CA2498275C - Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of orl-1 receptor mediated disorders - Google Patents

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Publication number

CA2498275C

CA2498275C CA2498275A CA2498275A CA2498275C CA 2498275 C CA2498275 C CA 2498275C CA 2498275 A CA2498275 A CA 2498275A CA 2498275 A CA2498275 A CA 2498275A CA 2498275 C CA2498275 C CA 2498275C

Authority

CA

Canada

Prior art keywords

methyl

phenyl

ethyl

group

4alkyl

Prior art date

2002-09-09

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.)

Expired - Fee Related

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• 230000001404 mediated effect Effects 0.000 title claims abstract description 15
• 108010020615 nociceptin receptor Proteins 0.000 title claims description 30
• 150000008631 1,3,8-triazaspiro[4.5]decan-4-ones Chemical class 0.000 title abstract description 6
• 125000002768 hydroxyalkyl group Chemical group 0.000 title abstract description 4
• 150000001875 compounds Chemical class 0.000 claims abstract description 435
• 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims abstract description 31
• 208000002193 Pain Diseases 0.000 claims abstract description 24
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 22
• 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims abstract description 21
• 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims abstract description 21
• 208000035475 disorder Diseases 0.000 claims abstract description 20
• 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims abstract description 20
• 208000019901 Anxiety disease Diseases 0.000 claims abstract description 12
• 206010011224 Cough Diseases 0.000 claims abstract description 12
• 208000019695 Migraine disease Diseases 0.000 claims abstract description 12
• 230000036506 anxiety Effects 0.000 claims abstract description 12
• 206010027599 migraine Diseases 0.000 claims abstract description 12
• 208000020576 Adrenal disease Diseases 0.000 claims abstract description 11
• 208000000094 Chronic Pain Diseases 0.000 claims abstract description 11
• 208000011231 Crohn disease Diseases 0.000 claims abstract description 11
• 208000030814 Eating disease Diseases 0.000 claims abstract description 11
• 208000019454 Feeding and Eating disease Diseases 0.000 claims abstract description 11
• 206010020772 Hypertension Diseases 0.000 claims abstract description 11
• 208000005298 acute pain Diseases 0.000 claims abstract description 11
• 206010003119 arrhythmia Diseases 0.000 claims abstract description 11
• 208000006673 asthma Diseases 0.000 claims abstract description 11
• 230000019771 cognition Effects 0.000 claims abstract description 11
• 235000014632 disordered eating Nutrition 0.000 claims abstract description 11
• 208000002551 irritable bowel syndrome Diseases 0.000 claims abstract description 11
• 208000004296 neuralgia Diseases 0.000 claims abstract description 11
• 208000021722 neuropathic pain Diseases 0.000 claims abstract description 11
• 201000009032 substance abuse Diseases 0.000 claims abstract description 11
• 231100000736 substance abuse Toxicity 0.000 claims abstract description 11
• 208000011117 substance-related disease Diseases 0.000 claims abstract description 11
• 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 10
• 208000020925 Bipolar disease Diseases 0.000 claims abstract description 10
• 206010012289 Dementia Diseases 0.000 claims abstract description 10
• 206010026749 Mania Diseases 0.000 claims abstract description 10
• 208000008589 Obesity Diseases 0.000 claims abstract description 10
• 208000028017 Psychotic disease Diseases 0.000 claims abstract description 10
• 206010046543 Urinary incontinence Diseases 0.000 claims abstract description 10
• 235000019788 craving Nutrition 0.000 claims abstract description 10
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 10
• 206010015037 epilepsy Diseases 0.000 claims abstract description 10
• 230000036651 mood Effects 0.000 claims abstract description 10
• 235000020824 obesity Nutrition 0.000 claims abstract description 10
• 201000000980 schizophrenia Diseases 0.000 claims abstract description 10
• 230000006641 stabilisation Effects 0.000 claims abstract description 10
• 238000011105 stabilization Methods 0.000 claims abstract description 10
• -1 heteroaryl-C1-4alkyl Chemical group 0.000 claims description 983
• 229910052739 hydrogen Inorganic materials 0.000 claims description 133
• 125000001424 substituent group Chemical group 0.000 claims description 103
• 125000001072 heteroaryl group Chemical group 0.000 claims description 99
• 238000000034 method Methods 0.000 claims description 95
• 125000003118 aryl group Chemical group 0.000 claims description 85
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 72
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 65
• 239000001257 hydrogen Substances 0.000 claims description 62
• 229910052757 nitrogen Inorganic materials 0.000 claims description 57
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 56
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 54
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 51
• 229910052736 halogen Inorganic materials 0.000 claims description 48
• 150000002367 halogens Chemical class 0.000 claims description 48
• 150000002431 hydrogen Chemical group 0.000 claims description 48
