JP2012519153A5

JP2012519153A5 -

Download PDF

Info

Publication number: JP2012519153A5
Authority: JP; Japan
Prior art keywords: piperidin; dimethyl; oxoindolin; oxo; alkyl
Prior art date: 2010-03-01
Legal status : Granted

Application number

JP2011536661A

Other languages

English (en)

Japanese (ja)

Other versions

JP5663743B2 (ja

JP2012519153A (ja

Filing date

2010-03-01

Publication date

2013-05-02

2010-03-01 Application filed filed Critical

2010-03-01 Priority claimed from PCT/JP2010/001368 external-priority patent/WO2010098145A1/en

2012-08-23 Publication of JP2012519153A publication Critical patent/JP2012519153A/ja

2013-05-02 Publication of JP2012519153A5 publication Critical patent/JP2012519153A5/ja

2015-02-04 Application granted granted Critical

2015-02-04 Publication of JP5663743B2 publication Critical patent/JP5663743B2/ja

Status Active legal-status Critical Current

2030-03-01 Anticipated expiration legal-status Critical

Links

150000001875 compounds Chemical class 0.000 claims description 175
238000000034 method Methods 0.000 claims description 72
-1 C 1 -C 4 alkyl Chemical group 0.000 claims description 67
150000003839 salts Chemical class 0.000 claims description 50
229910052739 hydrogen Inorganic materials 0.000 claims description 29
239000001257 hydrogen Substances 0.000 claims description 29
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
230000000694 effects Effects 0.000 claims description 26
208000035475 disorder Diseases 0.000 claims description 17
150000002431 hydrogen Chemical class 0.000 claims description 15
229910052736 halogen Inorganic materials 0.000 claims description 14
150000002367 halogens Chemical class 0.000 claims description 14
229910052757 nitrogen Inorganic materials 0.000 claims description 14
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 13
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
239000003814 drug Substances 0.000 claims description 11
125000000217 alkyl group Chemical group 0.000 claims description 10
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
125000000753 cycloalkyl group Chemical group 0.000 claims description 10
201000010099 disease Diseases 0.000 claims description 10
229910052760 oxygen Inorganic materials 0.000 claims description 10
239000001301 oxygen Substances 0.000 claims description 10
125000005843 halogen group Chemical group 0.000 claims description 9
239000008194 pharmaceutical composition Substances 0.000 claims description 9
125000001424 substituent group Chemical group 0.000 claims description 9
208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 8
125000000623 heterocyclic group Chemical group 0.000 claims description 8
229940079593 drug Drugs 0.000 claims description 7
238000004519 manufacturing process Methods 0.000 claims description 7
230000001404 mediated effect Effects 0.000 claims description 7
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
238000002560 therapeutic procedure Methods 0.000 claims description 6
SUJQKAFVJRKOOT-BVAGGSTKSA-N (3r)-n-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]piperidine-3-carboxamide Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)[C@H]1CNCCC1)CC1=CC=CC=C1 SUJQKAFVJRKOOT-BVAGGSTKSA-N 0.000 claims description 5
229940098749 Motilin receptor agonist Drugs 0.000 claims description 5
206010028980 Neoplasm Diseases 0.000 claims description 5
XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 5
125000004429 atom Chemical group 0.000 claims description 5
201000011510 cancer Diseases 0.000 claims description 5
239000003937 drug carrier Substances 0.000 claims description 5
208000002551 irritable bowel syndrome Diseases 0.000 claims description 5
235000016709 nutrition Nutrition 0.000 claims description 5
230000035764 nutrition Effects 0.000 claims description 5
JUAAZCIVIRFTDV-SQHAQQRYSA-N (3r)-n-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-1-methylpiperidine-3-carboxamide Chemical compound C1N(C)CCC[C@H]1C(=O)N[C@H](C(=O)N1CCC(CC1)N1C2=CC=CC=C2C(C)(C)C1=O)CCC1=CC=CC=C1 JUAAZCIVIRFTDV-SQHAQQRYSA-N 0.000 claims description 4
PMHBZGFTVBIEDK-GJZUVCINSA-N (3r)-n-[(2s)-1-[4-(5-fluoro-3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]piperidine-3-carboxamide Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC(F)=CC=C21)(C)C)NC(=O)[C@H]1CNCCC1)CC1=CC=CC=C1 PMHBZGFTVBIEDK-GJZUVCINSA-N 0.000 claims description 4
206010006895 Cachexia Diseases 0.000 claims description 4
206010010774 Constipation Diseases 0.000 claims description 4
208000011231 Crohn disease Diseases 0.000 claims description 4
206010021333 Ileus paralytic Diseases 0.000 claims description 4
206010021518 Impaired gastric emptying Diseases 0.000 claims description 4
206010021639 Incontinence Diseases 0.000 claims description 4
201000005081 Intestinal Pseudo-Obstruction Diseases 0.000 claims description 4
125000003545 alkoxy group Chemical group 0.000 claims description 4
125000003282 alkyl amino group Chemical group 0.000 claims description 4
239000004202 carbamide Substances 0.000 claims description 4
125000004432 carbon atom Chemical group C* 0.000 claims description 4
206010009887 colitis Diseases 0.000 claims description 4
230000003247 decreasing effect Effects 0.000 claims description 4
208000010643 digestive system disease Diseases 0.000 claims description 4
208000018685 gastrointestinal system disease Diseases 0.000 claims description 4
208000001288 gastroparesis Diseases 0.000 claims description 4
201000007620 paralytic ileus Diseases 0.000 claims description 4
230000001575 pathological effect Effects 0.000 claims description 4
238000001356 surgical procedure Methods 0.000 claims description 4
206010047700 Vomiting Diseases 0.000 claims description 3
239000013543 active substance Substances 0.000 claims description 3
125000002947 alkylene group Chemical group 0.000 claims description 3
239000003795 chemical substances by application Substances 0.000 claims description 3
230000030135 gastric motility Effects 0.000 claims description 3
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
208000003243 intestinal obstruction Diseases 0.000 claims description 3
125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
208000037821 progressive disease Diseases 0.000 claims description 3
LCDCPQHFCOBUEF-UHFFFAOYSA-N pyrrolidine-1-carboxamide Chemical compound NC(=O)N1CCCC1 LCDCPQHFCOBUEF-UHFFFAOYSA-N 0.000 claims description 3
230000008673 vomiting Effects 0.000 claims description 3
JFVSUBWINXXICZ-AZGAKELHSA-N (2s)-2-amino-n-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-3,3-dimethylbutanamide Chemical compound C([C@H](NC(=O)[C@@H](N)C(C)(C)C)C(=O)N1CCC(CC1)N1C2=CC=CC=C2C(C)(C)C1=O)CC1=CC=CC=C1 JFVSUBWINXXICZ-AZGAKELHSA-N 0.000 claims description 2
NUMDEMPVMRLUAJ-UIOOFZCWSA-N (2s)-n-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]piperidine-2-carboxamide Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)[C@H]1NCCCC1)CC1=CC=CC=C1 NUMDEMPVMRLUAJ-UIOOFZCWSA-N 0.000 claims description 2
AOLDFDSXAJJDIO-BWKNWUBXSA-N (3r)-n-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-3-[2-(trifluoromethyl)phenyl]propan-2-yl]piperidine-3-carboxamide Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)[C@H]1CNCCC1)C1=CC=CC=C1C(F)(F)F AOLDFDSXAJJDIO-BWKNWUBXSA-N 0.000 claims description 2
OWMKHLDXAQDXGM-RDGATRHJSA-N (3r)-n-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-3-phenylpropan-2-yl]piperidine-3-carboxamide Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)[C@H]1CNCCC1)C1=CC=CC=C1 OWMKHLDXAQDXGM-RDGATRHJSA-N 0.000 claims description 2
ASTZPWGSMZUPMR-GJZUVCINSA-N (3r)-n-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-3-methylpiperazine-1-carboxamide Chemical compound C1CN[C@H](C)CN1C(=O)N[C@H](C(=O)N1CCC(CC1)N1C2=CC=CC=C2C(C)(C)C1=O)CCC1=CC=CC=C1 ASTZPWGSMZUPMR-GJZUVCINSA-N 0.000 claims description 2
XGEJCCLCXANNIR-BWKNWUBXSA-N (3r)-n-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-3-(2-fluorophenyl)-1-oxopropan-2-yl]piperidine-3-carboxamide Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)[C@H]1CNCCC1)C1=CC=CC=C1F XGEJCCLCXANNIR-BWKNWUBXSA-N 0.000 claims description 2
LMUHVYYXPZOKPF-BWKNWUBXSA-N (3r)-n-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-3-(3-fluorophenyl)-1-oxopropan-2-yl]piperidine-3-carboxamide Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)[C@H]1CNCCC1)C1=CC=CC(F)=C1 LMUHVYYXPZOKPF-BWKNWUBXSA-N 0.000 claims description 2
