BR112020002325A2 - composições farmacêuticas - Google Patents
composições farmacêuticas Download PDFInfo
- Publication number
- BR112020002325A2 BR112020002325A2 BR112020002325-6A BR112020002325A BR112020002325A2 BR 112020002325 A2 BR112020002325 A2 BR 112020002325A2 BR 112020002325 A BR112020002325 A BR 112020002325A BR 112020002325 A2 BR112020002325 A2 BR 112020002325A2
- Authority
- BR
- Brazil
- Prior art keywords
- phenyl
- ethyl
- aminomethyl
- ethoxy
- benzylcarbamoyl
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 40
- 239000000203 mixture Substances 0.000 claims abstract description 166
- 239000004480 active ingredient Substances 0.000 claims abstract description 52
- 238000000034 method Methods 0.000 claims abstract description 45
- 239000000872 buffer Substances 0.000 claims abstract description 39
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 239000012929 tonicity agent Substances 0.000 claims abstract description 27
- 239000007864 aqueous solution Substances 0.000 claims abstract description 21
- 238000011282 treatment Methods 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- -1 2-4-dichlorophenyl Chemical group 0.000 claims description 231
- 125000000217 alkyl group Chemical group 0.000 claims description 61
- 238000002347 injection Methods 0.000 claims description 46
- 239000007924 injection Substances 0.000 claims description 46
- 239000000243 solution Substances 0.000 claims description 37
- 102000003827 Plasma Kallikrein Human genes 0.000 claims description 36
- 108090000113 Plasma Kallikrein Proteins 0.000 claims description 36
- 125000004432 carbon atom Chemical group C* 0.000 claims description 35
- 125000003545 alkoxy group Chemical group 0.000 claims description 31
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 25
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 230000002207 retinal effect Effects 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 210000001525 retina Anatomy 0.000 claims description 17
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 230000001404 mediated effect Effects 0.000 claims description 14
- 206010012688 Diabetic retinal oedema Diseases 0.000 claims description 13
- 201000011190 diabetic macular edema Diseases 0.000 claims description 13
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 13
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 13
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 12
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 12
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 150000002430 hydrocarbons Chemical class 0.000 claims description 12
- 229920000136 polysorbate Polymers 0.000 claims description 12
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 11
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 11
- 125000002619 bicyclic group Chemical group 0.000 claims description 11
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 11
- 229930195729 fatty acid Natural products 0.000 claims description 11
- 239000000194 fatty acid Substances 0.000 claims description 11
- 230000008728 vascular permeability Effects 0.000 claims description 11
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 10
- 125000002950 monocyclic group Chemical group 0.000 claims description 10
- 238000007911 parenteral administration Methods 0.000 claims description 10
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 10
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 10
- 239000008227 sterile water for injection Substances 0.000 claims description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 9
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 9
- 239000004215 Carbon black (E152) Substances 0.000 claims description 8
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 206010012601 diabetes mellitus Diseases 0.000 claims description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 239000012458 free base Substances 0.000 claims description 8
- 229930195733 hydrocarbon Natural products 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 239000002736 nonionic surfactant Substances 0.000 claims description 8
- 230000001954 sterilising effect Effects 0.000 claims description 8
- 206010008111 Cerebral haemorrhage Diseases 0.000 claims description 7
- 229910019142 PO4 Inorganic materials 0.000 claims description 7
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000008121 dextrose Substances 0.000 claims description 7
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 6
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 6
- 206010038903 Retinal vascular occlusion Diseases 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 claims description 6
- 150000002334 glycols Chemical class 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 230000001771 impaired effect Effects 0.000 claims description 6
- 239000002953 phosphate buffered saline Substances 0.000 claims description 6
- 238000004659 sterilization and disinfection Methods 0.000 claims description 6
- 239000004094 surface-active agent Substances 0.000 claims description 6
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 claims description 6
- 230000004304 visual acuity Effects 0.000 claims description 6
- 210000004127 vitreous body Anatomy 0.000 claims description 6
- 206010061218 Inflammation Diseases 0.000 claims description 5
- 150000004665 fatty acids Chemical class 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- 230000036651 mood Effects 0.000 claims description 5
