIIMCL-DEOSSOPVSA-N 0.000 description 1
• AORKWSDWFBHZBX-QHCPKHFHSA-N [4-[(2s)-2-[[5-(naphthalen-1-ylmethyl)-1,3,4-thiadiazol-2-yl]amino]-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound C1=CC(NS(=O)(=O)O)=CC=C1C[C@@H](C=1N=C(SC=1)C=1SC=CC=1)NC(S1)=NN=C1CC1=CC=CC2=CC=CC=C12 AORKWSDWFBHZBX-QHCPKHFHSA-N 0.000 description 1
• COAPYWDVTCISSL-GOTSBHOMSA-N [4-[(2s)-2-[[5-[(2s)-1-[(2-methylpropan-2-yl)oxy]-1-oxo-3-phenylpropan-2-yl]-1,3-oxazol-2-yl]amino]-2-(2-methyl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound S1C(C)=NC([C@H](CC=2C=CC(NS(O)(=O)=O)=CC=2)NC=2OC(=CN=2)[C@H](CC=2C=CC=CC=2)C(=O)OC(C)(C)C)=C1 COAPYWDVTCISSL-GOTSBHOMSA-N 0.000 description 1
• SYVIRVPHYFWHAA-NRFANRHFSA-N [4-[(2s)-2-[[5-[(3-methoxyphenyl)methyl]-1,3-oxazol-2-yl]amino]-2-(2-methyl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid Chemical compound COC1=CC=CC(CC=2OC(N[C@@H](CC=3C=CC(NS(O)(=O)=O)=CC=3)C=3N=C(C)SC=3)=NC=2)=C1 SYVIRVPHYFWHAA-NRFANRHFSA-N 0.000 description 1
• 238000010521 absorption reaction Methods 0.000 description 1
• OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical compound C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 description 1
• 150000007513 acids Chemical class 0.000 description 1
• 239000004480 active ingredient Substances 0.000 description 1
• 125000002015 acyclic group Chemical group 0.000 description 1
• 125000004423 acyloxy group Chemical group 0.000 description 1
• 239000000654 additive Substances 0.000 description 1
• 230000002411 adverse Effects 0.000 description 1
• 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
• 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
• 238000002266 amputation Methods 0.000 description 1
• 239000002870 angiogenesis inducing agent Substances 0.000 description 1
• 238000002583 angiography Methods 0.000 description 1
• 230000001772 anti-angiogenic effect Effects 0.000 description 1
• 210000002376 aorta thoracic Anatomy 0.000 description 1
• 238000013459 approach Methods 0.000 description 1
• 210000002565 arteriole Anatomy 0.000 description 1
• 208000011775 arteriosclerosis disease Diseases 0.000 description 1
• 230000003416 augmentation Effects 0.000 description 1
• 230000005784 autoimmunity Effects 0.000 description 1
• 208000022362 bacterial infectious disease Diseases 0.000 description 1
• AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
• 125000002619 bicyclic group Chemical group 0.000 description 1
• 230000004071 biological effect Effects 0.000 description 1
• 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
• 208000034158 bleeding Diseases 0.000 description 1
• 230000000740 bleeding effect Effects 0.000 description 1
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
• 150000007942 carboxylates Chemical group 0.000 description 1
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
• 150000001735 carboxylic acids Chemical class 0.000 description 1
• 239000003054 catalyst Substances 0.000 description 1
• 230000012292 cell migration Effects 0.000 description 1
• 230000036755 cellular response Effects 0.000 description 1
• 210000003169 central nervous system Anatomy 0.000 description 1
• 206010008118 cerebral infarction Diseases 0.000 description 1
• 231100000481 chemical toxicant Toxicity 0.000 description 1
• 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
• 210000003711 chorioallantoic membrane Anatomy 0.000 description 1
• 208000024980 claudication Diseases 0.000 description 1
• 239000011248 coating agent Substances 0.000 description 1
• 238000000576 coating method Methods 0.000 description 1
• 238000004891 communication Methods 0.000 description 1
• 230000001276 controlling effect Effects 0.000 description 1
• 201000000159 corneal neovascularization Diseases 0.000 description 1
• 210000004351 coronary vessel Anatomy 0.000 description 1
• 230000008878 coupling Effects 0.000 description 1
• 238000010168 coupling process Methods 0.000 description 1
• 238000005859 coupling reaction Methods 0.000 description 1
• 239000013058 crude material Substances 0.000 description 1
• 210000004748 cultured cell Anatomy 0.000 description 1
• 125000004802 cyanophenyl group Chemical group 0.000 description 1
