TWI538912B - Ｔｒｐｖ４拮抗劑 - Google Patents

Info

Publication number

TWI538912B

TWI538912B TW101121449A TW101121449A TWI538912B TW I538912 B TWI538912 B TW I538912B TW 101121449 A TW101121449 A TW 101121449A TW 101121449 A TW101121449 A TW 101121449A TW I538912 B TWI538912 B TW I538912B

Authority

TW

Taiwan

Prior art keywords

methyl

oxo

carbonitrile

azirocyclo

dec

Prior art date

2011-06-17

Links

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• Global Dossier
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• 101150098315 TRPV4 gene Proteins 0.000 title description 39
• 102000003567 TRPV4 Human genes 0.000 title description 38
• 239000005557 antagonist Substances 0.000 title description 12
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 281
• 125000000217 alkyl group Chemical group 0.000 claims description 144
• 150000001875 compounds Chemical class 0.000 claims description 142
• -1 C 3-6 cycloalkyl radical Chemical class 0.000 claims description 133
• 229910052739 hydrogen Inorganic materials 0.000 claims description 48
• 239000001257 hydrogen Substances 0.000 claims description 47
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 46
• 125000001424 substituent group Chemical group 0.000 claims description 42
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
• 229910052757 nitrogen Inorganic materials 0.000 claims description 31
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 30
• 150000002431 hydrogen Chemical class 0.000 claims description 29
• 150000002825 nitriles Chemical class 0.000 claims description 29
• 229910052799 carbon Inorganic materials 0.000 claims description 28
• 150000003839 salts Chemical class 0.000 claims description 25
• UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 23
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 23
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 22
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 21
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 21
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 20
• 125000004432 carbon atom Chemical group C* 0.000 claims description 19
• XLYOFNOQVPJJNP-UHFFFAOYSA-O oxonium Chemical compound [OH3+] XLYOFNOQVPJJNP-UHFFFAOYSA-O 0.000 claims description 19
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
• 239000008194 pharmaceutical composition Substances 0.000 claims description 15
• 125000004076 pyridyl group Chemical group 0.000 claims description 15
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 13
• 125000003943 azolyl group Chemical group 0.000 claims description 12
• WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 12
• 229910052760 oxygen Inorganic materials 0.000 claims description 12
• 238000006467 substitution reaction Methods 0.000 claims description 12
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
• 239000001301 oxygen Substances 0.000 claims description 11
• 125000003386 piperidinyl group Chemical group 0.000 claims description 9
• 206010019280 Heart failures Diseases 0.000 claims description 8
• 208000002193 Pain Diseases 0.000 claims description 8
• 206010037423 Pulmonary oedema Diseases 0.000 claims description 8
• 229910000062 azane Inorganic materials 0.000 claims description 8
• 208000005333 pulmonary edema Diseases 0.000 claims description 8
• 206010069351 acute lung injury Diseases 0.000 claims description 7
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
• JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims description 7
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 6
• 206010030113 Oedema Diseases 0.000 claims description 6
• 208000006673 asthma Diseases 0.000 claims description 6
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
• 238000002360 preparation method Methods 0.000 claims description 6
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 5
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
• 206010061218 Inflammation Diseases 0.000 claims description 5
• 208000027418 Wounds and injury Diseases 0.000 claims description 5
• 210000000988 bone and bone Anatomy 0.000 claims description 5
• 230000006378 damage Effects 0.000 claims description 5
• 239000003814 drug Substances 0.000 claims description 5
• 230000004054 inflammatory process Effects 0.000 claims description 5
• 208000014674 injury Diseases 0.000 claims description 5
• 230000000968 intestinal effect Effects 0.000 claims description 5
• 208000005264 motor neuron disease Diseases 0.000 claims description 5
• 201000008482 osteoarthritis Diseases 0.000 claims description 5
• 208000005069 pulmonary fibrosis Diseases 0.000 claims description 5
• 230000000241 respiratory effect Effects 0.000 claims description 5
• 201000009890 sinusitis Diseases 0.000 claims description 5
• 230000009885 systemic effect Effects 0.000 claims description 5
• 206010003210 Arteriosclerosis Diseases 0.000 claims description 4
• 206010016807 Fluid retention Diseases 0.000 claims description 4
• 206010058061 Gastrointestinal oedema Diseases 0.000 claims description 4
• 208000019693 Lung disease Diseases 0.000 claims description 4
• 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 4
• 206010040047 Sepsis Diseases 0.000 claims description 4
• 208000037919 acquired disease Diseases 0.000 claims description 4
• 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 4
• 208000011775 arteriosclerosis disease Diseases 0.000 claims description 4
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 230000004064 dysfunction Effects 0.000 claims description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• 230000002980 postoperative effect Effects 0.000 claims description 4
• 230000009257 reactivity Effects 0.000 claims description 4
