ES2642737T3 - Sal de hemisulfato de N-(5S,6S,9R)-5-amino-6-(2,3-difluorofenil)-6,7,8,9-tetrahidro-5H-ciclohepta[b]piridin-9-il-4-(2-oxo-2,3-dihidro-1H-imidazo[4,5-b]piridin-1-il)piperidina-1-carboxilato - Google Patents
Sal de hemisulfato de N-(5S,6S,9R)-5-amino-6-(2,3-difluorofenil)-6,7,8,9-tetrahidro-5H-ciclohepta[b]piridin-9-il-4-(2-oxo-2,3-dihidro-1H-imidazo[4,5-b]piridin-1-il)piperidina-1-carboxilato Download PDFInfo
- Publication number
- ES2642737T3 ES2642737T3 ES13708603.9T ES13708603T ES2642737T3 ES 2642737 T3 ES2642737 T3 ES 2642737T3 ES 13708603 T ES13708603 T ES 13708603T ES 2642737 T3 ES2642737 T3 ES 2642737T3
- Authority
- ES
- Spain
- Prior art keywords
- compound
- salt
- hemisulfate salt
- hemisulfate
- crystalline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000003839 salts Chemical class 0.000 title claims description 129
- -1 2,3-difluorophenyl Chemical group 0.000 title description 19
- 150000001875 compounds Chemical class 0.000 claims description 188
- 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 claims description 25
- 208000019695 Migraine disease Diseases 0.000 claims description 20
- 206010027599 migraine Diseases 0.000 claims description 19
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 239000003085 diluting agent Substances 0.000 claims description 8
- 208000035475 disorder Diseases 0.000 claims description 8
- 208000027418 Wounds and injury Diseases 0.000 claims description 7
- 230000006378 damage Effects 0.000 claims description 7
- 208000014674 injury Diseases 0.000 claims description 7
- 238000005259 measurement Methods 0.000 claims description 7
- 230000001272 neurogenic effect Effects 0.000 claims description 7
- 230000005796 circulatory shock Effects 0.000 claims description 6
- 230000009245 menopause Effects 0.000 claims description 6
- 230000024883 vasodilation Effects 0.000 claims description 6
- 208000033830 Hot Flashes Diseases 0.000 claims description 5
- 206010060800 Hot flush Diseases 0.000 claims description 5
- 238000001228 spectrum Methods 0.000 claims description 5
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- 208000007920 Neurogenic Inflammation Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229910016523 CuKa Inorganic materials 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 230000000241 respiratory effect Effects 0.000 claims description 2
- 102100025588 Calcitonin gene-related peptide 1 Human genes 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 35
- 239000000243 solution Substances 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 238000000034 method Methods 0.000 description 28
- 102000004414 Calcitonin Gene-Related Peptide Human genes 0.000 description 24
- 108010078311 Calcitonin Gene-Related Peptide Receptors Proteins 0.000 description 24
- 102000008323 calcitonin gene-related peptide receptor activity proteins Human genes 0.000 description 22
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 239000000523 sample Substances 0.000 description 19
- 239000000203 mixture Substances 0.000 description 18
- 239000002253 acid Substances 0.000 description 17
- 229960001596 famotidine Drugs 0.000 description 17
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 17
- 239000012458 free base Substances 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 241000282472 Canis lupus familiaris Species 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 238000004458 analytical method Methods 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 11
- 206010019233 Headaches Diseases 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 10
- 238000001819 mass spectrum Methods 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 9
- 239000002775 capsule Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 238000001144 powder X-ray diffraction data Methods 0.000 description 9