JMPQSGUNKHHXKE-BWKNWUBXSA-N (3r)-n-[(2s)-3-(2-chlorophenyl)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxopropan-2-yl]piperidine-3-carboxamide Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)[C@H]1CNCCC1)C1=CC=CC=C1Cl JMPQSGUNKHHXKE-BWKNWUBXSA-N 0.000 claims description 2
AAGPPBBGUDJEPY-BWKNWUBXSA-N (3r)-n-[(2s)-3-(4-chlorophenyl)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxopropan-2-yl]piperidine-3-carboxamide Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)[C@H]1CNCCC1)C1=CC=C(Cl)C=C1 AAGPPBBGUDJEPY-BWKNWUBXSA-N 0.000 claims description 2
BIRKVPJXLVEMCG-DEOSSOPVSA-N 1-(2-amino-2-methylpropyl)-3-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]urea Chemical compound C([C@H](NC(=O)NCC(C)(N)C)C(=O)N1CCC(CC1)N1C2=CC=CC=C2C(C)(C)C1=O)CC1=CC=CC=C1 BIRKVPJXLVEMCG-DEOSSOPVSA-N 0.000 claims description 2
HAEAQWKYVREOIL-MHZLTWQESA-N 1-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-3-(1,4-dimethylpiperidin-4-yl)urea Chemical compound C1CN(C)CCC1(C)NC(=O)N[C@H](C(=O)N1CCC(CC1)N1C2=CC=CC=C2C(C)(C)C1=O)CCC1=CC=CC=C1 HAEAQWKYVREOIL-MHZLTWQESA-N 0.000 claims description 2
QXHHOTWZDARDPY-MHZLTWQESA-N 1-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-3-(2-pyrrolidin-1-ylethyl)urea Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)NCCN1CCCC1)CC1=CC=CC=C1 QXHHOTWZDARDPY-MHZLTWQESA-N 0.000 claims description 2
SOXUZUZHRXAORE-MHZLTWQESA-N 1-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-3-(4-ethylpiperidin-4-yl)urea Chemical compound N([C@@H](CCC=1C=CC=CC=1)C(=O)N1CCC(CC1)N1C2=CC=CC=C2C(C)(C)C1=O)C(=O)NC1(CC)CCNCC1 SOXUZUZHRXAORE-MHZLTWQESA-N 0.000 claims description 2
YVWMKXMHOJIROP-SANMLTNESA-N 1-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-3-(4-methylpiperidin-4-yl)urea Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)NC1(C)CCNCC1)CC1=CC=CC=C1 YVWMKXMHOJIROP-SANMLTNESA-N 0.000 claims description 2
VWZFFEYYECYQOP-BVAGGSTKSA-N 1-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-3-[(3r)-piperidin-3-yl]urea Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)N[C@H]1CNCCC1)CC1=CC=CC=C1 VWZFFEYYECYQOP-BVAGGSTKSA-N 0.000 claims description 2
RSJXXLQTNHDVFQ-RDGATRHJSA-N 1-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-3-[(3r)-pyrrolidin-3-yl]urea Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)N[C@H]1CNCC1)CC1=CC=CC=C1 RSJXXLQTNHDVFQ-RDGATRHJSA-N 0.000 claims description 2
RSJXXLQTNHDVFQ-DHLKQENFSA-N 1-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-3-[(3s)-pyrrolidin-3-yl]urea Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)N[C@@H]1CNCC1)CC1=CC=CC=C1 RSJXXLQTNHDVFQ-DHLKQENFSA-N 0.000 claims description 2
VKQQHTMBYGXNCC-BVAGGSTKSA-N 1-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-3-[[(2r)-pyrrolidin-2-yl]methyl]urea Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)NC[C@@H]1NCCC1)CC1=CC=CC=C1 VKQQHTMBYGXNCC-BVAGGSTKSA-N 0.000 claims description 2
CWXVXWQQZOZPQQ-IGKIAQTJSA-N 1-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-3-[[(2s)-piperidin-2-yl]methyl]urea Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)NC[C@H]1NCCCC1)CC1=CC=CC=C1 CWXVXWQQZOZPQQ-IGKIAQTJSA-N 0.000 claims description 2
VKQQHTMBYGXNCC-OZXSUGGESA-N 1-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-3-[[(2s)-pyrrolidin-2-yl]methyl]urea Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)NC[C@H]1NCCC1)CC1=CC=CC=C1 VKQQHTMBYGXNCC-OZXSUGGESA-N 0.000 claims description 2
ZLXHOBNMQAMSHB-SQHAQQRYSA-N 1-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-3-[[(3r)-piperidin-3-yl]methyl]urea Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)NC[C@H]1CNCCC1)CC1=CC=CC=C1 ZLXHOBNMQAMSHB-SQHAQQRYSA-N 0.000 claims description 2
GVZFYSOCPJTYMJ-BVAGGSTKSA-N 1-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-3-[[(3r)-pyrrolidin-3-yl]methyl]urea Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)NC[C@H]1CNCC1)CC1=CC=CC=C1 GVZFYSOCPJTYMJ-BVAGGSTKSA-N 0.000 claims description 2
LKEZAXJRBUUBQQ-SANMLTNESA-N 1-[(2s)-1-[4-(5-fluoro-3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-3-(4-methylpiperidin-4-yl)urea Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC(F)=CC=C21)(C)C)NC(=O)NC1(C)CCNCC1)CC1=CC=CC=C1 LKEZAXJRBUUBQQ-SANMLTNESA-N 0.000 claims description 2
OCXOKEUQIIJEKP-OZXSUGGESA-N 1-[(2s)-1-[4-(5-fluoro-3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-3-[[(2s)-pyrrolidin-2-yl]methyl]urea Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC(F)=CC=C21)(C)C)NC(=O)NC[C@H]1NCCC1)CC1=CC=CC=C1 OCXOKEUQIIJEKP-OZXSUGGESA-N 0.000 claims description 2
PRAUQPNEIHQQBD-VWLOTQADSA-N 1-[2-(dimethylamino)ethyl]-3-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]urea Chemical compound C([C@H](NC(=O)NCCN(C)C)C(=O)N1CCC(CC1)N1C2=CC=CC=C2C(C)(C)C1=O)CC1=CC=CC=C1 PRAUQPNEIHQQBD-VWLOTQADSA-N 0.000 claims description 2
WTMHNAXPHQIRNZ-IGKIAQTJSA-N 3-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-1-methyl-1-[[(2s)-pyrrolidin-2-yl]methyl]urea Chemical compound N([C@@H](CCC=1C=CC=CC=1)C(=O)N1CCC(CC1)N1C2=CC=CC=C2C(C)(C)C1=O)C(=O)N(C)C[C@@H]1CCCN1 WTMHNAXPHQIRNZ-IGKIAQTJSA-N 0.000 claims description 2
125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
125000006312 cyclopentyl amino group Chemical group [H]N(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
239000012530 fluid Substances 0.000 claims description 2
HXKCOXFOJCNVJP-VWLOTQADSA-N n-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-3-[2-(trifluoromethyl)phenyl]propan-2-yl]piperidine-4-carboxamide Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)C1CCNCC1)C1=CC=CC=C1C(F)(F)F HXKCOXFOJCNVJP-VWLOTQADSA-N 0.000 claims description 2
IDNCVQCWTIJXBD-DEOSSOPVSA-N n-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]azetidine-3-carboxamide Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)C1CNC1)CC1=CC=CC=C1 IDNCVQCWTIJXBD-DEOSSOPVSA-N 0.000 claims description 2
PQAWEOXYRRAYNI-SANMLTNESA-N n-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]piperidine-4-carboxamide Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)C1CCNCC1)CC1=CC=CC=C1 PQAWEOXYRRAYNI-SANMLTNESA-N 0.000 claims description 2
LMJVHFIHVNHVDL-VWLOTQADSA-N n-[(2s)-3-(2-chlorophenyl)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxopropan-2-yl]piperidine-4-carboxamide Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)C1CCNCC1)C1=CC=CC=C1Cl LMJVHFIHVNHVDL-VWLOTQADSA-N 0.000 claims description 2
GIOBFJUYHPVVOX-VWLOTQADSA-N n-[(2s)-3-(4-chlorophenyl)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxopropan-2-yl]piperidine-4-carboxamide Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NC(=O)C1CCNCC1)C1=CC=C(Cl)C=C1 GIOBFJUYHPVVOX-VWLOTQADSA-N 0.000 claims description 2
QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 2
229940124597 therapeutic agent Drugs 0.000 claims description 2
230000036528 appetite Effects 0.000 claims 2
235000019789 appetite Nutrition 0.000 claims 2
230000004060 metabolic process Effects 0.000 claims 2
125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 1
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 93
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
239000000203 mixture Substances 0.000 description 77
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 66
239000000243 solution Substances 0.000 description 61
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
230000002829 reductive effect Effects 0.000 description 33
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 27
238000006243 chemical reaction Methods 0.000 description 26
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
239000000543 intermediate Substances 0.000 description 22
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
101001132878 Homo sapiens Motilin receptor Proteins 0.000 description 20
238000004128 high performance liquid chromatography Methods 0.000 description 20
238000012799 strong cation exchange Methods 0.000 description 20
102100033818 Motilin receptor Human genes 0.000 description 19
101800002372 Motilin Proteins 0.000 description 18
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
235000001014 amino acid Nutrition 0.000 description 18
125000006239 protecting group Chemical group 0.000 description 18
239000002904 solvent Substances 0.000 description 18