• 125000000217 alkyl group Chemical group 0.000 claims description 46
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 45
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 45
• 239000000203 mixture Substances 0.000 claims description 43
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 42
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 40
• 125000004452 carbocyclyl group Chemical group 0.000 claims description 37
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 36
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 34
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 31
• 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 28
• 230000008569 process Effects 0.000 claims description 28
• 150000003839 salts Chemical class 0.000 claims description 28
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 26
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 25
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 23
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 22
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 18
• 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 17
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 16
• 125000006509 3,4-difluorobenzyl group Chemical group [H]C1=C(F)C(F)=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 16
• 239000003814 drug Substances 0.000 claims description 16
• 238000002360 preparation method Methods 0.000 claims description 14
• 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 claims description 13
• 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 12
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
• 125000006280 2-bromobenzyl group Chemical group [H]C1=C([H])C(Br)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
• 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 11
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 11
• 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 11
• 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 claims description 11
• WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical group [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 claims description 11
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 11
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
• 239000003937 drug carrier Substances 0.000 claims description 11
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 11
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 10
• 125000006507 2,4-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(F)C(=C1[H])C([H])([H])* 0.000 claims description 10
• 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
• 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 10
• 125000005806 3,4,5-trimethoxybenzyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1C([H])([H])* 0.000 claims description 10
• 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 10
• 125000006279 3-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Br)=C1[H])C([H])([H])* 0.000 claims description 10
• 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 claims description 10
• 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 10
• 125000006495 3-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 claims description 10
• 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 claims description 10
• 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 10
• 125000000173 4-trifluoromethoxy benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC(F)(F)F)C([H])([H])* 0.000 claims description 10
• DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 claims description 10
• 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 10
• 229910052799 carbon Inorganic materials 0.000 claims description 10
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
• 125000006494 2-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 claims description 9
• 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 9
• 125000006482 3-iodobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(I)=C1[H])C([H])([H])* 0.000 claims description 9
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
• 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 9
• 125000001318 4-trifluoromethylbenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(F)(F)F 0.000 claims description 9
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 9
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
• 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 8
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 7
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
• 125000001153 fluoro group Chemical group F* 0.000 claims description 7
• 125000005322 morpholin-1-yl group Chemical group 0.000 claims description 7
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
• ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims description 6
• 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 6
• 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 6
• 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 6
• 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 claims description 6
• 125000001847 2-phenylcyclopropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1([H])C([H])([H])C1([H])* 0.000 claims description 5
• 238000002156 mixing Methods 0.000 claims description 5