- 238000003908 quality control method Methods 0.000 description 9
- 235000011149 sulphuric acid Nutrition 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 230000008901 benefit Effects 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 231100000869 headache Toxicity 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 229910002483 Cu Ka Inorganic materials 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 208000006673 asthma Diseases 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 238000012545 processing Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 108010079943 Pentagastrin Proteins 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 239000002671 adjuvant Substances 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 238000000113 differential scanning calorimetry Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 229960000444 pentagastrin Drugs 0.000 description 5
- ANRIQLNBZQLTFV-DZUOILHNSA-N pentagastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1[C]2C=CC=CC2=NC=1)NC(=O)CCNC(=O)OC(C)(C)C)CCSC)C(N)=O)C1=CC=CC=C1 ANRIQLNBZQLTFV-DZUOILHNSA-N 0.000 description 5
- 230000005855 radiation Effects 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- 230000000391 smoking effect Effects 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 5
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 5
- 239000005711 Benzoic acid Substances 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 description 4
- 235000010233 benzoic acid Nutrition 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 229960001270 d- tartaric acid Drugs 0.000 description 4
- 238000013480 data collection Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
- 239000011976 maleic acid Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000006186 oral dosage form Substances 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000000279 solid-state nuclear magnetic resonance spectrum Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- 230000029305 taxis Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000002411 thermogravimetry Methods 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 238000004293 19F NMR spectroscopy Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000012131 assay buffer Substances 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 230000036571 hydration Effects 0.000 description 3
- 238000006703 hydration reaction Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 241000894007 species Species 0.000 description 3
- HFAMMJDRXIUNAY-SWHJIRTISA-N (5s,6s,9r)-6-(2,3-difluorophenyl)-9-tri(propan-2-yl)silyloxy-6,7,8,9-tetrahydro-5h-cyclohepta[b]pyridin-5-ol Chemical compound C1([C@@H]2CC[C@H](C3=NC=CC=C3[C@H]2O)O[Si](C(C)C)(C(C)C)C(C)C)=CC=CC(F)=C1F HFAMMJDRXIUNAY-SWHJIRTISA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- 102100027499 5-hydroxytryptamine receptor 1B Human genes 0.000 description 2
- 101710138639 5-hydroxytryptamine receptor 1B Proteins 0.000 description 2
- 229940127597 CGRP antagonist Drugs 0.000 description 2
- 102000014468 Calcitonin Gene-Related Peptide Receptors Human genes 0.000 description 2
- 102100024654 Calcitonin gene-related peptide type 1 receptor Human genes 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 208000006561 Cluster Headache Diseases 0.000 description 2
- 229910016860 FaSSIF Inorganic materials 0.000 description 2
- 229910005429 FeSSIF Inorganic materials 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Substances ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 206010047139 Vasoconstriction Diseases 0.000 description 2
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 239000000538 analytical sample Substances 0.000 description 2
- 229940069428 antacid Drugs 0.000 description 2