- UCIXIQRCAGGOJY-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]benzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CC=C1 UCIXIQRCAGGOJY-AJQTZOPKSA-N 0.000 claims description 5
- 238000001356 surgical procedure Methods 0.000 claims description 5
- NEBYAWKJGPMGBV-VEEOACQBSA-N 3-acetamido-4-[(2R)-1-[[(2S)-1-[[4-(aminomethyl)phenyl]methylamino]-3-(1-benzothiophen-3-yl)-1-oxopropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]thiophene-2-carboxamide Chemical compound NCC1=CC=C(CNC(=O)[C@H](CC=2C3=C(SC=2)C=CC=C3)NC(=O)[C@H](CC2=CC=C(C=C2)OCC)C=2C(=C(SC=2)C(=O)N)NC(C)=O)C=C1 NEBYAWKJGPMGBV-VEEOACQBSA-N 0.000 claims description 4
- LLKLTQJOEPWBOE-UHFFFAOYSA-N 3-acetamidothiophene-2-carboxylic acid Chemical compound CC(=O)NC=1C=CSC=1C(O)=O LLKLTQJOEPWBOE-UHFFFAOYSA-N 0.000 claims description 4
- CQSJDKGNONPQOQ-UHFFFAOYSA-N 3-aminothiophene-2-carboxylic acid Chemical compound NC=1C=CSC=1C(O)=O CQSJDKGNONPQOQ-UHFFFAOYSA-N 0.000 claims description 4
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 206010033645 Pancreatitis Diseases 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 208000017169 kidney disease Diseases 0.000 claims description 4
- 201000001119 neuropathy Diseases 0.000 claims description 4
- 230000007823 neuropathy Effects 0.000 claims description 4
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims description 4
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 4
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 claims description 4
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 claims description 4
- 229920000053 polysorbate 80 Polymers 0.000 claims description 4
- 229940068965 polysorbates Drugs 0.000 claims description 4
- 238000011146 sterile filtration Methods 0.000 claims description 4
- BXEAAHIHFFIMIE-UHFFFAOYSA-N 3-chlorothiophene-2-carboxylic acid Chemical compound OC(=O)C=1SC=CC=1Cl BXEAAHIHFFIMIE-UHFFFAOYSA-N 0.000 claims description 3
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 3
- 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 claims description 3
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- 206010019860 Hereditary angioedema Diseases 0.000 claims description 3
- 208000001953 Hypotension Diseases 0.000 claims description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229920001219 Polysorbate 40 Polymers 0.000 claims description 3
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 3
- 206010040070 Septic Shock Diseases 0.000 claims description 3
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 3
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 3
- 206010003246 arthritis Diseases 0.000 claims description 3
- 230000023555 blood coagulation Effects 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 230000002612 cardiopulmonary effect Effects 0.000 claims description 3
- 208000009190 disseminated intravascular coagulation Diseases 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 claims description 3
- 230000003345 hyperglycaemic effect Effects 0.000 claims description 3
- 230000036543 hypotension Effects 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 230000036303 septic shock Effects 0.000 claims description 3
- 235000000346 sugar Nutrition 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- QGLIUKRHFCPRGS-WDYNHAJCSA-N (2r)-n-[(2s)-1-[[4-(aminomethyl)-3-fluorophenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]-3-(4-ethoxyphenyl)-n-methyl-2-(propanoylamino)propanamide Chemical compound C1=CC(OCC)=CC=C1C[C@@H](NC(=O)CC)C(=O)N(C)[C@H](C(=O)NCC=1C=C(F)C(CN)=CC=1)CC1=CC=CC=C1 QGLIUKRHFCPRGS-WDYNHAJCSA-N 0.000 claims description 2
- ZIYJRZTZMWYTBK-SXOMAYOGSA-N (2r)-n-[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-pyridin-2-ylpropan-2-yl]-3-(4-ethoxyphenyl)-2-(propanoylamino)propanamide Chemical compound C1=CC(OCC)=CC=C1C[C@@H](NC(=O)CC)C(=O)N[C@H](C(=O)NCC=1C=CC(CN)=CC=1)CC1=CC=CC=N1 ZIYJRZTZMWYTBK-SXOMAYOGSA-N 0.000 claims description 2
- CNHNTLTXVFZCRI-WUFINQPMSA-N (2r)-n-[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-3-(3,4-dichlorophenyl)-1-oxopropan-2-yl]-3-(4-ethoxyphenyl)-2-(propanoylamino)propanamide Chemical compound C1=CC(OCC)=CC=C1C[C@@H](NC(=O)CC)C(=O)N[C@H](C(=O)NCC=1C=CC(CN)=CC=1)CC1=CC=C(Cl)C(Cl)=C1 CNHNTLTXVFZCRI-WUFINQPMSA-N 0.000 claims description 2
- ANPYKKLCIGJLNM-WUFINQPMSA-N (2s)-n-[[4-(aminomethyl)-2-chlorophenyl]methyl]-2-[[(2r)-3-(4-ethoxyphenyl)-2-(propanoylamino)propanoyl]amino]-3-phenylpropanamide Chemical compound C1=CC(OCC)=CC=C1C[C@@H](NC(=O)CC)C(=O)N[C@H](C(=O)NCC=1C(=CC(CN)=CC=1)Cl)CC1=CC=CC=C1 ANPYKKLCIGJLNM-WUFINQPMSA-N 0.000 claims description 2
- SEJXLFFOFZOISI-WUFINQPMSA-N (2s)-n-[[4-(aminomethyl)-3-chlorophenyl]methyl]-2-[[(2r)-3-(4-ethoxyphenyl)-2-(propanoylamino)propanoyl]amino]-3-phenylpropanamide Chemical compound C1=CC(OCC)=CC=C1C[C@@H](NC(=O)CC)C(=O)N[C@H](C(=O)NCC=1C=C(Cl)C(CN)=CC=1)CC1=CC=CC=C1 SEJXLFFOFZOISI-WUFINQPMSA-N 0.000 claims description 2
- ACETVQBBGBLDQG-AJQTZOPKSA-N (2s)-n-[[4-(aminomethyl)phenyl]methyl]-2-[[(2r)-2-[(4-chlorophenyl)sulfonylamino]-3-(4-ethoxyphenyl)propanoyl]amino]-3-phenylpropanamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NS(=O)(=O)C1=CC=C(Cl)C=C1 ACETVQBBGBLDQG-AJQTZOPKSA-N 0.000 claims description 2
- BCVMEJPYJNFSMU-WUFINQPMSA-N (2s)-n-[[4-(aminomethyl)phenyl]methyl]-2-[[(2r)-3-(4-ethoxyphenyl)-2-(propanoylamino)propanoyl]amino]-3-phenylpropanamide Chemical compound C1=CC(OCC)=CC=C1C[C@@H](NC(=O)CC)C(=O)N[C@H](C(=O)NCC=1C=CC(CN)=CC=1)CC1=CC=CC=C1 BCVMEJPYJNFSMU-WUFINQPMSA-N 0.000 claims description 2