• 230000008085 renal dysfunction Effects 0.000 claims description 4
• 206010039083 rhinitis Diseases 0.000 claims description 4
• 208000004998 Abdominal Pain Diseases 0.000 claims description 3
• 208000015943 Coeliac disease Diseases 0.000 claims description 3
• 208000002881 Colic Diseases 0.000 claims description 3
• 206010010774 Constipation Diseases 0.000 claims description 3
• 208000011231 Crohn disease Diseases 0.000 claims description 3
• 206010012735 Diarrhoea Diseases 0.000 claims description 3
• 208000034347 Faecal incontinence Diseases 0.000 claims description 3
• 206010020772 Hypertension Diseases 0.000 claims description 3
• 206010020853 Hypertonic bladder Diseases 0.000 claims description 3
• 208000008081 Intestinal Fistula Diseases 0.000 claims description 3
• 201000010538 Lactose Intolerance Diseases 0.000 claims description 3
• 208000009722 Overactive Urinary Bladder Diseases 0.000 claims description 3
• 230000003187 abdominal effect Effects 0.000 claims description 3
• 208000008445 altitude sickness Diseases 0.000 claims description 3
• 201000010099 disease Diseases 0.000 claims description 3
• QCKLYDQORUPOIR-UHFFFAOYSA-N ethyl dimethyl phosphite Chemical compound CCOP(OC)OC QCKLYDQORUPOIR-UHFFFAOYSA-N 0.000 claims description 3
• 206010016766 flatulence Diseases 0.000 claims description 3
• 125000002757 morpholinyl group Chemical group 0.000 claims description 3
• 208000020629 overactive bladder Diseases 0.000 claims description 3
• XAGZJIQIVXSURR-UHFFFAOYSA-N 1-[4-(trifluoromethyl)phenyl]piperidin-2-one Chemical group C1=CC(C(F)(F)F)=CC=C1N1C(=O)CCCC1 XAGZJIQIVXSURR-UHFFFAOYSA-N 0.000 claims description 2
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
• URMFHFVYCDGDEC-UHFFFAOYSA-N 3-ethoxypyridine Chemical compound CCOC1=CC=CN=C1 URMFHFVYCDGDEC-UHFFFAOYSA-N 0.000 claims description 2
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
• 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
• BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 2
• DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
• 229930192474 thiophene Natural products 0.000 claims description 2
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
• 125000001475 halogen functional group Chemical group 0.000 claims 22
• ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims 1
• 208000005577 Gastroenteritis Diseases 0.000 claims 1
• 239000003937 drug carrier Substances 0.000 claims 1
• 230000001788 irregular Effects 0.000 claims 1
• 210000002429 large intestine Anatomy 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 312
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 277
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 258
• 239000000243 solution Substances 0.000 description 145
• 239000000203 mixture Substances 0.000 description 137
• 235000019439 ethyl acetate Nutrition 0.000 description 134
• 238000006243 chemical reaction Methods 0.000 description 113
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 113
• 239000007787 solid Substances 0.000 description 96
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 87
• 239000011541 reaction mixture Substances 0.000 description 85
• 239000000047 product Substances 0.000 description 72
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 55
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 48
• 239000012044 organic layer Substances 0.000 description 46
• 238000000034 method Methods 0.000 description 43
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
• 210000004027 cell Anatomy 0.000 description 40
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 39
• 239000010410 layer Substances 0.000 description 37
• 239000011734 sodium Substances 0.000 description 36
• 125000005843 halogen group Chemical group 0.000 description 35
• 238000005481 NMR spectroscopy Methods 0.000 description 34
• 239000003921 oil Substances 0.000 description 34
• 235000019198 oils Nutrition 0.000 description 34
• 229920006395 saturated elastomer Polymers 0.000 description 32
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
• 239000000543 intermediate Substances 0.000 description 31
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 31
• 238000003756 stirring Methods 0.000 description 30
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 27
• 230000002829 reductive effect Effects 0.000 description 27
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
• 239000000706 filtrate Substances 0.000 description 24
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 24
• 238000010992 reflux Methods 0.000 description 24
• 239000007858 starting material Substances 0.000 description 24
• 239000002904 solvent Substances 0.000 description 23
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
• 239000012267 brine Substances 0.000 description 22
• 238000000746 purification Methods 0.000 description 22
• 239000002002 slurry Substances 0.000 description 22
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
• 206010057190 Respiratory tract infections Diseases 0.000 description 20
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 19
• 239000000741 silica gel Substances 0.000 description 19
• 229910002027 silica gel Inorganic materials 0.000 description 19
• 238000004128 high performance liquid chromatography Methods 0.000 description 17
• 239000000725 suspension Substances 0.000 description 17
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 16
• 239000000460 chlorine Substances 0.000 description 16
• 238000010438 heat treatment Methods 0.000 description 16
• XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 16
• 239000003643 water by type Substances 0.000 description 16