• 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 5
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
• 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 3
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 3
• 125000004104 aryloxy group Chemical group 0.000 claims description 3
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
• 125000004432 carbon atom Chemical group C* 0.000 claims description 3
• 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 3
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
• 125000000068 chlorophenyl group Chemical group 0.000 claims description 3
• AWYSBTQCCOWYQC-HHHXNRCGSA-N 3-[(2r)-3-(dimethylamino)-2-hydroxypropyl]-1-(4-fluorophenyl)-8-[(8-methylnaphthalen-1-yl)methyl]-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound C1CN(CC=2C3=C(C)C=CC=C3C=CC=2)CCC21C(=O)N(C[C@H](O)CN(C)C)CN2C1=CC=C(F)C=C1 AWYSBTQCCOWYQC-HHHXNRCGSA-N 0.000 claims description 2
• HWQFSZPVJZOLNP-SSEXGKCCSA-N 3-[(2r)-3-[3-(dimethylamino)propylamino]-2-hydroxypropyl]-1-(4-fluorophenyl)-8-[(8-methylnaphthalen-1-yl)methyl]-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound C1CN(CC=2C3=C(C)C=CC=C3C=CC=2)CCC21C(=O)N(C[C@H](O)CNCCCN(C)C)CN2C1=CC=C(F)C=C1 HWQFSZPVJZOLNP-SSEXGKCCSA-N 0.000 claims description 2
• ALXBWOVLKSYZNY-RUZDIDTESA-N 3-[(2r)-3-amino-2-hydroxypropyl]-1-(4-fluorophenyl)-8-[(8-methylnaphthalen-1-yl)methyl]-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound C=12C(C)=CC=CC2=CC=CC=1CN(CC1)CCC1(C(N(C[C@H](O)CN)C1)=O)N1C1=CC=C(F)C=C1 ALXBWOVLKSYZNY-RUZDIDTESA-N 0.000 claims description 2
• NNFWJRYNXMYWJE-JOCHJYFZSA-N 3-[(2r)-3-amino-2-hydroxypropyl]-8-cyclooctyl-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound C1CN(C2CCCCCCC2)CCC21C(=O)N(C[C@H](O)CN)CN2C1=CC=C(F)C=C1 NNFWJRYNXMYWJE-JOCHJYFZSA-N 0.000 claims description 2
• MKJDUHZPLQYUCB-UHFFFAOYSA-N decan-4-one Chemical compound CCCCCCC(=O)CCC MKJDUHZPLQYUCB-UHFFFAOYSA-N 0.000 claims description 2
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 2
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 1
• 125000006278 bromobenzyl group Chemical group 0.000 claims 1
• 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
• 125000006480 iodobenzyl group Chemical group 0.000 claims 1
• 125000006502 nitrobenzyl group Chemical group 0.000 claims 1
• 102000003688 G-Protein-Coupled Receptors Human genes 0.000 abstract description 4
• 108090000045 G-Protein-Coupled Receptors Proteins 0.000 abstract description 4
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 164
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 135
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
• 239000011541 reaction mixture Substances 0.000 description 117
• 239000010779 crude oil Substances 0.000 description 75
• 239000002904 solvent Substances 0.000 description 74
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 67
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 53
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 50
• 238000012360 testing method Methods 0.000 description 48
• 238000005160 1H NMR spectroscopy Methods 0.000 description 45
• 239000012044 organic layer Substances 0.000 description 45
• 235000019439 ethyl acetate Nutrition 0.000 description 43
• 241000700159 Rattus Species 0.000 description 38
• 238000003818 flash chromatography Methods 0.000 description 38
• 239000000243 solution Substances 0.000 description 36
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 35
• 239000003921 oil Substances 0.000 description 35
• 235000019198 oils Nutrition 0.000 description 35
• 229910052938 sodium sulfate Inorganic materials 0.000 description 35
• 235000011152 sodium sulphate Nutrition 0.000 description 35
• 239000007787 solid Substances 0.000 description 35
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
• 239000012299 nitrogen atmosphere Substances 0.000 description 34
• 239000003981 vehicle Substances 0.000 description 34
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
• 230000008859 change Effects 0.000 description 33
• RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
• 241001465754 Metazoa Species 0.000 description 32
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 32
• 239000011777 magnesium Substances 0.000 description 32
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 30
• 239000007832 Na2SO4 Substances 0.000 description 30
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 29
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 25
• 235000019441 ethanol Nutrition 0.000 description 25
• 235000002639 sodium chloride Nutrition 0.000 description 25
• 239000012267 brine Substances 0.000 description 24
• 239000006260 foam Substances 0.000 description 24
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 23
• 229910052698 phosphorus Inorganic materials 0.000 description 23
• 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 22
• 101100537937 Caenorhabditis elegans arc-1 gene Proteins 0.000 description 21
• 238000006243 chemical reaction Methods 0.000 description 20
• 239000003446 ligand Substances 0.000 description 20
• 238000005481 NMR spectroscopy Methods 0.000 description 19
• 239000002585 base Substances 0.000 description 19
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 19
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
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