- MGGBSAQLSGHPLF-IOWSJCHKSA-N 1-[(2R)-1-[[(2S)-1-[[4-(aminomethyl)phenyl]methylamino]-3-(1-benzothiophen-3-yl)-1-oxopropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-3-methylpyrrole-2-carboxamide Chemical compound NCC1=CC=C(CNC(=O)[C@H](CC=2C3=C(SC=2)C=CC=C3)NC(=O)[C@@H](CC2=CC=C(C=C2)OCC)N2C(=C(C=C2)C)C(=O)N)C=C1 MGGBSAQLSGHPLF-IOWSJCHKSA-N 0.000 claims description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- MQGBARXPCXAFRZ-UHFFFAOYSA-N 2,4-dimethyl-1,3-thiazole-5-carboxylic acid Chemical compound CC1=NC(C)=C(C(O)=O)S1 MQGBARXPCXAFRZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- XQGVQRPSTODODM-UHFFFAOYSA-N 3,5-dimethyl-1h-pyrrole-2-carboxylic acid Chemical compound CC1=CC(C)=C(C(O)=O)N1 XQGVQRPSTODODM-UHFFFAOYSA-N 0.000 claims description 2
- CORSVPRVMFWJEE-PXJZQJOASA-N 3-amino-4-[(2R)-1-[[(2S)-1-[[4-(aminomethyl)phenyl]methylamino]-3-(1-benzothiophen-3-yl)-1-oxopropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]thiophene-2-carboxamide Chemical compound NCC1=CC=C(CNC(=O)[C@H](CC=2C3=C(SC=2)C=CC=C3)NC(=O)[C@H](CC2=CC=C(C=C2)OCC)C=2C(=C(SC=2)C(=O)N)N)C=C1 CORSVPRVMFWJEE-PXJZQJOASA-N 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 239000004475 Arginine Substances 0.000 claims description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- 208000032843 Hemorrhage Diseases 0.000 claims description 2
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 claims description 2
- 229920001612 Hydroxyethyl starch Polymers 0.000 claims description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 2
- 235000004279 alanine Nutrition 0.000 claims description 2
- 239000013011 aqueous formulation Substances 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 229960001230 asparagine Drugs 0.000 claims description 2
- 235000009582 asparagine Nutrition 0.000 claims description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 2
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 claims description 2
- 230000000740 bleeding effect Effects 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 238000002648 combination therapy Methods 0.000 claims description 2
- OGGXGZAMXPVRFZ-UHFFFAOYSA-M dimethylarsinate Chemical compound C[As](C)([O-])=O OGGXGZAMXPVRFZ-UHFFFAOYSA-M 0.000 claims description 2
- 150000002148 esters Chemical group 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims description 2
- 229940027278 hetastarch Drugs 0.000 claims description 2
- 229940050526 hydroxyethylstarch Drugs 0.000 claims description 2
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 claims description 2
- 229960000367 inositol Drugs 0.000 claims description 2
- 238000001361 intraarterial administration Methods 0.000 claims description 2
- 238000007917 intracranial administration Methods 0.000 claims description 2
- 238000007918 intramuscular administration Methods 0.000 claims description 2
- 238000007912 intraperitoneal administration Methods 0.000 claims description 2
- 238000007919 intrasynovial administration Methods 0.000 claims description 2
- 238000007913 intrathecal administration Methods 0.000 claims description 2
- 238000007914 intraventricular administration Methods 0.000 claims description 2
- 229940047889 isobutyramide Drugs 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 238000013532 laser treatment Methods 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- XXXMZDCXONCQMR-IHLOFXLRSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-(1,3-thiazol-4-yl)propan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-4-methylbenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1N=CSC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=C(C)C=C1 XXXMZDCXONCQMR-IHLOFXLRSA-N 0.000 claims description 2
- OTUOSRRHYVCHTB-JHOUSYSJSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxo-3-(4-propoxyphenyl)propan-2-yl]benzamide Chemical compound C1=CC(OCCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CC=C1 OTUOSRRHYVCHTB-JHOUSYSJSA-N 0.000 claims description 2
- DCOSMQNHYNPFQB-WUFINQPMSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-2,3,6-trifluoropyridine-4-carboxamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC(F)=NC(F)=C1F DCOSMQNHYNPFQB-WUFINQPMSA-N 0.000 claims description 2
- NXZSBRDPYXWYMY-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-2,4-dichlorobenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=C(Cl)C=C1Cl NXZSBRDPYXWYMY-AJQTZOPKSA-N 0.000 claims description 2
- QQYJHIVCRMOELR-URLMMPGGSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-2,6-dichloropyridine-3-carboxamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=C(Cl)N=C1Cl QQYJHIVCRMOELR-URLMMPGGSA-N 0.000 claims description 2
- ZJPROBBYIUYLCH-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-2-chlorobenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CC=C1Cl ZJPROBBYIUYLCH-AJQTZOPKSA-N 0.000 claims description 2
- MHNXCQNJTDJPBJ-IOWSJCHKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-2-methoxypyridine-4-carboxamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=NC(OC)=C1 MHNXCQNJTDJPBJ-IOWSJCHKSA-N 0.000 claims description 2
- ALBLURFVONFERJ-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-2-methylpyridine-3-carboxamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CN=C1C ALBLURFVONFERJ-AJQTZOPKSA-N 0.000 claims description 2
- DBUIROVIMOGHBT-RRPNLBNLSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-3,3,3-trifluoropropanamide Chemical compound C1=CC(OCC)=CC=C1C[C@@H](NC(=O)CC(F)(F)F)C(=O)N[C@H](C(=O)NCC=1C=CC(CN)=CC=1)CC1=CC=CC=C1 DBUIROVIMOGHBT-RRPNLBNLSA-N 0.000 claims description 2