- 239000003159 antacid agent Substances 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000003735 calcitonin gene related peptide receptor antagonist Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- 208000018912 cluster headache syndrome Diseases 0.000 description 2
- 238000005388 cross polarization Methods 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 238000002447 crystallographic data Methods 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000000004 hemodynamic effect Effects 0.000 description 2
- 229940077716 histamine h2 receptor antagonists for peptic ulcer and gord Drugs 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000010829 isocratic elution Methods 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 238000012417 linear regression Methods 0.000 description 2
- 238000000622 liquid--liquid extraction Methods 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000002552 multiple reaction monitoring Methods 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 230000004963 pathophysiological condition Effects 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 210000001428 peripheral nervous system Anatomy 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229940126409 proton pump inhibitor Drugs 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 230000004895 regional blood flow Effects 0.000 description 2
- 230000000284 resting effect Effects 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 2
- 229960003708 sumatriptan Drugs 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 2
- 230000025033 vasoconstriction Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- MBACCAVFVLZDPN-UHFFFAOYSA-N (2-oxo-3H-imidazo[4,5-b]pyridin-1-yl) piperidine-1-carboxylate Chemical compound N1(CCCCC1)C(=O)ON1C(NC2=NC=CC=C21)=O MBACCAVFVLZDPN-UHFFFAOYSA-N 0.000 description 1
- FDRJKNCUNGOCJL-SWHJIRTISA-N (5R,6S,9R)-5-chloro-6-(2,3-difluorophenyl)-9-tri(propan-2-yl)silyloxy-6,7,8,9-tetrahydrocyclohepta[b]pyridin-5-ol Chemical compound Cl[C@@]1([C@@H](CC[C@H](C2=NC=CC=C21)O[Si](C(C)C)(C(C)C)C(C)C)C1=C(C(=CC=C1)F)F)O FDRJKNCUNGOCJL-SWHJIRTISA-N 0.000 description 1
- DNXWZNNGGWGFHE-ZBINZKHDSA-N (5s,6s,9r)-5-azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5h-cyclohepta[b]pyridin-9-ol Chemical compound C1([C@@H]2CC[C@H](C3=NC=CC=C3[C@H]2N=[N+]=[N-])O)=CC=CC(F)=C1F DNXWZNNGGWGFHE-ZBINZKHDSA-N 0.000 description 1
- QDFYUAGUZJUUTN-GXFFZTMASA-N (6s,9r)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydrocyclohepta[b]pyridin-5-one Chemical compound C1([C@@H]2CC[C@H](C3=NC=CC=C3C2=O)O)=CC=CC(F)=C1F QDFYUAGUZJUUTN-GXFFZTMASA-N 0.000 description 1
- AIVVBBARCYSYDU-SIKLNZKXSA-N (6s,9r)-6-(2,3-difluorophenyl)-9-tri(propan-2-yl)silyloxy-6,7,8,9-tetrahydrocyclohepta[b]pyridin-5-one Chemical compound C1([C@@H]2CC[C@H](C3=NC=CC=C3C2=O)O[Si](C(C)C)(C(C)C)C(C)C)=CC=CC(F)=C1F AIVVBBARCYSYDU-SIKLNZKXSA-N 0.000 description 1
- UKDOTCFNLHHKOF-FGRDZWBJSA-N (z)-1-chloroprop-1-ene;(z)-1,2-dichloroethene Chemical group C\C=C/Cl.Cl\C=C/Cl UKDOTCFNLHHKOF-FGRDZWBJSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 101100438156 Arabidopsis thaliana CAD7 gene Proteins 0.000 description 1
- 206010062542 Arterial insufficiency Diseases 0.000 description 1
- 206010003497 Asphyxia Diseases 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 101150071647 CAD4 gene Proteins 0.000 description 1
- 108010001789 Calcitonin Receptors Proteins 0.000 description 1
- 101710118454 Calcitonin gene-related peptide type 1 receptor Proteins 0.000 description 1
- 102100038520 Calcitonin receptor Human genes 0.000 description 1
- 101100322652 Catharanthus roseus ADH13 gene Proteins 0.000 description 1
- 101100087088 Catharanthus roseus Redox1 gene Proteins 0.000 description 1