LVRVABPNVHYXRT-BQWXUCBYSA-N 52906-92-0 Chemical compound C([C@H](N)C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O)C(C)C)C1=CC=CC=C1 LVRVABPNVHYXRT-BQWXUCBYSA-N 0.000 description 17
150000001413 amino acids Chemical class 0.000 description 17
239000003153 chemical reaction reagent Substances 0.000 description 17
230000014759 maintenance of location Effects 0.000 description 17
ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 16
102000002419 Motilin Human genes 0.000 description 16
102000057413 Motilin receptors Human genes 0.000 description 16
108700040483 Motilin receptors Proteins 0.000 description 16
239000002253 acid Substances 0.000 description 16
239000012044 organic layer Substances 0.000 description 16
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
239000002585 base Substances 0.000 description 14
239000000556 agonist Substances 0.000 description 13
150000001412 amines Chemical class 0.000 description 13
238000005859 coupling reaction Methods 0.000 description 13
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
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 12
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
239000002243 precursor Substances 0.000 description 11
239000011541 reaction mixture Substances 0.000 description 11
229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
235000017557 sodium bicarbonate Nutrition 0.000 description 11
229910052938 sodium sulfate Inorganic materials 0.000 description 11
235000011152 sodium sulphate Nutrition 0.000 description 11
VCAXPZZEPPJDRM-BOXHHOBZSA-N 1-[1-[(2s)-2-amino-4-phenylbutanoyl]piperidin-4-yl]-3,3-dimethylindol-2-one;hydrochloride Chemical compound Cl.C([C@H](N)C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)CC1=CC=CC=C1 VCAXPZZEPPJDRM-BOXHHOBZSA-N 0.000 description 10
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 10
235000019441 ethanol Nutrition 0.000 description 10
239000012442 inert solvent Substances 0.000 description 10
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
239000003643 water by type Substances 0.000 description 10
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
230000008878 coupling Effects 0.000 description 9
238000010168 coupling process Methods 0.000 description 9
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
239000011259 mixed solution Substances 0.000 description 9
238000012360 testing method Methods 0.000 description 9
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
239000003981 vehicle Substances 0.000 description 9
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
238000005481 NMR spectroscopy Methods 0.000 description 8
239000012267 brine Substances 0.000 description 8
229910052799 carbon Inorganic materials 0.000 description 8
239000011159 matrix material Substances 0.000 description 8
238000002360 preparation method Methods 0.000 description 8
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
239000007787 solid Substances 0.000 description 8
239000007790 solid phase Substances 0.000 description 8
238000003756 stirring Methods 0.000 description 8
0 CC(C)(c(cccc1)c1N1C(CC2)CCN2C([C@](CCc2ccccc2)NC(*N(*)*)=O)=O)C1=O Chemical compound CC(C)(c(cccc1)c1N1C(CC2)CCN2C([C@](CCc2ccccc2)NC(*N(*)*)=O)=O)C1=O 0.000 description 7
239000000460 chlorine Substances 0.000 description 7
229960003276 erythromycin Drugs 0.000 description 7
239000000706 filtrate Substances 0.000 description 7
238000001727 in vivo Methods 0.000 description 7
238000010898 silica gel chromatography Methods 0.000 description 7
238000003786 synthesis reaction Methods 0.000 description 7
BETBOAZCLSJOBQ-NSHDSACASA-N (2s)-3-(4-chlorophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(Cl)C=C1 BETBOAZCLSJOBQ-NSHDSACASA-N 0.000 description 6
NXILIHONWRXHFA-MRVPVSSYSA-N (3r)-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H](C(O)=O)C1 NXILIHONWRXHFA-MRVPVSSYSA-N 0.000 description 6
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 6
150000001721 carbon Chemical group 0.000 description 6
230000005176 gastrointestinal motility Effects 0.000 description 6
210000001035 gastrointestinal tract Anatomy 0.000 description 6
239000000499 gel Substances 0.000 description 6
229910052740 iodine Inorganic materials 0.000 description 6
229910052763 palladium Inorganic materials 0.000 description 6
238000000746 purification Methods 0.000 description 6
229940044601 receptor agonist Drugs 0.000 description 6
239000000018 receptor agonist Substances 0.000 description 6
229920006395 saturated elastomer Polymers 0.000 description 6
235000011121 sodium hydroxide Nutrition 0.000 description 6
239000000725 suspension Substances 0.000 description 6
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
XYKYUXYNQDXZTD-QMMMGPOBSA-N tert-butyl n-methyl-n-[(3s)-pyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N(C)[C@H]1CCNC1 XYKYUXYNQDXZTD-QMMMGPOBSA-N 0.000 description 6
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 5
239000007864 aqueous solution Substances 0.000 description 5
239000012043 crude product Substances 0.000 description 5
230000008030 elimination Effects 0.000 description 5
238000003379 elimination reaction Methods 0.000 description 5
235000019253 formic acid Nutrition 0.000 description 5
230000002496 gastric effect Effects 0.000 description 5
229910052943 magnesium sulfate Inorganic materials 0.000 description 5
235000019341 magnesium sulphate Nutrition 0.000 description 5
LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 5
238000005897 peptide coupling reaction Methods 0.000 description 5
108090000765 processed proteins & peptides Proteins 0.000 description 5
239000000651 prodrug Substances 0.000 description 5
229940002612 prodrug Drugs 0.000 description 5
102000005962 receptors Human genes 0.000 description 5
108020003175 receptors Proteins 0.000 description 5
239000000126 substance Substances 0.000 description 5
238000004809 thin layer chromatography Methods 0.000 description 5
239000003039 volatile agent Substances 0.000 description 5
SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 4
PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 4
OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 4
HYOOXXQFBONQDD-UHFFFAOYSA-N 3,3-dimethyl-1-piperidin-4-ylindol-2-one;hydrochloride Chemical compound Cl.C12=CC=CC=C2C(C)(C)C(=O)N1C1CCNCC1 HYOOXXQFBONQDD-UHFFFAOYSA-N 0.000 description 4
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
239000012981 Hank's balanced salt solution Substances 0.000 description 4
FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
150000001408 amides Chemical class 0.000 description 4
239000005557 antagonist Substances 0.000 description 4
239000003054 catalyst Substances 0.000 description 4
229910052801 chlorine Inorganic materials 0.000 description 4
MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
238000004440 column chromatography Methods 0.000 description 4
JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 4
GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 4
239000002552 dosage form Substances 0.000 description 4
239000006196 drop Substances 0.000 description 4
238000009472 formulation Methods 0.000 description 4
230000006870 function Effects 0.000 description 4
238000002825 functional assay Methods 0.000 description 4
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
230000004899 motility Effects 0.000 description 4
239000003921 oil Substances 0.000 description 4
235000019198 oils Nutrition 0.000 description 4
230000003287 optical effect Effects 0.000 description 4
239000002245 particle Substances 0.000 description 4
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
239000003755 preservative agent Substances 0.000 description 4
239000000047 product Substances 0.000 description 4
239000003586 protic polar solvent Substances 0.000 description 4
230000009467 reduction Effects 0.000 description 4
238000006722 reduction reaction Methods 0.000 description 4
239000012321 sodium triacetoxyborohydride Substances 0.000 description 4
UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
239000000375 suspending agent Substances 0.000 description 4
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 4
RDHXHFVOCIMACS-DTWKUNHWSA-N (1s,3r)-3-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]cyclopentane-1-carboxylic acid Chemical compound CC(C)(C)OC(=O)N(C)[C@@H]1CC[C@H](C(O)=O)C1 RDHXHFVOCIMACS-DTWKUNHWSA-N 0.000 description 3
ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 description 3
NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 3
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 3
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
241000282412 Homo Species 0.000 description 3
150000008575 L-amino acids Chemical group 0.000 description 3
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
229910052783 alkali metal Inorganic materials 0.000 description 3
230000029936 alkylation Effects 0.000 description 3
238000005804 alkylation reaction Methods 0.000 description 3
150000003862 amino acid derivatives Chemical class 0.000 description 3
239000000823 artificial membrane Substances 0.000 description 3
230000015572 biosynthetic process Effects 0.000 description 3
229910052794 bromium Inorganic materials 0.000 description 3
229910002091 carbon monoxide Inorganic materials 0.000 description 3
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
206010012601 diabetes mellitus Diseases 0.000 description 3
FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 3
239000002270 dispersing agent Substances 0.000 description 3
238000010828 elution Methods 0.000 description 3
239000000839 emulsion Substances 0.000 description 3
150000002148 esters Chemical class 0.000 description 3
FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 3
230000005714 functional activity Effects 0.000 description 3
230000030136 gastric emptying Effects 0.000 description 3
239000001963 growth medium Substances 0.000 description 3
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
238000011534 incubation Methods 0.000 description 3
230000000968 intestinal effect Effects 0.000 description 3
239000011630 iodine Substances 0.000 description 3
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
239000006210 lotion Substances 0.000 description 3
239000000463 material Substances 0.000 description 3
230000003278 mimic effect Effects 0.000 description 3
239000002674 ointment Substances 0.000 description 3
150000005623 oxindoles Chemical class 0.000 description 3
239000000546 pharmaceutical excipient Substances 0.000 description 3
229910052700 potassium Inorganic materials 0.000 description 3
239000011591 potassium Substances 0.000 description 3
229960003975 potassium Drugs 0.000 description 3
235000011118 potassium hydroxide Nutrition 0.000 description 3
239000000843 powder Substances 0.000 description 3
230000008569 process Effects 0.000 description 3
230000001737 promoting effect Effects 0.000 description 3
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
239000000377 silicon dioxide Substances 0.000 description 3
150000003384 small molecules Chemical class 0.000 description 3
239000012312 sodium hydride Substances 0.000 description 3
229910000104 sodium hydride Inorganic materials 0.000 description 3
239000012453 solvate Substances 0.000 description 3
239000003381 stabilizer Substances 0.000 description 3
229940124530 sulfonamide Drugs 0.000 description 3
150000003456 sulfonamides Chemical class 0.000 description 3
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
239000003826 tablet Substances 0.000 description 3
230000001225 therapeutic effect Effects 0.000 description 3
IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 3
YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 3
MCODLPJUFHPVQP-GFCCVEGCSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-phenylbutanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](C(O)=O)CCC1=CC=CC=C1 MCODLPJUFHPVQP-GFCCVEGCSA-N 0.000 description 2
HVJSITPJGZYZLH-YWEHKCAJSA-N (3r)-n-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-n-methylpiperidine-3-carboxamide Chemical compound C([C@H](N(C)C(=O)[C@H]1CNCCC1)C(=O)N1CCC(CC1)N1C2=CC=CC=C2C(C)(C)C1=O)CC1=CC=CC=C1 HVJSITPJGZYZLH-YWEHKCAJSA-N 0.000 description 2
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 2
ZNXJYKUZUOEJAV-UHFFFAOYSA-N 1-(1-benzylpiperidin-4-yl)-3,3-dimethylindol-2-one Chemical compound C12=CC=CC=C2C(C)(C)C(=O)N1C(CC1)CCN1CC1=CC=CC=C1 ZNXJYKUZUOEJAV-UHFFFAOYSA-N 0.000 description 2
MZFMPDDEWRYRFT-UHFFFAOYSA-N 1-(1-benzylpiperidin-4-yl)-5-fluoro-3,3-dimethylindol-2-one Chemical compound C12=CC=C(F)C=C2C(C)(C)C(=O)N1C(CC1)CCN1CC1=CC=CC=C1 MZFMPDDEWRYRFT-UHFFFAOYSA-N 0.000 description 2
MSKHCMRUDDYZGG-YWEHKCAJSA-N 1-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-1-methyl-3-[(3r)-piperidin-3-yl]urea Chemical compound C([C@H](N(C)C(=O)N[C@H]1CNCCC1)C(=O)N1CCC(CC1)N1C2=CC=CC=C2C(C)(C)C1=O)CC1=CC=CC=C1 MSKHCMRUDDYZGG-YWEHKCAJSA-N 0.000 description 2
FZUFYNBNRFNPCZ-OAQYLSRUSA-N 1-[1-[(2r)-2-amino-4-phenylbutanoyl]piperidin-4-yl]-3,3-dimethylindol-2-one Chemical compound C([C@@H](N)C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)CC1=CC=CC=C1 FZUFYNBNRFNPCZ-OAQYLSRUSA-N 0.000 description 2
TTZNXTDIPQVIFO-FQEVSTJZSA-N 1-[1-[(2s)-2-amino-3-(4-chlorophenyl)propanoyl]piperidin-4-yl]-3,3-dimethylindol-2-one Chemical compound C([C@H](N)C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)C1=CC=C(Cl)C=C1 TTZNXTDIPQVIFO-FQEVSTJZSA-N 0.000 description 2
PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 2
NVYAJHUUOSUSGC-UHFFFAOYSA-N 2-(2-bromo-5-fluorophenyl)-2-methylpropanoic acid Chemical compound OC(=O)C(C)(C)C1=CC(F)=CC=C1Br NVYAJHUUOSUSGC-UHFFFAOYSA-N 0.000 description 2
OZMLUMPWPFZWTP-UHFFFAOYSA-N 2-(tributyl-$l^{5}-phosphanylidene)acetonitrile Chemical compound CCCCP(CCCC)(CCCC)=CC#N OZMLUMPWPFZWTP-UHFFFAOYSA-N 0.000 description 2
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 2
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
KEZHRKOVLKUYCQ-UHFFFAOYSA-N 3,3-dimethyl-1h-indol-2-one Chemical compound C1=CC=C2C(C)(C)C(=O)NC2=C1 KEZHRKOVLKUYCQ-UHFFFAOYSA-N 0.000 description 2
OGYLDTLJKYCYTB-UHFFFAOYSA-N 5-fluoro-3,3-dimethyl-1-piperidin-4-ylindol-2-one Chemical compound C12=CC=C(F)C=C2C(C)(C)C(=O)N1C1CCNCC1 OGYLDTLJKYCYTB-UHFFFAOYSA-N 0.000 description 2
DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
239000005695 Ammonium acetate Substances 0.000 description 2
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
150000008574 D-amino acids Chemical class 0.000 description 2
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
239000006144 Dulbecco’s modiﬁed Eagle's medium Substances 0.000 description 2
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
238000005727 Friedel-Crafts reaction Methods 0.000 description 2
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
208000018522 Gastrointestinal disease Diseases 0.000 description 2
239000007995 HEPES buffer Substances 0.000 description 2
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
206010062767 Hypophysitis Diseases 0.000 description 2
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
241000124008 Mammalia Species 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
238000006751 Mitsunobu reaction Methods 0.000 description 2
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
229930040373 Paraformaldehyde Natural products 0.000 description 2
229930182555 Penicillin Natural products 0.000 description 2
JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
150000007513 acids Chemical class 0.000 description 2
210000000577 adipose tissue Anatomy 0.000 description 2
230000002411 adverse Effects 0.000 description 2
150000001298 alcohols Chemical class 0.000 description 2
235000019257 ammonium acetate Nutrition 0.000 description 2
229940043376 ammonium acetate Drugs 0.000 description 2
235000011114 ammonium hydroxide Nutrition 0.000 description 2
239000003708 ampul Substances 0.000 description 2
230000000202 analgesic effect Effects 0.000 description 2
HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 2
150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
238000003556 assay Methods 0.000 description 2
RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 2
229910001863 barium hydroxide Inorganic materials 0.000 description 2
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
230000003115 biocidal effect Effects 0.000 description 2
210000004556 brain Anatomy 0.000 description 2
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
125000001246 bromo group Chemical group Br* 0.000 description 2
FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