- MOIZOCHEDGLANE-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-3,4-dichlorobenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=C(Cl)C(Cl)=C1 MOIZOCHEDGLANE-AJQTZOPKSA-N 0.000 claims description 2
- QWEGEWLFUNVAFH-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-3,4-difluorobenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=C(F)C(F)=C1 QWEGEWLFUNVAFH-AJQTZOPKSA-N 0.000 claims description 2
- TYGDGTFXXYUGSN-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-3-(trifluoromethyl)benzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CC(C(F)(F)F)=C1 TYGDGTFXXYUGSN-AJQTZOPKSA-N 0.000 claims description 2
- SGUFCVJNEPZKMW-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-3-chlorobenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CC(Cl)=C1 SGUFCVJNEPZKMW-AJQTZOPKSA-N 0.000 claims description 2
- WQZFDLDYUJSANS-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-4-chlorobenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=C(Cl)C=C1 WQZFDLDYUJSANS-AJQTZOPKSA-N 0.000 claims description 2
- HAVAYEXOBKJLDE-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-4-fluorobenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=C(F)C=C1 HAVAYEXOBKJLDE-AJQTZOPKSA-N 0.000 claims description 2
- PQYXYUJVSKCKFL-JHOUSYSJSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-4-methylbenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=C(C)C=C1 PQYXYUJVSKCKFL-JHOUSYSJSA-N 0.000 claims description 2
- XKUREAYXZXNALY-XZWHSSHBSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-5,6-dichloropyridine-3-carboxamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CN=C(Cl)C(Cl)=C1 XKUREAYXZXNALY-XZWHSSHBSA-N 0.000 claims description 2
- AWZDEIQJFXSYJV-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-6-methylpyridine-3-carboxamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=C(C)N=C1 AWZDEIQJFXSYJV-AJQTZOPKSA-N 0.000 claims description 2
- NBUOOLFOHRYQNL-IOWSJCHKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]pyridine-3-carboxamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CN=C1 NBUOOLFOHRYQNL-IOWSJCHKSA-N 0.000 claims description 2
- KUPKLNUHJXRSMI-IOWSJCHKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]pyridine-4-carboxamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=NC=C1 KUPKLNUHJXRSMI-IOWSJCHKSA-N 0.000 claims description 2
- SJQWETDPGAMVES-JSOSNVBQSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-pyridin-2-ylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-4-chlorobenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1N=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=C(Cl)C=C1 SJQWETDPGAMVES-JSOSNVBQSA-N 0.000 claims description 2
- XTDUCJDRKRNRPM-ZWXJPIIXSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-pyridin-2-ylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-4-methylbenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1N=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=C(C)C=C1 XTDUCJDRKRNRPM-ZWXJPIIXSA-N 0.000 claims description 2
- BHVUGAWTPFXTSW-JSOSNVBQSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-pyridin-2-ylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]benzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1N=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CC=C1 BHVUGAWTPFXTSW-JSOSNVBQSA-N 0.000 claims description 2
- YBYIYRFQMSDYKZ-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-pyridin-3-ylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-2-methylbenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=NC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CC=C1C YBYIYRFQMSDYKZ-AJQTZOPKSA-N 0.000 claims description 2
- SYHVZEPQLZQVQE-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-pyridin-3-ylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-3-methylbenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=NC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CC(C)=C1 SYHVZEPQLZQVQE-AJQTZOPKSA-N 0.000 claims description 2
- COXMDBLAIZHMPI-IOWSJCHKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-pyridin-3-ylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-4-chlorobenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=NC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=C(Cl)C=C1 COXMDBLAIZHMPI-IOWSJCHKSA-N 0.000 claims description 2
- AJYZUIMBRBUFPQ-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-pyridin-3-ylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-4-methoxybenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=NC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=C(OC)C=C1 AJYZUIMBRBUFPQ-AJQTZOPKSA-N 0.000 claims description 2
- QLQUHMZRFARDGM-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-pyridin-3-ylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-4-methylbenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=NC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=C(C)C=C1 QLQUHMZRFARDGM-AJQTZOPKSA-N 0.000 claims description 2
- IOKOMILCLYAEGO-IOWSJCHKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-pyridin-3-ylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]benzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=NC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CC=C1 IOKOMILCLYAEGO-IOWSJCHKSA-N 0.000 claims description 2
- BAAMDLCQQMJQAZ-RRPNLBNLSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-3-(3,4-dichlorophenyl)-1-oxopropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-3,3,3-trifluoropropanamide Chemical compound C1=CC(OCC)=CC=C1C[C@@H](NC(=O)CC(F)(F)F)C(=O)N[C@H](C(=O)NCC=1C=CC(CN)=CC=1)CC1=CC=C(Cl)C(Cl)=C1 BAAMDLCQQMJQAZ-RRPNLBNLSA-N 0.000 claims description 2
