HRP970426A2 - Fluorine containing 1,4-disubstituted piperidine derivatives - Google Patents

Fluorine containing 1,4-disubstituted piperidine derivatives

Info

Publication number: HRP970426A2
Authority: HR; Croatia
Prior art keywords: phenylacetamide; hydroxy; difluorocyclopentyl; piperidin; methyl
Prior art date: 1996-08-01

Application number

HR53,979/97A

Other languages

English (en)

Croatian (hr)

Inventor

Masaru Nishikibe

Original Assignee

Masaru Nishikibe

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1996-08-01

Filing date

1997-07-30

Publication date

1998-08-31

1997-07-30 Application filed by Masaru Nishikibe filed Critical Masaru Nishikibe

1998-08-31 Publication of HRP970426A2 publication Critical patent/HRP970426A2/hr

Links

-1 1,4-disubstituted piperidine Chemical class 0.000 title claims description 680
229910052731 fluorine Inorganic materials 0.000 title claims description 36
239000011737 fluorine Substances 0.000 title claims description 7
YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title description 5
150000001875 compounds Chemical class 0.000 claims description 216
OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 82
238000000034 method Methods 0.000 claims description 81
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 57
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 56
125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 50
229920006395 saturated elastomer Polymers 0.000 claims description 44
125000000217 alkyl group Chemical group 0.000 claims description 36
150000003839 salts Chemical class 0.000 claims description 33
150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 32
125000001153 fluoro group Chemical group F* 0.000 claims description 32
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
125000003282 alkyl amino group Chemical group 0.000 claims description 29
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 27
238000006243 chemical reaction Methods 0.000 claims description 27
125000003545 alkoxy group Chemical group 0.000 claims description 24
229910052736 halogen Inorganic materials 0.000 claims description 23
150000002367 halogens Chemical class 0.000 claims description 23
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 22
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 21
125000004446 heteroarylalkyl group Chemical group 0.000 claims description 19
125000003710 aryl alkyl group Chemical group 0.000 claims description 18
229910052760 oxygen Inorganic materials 0.000 claims description 18
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
238000002360 preparation method Methods 0.000 claims description 17
125000005018 aryl alkenyl group Chemical group 0.000 claims description 16
125000003118 aryl group Chemical group 0.000 claims description 16
229910052757 nitrogen Inorganic materials 0.000 claims description 16
125000004043 oxo group Chemical group O=* 0.000 claims description 16
125000004447 heteroarylalkenyl group Chemical group 0.000 claims description 15
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 14
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
239000001301 oxygen Substances 0.000 claims description 14
125000006239 protecting group Chemical group 0.000 claims description 14
229910052717 sulfur Inorganic materials 0.000 claims description 14
239000011593 sulfur Substances 0.000 claims description 14
125000001931 aliphatic group Chemical group 0.000 claims description 13
125000001072 heteroaryl group Chemical group 0.000 claims description 13
125000005842 heteroatom Chemical group 0.000 claims description 13
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
GPUGYUSBIRXKND-MFKMUULPSA-N (2r)-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid Chemical group C([C@H]1[C@](O)(C(=O)O)C=2C=CC=CC=2)CC(F)(F)C1 GPUGYUSBIRXKND-MFKMUULPSA-N 0.000 claims description 10
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
238000011282 treatment Methods 0.000 claims description 10
206010036018 Pollakiuria Diseases 0.000 claims description 9