- 241000723347 Cinnamomum Species 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 101000760563 Homo sapiens Calcitonin gene-related peptide type 1 receptor Proteins 0.000 description 1
- 101000584583 Homo sapiens Receptor activity-modifying protein 1 Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 125000003338 L-glutaminyl group Chemical class O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C(=O)N([H])[H] 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 206010027603 Migraine headaches Diseases 0.000 description 1
- 101100219404 Mus musculus Calcrl gene Proteins 0.000 description 1
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 description 1
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 229940083963 Peptide antagonist Drugs 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 102100030697 Receptor activity-modifying protein 1 Human genes 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 208000021017 Weight Gain Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- BZSPSYVCLODKAE-KWOQKUFVSA-N [(5s,6s,9r)-5-azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5h-cyclohepta[b]pyridin-9-yl]oxy-tri(propan-2-yl)silane Chemical compound C1([C@@H]2CC[C@H](C3=NC=CC=C3[C@H]2N=[N+]=[N-])O[Si](C(C)C)(C(C)C)C(C)C)=CC=CC(F)=C1F BZSPSYVCLODKAE-KWOQKUFVSA-N 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- DNKYDHSONDSTNJ-XJVRLEFXSA-N chembl1910953 Chemical compound C([C@@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)N)[C@@H](C)O)[C@@H](C)O)C(C)C)[C@@H](C)O)C1=CN=CN1 DNKYDHSONDSTNJ-XJVRLEFXSA-N 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000017803 cinnamon Nutrition 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 230000009137 competitive binding Effects 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 238000012937 correction Methods 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
- 238000005384 cross polarization magic-angle spinning Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001633 decoupling pulse sequence Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 125000004212 difluorophenyl group Chemical group 0.000 description 1
- VCSZKSHWUBFOOE-UHFFFAOYSA-N dioxidanium;sulfate Chemical compound O.O.OS(O)(=O)=O VCSZKSHWUBFOOE-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000011152 fibreglass Substances 0.000 description 1
- 238000013100 final test Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000003736 gastrointestinal content Anatomy 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000003832 immune regulation Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 102000027411 intracellular receptors Human genes 0.000 description 1
- 108091008582 intracellular receptors Proteins 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940116298 l- malic acid Drugs 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000013062 quality control Sample Substances 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000003653 radioligand binding assay Methods 0.000 description 1
- JWEQRJSCTFBRSI-PCLIKHOPSA-N rboxylate Chemical compound COC(=O)C1C(N2C3=O)C4=CC=CC=C4OC1(C)N=C2S\C3=C\C(C=1)=CC=C(OC)C=1COC1=CC=CC=C1C JWEQRJSCTFBRSI-PCLIKHOPSA-N 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 210000005250 spinal neuron Anatomy 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- TXKRWVMEUQBFSO-UHFFFAOYSA-N sulfuric acid;trihydrate Chemical compound O.O.O.OS(O)(=O)=O TXKRWVMEUQBFSO-UHFFFAOYSA-N 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000001622 two pulse phase modulation pulse sequence Methods 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 230000004580 weight loss Effects 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261603598P | 2012-02-27 | 2012-02-27 | |
| US201261603598P | 2012-02-27 | ||