- XRXPBLITZSRMPK-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-3-(4-chlorophenyl)-1-oxopropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]benzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC(Cl)=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CC=C1 XRXPBLITZSRMPK-AJQTZOPKSA-N 0.000 claims description 2
- 229940101738 pentastarch Drugs 0.000 claims description 2
- 229920001983 poloxamer Polymers 0.000 claims description 2
- 230000002980 postoperative effect Effects 0.000 claims description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 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
- 239000005720 sucrose Substances 0.000 claims description 2
- 150000008163 sugars Chemical class 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 230000001988 toxicity Effects 0.000 claims description 2
- 231100000419 toxicity Toxicity 0.000 claims description 2
- YZVFSQQHQPPKNX-UHFFFAOYSA-N 1,3-thiazole-5-carboxylic acid Chemical compound OC(=O)C1=CN=CS1 YZVFSQQHQPPKNX-UHFFFAOYSA-N 0.000 claims 2
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims 2
- MPVUIMKTPCOLBX-RRPNLBNLSA-N (2r)-n-[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-pyridin-3-ylpropan-2-yl]-3-(4-ethoxyphenyl)-2-(propanoylamino)propanamide Chemical compound C1=CC(OCC)=CC=C1C[C@@H](NC(=O)CC)C(=O)N[C@H](C(=O)NCC=1C=CC(CN)=CC=1)CC1=CC=CN=C1 MPVUIMKTPCOLBX-RRPNLBNLSA-N 0.000 claims 1
- KNHURXIHYWTCFE-OIDHKYIRSA-N (2s)-2-[[(2r)-2-[acetyl-[(2-phenylacetyl)amino]amino]-3-(4-ethoxyphenyl)propanoyl]amino]-n-[[4-(aminomethyl)phenyl]methyl]-3-phenylpropanamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)N(C(C)=O)NC(=O)CC1=CC=CC=C1 KNHURXIHYWTCFE-OIDHKYIRSA-N 0.000 claims 1
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims 1
- PEFWAMCTJZVVMK-UHSQPCAPSA-N 3-[(2R)-1-[[(2S)-1-[[4-(aminomethyl)phenyl]methylamino]-3-(3,4-dichlorophenyl)-1-oxopropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]thiophene-2-carboxamide Chemical compound NCC1=CC=C(CNC(=O)[C@H](CC2=CC(=C(C=C2)Cl)Cl)NC(=O)[C@H](CC2=CC=C(C=C2)OCC)C2=C(SC=C2)C(=O)N)C=C1 PEFWAMCTJZVVMK-UHSQPCAPSA-N 0.000 claims 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- WFKAJVHLWXSISD-UHFFFAOYSA-N anhydrous dimethyl-acetamide Natural products CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims 1
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 claims 1
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims 1
- 238000007915 intraurethral administration Methods 0.000 claims 1
- HODNEEJOSRVWQT-JHOUSYSJSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-4-methoxybenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=C(OC)C=C1 HODNEEJOSRVWQT-JHOUSYSJSA-N 0.000 claims 1
- OVUYMWPCQQBURI-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-3-(4-fluorophenyl)-1-oxopropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]benzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC(F)=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CC=C1 OVUYMWPCQQBURI-AJQTZOPKSA-N 0.000 claims 1
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 3
- 208000030533 eye disease Diseases 0.000 abstract 1
- 229940125904 compound 1 Drugs 0.000 description 39
- 210000001519 tissue Anatomy 0.000 description 30
- 210000001508 eye Anatomy 0.000 description 24
- 238000009472 formulation Methods 0.000 description 19
- 229910052799 carbon Inorganic materials 0.000 description 17
- 229940126155 plasma kallikrein inhibitor Drugs 0.000 description 16
- 239000003112 inhibitor Substances 0.000 description 15
- 239000002245 particle Substances 0.000 description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 14
- 229960002885 histidine Drugs 0.000 description 13
- 238000012360 testing method Methods 0.000 description 12
- 229940127379 Kallikrein Inhibitors Drugs 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 11
- 125000004193 piperazinyl group Chemical group 0.000 description 11
- 230000002146 bilateral effect Effects 0.000 description 10
- 210000003161 choroid Anatomy 0.000 description 10
- 229940068977 polysorbate 20 Drugs 0.000 description 9
- 229940074410 trehalose Drugs 0.000 description 9
- 241000283973 Oryctolagus cuniculus Species 0.000 description 8
- 230000009471 action Effects 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 238000005070 sampling Methods 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 239000013618 particulate matter Substances 0.000 description 6
- 235000021317 phosphate Nutrition 0.000 description 6
- 150000003384 small molecules Chemical class 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 235000010323 ascorbic acid Nutrition 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 150000003900 succinic acid esters Chemical class 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- 150000000994 L-ascorbates Chemical class 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 229950008882 polysorbate Drugs 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 241000282693 Cercopithecidae Species 0.000 description 3
- 102000001399 Kallikrein Human genes 0.000 description 3
- 108060005987 Kallikrein Proteins 0.000 description 3