• 125000000753 cycloalkyl group Chemical group 0.000 description 1
• UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 1
• IIPJWNFOLPDTEQ-UHFFFAOYSA-N cyclopropanecarbothioamide Chemical group NC(=S)C1CC1 IIPJWNFOLPDTEQ-UHFFFAOYSA-N 0.000 description 1
• 230000007123 defense Effects 0.000 description 1
• 230000002939 deleterious effect Effects 0.000 description 1
• 230000001419 dependent effect Effects 0.000 description 1
• 230000003292 diminished effect Effects 0.000 description 1
• 230000005059 dormancy Effects 0.000 description 1
• 229940079593 drug Drugs 0.000 description 1
• 230000010595 endothelial cell migration Effects 0.000 description 1
• 230000003511 endothelial effect Effects 0.000 description 1
• 230000007613 environmental effect Effects 0.000 description 1
• PNZDZRMOBIIQTC-UHFFFAOYSA-N ethanamine;hydron;bromide Chemical class Br.CCN PNZDZRMOBIIQTC-UHFFFAOYSA-N 0.000 description 1
• CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
• 238000011156 evaluation Methods 0.000 description 1
• 210000002744 extracellular matrix Anatomy 0.000 description 1
• 208000030533 eye disease Diseases 0.000 description 1
• 229940126864 fibroblast growth factor Drugs 0.000 description 1
• 239000000945 filler Substances 0.000 description 1
• 239000003269 fluorescent indicator Substances 0.000 description 1
• 125000001153 fluoro group Chemical group F* 0.000 description 1
• 238000009472 formulation Methods 0.000 description 1
• 230000006870 function Effects 0.000 description 1
• 125000004438 haloalkoxy group Chemical group 0.000 description 1
• 125000001188 haloalkyl group Chemical group 0.000 description 1
• 235000015220 hamburgers Nutrition 0.000 description 1
• 229920006258 high performance thermoplastic Polymers 0.000 description 1
• 230000002962 histologic effect Effects 0.000 description 1
• 239000008240 homogeneous mixture Substances 0.000 description 1
• 239000012456 homogeneous solution Substances 0.000 description 1
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
• 230000007954 hypoxia Effects 0.000 description 1
• 238000003384 imaging method Methods 0.000 description 1
• 229940088592 immunologic factor Drugs 0.000 description 1
• 239000000367 immunologic factor Substances 0.000 description 1
• 238000002513 implantation Methods 0.000 description 1
• 238000000099 in vitro assay Methods 0.000 description 1
• 238000005462 in vivo assay Methods 0.000 description 1
• 230000006698 induction Effects 0.000 description 1
• 229940125396 insulin Drugs 0.000 description 1
• 238000012977 invasive surgical procedure Methods 0.000 description 1
• 210000004153 islets of langerhan Anatomy 0.000 description 1
• 201000006370 kidney failure Diseases 0.000 description 1
• 239000003446 ligand Substances 0.000 description 1
• 201000002818 limb ischemia Diseases 0.000 description 1
• 210000004072 lung Anatomy 0.000 description 1
• 238000012423 maintenance Methods 0.000 description 1
• 239000003550 marker Substances 0.000 description 1
• 230000035800 maturation Effects 0.000 description 1
• 230000001404 mediated effect Effects 0.000 description 1
• 230000009401 metastasis Effects 0.000 description 1
• RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 1
• CRXFROMHHBMNAB-UHFFFAOYSA-N methyl 2-isocyanoacetate Chemical compound COC(=O)C[N+]#[C-] CRXFROMHHBMNAB-UHFFFAOYSA-N 0.000 description 1
• GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
• 244000005700 microbiome Species 0.000 description 1
• 230000009456 molecular mechanism Effects 0.000 description 1
• 210000003205 muscle Anatomy 0.000 description 1
• BSOGGKQQJOHCNK-KEKNWZKVSA-N n-[(1s)-1-(4-ethyl-1,3-thiazol-2-yl)-2-(4-nitrophenyl)ethyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-phenylpropanamide Chemical compound CCC1=CSC([C@H](CC=2C=CC(=CC=2)[N+]([O-])=O)NC(=O)C(CC=2C=CC=CC=2)C=2ON=C(C)N=2)=N1 BSOGGKQQJOHCNK-KEKNWZKVSA-N 0.000 description 1
• 125000001624 naphthyl group Chemical group 0.000 description 1
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
• 210000000056 organ Anatomy 0.000 description 1
• 125000005646 oximino group Chemical group 0.000 description 1
• 238000010979 pH adjustment Methods 0.000 description 1
• 244000052769 pathogen Species 0.000 description 1