229910000024 caesium carbonate Inorganic materials 0.000 description 2
239000011575 calcium Substances 0.000 description 2
229910052791 calcium Inorganic materials 0.000 description 2
239000002775 capsule Substances 0.000 description 2
150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
239000003638 chemical reducing agent Substances 0.000 description 2
125000001309 chloro group Chemical group Cl* 0.000 description 2
IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 2
239000003086 colorant Substances 0.000 description 2
239000012230 colorless oil Substances 0.000 description 2
238000007796 conventional method Methods 0.000 description 2
239000006071 cream Substances 0.000 description 2
239000013078 crystal Substances 0.000 description 2
238000003795 desorption Methods 0.000 description 2
229940117389 dichlorobenzene Drugs 0.000 description 2
DMGLSPAZGKUICV-UHFFFAOYSA-N dimethyl 2-(tributyl-$l^{5}-phosphanylidene)propanedioate Chemical compound CCCCP(CCCC)(CCCC)=C(C(=O)OC)C(=O)OC DMGLSPAZGKUICV-UHFFFAOYSA-N 0.000 description 2
NCBFTYFOPLPRBX-UHFFFAOYSA-N dimethyl azodicarboxylate Substances COC(=O)N=NC(=O)OC NCBFTYFOPLPRBX-UHFFFAOYSA-N 0.000 description 2
HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 2
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
238000009826 distribution Methods 0.000 description 2
SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
239000003995 emulsifying agent Substances 0.000 description 2
150000002170 ethers Chemical class 0.000 description 2
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
238000002474 experimental method Methods 0.000 description 2
230000004634 feeding behavior Effects 0.000 description 2
238000011049 filling Methods 0.000 description 2
238000001914 filtration Methods 0.000 description 2
229910052731 fluorine Inorganic materials 0.000 description 2
239000011737 fluorine Substances 0.000 description 2
125000000524 functional group Chemical group 0.000 description 2
210000004211 gastric acid Anatomy 0.000 description 2
239000003324 growth hormone secretagogue Substances 0.000 description 2
150000008282 halocarbons Chemical class 0.000 description 2
150000004677 hydrates Chemical class 0.000 description 2
238000005984 hydrogenation reaction Methods 0.000 description 2
FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical class Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 2
230000002209 hydrophobic effect Effects 0.000 description 2
238000011065 in-situ storage Methods 0.000 description 2
239000012669 liquid formulation Substances 0.000 description 2
229910052744 lithium Inorganic materials 0.000 description 2
ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 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
238000005259 measurement Methods 0.000 description 2
230000002503 metabolic effect Effects 0.000 description 2
NCBFTYFOPLPRBX-AATRIKPKSA-N methyl (ne)-n-methoxycarbonyliminocarbamate Chemical compound COC(=O)\N=N\C(=O)OC NCBFTYFOPLPRBX-AATRIKPKSA-N 0.000 description 2
125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
238000002156 mixing Methods 0.000 description 2
230000004048 modification Effects 0.000 description 2
238000012986 modification Methods 0.000 description 2
BLPWJKHDQGIDKZ-UHFFFAOYSA-N n-(1-benzylpiperidin-4-yl)-2-(2-bromo-5-fluorophenyl)-2-methylpropanamide Chemical compound C=1C(F)=CC=C(Br)C=1C(C)(C)C(=O)NC(CC1)CCN1CC1=CC=CC=C1 BLPWJKHDQGIDKZ-UHFFFAOYSA-N 0.000 description 2
150000002825 nitriles Chemical class 0.000 description 2
239000012299 nitrogen atmosphere Substances 0.000 description 2
238000010534 nucleophilic substitution reaction Methods 0.000 description 2
230000036407 pain Effects 0.000 description 2
NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 2
229920002866 paraformaldehyde Polymers 0.000 description 2
238000007911 parenteral administration Methods 0.000 description 2
229940049954 penicillin Drugs 0.000 description 2
FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
238000013148 permeation assay Methods 0.000 description 2
239000012071 phase Substances 0.000 description 2
HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
229910052698 phosphorus Inorganic materials 0.000 description 2
239000011574 phosphorus Substances 0.000 description 2
125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 2
DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 2
150000003053 piperidines Chemical class 0.000 description 2
210000003635 pituitary gland Anatomy 0.000 description 2
BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
238000002600 positron emission tomography Methods 0.000 description 2
229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
235000015497 potassium bicarbonate Nutrition 0.000 description 2
239000011736 potassium bicarbonate Substances 0.000 description 2
229910000027 potassium carbonate Inorganic materials 0.000 description 2
235000011181 potassium carbonates Nutrition 0.000 description 2
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
238000002953 preparative HPLC Methods 0.000 description 2
BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 2
WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
238000010992 reflux Methods 0.000 description 2
239000011734 sodium Substances 0.000 description 2
229910052708 sodium Inorganic materials 0.000 description 2
229910000029 sodium carbonate Inorganic materials 0.000 description 2
235000017550 sodium carbonate Nutrition 0.000 description 2
DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
230000000707 stereoselective effect Effects 0.000 description 2
229960005322 streptomycin Drugs 0.000 description 2
HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
150000003462 sulfoxides Chemical class 0.000 description 2
GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 2
208000024891 symptom Diseases 0.000 description 2
238000010189 synthetic method Methods 0.000 description 2
UYJKDWNBKZBGTA-DEOSSOPVSA-N tert-butyl n-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C([C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(CC1)N1C2=CC=CC=C2C(C)(C)C1=O)CC1=CC=CC=C1 UYJKDWNBKZBGTA-DEOSSOPVSA-N 0.000 description 2
239000002562 thickening agent Substances 0.000 description 2
CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
238000011200 topical administration Methods 0.000 description 2
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
230000009466 transformation Effects 0.000 description 2
238000000844 transformation Methods 0.000 description 2
125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 2
FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 2
210000001186 vagus nerve Anatomy 0.000 description 2
239000000080 wetting agent Substances 0.000 description 2
239000008096 xylene Substances 0.000 description 2
OBETXYAYXDNJHR-SSDOTTSWSA-M (2r)-2-ethylhexanoate Chemical compound CCCC[C@@H](CC)C([O-])=O OBETXYAYXDNJHR-SSDOTTSWSA-M 0.000 description 1
JQAOHGMPAAWWQO-QMMMGPOBSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCCC[C@H]1C(O)=O JQAOHGMPAAWWQO-QMMMGPOBSA-N 0.000 description 1
MCODLPJUFHPVQP-LBPRGKRZSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-phenylbutanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CCC1=CC=CC=C1 MCODLPJUFHPVQP-LBPRGKRZSA-N 0.000 description 1
DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
VLSDXINSOMDCBK-BQYQJAHWSA-N (E)-1,1'-azobis(N,N-dimethylformamide) Chemical compound CN(C)C(=O)\N=N\C(=O)N(C)C VLSDXINSOMDCBK-BQYQJAHWSA-N 0.000 description 1
125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 description 1
ZGEXDLWUNWEAIA-UHFFFAOYSA-N 1,3-dihydroindol-2-one;hydrochloride Chemical compound Cl.C1=CC=C2NC(=O)CC2=C1 ZGEXDLWUNWEAIA-UHFFFAOYSA-N 0.000 description 1
SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 1
ZRIOIQJUIUJPED-UHFFFAOYSA-N 1-(1-benzylpiperidin-4-yl)-3h-indol-2-one Chemical compound O=C1CC2=CC=CC=C2N1C(CC1)CCN1CC1=CC=CC=C1 ZRIOIQJUIUJPED-UHFFFAOYSA-N 0.000 description 1
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
JWOHBPPVVDQMKB-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC(C(O)=O)CC1 JWOHBPPVVDQMKB-UHFFFAOYSA-N 0.000 description 1
JTSJPPQOZKHHBM-FQEVSTJZSA-N 1-[1-[(2s)-2-amino-3-phenylpropanoyl]piperidin-4-yl]-3,3-dimethylindol-2-one Chemical compound C([C@H](N)C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)C1=CC=CC=C1 JTSJPPQOZKHHBM-FQEVSTJZSA-N 0.000 description 1