- 238000011887 Necropsy Methods 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 210000001742 aqueous humor Anatomy 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 150000003939 benzylamines Chemical class 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 125000002098 pyridazinyl group Chemical group 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000011002 quantification Methods 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 239000003001 serine protease inhibitor Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- YIVHOQIKHMTVRG-UHFFFAOYSA-N 3-methyl-1h-pyrrole-2-carboxylic acid Chemical compound CC=1C=CNC=1C(O)=O YIVHOQIKHMTVRG-UHFFFAOYSA-N 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- 241000282567 Macaca fascicularis Species 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 150000001409 amidines Chemical class 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical class NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000007975 buffered saline Substances 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 239000002997 ophthalmic solution Substances 0.000 description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 206010033675 panniculitis Diseases 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 229940012957 plasmin Drugs 0.000 description 2
- 229940101027 polysorbate 40 Drugs 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 229960000948 quinine Drugs 0.000 description 2
- 230000004291 retinal vascular dysfunctions Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 210000004304 subcutaneous tissue Anatomy 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical class CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- DPVHGFAJLZWDOC-PVXXTIHASA-N (2r,3s,4s,5r,6r)-2-(hydroxymethyl)-6-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxane-3,4,5-triol;dihydrate Chemical compound O.O.O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DPVHGFAJLZWDOC-PVXXTIHASA-N 0.000 description 1
- QZNNVYOVQUKYSC-JEDNCBNOSA-N (2s)-2-amino-3-(1h-imidazol-5-yl)propanoic acid;hydron;chloride Chemical compound Cl.OC(=O)[C@@H](N)CC1=CN=CN1 QZNNVYOVQUKYSC-JEDNCBNOSA-N 0.000 description 1
- YKYIFUROKBDHCY-ONEGZZNKSA-N (e)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one Chemical group CCO\C=C\C(=O)C(F)(F)F YKYIFUROKBDHCY-ONEGZZNKSA-N 0.000 description 1
- GFEPEQYRZIPEIX-UHFFFAOYSA-N 1-(2-aminophenyl)-2-phenylethane-1,2-dione Chemical class NC1=CC=CC=C1C(=O)C(=O)C1=CC=CC=C1 GFEPEQYRZIPEIX-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- GLDQAMYCGOIJDV-UHFFFAOYSA-N 2,3-dihydroxybenzoic acid Chemical class OC(=O)C1=CC=CC(O)=C1O GLDQAMYCGOIJDV-UHFFFAOYSA-N 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
- SXGZJKUKBWWHRA-UHFFFAOYSA-N 2-(N-morpholiniumyl)ethanesulfonate Chemical compound [O-]S(=O)(=O)CC[NH+]1CCOCC1 SXGZJKUKBWWHRA-UHFFFAOYSA-N 0.000 description 1
- AKTFIQYVASYRMU-UHFFFAOYSA-N 2-aminoethanol;2,5-dihydroxybenzoic acid Chemical compound NCCO.OC(=O)C1=CC(O)=CC=C1O AKTFIQYVASYRMU-UHFFFAOYSA-N 0.000 description 1
- QCXCIYPOMMIBHO-UHFFFAOYSA-N 2-methyl-1,3-thiazole-5-carboxylic acid Chemical compound CC1=NC=C(C(O)=O)S1 QCXCIYPOMMIBHO-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 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
- QCXJEYYXVJIFCE-UHFFFAOYSA-N 4-acetamidobenzoic acid Chemical class CC(=O)NC1=CC=C(C(O)=O)C=C1 QCXJEYYXVJIFCE-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- MBBZMMPHUWSWHV-UHFFFAOYSA-N 6-(methylamino)hexane-1,2,3,4,5-pentol Chemical compound CNCC(O)C(O)C(O)C(O)CO MBBZMMPHUWSWHV-UHFFFAOYSA-N 0.000 description 1
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical class CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 229940123765 Bradykinin B2 receptor antagonist Drugs 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 108010041308 Endothelial Growth Factors Proteins 0.000 description 1
- 101000975003 Homo sapiens Kallistatin Proteins 0.000 description 1
- 101001077723 Homo sapiens Serine protease inhibitor Kazal-type 6 Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-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
- 229940122920 Kallikrein inhibitor Drugs 0.000 description 1
- 102100038297 Kallikrein-1 Human genes 0.000 description 1
- 101710176219 Kallikrein-1 Proteins 0.000 description 1
- 102100023012 Kallistatin Human genes 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 108010077861 Kininogens Proteins 0.000 description 1
- 102000010631 Kininogens Human genes 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- 239000006057 Non-nutritive feed additive Substances 0.000 description 1
- 206010033647 Pancreatitis acute Diseases 0.000 description 1
- 206010051077 Post procedural haemorrhage Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 208000002847 Surgical Wound Diseases 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 201000003229 acute pancreatitis Diseases 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001412 amines Chemical class 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
- 125000003277 amino group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000012865 aseptic processing Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000003359 bradykinin B2 receptor antagonist Substances 0.000 description 1
- 239000003152 bradykinin antagonist Substances 0.000 description 1
- 239000008364 bulk solution Substances 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229920005556 chlorobutyl Polymers 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000009109 curative therapy Methods 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
- 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- KZTYYGOKRVBIMI-UHFFFAOYSA-N diphenyl sulfone Chemical compound C=1C=CC=CC=1S(=O)(=O)C1=CC=CC=C1 KZTYYGOKRVBIMI-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002085 enols Chemical group 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229960005219 gentisic acid Drugs 0.000 description 1