| PCT/US2013/027648 WO2013130402A1 (en) | 2012-02-27 | 2013-02-25 | N- (5s, 6s, 9r) - 5 -amino- 6 - (2, 3 - difluorophenyl) -6, 7, 8, 9 - tetrahydro - 5h - cyclohepta [b] pyridin-9 -yl- 4 - (2 - oxo-2, 3 - dihydro - 1h- imidazo [4, 5 -b] pyridin - 1 - yl) piperidine - 1 - carboxylate, hemisulfate salt |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2642737T3 true ES2642737T3 (es) | 2017-11-17 |
Family
ID=47844498
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES17180587T Active ES2746031T3 (es) | 2012-02-27 | 2013-02-25 | Sal de N-(5S,6S,9R)-5-amino-6-(2,3-difluorofenil)-6,7,8,9-tetrahidro-5H-ciclohepta[B]piridin-9-IL-4-(2-oxo-2,3-dihidro-1H-imidazo[4,5-B]piridin-1-il)piperidina-1-carboxilato |
| ES13708603.9T Active ES2642737T3 (es) | 2012-02-27 | 2013-02-25 | Sal de hemisulfato de N-(5S,6S,9R)-5-amino-6-(2,3-difluorofenil)-6,7,8,9-tetrahidro-5H-ciclohepta[b]piridin-9-il-4-(2-oxo-2,3-dihidro-1H-imidazo[4,5-b]piridin-1-il)piperidina-1-carboxilato |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES17180587T Active ES2746031T3 (es) | 2012-02-27 | 2013-02-25 | Sal de N-(5S,6S,9R)-5-amino-6-(2,3-difluorofenil)-6,7,8,9-tetrahidro-5H-ciclohepta[B]piridin-9-IL-4-(2-oxo-2,3-dihidro-1H-imidazo[4,5-B]piridin-1-il)piperidina-1-carboxilato |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US8759372B2 (enExample) |
| EP (2) | EP3254681B1 (enExample) |
| JP (2) | JP6208154B2 (enExample) |
| KR (2) | KR102076118B1 (enExample) |
| CN (1) | CN104136437B (enExample) |
| AU (1) | AU2013226361B2 (enExample) |
| BR (1) | BR112014021032B1 (enExample) |
| CA (1) | CA2865585C (enExample) |
| CY (2) | CY1119448T1 (enExample) |
| DK (2) | DK2820016T3 (enExample) |
| EA (1) | EA025358B1 (enExample) |
| ES (2) | ES2746031T3 (enExample) |
| HK (1) | HK1248111B (enExample) |
| HR (2) | HRP20171620T1 (enExample) |
| HU (2) | HUE034936T2 (enExample) |
| IL (1) | IL234272B (enExample) |
| LT (2) | LT2820016T (enExample) |
| MX (1) | MX352171B (enExample) |
| NO (1) | NO2935439T3 (enExample) |
| PL (2) | PL2820016T3 (enExample) |
| PT (2) | PT3254681T (enExample) |
| RS (2) | RS56556B1 (enExample) |
| SG (1) | SG11201404834XA (enExample) |
| SI (2) | SI2820016T1 (enExample) |
| SM (1) | SMT201700489T1 (enExample) |
| WO (1) | WO2013130402A1 (enExample) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2013211929B2 (en) | 2012-01-26 | 2016-05-26 | Christopher J. Soares | Peptide antagonists of the calcitonin CGRP family of peptide hormones and their use |
| ES2746031T3 (es) * | 2012-02-27 | 2020-03-04 | Bristol Myers Squibb Co | Sal de N-(5S,6S,9R)-5-amino-6-(2,3-difluorofenil)-6,7,8,9-tetrahidro-5H-ciclohepta[B]piridin-9-IL-4-(2-oxo-2,3-dihidro-1H-imidazo[4,5-B]piridin-1-il)piperidina-1-carboxilato |
| EP2815749A1 (en) | 2013-06-20 | 2014-12-24 | IP Gesellschaft für Management mbH | Solid form of 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione having specified X-ray diffraction pattern |
| WO2016144918A1 (en) | 2015-03-06 | 2016-09-15 | Atea Pharmaceuticals, Inc. | β-D-2'-DEOXY-2'α-FLUORO-2'-β-C-SUBSTITUTED-2-MODIFIED-N6-SUBSTITUTED PURINE NUCLEOTIDES FOR HCV TREATMENT |
| CA3035561A1 (en) * | 2016-09-02 | 2018-03-08 | Christopher J. Soares | Use of cgrp receptor antagonists in neuroprotection and neurological disorders |
| SG11201901457TA (en) | 2016-09-07 | 2019-03-28 | Atea Pharmaceuticals Inc | 2'-substituted-n6-substituted purine nucleotides for rna virus treatment |
| IL295609B2 (en) * | 2017-02-01 | 2023-11-01 | Atea Pharmaceuticals Inc | Nucleotide hemisulfate salt for the treatment of hepatitis C virus |
| SG11202009199YA (en) * | 2018-03-25 | 2020-10-29 | Biohaven Pharm Holding Co Ltd | Rimegepant for cgrp related disorders |
| CN112351799A (zh) | 2018-04-10 | 2021-02-09 | 阿堤亚制药公司 | 具有硬化的hcv感染患者的治疗 |
| JP2022517433A (ja) * | 2019-01-20 | 2022-03-08 | バイオヘイブン・ファーマシューティカル・ホールディング・カンパニー・リミテッド | 突出性の片頭痛を処置するためのｃｇｒｐアンタゴニスト |