FZUFYNBNRFNPCZ-NRFANRHFSA-N 1-[1-[(2s)-2-amino-4-phenylbutanoyl]piperidin-4-yl]-3,3-dimethylindol-2-one Chemical compound C([C@H](N)C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)CC1=CC=CC=C1 FZUFYNBNRFNPCZ-NRFANRHFSA-N 0.000 description 1
UBJYNTVRIMOXKW-NRFANRHFSA-N 1-[1-[(2s)-2-amino-4-phenylbutanoyl]piperidin-4-yl]-5-fluoro-3,3-dimethylindol-2-one Chemical compound C([C@H](N)C(=O)N1CCC(CC1)N1C(=O)C(C2=CC(F)=CC=C21)(C)C)CC1=CC=CC=C1 UBJYNTVRIMOXKW-NRFANRHFSA-N 0.000 description 1
YUBDLZGUSSWQSS-UHFFFAOYSA-N 1-benzylpiperidin-4-amine Chemical compound C1CC(N)CCN1CC1=CC=CC=C1 YUBDLZGUSSWQSS-UHFFFAOYSA-N 0.000 description 1
IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 description 1
HVHZEKKZMFRULH-UHFFFAOYSA-N 2,6-ditert-butyl-4-methylpyridine Chemical compound CC1=CC(C(C)(C)C)=NC(C(C)(C)C)=C1 HVHZEKKZMFRULH-UHFFFAOYSA-N 0.000 description 1
SXGZJKUKBWWHRA-UHFFFAOYSA-N 2-(N-morpholiniumyl)ethanesulfonate Chemical compound [O-]S(=O)(=O)CC[NH+]1CCOCC1 SXGZJKUKBWWHRA-UHFFFAOYSA-N 0.000 description 1
KJFJIEHJCVSAKJ-UHFFFAOYSA-N 2-(trimethyl-$l^{5}-phosphanylidene)acetonitrile Chemical compound CP(C)(C)=CC#N KJFJIEHJCVSAKJ-UHFFFAOYSA-N 0.000 description 1
ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 description 1
YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
GNDKYAWHEKZHPJ-UHFFFAOYSA-N 2-nitrobenzenesulfonimidic acid Chemical compound NS(=O)(=O)C1=CC=CC=C1[N+]([O-])=O GNDKYAWHEKZHPJ-UHFFFAOYSA-N 0.000 description 1
WPHUUIODWRNJLO-UHFFFAOYSA-N 2-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1S(Cl)(=O)=O WPHUUIODWRNJLO-UHFFFAOYSA-N 0.000 description 1
RFBSYDCQZYNAPH-QFIPXVFZSA-N 3,3-dimethyl-1-[1-[(2s)-2-(methylamino)-4-phenylbutanoyl]piperidin-4-yl]indol-2-one Chemical compound C([C@H](NC)C(=O)N1CCC(CC1)N1C2=CC=CC=C2C(C)(C)C1=O)CC1=CC=CC=C1 RFBSYDCQZYNAPH-QFIPXVFZSA-N 0.000 description 1
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
YVDJGABOVHJDAV-UHFFFAOYSA-N 3-methyl-2-nitrobenzenesulfonamide Chemical compound CC1=CC=CC(S(N)(=O)=O)=C1[N+]([O-])=O YVDJGABOVHJDAV-UHFFFAOYSA-N 0.000 description 1
239000003185 4 aminobutyric acid B receptor stimulating agent Substances 0.000 description 1
125000006418 4-methylphenylsulfonyl group Chemical group 0.000 description 1
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
206010002091 Anaesthesia Diseases 0.000 description 1
102100033367 Appetite-regulating hormone Human genes 0.000 description 1
101710111255 Appetite-regulating hormone Proteins 0.000 description 1
125000006847 BOC protecting group Chemical group 0.000 description 1
239000005711 Benzoic acid Substances 0.000 description 1
108091003079 Bovine Serum Albumin Proteins 0.000 description 1
WDEDSODLDCECHY-SYVJQLTCSA-N CC(C)(c1ccccc1N1C(CC2)CCN2C([C@H](Cc(cc2)ccc2Cl)NC([C@@H](CC2)C[C@@H]2NC)=O)=O)C1=O Chemical compound CC(C)(c1ccccc1N1C(CC2)CCN2C([C@H](Cc(cc2)ccc2Cl)NC([C@@H](CC2)C[C@@H]2NC)=O)=O)C1=O WDEDSODLDCECHY-SYVJQLTCSA-N 0.000 description 1
OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
229920002261 Corn starch Polymers 0.000 description 1
102100038019 Corticotropin-releasing factor receptor 2 Human genes 0.000 description 1
YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
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 1
241000792859 Enema Species 0.000 description 1
206010063655 Erosive oesophagitis Diseases 0.000 description 1
IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
206010017943 Gastrointestinal conditions Diseases 0.000 description 1
102000000393 Ghrelin Receptors Human genes 0.000 description 1
108010016122 Ghrelin Receptors Proteins 0.000 description 1
101000878664 Homo sapiens Corticotropin-releasing factor receptor 2 Proteins 0.000 description 1
235000010650 Hyssopus officinalis Nutrition 0.000 description 1
240000001812 Hyssopus officinalis Species 0.000 description 1
206010061218 Inflammation Diseases 0.000 description 1
JTTHKOPSMAVJFE-VIFPVBQESA-N L-homophenylalanine Chemical compound OC(=O)[C@@H](N)CCC1=CC=CC=C1 JTTHKOPSMAVJFE-VIFPVBQESA-N 0.000 description 1
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
240000007472 Leucaena leucocephala Species 0.000 description 1
235000010643 Leucaena leucocephala Nutrition 0.000 description 1
FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
241001465754 Metazoa Species 0.000 description 1
229920000168 Microcrystalline cellulose Polymers 0.000 description 1
HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
FNPGXDSWMVHFQF-UHFFFAOYSA-N N1CCCCC1.N1C(CC2=CC=CC=C12)=O Chemical class N1CCCCC1.N1C(CC2=CC=CC=C12)=O FNPGXDSWMVHFQF-UHFFFAOYSA-N 0.000 description 1
102000009493 Neurokinin receptors Human genes 0.000 description 1
108050000302 Neurokinin receptors Proteins 0.000 description 1
PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
208000008589 Obesity Diseases 0.000 description 1
108010016076 Octreotide Proteins 0.000 description 1
229910019142 PO4 Inorganic materials 0.000 description 1
OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
241000350481 Pterogyne nitens Species 0.000 description 1
108700008625 Reporter Genes Proteins 0.000 description 1
101150084577 SST2 gene Proteins 0.000 description 1
108010052164 Sodium Channels Proteins 0.000 description 1
102000018674 Sodium Channels Human genes 0.000 description 1
UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
235000021355 Stearic acid Nutrition 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
102000003566 TRPV1 Human genes 0.000 description 1
FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
101150016206 Trpv1 gene Proteins 0.000 description 1
102000004142 Trypsin Human genes 0.000 description 1
108090000631 Trypsin Proteins 0.000 description 1
235000010724 Wisteria floribunda Nutrition 0.000 description 1
238000002441 X-ray diffraction Methods 0.000 description 1
108010084455 Zeocin Proteins 0.000 description 1
238000010521 absorption reaction Methods 0.000 description 1
230000002378 acidificating effect Effects 0.000 description 1
230000009471 action Effects 0.000 description 1
230000003213 activating effect Effects 0.000 description 1
230000004913 activation Effects 0.000 description 1
239000004480 active ingredient Substances 0.000 description 1
239000000654 additive Substances 0.000 description 1
239000002671 adjuvant Substances 0.000 description 1
239000000443 aerosol Substances 0.000 description 1
230000001270 agonistic effect Effects 0.000 description 1
150000001299 aldehydes Chemical class 0.000 description 1
150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
150000008041 alkali metal carbonates Chemical class 0.000 description 1
229910000102 alkali metal hydride Inorganic materials 0.000 description 1
150000008046 alkali metal hydrides Chemical class 0.000 description 1
150000008044 alkali metal hydroxides Chemical class 0.000 description 1
125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
230000002152 alkylating effect Effects 0.000 description 1
150000001370 alpha-amino acid derivatives Chemical class 0.000 description 1
235000008206 alpha-amino acids Nutrition 0.000 description 1
OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
229910000147 aluminium phosphate Inorganic materials 0.000 description 1
125000003277 amino group Chemical group 0.000 description 1
235000019270 ammonium chloride Nutrition 0.000 description 1
238000001949 anaesthesia Methods 0.000 description 1
230000037005 anaesthesia Effects 0.000 description 1
230000003444 anaesthetic effect Effects 0.000 description 1
239000012491 analyte Substances 0.000 description 1
239000008135 aqueous vehicle Substances 0.000 description 1
125000004391 aryl sulfonyl group Chemical group 0.000 description 1
239000012131 assay buffer Substances 0.000 description 1
239000012911 assay medium Substances 0.000 description 1
239000012298 atmosphere Substances 0.000 description 1
125000005604 azodicarboxylate group Chemical group 0.000 description 1
230000008901 benefit Effects 0.000 description 1
235000010233 benzoic acid Nutrition 0.000 description 1
FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
150000001576 beta-amino acids Chemical class 0.000 description 1