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical class COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- BNRNAKTVFSZAFA-UHFFFAOYSA-N hydrindane Chemical compound C1CCCC2CCCC21 BNRNAKTVFSZAFA-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 229940039088 kininogenase Drugs 0.000 description 1
- 150000003903 lactic acid esters Chemical class 0.000 description 1
- 238000002647 laser therapy Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- LPUQAYUQRXPFSQ-DFWYDOINSA-M monosodium L-glutamate Chemical compound [Na+].[O-]C(=O)[C@@H](N)CCC(O)=O LPUQAYUQRXPFSQ-DFWYDOINSA-M 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 239000004223 monosodium glutamate Substances 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- NOORMTUTGSQYIZ-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)-3-chlorophenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]benzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=C(Cl)C(CN)=CC=1)NC(=O)C1=CC=CC=C1 NOORMTUTGSQYIZ-AJQTZOPKSA-N 0.000 description 1
- KFOYMQXIDOVWGR-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)-3-methylphenyl]methylamino]-1-oxo-3-pyridin-3-ylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]benzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=NC=CC=1)C(=O)NCC=1C=C(C)C(CN)=CC=1)NC(=O)C1=CC=CC=C1 KFOYMQXIDOVWGR-AJQTZOPKSA-N 0.000 description 1
- FHHIRUSMTLKWSO-WDYNHAJCSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-(1,3-thiazol-4-yl)propan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]benzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1N=CSC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CC=C1 FHHIRUSMTLKWSO-WDYNHAJCSA-N 0.000 description 1
- NKONHEXDLBKQFF-URLMMPGGSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-4-methyl-1,3-thiazole-5-carboxamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=C(C)N=CS1 NKONHEXDLBKQFF-URLMMPGGSA-N 0.000 description 1
- KGASRYBCGZUNAS-ZWXJPIIXSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-pyridin-2-ylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]-4-methoxybenzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1N=CC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=C(OC)C=C1 KGASRYBCGZUNAS-ZWXJPIIXSA-N 0.000 description 1
- MGPOPQVVNMABOI-IOWSJCHKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-pyridin-4-ylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]benzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CN=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CC=C1 MGPOPQVVNMABOI-IOWSJCHKSA-N 0.000 description 1
- IBCRPNPROJRPGD-IHLOFXLRSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-1-oxo-3-thiophen-2-ylpropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]benzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1SC=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CC=C1 IBCRPNPROJRPGD-IHLOFXLRSA-N 0.000 description 1
- GAEPCQZQRDPARJ-NOCHOARKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-3-(1h-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]benzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CC=C1 GAEPCQZQRDPARJ-NOCHOARKSA-N 0.000 description 1
- OYMHEDPIXZJWGT-AJQTZOPKSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-3-(3-fluorophenyl)-1-oxopropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]benzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=C(F)C=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CC=C1 OYMHEDPIXZJWGT-AJQTZOPKSA-N 0.000 description 1
- MNENVOCWAYYIHM-JHOUSYSJSA-N n-[(2r)-1-[[(2s)-1-[[4-(aminomethyl)phenyl]methylamino]-3-(4-methoxyphenyl)-1-oxopropan-2-yl]amino]-3-(4-ethoxyphenyl)-1-oxopropan-2-yl]benzamide Chemical compound C1=CC(OCC)=CC=C1C[C@H](C(=O)N[C@@H](CC=1C=CC(OC)=CC=1)C(=O)NCC=1C=CC(CN)=CC=1)NC(=O)C1=CC=CC=C1 MNENVOCWAYYIHM-JHOUSYSJSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 150000003901 oxalic acid esters Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 239000001120 potassium sulphate Substances 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229960003876 ranibizumab Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000004268 retinal thickening Effects 0.000 description 1
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- GNBVPFITFYNRCN-UHFFFAOYSA-M sodium thioglycolate Chemical compound [Na+].[O-]C(=O)CS GNBVPFITFYNRCN-UHFFFAOYSA-M 0.000 description 1
- 229940046307 sodium thioglycolate Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 150000003899 tartaric acid esters Chemical class 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 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
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl 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
- 125000005490 tosylate group Chemical group 0.000 description 1
- NNBZCPXTIHJBJL-UHFFFAOYSA-N trans-decahydronaphthalene Natural products C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 1
- 229940074409 trehalose dihydrate Drugs 0.000 description 1
- 125000000647 trehalose group Chemical group 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 108010036927 trypsin-like serine protease Proteins 0.000 description 1
- 239000002525 vasculotropin inhibitor Substances 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000012905 visible particle Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Ophthalmology & Optometry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201762544346P | 2017-08-11 | 2017-08-11 | |
| US62/544,346 | 2017-08-11 | ||
| GBGB1713660.7A GB201713660D0 (en) | 2017-08-25 | 2017-08-25 | Pharmaceutical compositions |