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 15
• 208000024891 symptom Diseases 0.000 description 15
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
• 239000002253 acid Substances 0.000 description 14
• 150000001335 aliphatic alkanes Chemical class 0.000 description 14
• OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 14
• 239000006260 foam Substances 0.000 description 14
• 239000000463 material Substances 0.000 description 14
• 150000002924 oxiranes Chemical class 0.000 description 14
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 14
• PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 14
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 13
• 238000004587 chromatography analysis Methods 0.000 description 13
• 239000000284 extract Substances 0.000 description 13
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 13
• 238000004007 reversed phase HPLC Methods 0.000 description 13
• 238000010898 silica gel chromatography Methods 0.000 description 13
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
• 239000002585 base Substances 0.000 description 12
• 239000011575 calcium Substances 0.000 description 12
• 230000000694 effects Effects 0.000 description 12
• 235000019253 formic acid Nutrition 0.000 description 12
• FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 12
• UOIGZEPBOFNBHV-ZWKOTPCHSA-N C[C@](CN1C(C=C(C=C2)C#N)=C2N=C1)(CCC1)C[C@@]1(C1)C1=O Chemical compound C[C@](CN1C(C=C(C=C2)C#N)=C2N=C1)(CCC1)C[C@@]1(C1)C1=O UOIGZEPBOFNBHV-ZWKOTPCHSA-N 0.000 description 10
• 125000004429 atom Chemical group 0.000 description 10
• 150000004657 carbamic acid derivatives Chemical class 0.000 description 10
• 239000013078 crystal Substances 0.000 description 10
• DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 10
• VKCYHJWLYTUGCC-UHFFFAOYSA-N nonan-2-one Chemical compound CCCCCCCC(C)=O VKCYHJWLYTUGCC-UHFFFAOYSA-N 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• 230000008569 process Effects 0.000 description 10
• FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 10
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 9
• 210000001132 alveolar macrophage Anatomy 0.000 description 9
• 150000007942 carboxylates Chemical class 0.000 description 9
• 238000001727 in vivo Methods 0.000 description 9
• 108091006146 Channels Proteins 0.000 description 8
• JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 8
• LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 8
• 230000004913 activation Effects 0.000 description 8
• 239000012043 crude product Substances 0.000 description 8
• 239000002552 dosage form Substances 0.000 description 8
• 239000007788 liquid Substances 0.000 description 8
• 210000004072 lung Anatomy 0.000 description 8
• CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 8
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
• AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 7
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 7
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 7
• 150000001412 amines Chemical class 0.000 description 7
• 229910021529 ammonia Inorganic materials 0.000 description 7
• 230000008901 benefit Effects 0.000 description 7
• FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical compound O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 description 7
• 239000002027 dichloromethane extract Substances 0.000 description 7
• 229910052742 iron Inorganic materials 0.000 description 7
• 239000011591 potassium Substances 0.000 description 7
• 229910052700 potassium Inorganic materials 0.000 description 7
• 230000004044 response Effects 0.000 description 7
• 229910000104 sodium hydride Inorganic materials 0.000 description 7
• 239000000126 substance Substances 0.000 description 7
• YMCKUWNDXUEZAN-IRXDYDNUSA-N 3-[[(3s,5s)-5-methyl-1-oxaspiro[2.5]octan-5-yl]methyl]benzimidazole-5-carbonitrile Chemical compound C([C@@](C1)(CN2C3=CC(=CC=C3N=C2)C#N)C)CC[C@]21CO2 YMCKUWNDXUEZAN-IRXDYDNUSA-N 0.000 description 6
• JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 6
• 229960000549 4-dimethylaminophenol Drugs 0.000 description 6
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
• LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
• 108010010803 Gelatin Proteins 0.000 description 6
• 239000012981 Hank's balanced salt solution Substances 0.000 description 6
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 6
• 239000000556 agonist Substances 0.000 description 6
• 230000015572 biosynthetic process Effects 0.000 description 6
• 150000001721 carbon Chemical group 0.000 description 6
• 239000010949 copper Substances 0.000 description 6
• 125000000753 cycloalkyl group Chemical group 0.000 description 6
• 238000005516 engineering process Methods 0.000 description 6
• 238000001914 filtration Methods 0.000 description 6
• 230000006870 function Effects 0.000 description 6
• 239000008273 gelatin Substances 0.000 description 6
• 229920000159 gelatin Polymers 0.000 description 6
• 235000019322 gelatine Nutrition 0.000 description 6
• 235000011852 gelatine desserts Nutrition 0.000 description 6
• 150000002576 ketones Chemical class 0.000 description 6
• 239000002609 medium Substances 0.000 description 6
• 239000000843 powder Substances 0.000 description 6
• 125000006239 protecting group Chemical group 0.000 description 6
• 239000011780 sodium chloride Substances 0.000 description 6
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
• LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
• HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 5
• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 5
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
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