| US20220249471A1 (en) * | 2019-06-14 | 2022-08-11 | The Regents Of The University Of California | New therapeutic approach to lung disease |
| US10874687B1 (en) | 2020-02-27 | 2020-12-29 | Atea Pharmaceuticals, Inc. | Highly active compounds against COVID-19 |
| EP4301362A1 (en) | 2021-03-02 | 2024-01-10 | CGRP Diagnostics GmbH | Treatment and/or reduction of occurrence of migraine |
| JP2024525164A (ja) | 2021-06-17 | 2024-07-10 | アテア ファーマシューティカルズ， インコーポレイテッド | 有利な抗ｈｃｖ併用療法 |
| US20250109188A1 (en) | 2021-08-24 | 2025-04-03 | Cgrp Diagnostics Gmbh | Preventative treatment of migraine |
| WO2023034466A1 (en) * | 2021-09-02 | 2023-03-09 | Pfizer Ireland Pharmaceuticals | Cgrp antagonists for treating psoriasis |
| CN115850266A (zh) * | 2021-09-26 | 2023-03-28 | 奥锐特药业(天津)有限公司 | 瑞美吉泮新晶型及其制备方法 |
| CN116554164B (zh) * | 2022-01-27 | 2025-10-03 | 奥锐特药业(天津)有限公司 | 一种瑞美吉泮的制备方法 |
| WO2023175632A1 (en) * | 2022-03-17 | 2023-09-21 | Msn Laboratories Private Limited, R&D Center | Solid state forms of (5s,6s,9r)-5-amino-6-(2,3difluorophenyl)-6,7,8,9-tetrahydro-5h-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-1-yl)-1-piperidinecarboxylate hemisulfate and processes for preparation thereof |
| WO2024180562A1 (en) * | 2023-03-02 | 2024-09-06 | Natco Pharma Limited | A process for the preparation of pure crystalline rimegepant and its salts thereof |
| WO2025193980A2 (en) * | 2024-03-13 | 2025-09-18 | CNS Biosciences, Inc. | Method of treating neuropathic pain using an anti-cgrp inhibitor |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MA24500A1 (fr) * | 1997-03-21 | 1998-10-01 | Lg Life Sciences Ltd | Derive du sel d'acide carboxylique de naphthyridine . |
| JO2355B1 (en) | 2003-04-15 | 2006-12-12 | ميرك شارب اند دوم كوربوريشن | Hereditary calcitonin polypeptide receptor antagonists |
| CA2558274A1 (en) | 2004-03-05 | 2005-09-15 | Banyu Pharmaceutical Co., Ltd. | Cycloalkanopyridine derivative |
| CA2583536A1 (en) | 2004-10-13 | 2006-04-27 | Merck & Co., Inc. | Cgrp receptor antagonists |
| DE602005027230D1 (de) | 2004-10-22 | 2011-05-12 | Merck Sharp & Dohme | Cgrp-rezeptorantagonisten |
| EP2007763A2 (en) | 2006-04-10 | 2008-12-31 | Merck & Co., Inc. | Process for the preparation of pyridine heterocycle cgrp antagonist intermediate |
| DE102006017827A1 (de) * | 2006-04-13 | 2007-10-18 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue kristalline Verbindungen |
| US8044043B2 (en) | 2008-04-11 | 2011-10-25 | Bristol-Myers Squibb Company | CGRP receptor antagonists |
| US8143403B2 (en) | 2008-04-11 | 2012-03-27 | Bristol-Myers Squibb Company | CGRP receptor antagonists |
| US8314117B2 (en) * | 2009-10-14 | 2012-11-20 | Bristol-Myers Squibb Company | CGRP receptor antagonists |
| US8669368B2 (en) | 2010-10-12 | 2014-03-11 | Bristol-Myers Squibb Company | Process for the preparation of cycloheptapyridine CGRP receptor antagonists |
| US8748429B2 (en) | 2011-04-12 | 2014-06-10 | Bristol-Myers Squibb Company | CGRP receptor antagonists |
| ES2746031T3 (es) * | 2012-02-27 | 2020-03-04 | Bristol Myers Squibb Co | Sal de N-(5S,6S,9R)-5-amino-6-(2,3-difluorofenil)-6,7,8,9-tetrahidro-5H-ciclohepta[B]piridin-9-IL-4-(2-oxo-2,3-dihidro-1H-imidazo[4,5-B]piridin-1-il)piperidina-1-carboxilato |
-
2013
- 2013-02-25 ES ES17180587T patent/ES2746031T3/es active Active
- 2013-02-25 SI SI201330759T patent/SI2820016T1/sl unknown
- 2013-02-25 HU HUE13708603A patent/HUE034936T2/hu unknown
- 2013-02-25 EP EP17180587.2A patent/EP3254681B1/en active Active
- 2013-02-25 RS RS20171092A patent/RS56556B1/sr unknown
- 2013-02-25 MX MX2014009544A patent/MX352171B/es active IP Right Grant
- 2013-02-25 WO PCT/US2013/027648 patent/WO2013130402A1/en not_active Ceased
- 2013-02-25 DK DK13708603.9T patent/DK2820016T3/da active
- 2013-02-25 DK DK17180587.2T patent/DK3254681T3/da active