• 230000001575 pathological effect Effects 0.000 description 1
• 230000009054 pathological process Effects 0.000 description 1
• 210000003668 pericyte Anatomy 0.000 description 1
• 208000028169 periodontal disease Diseases 0.000 description 1
• 239000003208 petroleum Substances 0.000 description 1
• 239000012071 phase Substances 0.000 description 1
• 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
• OAHKWDDSKCRNFE-UHFFFAOYSA-N phenylmethanesulfonyl chloride Chemical compound ClS(=O)(=O)CC1=CC=CC=C1 OAHKWDDSKCRNFE-UHFFFAOYSA-N 0.000 description 1
• 229910052698 phosphorus Inorganic materials 0.000 description 1
• 239000011574 phosphorus Substances 0.000 description 1
• UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
• 230000035790 physiological processes and functions Effects 0.000 description 1
• 229920000642 polymer Polymers 0.000 description 1
• 230000003389 potentiating effect Effects 0.000 description 1
• 239000002243 precursor Substances 0.000 description 1
• 238000002953 preparative HPLC Methods 0.000 description 1
• 230000002062 proliferating effect Effects 0.000 description 1
• 230000002035 prolonged effect Effects 0.000 description 1
• 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
• 239000000700 radioactive tracer Substances 0.000 description 1
• 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
• 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
• 108020003175 receptors Proteins 0.000 description 1
• 102000005962 receptors Human genes 0.000 description 1
• 230000009467 reduction Effects 0.000 description 1
• 102000037983 regulatory factors Human genes 0.000 description 1
• 108091008025 regulatory factors Proteins 0.000 description 1
• 210000001525 retina Anatomy 0.000 description 1
• 230000000250 revascularization Effects 0.000 description 1
• 230000002441 reversible effect Effects 0.000 description 1
• 239000002151 riboflavin Substances 0.000 description 1
• 238000002390 rotary evaporation Methods 0.000 description 1
• 238000007423 screening assay Methods 0.000 description 1
• 230000028327 secretion Effects 0.000 description 1
• 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
• 235000010265 sodium sulphite Nutrition 0.000 description 1
• 230000000087 stabilizing effect Effects 0.000 description 1
• 238000010561 standard procedure Methods 0.000 description 1
• 230000036262 stenosis Effects 0.000 description 1
• 230000004936 stimulating effect Effects 0.000 description 1
• 210000002784 stomach Anatomy 0.000 description 1
• 239000000126 substance Substances 0.000 description 1
• 125000005415 substituted alkoxy group Chemical group 0.000 description 1
• 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
• 239000000758 substrate Substances 0.000 description 1
• IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid group Chemical class S(N)(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
• 229940035789 sulfoam Drugs 0.000 description 1
• 208000024891 symptom Diseases 0.000 description 1
• SCJUJSALLQBBNS-NSHDSACASA-N tert-butyl n-[(2s)-1-amino-3-(4-nitrophenyl)-1-oxopropan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C(N)=O)CC1=CC=C([N+]([O-])=O)C=C1 SCJUJSALLQBBNS-NSHDSACASA-N 0.000 description 1
• 238000012360 testing method Methods 0.000 description 1
• 238000011285 therapeutic regimen Methods 0.000 description 1
• 230000004797 therapeutic response Effects 0.000 description 1
• 125000004001 thioalkyl group Chemical group 0.000 description 1
• DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical compound NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 description 1
• 239000003440 toxic substance Substances 0.000 description 1
• 230000008736 traumatic injury Effects 0.000 description 1
• 230000005747 tumor angiogenesis Effects 0.000 description 1
• 230000004614 tumor growth Effects 0.000 description 1
• 210000005166 vasculature Anatomy 0.000 description 1
• 201000002282 venous insufficiency Diseases 0.000 description 1
• 230000007998 vessel formation Effects 0.000 description 1
• 230000009385 viral infection Effects 0.000 description 1
• 210000004127 vitreous body Anatomy 0.000 description 1
• 230000029663 wound healing Effects 0.000 description 1