125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 9
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
206010046543 Urinary incontinence Diseases 0.000 claims description 8
125000001424 substituent group Chemical group 0.000 claims description 8
239000003513 alkali Substances 0.000 claims description 7
230000008602 contraction Effects 0.000 claims description 7
125000000392 cycloalkenyl group Chemical group 0.000 claims description 7
210000002249 digestive system Anatomy 0.000 claims description 7
210000002460 smooth muscle Anatomy 0.000 claims description 7
230000002485 urinary effect Effects 0.000 claims description 7
125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 6
206010006458 Bronchitis chronic Diseases 0.000 claims description 6
208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 6
206010063057 Cystitis noninfective Diseases 0.000 claims description 6
208000008967 Enuresis Diseases 0.000 claims description 6
206010053155 Epigastric discomfort Diseases 0.000 claims description 6
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
208000000693 Neurogenic Urinary Bladder Diseases 0.000 claims description 6
206010029279 Neurogenic bladder Diseases 0.000 claims description 6
206010006451 bronchitis Diseases 0.000 claims description 6
208000023819 chronic asthma Diseases 0.000 claims description 6
208000007451 chronic bronchitis Diseases 0.000 claims description 6
201000003139 chronic cystitis Diseases 0.000 claims description 6
201000009151 chronic rhinitis Diseases 0.000 claims description 6
238000010511 deprotection reaction Methods 0.000 claims description 6
208000010643 digestive system disease Diseases 0.000 claims description 6
208000035475 disorder Diseases 0.000 claims description 6
208000007784 diverticulitis Diseases 0.000 claims description 6
201000003152 motion sickness Diseases 0.000 claims description 6
230000001272 neurogenic effect Effects 0.000 claims description 6
208000005346 nocturnal enuresis Diseases 0.000 claims description 6
238000005932 reductive alkylation reaction Methods 0.000 claims description 6
208000023504 respiratory system disease Diseases 0.000 claims description 6
206010039083 rhinitis Diseases 0.000 claims description 6
208000011580 syndromic disease Diseases 0.000 claims description 6
208000022934 urinary frequency Diseases 0.000 claims description 6
125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 5
102000007202 Muscarinic M3 Receptor Human genes 0.000 claims description 5
108010008405 Muscarinic M3 Receptor Proteins 0.000 claims description 5
239000002671 adjuvant Substances 0.000 claims description 5
201000010099 disease Diseases 0.000 claims description 5
125000001841 imino group Chemical group [H]N=* 0.000 claims description 5
239000000825 pharmaceutical preparation Substances 0.000 claims description 5
125000004344 phenylpropyl group Chemical group 0.000 claims description 5
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
125000005356 cycloalkylalkenyl group Chemical group 0.000 claims description 4
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
JQYGRHVCXSKCAQ-JPYJTQIMSA-N (2r)-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenyl-n-[1-(thiophen-2-ylmethyl)piperidin-4-yl]acetamide Chemical compound C([C@H]1[C@](O)(C(=O)NC2CCN(CC=3SC=CC=3)CC2)C=2C=CC=CC=2)CC(F)(F)C1 JQYGRHVCXSKCAQ-JPYJTQIMSA-N 0.000 claims description 3
MXMXMYWNGBMDEJ-LGVFNWMJSA-N (2r)-2-[(1r,3r)-3-fluorocyclopentyl]-2-hydroxy-n-[1-(4-methylpent-3-enyl)piperidin-4-yl]-2-phenylacetamide Chemical compound C1CN(CCC=C(C)C)CCC1NC(=O)[C@](O)(C=1C=CC=CC=1)[C@H]1C[C@H](F)CC1 MXMXMYWNGBMDEJ-LGVFNWMJSA-N 0.000 claims description 3
MXMXMYWNGBMDEJ-IMSXRSKXSA-N (2r)-2-[(1s,3r)-3-fluorocyclopentyl]-2-hydroxy-n-[1-(4-methylpent-3-enyl)piperidin-4-yl]-2-phenylacetamide Chemical compound C1CN(CCC=C(C)C)CCC1NC(=O)[C@](O)(C=1C=CC=CC=1)[C@@H]1C[C@H](F)CC1 MXMXMYWNGBMDEJ-IMSXRSKXSA-N 0.000 claims description 3