| GB1713660.7 | 2017-08-25 | ||
| PCT/GB2018/052292 WO2019030540A1 (en) | 2017-08-11 | 2018-08-13 | PHARMACEUTICAL COMPOSITIONS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BR112020002325A2 true BR112020002325A2 (pt) | 2020-09-01 |
Family
ID=60037096
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BR112020002325-6A BR112020002325A2 (pt) | 2017-08-11 | 2018-08-13 | composições farmacêuticas |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US20200261383A1 (enExample) |
| EP (1) | EP3664780A1 (enExample) |
| JP (1) | JP2020530475A (enExample) |
| KR (1) | KR20200038987A (enExample) |
| CN (1) | CN111032018A (enExample) |
| AU (1) | AU2018315034A1 (enExample) |
| BR (1) | BR112020002325A2 (enExample) |
| CA (1) | CA3071772A1 (enExample) |
| GB (1) | GB201713660D0 (enExample) |
| MA (1) | MA49837A (enExample) |
| SG (1) | SG11202001179YA (enExample) |
| TW (1) | TW201919600A (enExample) |
| WO (1) | WO2019030540A1 (enExample) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB201609607D0 (en) | 2016-06-01 | 2016-07-13 | Kalvista Pharmaceuticals Ltd | Polymorphs of N-(3-Fluoro-4-methoxypyridin-2-yl)methyl)-3-(methoxymethyl)-1-({4-((2-oxopy ridin-1-yl)methyl)phenyl}methyl)pyrazole-4-carboxamide and salts |
| GB201719881D0 (en) | 2017-11-29 | 2018-01-10 | Kalvista Pharmaceuticals Ltd | Solid forms of plasma kallikrein inhibitor and salts thereof |
| EP4010333A1 (en) | 2019-08-09 | 2022-06-15 | Kalvista Pharmaceuticals Limited | Plasma kallikrein inhibitors |
| GB2591730A (en) * | 2019-12-09 | 2021-08-11 | Kalvista Pharmaceuticals Ltd | New polymorphs |
| GB201918994D0 (en) | 2019-12-20 | 2020-02-05 | Kalvista Pharmaceuticals Ltd | Treatments of diabetic macular edema and impaired visual acuity |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070258976A1 (en) * | 2006-05-04 | 2007-11-08 | Ward Keith W | Combination Therapy for Diseases Involving Angiogenesis |
| GB2494851A (en) * | 2011-07-07 | 2013-03-27 | Kalvista Pharmaceuticals Ltd | Plasma kallikrein inhibitors |
| AU2013265255B2 (en) * | 2012-05-25 | 2018-03-29 | Novartis Ag | Aqueous pharmaceutical composition containing a biologic therapeutic agent and guanidine or a guanidine derivative and an injection including the composition |
| GB2510407A (en) * | 2013-02-04 | 2014-08-06 | Kalvista Pharmaceuticals Ltd | Aqueous suspensions of kallikrein inhibitors for parenteral administration |
-
2017
- 2017-08-25 GB GBGB1713660.7A patent/GB201713660D0/en not_active Ceased
-
2018
- 2018-08-13 KR KR1020207007099A patent/KR20200038987A/ko not_active Ceased
- 2018-08-13 BR BR112020002325-6A patent/BR112020002325A2/pt not_active IP Right Cessation
- 2018-08-13 WO PCT/GB2018/052292 patent/WO2019030540A1/en not_active Ceased
- 2018-08-13 JP JP2020507672A patent/JP2020530475A/ja active Pending
- 2018-08-13 TW TW107128107A patent/TW201919600A/zh unknown
- 2018-08-13 CA CA3071772A patent/CA3071772A1/en active Pending
- 2018-08-13 EP EP18758700.1A patent/EP3664780A1/en not_active Withdrawn
- 2018-08-13 SG SG11202001179YA patent/SG11202001179YA/en unknown
- 2018-08-13 US US16/637,953 patent/US20200261383A1/en not_active Abandoned
- 2018-08-13 AU AU2018315034A patent/AU2018315034A1/en not_active Abandoned
- 2018-08-13 MA MA049837A patent/MA49837A/fr unknown
- 2018-08-13 CN CN201880052445.0A patent/CN111032018A/zh active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| CA3071772A1 (en) | 2019-02-14 |
| US20200261383A1 (en) | 2020-08-20 |
| KR20200038987A (ko) | 2020-04-14 |
| SG11202001179YA (en) | 2020-03-30 |
| TW201919600A (zh) | 2019-06-01 |
| MA49837A (fr) | 2020-06-17 |
| CN111032018A (zh) | 2020-04-17 |
| EP3664780A1 (en) | 2020-06-17 |
| WO2019030540A1 (en) | 2019-02-14 |
| JP2020530475A (ja) | 2020-10-22 |
| GB201713660D0 (en) | 2017-10-11 |
| AU2018315034A1 (en) | 2020-02-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2728967T3 (es) | Composiciones farmacéuticas | |
| AU2022202629B2 (en) | Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization | |
| BR112020002325A2 (pt) | composições farmacêuticas | |
| CN104379129A (zh) | 含有帕唑帕尼的局部眼科药物组合物 | |
| CN104582685A (zh) | 含有舒尼替尼的局部眼科药物组合物 | |
| US20220401390A1 (en) | Treatments of diabetic macular edema and impaired visual acuity | |
| CN104379128A (zh) | 含有西地尼布的局部眼科药物组合物 | |
| JP2017505350A (ja) | 硫黄含有部分を含む糖誘導体ならびにその作製方法およびｍｐｓ ｉｉｉｃの処置のためのその使用方法 | |
| JP6162954B2 (ja) | 微小循環障害に起因する疾患を予防及び治療するための医薬の調製におけるダンシェンス、ノトギンセノシドｒ１又はそれらの組み合わせの使用 | |
| JP2019163227A (ja) | 医薬組成物 | |
| UA125537C2 (uk) | Фармацевтична композиція інгібітора плазмового калікреїну, способи її отримання (варіанти) і застосування | |
| BR122024009541A2 (pt) | Composição compreendendo nintedanib para tratar doenças oculares com neovascularização anormal |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B350 | Update of information on the portal [chapter 15.35 patent gazette] | ||
| B06W | Patent application suspended after preliminary examination (for patents with searches from other patent authorities) chapter 6.23 patent gazette] | ||
| B08F | Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette] |
Free format text: REFERENTE A 6A ANUIDADE. |
|
| B08K | Patent lapsed as no evidence of payment of the annual fee has been furnished to inpi [chapter 8.11 patent gazette] |
Free format text: EM VIRTUDE DO ARQUIVAMENTO PUBLICADO NA RPI 2787 DE 04-06-2024 E CONSIDERANDO AUSENCIA DE MANIFESTACAO DENTRO DOS PRAZOS LEGAIS, INFORMO QUE CABE SER MANTIDO O ARQUIVAMENTO DO PEDIDO DE PATENTE, CONFORME O DISPOSTO NO ARTIGO 12, DA RESOLUCAO 113/2013. |