239000011230 binding agent Substances 0.000 description 1
230000033228 biological regulation Effects 0.000 description 1
239000000337 buffer salt Substances 0.000 description 1
239000006172 buffering agent Substances 0.000 description 1
KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
150000004657 carbamic acid derivatives Chemical class 0.000 description 1
BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
150000004649 carbonic acid derivatives Chemical class 0.000 description 1
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
239000001913 cellulose Substances 0.000 description 1
235000010980 cellulose Nutrition 0.000 description 1
229920002678 cellulose Polymers 0.000 description 1
230000001713 cholinergic effect Effects 0.000 description 1
230000002759 chromosomal effect Effects 0.000 description 1
235000015165 citric acid Nutrition 0.000 description 1
229940110456 cocoa butter Drugs 0.000 description 1
235000019868 cocoa butter Nutrition 0.000 description 1
230000004600 colonic motility Effects 0.000 description 1
238000013270 controlled release Methods 0.000 description 1
239000008120 corn starch Substances 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
206010061428 decreased appetite Diseases 0.000 description 1
239000003405 delayed action preparation Substances 0.000 description 1
229910052805 deuterium Inorganic materials 0.000 description 1
KJOZJSGOIJQCGA-UHFFFAOYSA-N dichloromethane;2,2,2-trifluoroacetic acid Chemical compound ClCCl.OC(=O)C(F)(F)F KJOZJSGOIJQCGA-UHFFFAOYSA-N 0.000 description 1
IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
239000007884 disintegrant Substances 0.000 description 1
231100000673 dose–response relationship Toxicity 0.000 description 1
229940000406 drug candidate Drugs 0.000 description 1
230000008406 drug-drug interaction Effects 0.000 description 1
210000001198 duodenum Anatomy 0.000 description 1
239000003221 ear drop Substances 0.000 description 1
229940047652 ear drops Drugs 0.000 description 1
239000008157 edible vegetable oil Substances 0.000 description 1
238000005868 electrolysis reaction Methods 0.000 description 1
239000007920 enema Substances 0.000 description 1
229940079360 enema for constipation Drugs 0.000 description 1
230000003628 erosive effect Effects 0.000 description 1
239000003797 essential amino acid Substances 0.000 description 1
235000020776 essential amino acid Nutrition 0.000 description 1
BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 1
125000004494 ethyl ester group Chemical group 0.000 description 1
230000005284 excitation Effects 0.000 description 1
230000002964 excitative effect Effects 0.000 description 1
239000003889 eye drop Substances 0.000 description 1
229940012356 eye drops Drugs 0.000 description 1
239000003925 fat Substances 0.000 description 1
235000019197 fats Nutrition 0.000 description 1
230000002349 favourable effect Effects 0.000 description 1
239000012091 fetal bovine serum Substances 0.000 description 1
239000000945 filler Substances 0.000 description 1
238000003818 flash chromatography Methods 0.000 description 1
239000000796 flavoring agent Substances 0.000 description 1
125000001153 fluoro group Chemical group F* 0.000 description 1
235000003599 food sweetener Nutrition 0.000 description 1
239000001530 fumaric acid Substances 0.000 description 1
235000011087 fumaric acid Nutrition 0.000 description 1
239000003349 gelling agent Substances 0.000 description 1
125000005456 glyceride group Chemical group 0.000 description 1
239000008187 granular material Substances 0.000 description 1
IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
125000005842 heteroatom Chemical group 0.000 description 1
GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
229940077716 histamine h2 receptor antagonists for peptic ulcer and gord Drugs 0.000 description 1
238000007327 hydrogenolysis reaction Methods 0.000 description 1
230000007062 hydrolysis Effects 0.000 description 1
238000006460 hydrolysis reaction Methods 0.000 description 1
125000002768 hydroxyalkyl group Chemical group 0.000 description 1
230000033444 hydroxylation Effects 0.000 description 1
238000005805 hydroxylation reaction Methods 0.000 description 1
239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
150000002466 imines Chemical class 0.000 description 1
150000007975 iminium salts Chemical class 0.000 description 1
238000002513 implantation Methods 0.000 description 1
239000012535 impurity Substances 0.000 description 1
230000002757 inflammatory effect Effects 0.000 description 1
230000004054 inflammatory process Effects 0.000 description 1
239000004615 ingredient Substances 0.000 description 1
239000007924 injection Substances 0.000 description 1
238000002347 injection Methods 0.000 description 1
229910017053 inorganic salt Inorganic materials 0.000 description 1
210000000936 intestine Anatomy 0.000 description 1
238000010255 intramuscular injection Methods 0.000 description 1
239000007927 intramuscular injection Substances 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
125000002346 iodo group Chemical group I* 0.000 description 1
239000003456 ion exchange resin Substances 0.000 description 1
229920003303 ion-exchange polymer Polymers 0.000 description 1
150000002500 ions Chemical class 0.000 description 1
230000007794 irritation Effects 0.000 description 1
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
239000012948 isocyanate Substances 0.000 description 1
150000002513 isocyanates Chemical class 0.000 description 1
238000002955 isolation Methods 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
210000001630 jejunum Anatomy 0.000 description 1
150000002576 ketones Chemical class 0.000 description 1
239000008101 lactose Substances 0.000 description 1
239000010410 layer Substances 0.000 description 1
239000000787 lecithin Substances 0.000 description 1
235000010445 lecithin Nutrition 0.000 description 1
229940067606 lecithin Drugs 0.000 description 1
230000000670 limiting effect Effects 0.000 description 1
239000007788 liquid Substances 0.000 description 1
239000012280 lithium aluminium hydride Substances 0.000 description 1
AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
229910052808 lithium carbonate Inorganic materials 0.000 description 1
229910000103 lithium hydride Inorganic materials 0.000 description 1
229910000032 lithium hydrogen carbonate Inorganic materials 0.000 description 1
FZRNJOXQNWVMIH-UHFFFAOYSA-N lithium;hydrate Chemical class [Li].O FZRNJOXQNWVMIH-UHFFFAOYSA-N 0.000 description 1
HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 description 1
238000011068 loading method Methods 0.000 description 1
231100000053 low toxicity Toxicity 0.000 description 1
210000000111 lower esophageal sphincter Anatomy 0.000 description 1
239000007937 lozenge Substances 0.000 description 1
239000000314 lubricant Substances 0.000 description 1
150000002678 macrocyclic compounds Chemical class 0.000 description 1
239000011777 magnesium Substances 0.000 description 1
229910052749 magnesium Inorganic materials 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
239000011976 maleic acid Substances 0.000 description 1
239000003550 marker Substances 0.000 description 1
238000004949 mass spectrometry Methods 0.000 description 1
230000007246 mechanism Effects 0.000 description 1
239000012528 membrane Substances 0.000 description 1
229910052751 metal Inorganic materials 0.000 description 1
239000002184 metal Substances 0.000 description 1
229940098779 methanesulfonic acid Drugs 0.000 description 1
125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
MFJZZRBJASNGAJ-UHFFFAOYSA-N methyl 2-(2-bromo-5-fluorophenyl)-2-methylpropanoate Chemical compound COC(=O)C(C)(C)C1=CC(F)=CC=C1Br MFJZZRBJASNGAJ-UHFFFAOYSA-N 0.000 description 1
150000004702 methyl esters Chemical class 0.000 description 1
239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
229940016286 microcrystalline cellulose Drugs 0.000 description 1
235000019813 microcrystalline cellulose Nutrition 0.000 description 1
239000008108 microcrystalline cellulose Substances 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
239000011812 mixed powder Substances 0.000 description 1
125000002757 morpholinyl group Chemical group 0.000 description 1
230000004118 muscle contraction Effects 0.000 description 1