- 2013-02-25 AU AU2013226361A patent/AU2013226361B2/en active Active
- 2013-02-25 PT PT171805872T patent/PT3254681T/pt unknown
- 2013-02-25 RS RSP20191191 patent/RS59295B1/sr unknown
- 2013-02-25 PT PT137086039T patent/PT2820016T/pt unknown
- 2013-02-25 CA CA2865585A patent/CA2865585C/en active Active
- 2013-02-25 US US13/775,528 patent/US8759372B2/en active Active
- 2013-02-25 EP EP13708603.9A patent/EP2820016B1/en active Active
- 2013-02-25 HU HUE17180587A patent/HUE047050T2/hu unknown
- 2013-02-25 CN CN201380011305.6A patent/CN104136437B/zh active Active
- 2013-02-25 SM SM20170489T patent/SMT201700489T1/it unknown
- 2013-02-25 KR KR1020147023856A patent/KR102076118B1/ko active Active
- 2013-02-25 BR BR112014021032-2A patent/BR112014021032B1/pt active IP Right Grant
- 2013-02-25 JP JP2014558927A patent/JP6208154B2/ja active Active
- 2013-02-25 PL PL13708603T patent/PL2820016T3/pl unknown
- 2013-02-25 ES ES13708603.9T patent/ES2642737T3/es active Active
- 2013-02-25 KR KR1020207003401A patent/KR102220969B1/ko active Active
- 2013-02-25 SG SG11201404834XA patent/SG11201404834XA/en unknown
- 2013-02-25 HR HRP20171620TT patent/HRP20171620T1/hr unknown
- 2013-02-25 LT LTEP13708603.9T patent/LT2820016T/lt unknown
- 2013-02-25 LT LTEP17180587.2T patent/LT3254681T/lt unknown
- 2013-02-25 PL PL17180587T patent/PL3254681T3/pl unknown
- 2013-02-25 EA EA201491585A patent/EA025358B1/ru not_active IP Right Cessation
- 2013-02-25 SI SI201331560T patent/SI3254681T1/sl unknown
- 2013-12-10 NO NO13811338A patent/NO2935439T3/no unknown
-
2014
- 2014-08-24 IL IL234272A patent/IL234272B/en active IP Right Grant
-
2017
- 2017-09-06 JP JP2017171358A patent/JP6476253B2/ja active Active
- 2017-10-10 CY CY20171101052T patent/CY1119448T1/el unknown
-
2018
- 2018-06-12 HK HK18107632.9A patent/HK1248111B/en unknown
-
2019
- 2019-09-11 CY CY20191100951T patent/CY1122121T1/el unknown
- 2019-09-16 HR HRP20191655 patent/HRP20191655T1/hr unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2642737T3 (es) | Sal de hemisulfato de N-(5S,6S,9R)-5-amino-6-(2,3-difluorofenil)-6,7,8,9-tetrahidro-5H-ciclohepta[b]piridin-9-il-4-(2-oxo-2,3-dihidro-1H-imidazo[4,5-b]piridin-1-il)piperidina-1-carboxilato | |
| HK1248111A1 (en) | N-(5s,6s,9r)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5h-cyclohepta[b]pyridin-9-yl-4-(2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate salt | |
| JP7700196B2 (ja) | Ａ２ａ／ａ２ｂ阻害剤としての縮合ピラジン誘導体 | |
| ES2900263T3 (es) | Modulador de regulador de conductancia transmembrana de fibrosis quística, composiciones farmacéuticas, métodos de tratamiento y proceso de fabricación del modulador | |
| US10577366B2 (en) | Crystalline forms of a compound that inhibits bromodomain | |
| ES2907622T3 (es) | Compuestos de heteroarilo como inhibidores de BTK y usos de estos | |
| ES2415863T3 (es) | Heterociclos sustituidos como inhibidores de Janus Quinasas | |
| ES2431466T3 (es) | Inhibidores de piridinonil pdk1 | |
| CN113906022B (zh) | 作为a2a/a2b抑制剂的吡唑并吡啶和三唑并吡啶 | |
| CN118108706A (zh) | 戊二酰亚胺 | |
| BR112018003634B1 (pt) | Forma cristalina de sesqui-hidrato de um inibidor parp, método de preparação da dita forma cristalina e composição farmacêutica compreendendo a dita forma | |
| ES2358445T3 (es) | Derivados de azabiciclo (3.1.0) hexano útiles como moduladores de los receptores d3 de dopamina. | |
| ES2339274T3 (es) | 3-triazoliltioalquil-3-azabiciclo(3-1-o)hexanos y su uso como ligandospara los receptores d3 de dopamina. | |
| CN119173514A (zh) | 作为jak2 v617f抑制剂的三环脲化合物 | |
| TWI869142B (zh) | 三肽環氧酮化合物、藥物組合物及其製備方法和用途 | |
| HK40043591B (zh) | 用作ii型irak抑制剂的杂芳基化合物及其用途 | |
| HK40064199A (en) | Pyrazolopyridines and triazolopyridines as a2a / a2b inhibitors | |
| HK40064199B (en) | Pyrazolopyridines and triazolopyridines as a2a / a2b inhibitors |