WQERYQQCYKPWGX-UHFFFAOYSA-N n,n-diethylaniline;methanol Chemical compound OC.CCN(CC)C1=CC=CC=C1 WQERYQQCYKPWGX-UHFFFAOYSA-N 0.000 description 1
YVMIOSNKJVYQRJ-VWLOTQADSA-N n-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-2-nitrobenzenesulfonamide Chemical compound C([C@@H](C(=O)N1CCC(CC1)N1C(=O)C(C2=CC=CC=C21)(C)C)NS(=O)(=O)C=1C(=CC=CC=1)[N+]([O-])=O)CC1=CC=CC=C1 YVMIOSNKJVYQRJ-VWLOTQADSA-N 0.000 description 1
PBMLIGRDJYOEIA-NDEPHWFRSA-N n-[(2s)-1-[4-(3,3-dimethyl-2-oxoindol-1-yl)piperidin-1-yl]-1-oxo-4-phenylbutan-2-yl]-n-methyl-2-nitrobenzenesulfonamide Chemical compound C([C@H](N(C)S(=O)(=O)C=1C(=CC=CC=1)[N+]([O-])=O)C(=O)N1CCC(CC1)N1C2=CC=CC=C2C(C)(C)C1=O)CC1=CC=CC=C1 PBMLIGRDJYOEIA-NDEPHWFRSA-N 0.000 description 1
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
XTFSPXGZPDPJNB-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine;pyridine Chemical compound C1=CC=NC=C1.CCN(C(C)C)C(C)C XTFSPXGZPDPJNB-UHFFFAOYSA-N 0.000 description 1
PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
239000007923 nasal drop Substances 0.000 description 1
229940100662 nasal drops Drugs 0.000 description 1
230000003880 negative regulation of appetite Effects 0.000 description 1
238000002610 neuroimaging Methods 0.000 description 1
201000001119 neuropathy Diseases 0.000 description 1
230000007823 neuropathy Effects 0.000 description 1
229910017604 nitric acid Inorganic materials 0.000 description 1
239000002687 nonaqueous vehicle Substances 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
239000012038 nucleophile Substances 0.000 description 1
238000005935 nucleophilic addition reaction Methods 0.000 description 1
230000000269 nucleophilic effect Effects 0.000 description 1
235000020824 obesity Nutrition 0.000 description 1
QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
229960002700 octreotide Drugs 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
150000007530 organic bases Chemical class 0.000 description 1
150000002924 oxiranes Chemical class 0.000 description 1
LVSJDHGRKAEGLX-UHFFFAOYSA-N oxolane;2,2,2-trifluoroacetic acid Chemical compound C1CCOC1.OC(=O)C(F)(F)F LVSJDHGRKAEGLX-UHFFFAOYSA-N 0.000 description 1
210000002741 palatine tonsil Anatomy 0.000 description 1
YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
230000007170 pathology Effects 0.000 description 1
239000008188 pellet Substances 0.000 description 1
208000033808 peripheral neuropathy Diseases 0.000 description 1
230000035699 permeability Effects 0.000 description 1
239000003208 petroleum Substances 0.000 description 1
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
235000021317 phosphate Nutrition 0.000 description 1
WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
VBQCHPIMZGQLAZ-UHFFFAOYSA-N phosphorane Chemical class [PH5] VBQCHPIMZGQLAZ-UHFFFAOYSA-N 0.000 description 1
150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
238000006303 photolysis reaction Methods 0.000 description 1
230000015843 photosynthesis, light reaction Effects 0.000 description 1
125000004193 piperazinyl group Chemical group 0.000 description 1
125000003386 piperidinyl group Chemical group 0.000 description 1
230000001817 pituitary effect Effects 0.000 description 1
229910052697 platinum Inorganic materials 0.000 description 1
102000054765 polymorphisms of proteins Human genes 0.000 description 1
239000001267 polyvinylpyrrolidone Substances 0.000 description 1
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
229910000105 potassium hydride Inorganic materials 0.000 description 1
NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
ZMJJCODMIXQWCQ-UHFFFAOYSA-N potassium;di(propan-2-yl)azanide Chemical compound [K+].CC(C)[N-]C(C)C ZMJJCODMIXQWCQ-UHFFFAOYSA-N 0.000 description 1
229920001592 potato starch Polymers 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
230000002335 preservative effect Effects 0.000 description 1
230000002265 prevention Effects 0.000 description 1
235000019260 propionic acid Nutrition 0.000 description 1
230000001141 propulsive effect Effects 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
235000018102 proteins Nutrition 0.000 description 1
102000004169 proteins and genes Human genes 0.000 description 1
108090000623 proteins and genes Proteins 0.000 description 1
239000000612 proton pump inhibitor Substances 0.000 description 1
229940126409 proton pump inhibitor Drugs 0.000 description 1
KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
125000000719 pyrrolidinyl group Chemical group 0.000 description 1
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
230000002285 radioactive effect Effects 0.000 description 1
230000035484 reaction time Effects 0.000 description 1
229940100618 rectal suppository Drugs 0.000 description 1
239000006215 rectal suppository Substances 0.000 description 1
238000005932 reductive alkylation reaction Methods 0.000 description 1
238000004366 reverse phase liquid chromatography Methods 0.000 description 1
230000002441 reversible effect Effects 0.000 description 1
238000007142 ring opening reaction Methods 0.000 description 1
238000007789 sealing Methods 0.000 description 1
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 0.000 description 1
ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
235000019333 sodium laurylsulphate Nutrition 0.000 description 1
229940054269 sodium pyruvate Drugs 0.000 description 1
229940079832 sodium starch glycolate Drugs 0.000 description 1
239000008109 sodium starch glycolate Substances 0.000 description 1
229920003109 sodium starch glycolate Polymers 0.000 description 1
YHOBGCSGTGDMLF-UHFFFAOYSA-N sodium;di(propan-2-yl)azanide Chemical compound [Na+].CC(C)[N-]C(C)C YHOBGCSGTGDMLF-UHFFFAOYSA-N 0.000 description 1
239000004334 sorbic acid Substances 0.000 description 1
235000010199 sorbic acid Nutrition 0.000 description 1
229940075582 sorbic acid Drugs 0.000 description 1
239000000600 sorbitol Substances 0.000 description 1
235000010356 sorbitol Nutrition 0.000 description 1
230000003595 spectral effect Effects 0.000 description 1
230000000087 stabilizing effect Effects 0.000 description 1
239000008117 stearic acid Substances 0.000 description 1
239000011550 stock solution Substances 0.000 description 1
210000002784 stomach Anatomy 0.000 description 1
125000000547 substituted alkyl group Chemical group 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
239000000758 substrate Substances 0.000 description 1
230000006103 sulfonylation Effects 0.000 description 1
238000005694 sulfonylation reaction Methods 0.000 description 1
229910052717 sulfur Chemical group 0.000 description 1
239000011593 sulfur Chemical group 0.000 description 1
YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
239000000829 suppository Substances 0.000 description 1
239000002511 suppository base Substances 0.000 description 1
239000004094 surface-active agent Substances 0.000 description 1
239000003765 sweetening agent Substances 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
239000000454 talc Substances 0.000 description 1
229910052623 talc Inorganic materials 0.000 description 1
230000008685 targeting Effects 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
AKQXKEBCONUWCL-MRVPVSSYSA-N tert-butyl (3r)-3-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H](N)C1 AKQXKEBCONUWCL-MRVPVSSYSA-N 0.000 description 1
DMBKWEHXTOCLTC-UHFFFAOYSA-N tert-butyl 4-amino-4-methylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C)(N)CC1 DMBKWEHXTOCLTC-UHFFFAOYSA-N 0.000 description 1
ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
150000007970 thio esters Chemical class 0.000 description 1
238000003354 tissue distribution assay Methods 0.000 description 1
IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
229910052722 tritium Inorganic materials 0.000 description 1
239000012588 trypsin Substances 0.000 description 1
238000009827 uniform distribution Methods 0.000 description 1
210000003932 urinary bladder Anatomy 0.000 description 1
230000001515 vagal effect Effects 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
230000037221 weight management Effects 0.000 description 1
UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 1

JP2011536661A 2009-02-27 2010-03-01 モチリン受容体作動活性を有するオキシインドール誘導体 Active JP5663743B2 (ja)