RAECMQBWGMLWIA-CLOONOSVSA-N (2r)-n-[1-[(3,5-diaminophenyl)methyl]piperidin-4-yl]-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide Chemical compound NC1=CC(N)=CC(CN2CCC(CC2)NC(=O)[C@@](O)([C@H]2CC(F)(F)CC2)C=2C=CC=CC=2)=C1 RAECMQBWGMLWIA-CLOONOSVSA-N 0.000 claims description 3
DRKATMYPAVJBMA-CLOONOSVSA-N (2r)-n-[1-[(3-amino-5-chlorophenyl)methyl]piperidin-4-yl]-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide Chemical compound NC1=CC(Cl)=CC(CN2CCC(CC2)NC(=O)[C@@](O)([C@H]2CC(F)(F)CC2)C=2C=CC=CC=2)=C1 DRKATMYPAVJBMA-CLOONOSVSA-N 0.000 claims description 3
SMYGAQBHAVQEEB-OSPHWJPCSA-N (2r)-n-[1-[(6-amino-4-chloropyridin-2-yl)methyl]piperidin-4-yl]-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide Chemical compound NC1=CC(Cl)=CC(CN2CCC(CC2)NC(=O)[C@@](O)([C@H]2CC(F)(F)CC2)C=2C=CC=CC=2)=N1 SMYGAQBHAVQEEB-OSPHWJPCSA-N 0.000 claims description 3
NYORKURJCJHUDY-OSPHWJPCSA-N (2r)-n-[1-[(6-aminopyridin-2-yl)methyl]piperidin-4-yl]-2-[(1r)-3,3-difluorocyclopentyl]-2-(4-fluorophenyl)-2-hydroxyacetamide Chemical compound NC1=CC=CC(CN2CCC(CC2)NC(=O)[C@@](O)([C@H]2CC(F)(F)CC2)C=2C=CC(F)=CC=2)=N1 NYORKURJCJHUDY-OSPHWJPCSA-N 0.000 claims description 3
HQRSMNLSFMUJPL-KOSHJBKYSA-N (2r)-n-[1-[(6-aminopyridin-2-yl)methyl]piperidin-4-yl]-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide Chemical compound NC1=CC=CC(CN2CCC(CC2)NC(=O)[C@@](O)([C@H]2CC(F)(F)CC2)C=2C=CC=CC=2)=N1 HQRSMNLSFMUJPL-KOSHJBKYSA-N 0.000 claims description 3
ZXPOIGFEWVCWLA-UHFFFAOYSA-N [6-[(2-methylpropan-2-yl)oxycarbonylamino]pyridin-2-yl]methyl methanesulfonate Chemical compound CC(C)(C)OC(=O)NC1=CC=CC(COS(C)(=O)=O)=N1 ZXPOIGFEWVCWLA-UHFFFAOYSA-N 0.000 claims description 3
DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 claims description 3
125000000304 alkynyl group Chemical group 0.000 claims description 3
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 3
125000000753 cycloalkyl group Chemical group 0.000 claims description 3
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
MTBIBWFHYCAYTO-DVECYGJZSA-N (2r)-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenyl-n-[1-(pyridin-2-ylmethyl)piperidin-4-yl]acetamide Chemical compound C([C@H]1[C@](O)(C(=O)NC2CCN(CC=3N=CC=CC=3)CC2)C=2C=CC=CC=2)CC(F)(F)C1 MTBIBWFHYCAYTO-DVECYGJZSA-N 0.000 claims description 2
ZHLYDKYZZGUNHA-GJZUVCINSA-N (2r)-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-n-[1-[(3-methylphenyl)methyl]piperidin-4-yl]-2-phenylacetamide Chemical compound CC1=CC=CC(CN2CCC(CC2)NC(=O)[C@@](O)([C@H]2CC(F)(F)CC2)C=2C=CC=CC=2)=C1 ZHLYDKYZZGUNHA-GJZUVCINSA-N 0.000 claims description 2
KYYKFSMOYWOWFU-RDPSFJRHSA-N (2r)-2-[(1s)-3,3-difluorocyclopentyl]-2-hydroxy-n-[1-(4-methylpent-3-enyl)piperidin-4-yl]-2-phenylacetamide Chemical compound C1CN(CCC=C(C)C)CCC1NC(=O)[C@](O)(C=1C=CC=CC=1)[C@@H]1CC(F)(F)CC1 KYYKFSMOYWOWFU-RDPSFJRHSA-N 0.000 claims description 2
MXMXMYWNGBMDEJ-HFMPRLQTSA-N (2r)-2-[(1s,3s)-3-fluorocyclopentyl]-2-hydroxy-n-[1-(4-methylpent-3-enyl)piperidin-4-yl]-2-phenylacetamide Chemical compound C1CN(CCC=C(C)C)CCC1NC(=O)[C@](O)(C=1C=CC=CC=1)[C@@H]1C[C@@H](F)CC1 MXMXMYWNGBMDEJ-HFMPRLQTSA-N 0.000 claims description 2
LOOQWAGETRBTHI-KOSHJBKYSA-N (2r)-n-[1-(6-amino-4-methylpyridin-2-yl)piperidin-4-yl]-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide Chemical compound CC1=CC(N)=NC(N2CCC(CC2)NC(=O)[C@@](O)([C@H]2CC(F)(F)CC2)C=2C=CC=CC=2)=C1 LOOQWAGETRBTHI-KOSHJBKYSA-N 0.000 claims description 2
PXKHIFJGFBPNCN-XYXOUFNOSA-N (2r)-n-[1-[(2-aminophenyl)methyl]piperidin-4-yl]-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide;dihydrochloride Chemical compound Cl.Cl.NC1=CC=CC=C1CN1CCC(NC(=O)[C@@](O)([C@H]2CC(F)(F)CC2)C=2C=CC=CC=2)CC1 PXKHIFJGFBPNCN-XYXOUFNOSA-N 0.000 claims description 2
GTNHGAJWRLOVOI-CLOONOSVSA-N (2r)-n-[1-[(3-amino-4-fluorophenyl)methyl]piperidin-4-yl]-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide Chemical compound C1=C(F)C(N)=CC(CN2CCC(CC2)NC(=O)[C@@](O)([C@H]2CC(F)(F)CC2)C=2C=CC=CC=2)=C1 GTNHGAJWRLOVOI-CLOONOSVSA-N 0.000 claims description 2
OOUXONCUYKIRLQ-SNGUCQNNSA-N (2r)-n-[1-[(3-amino-5-methylphenyl)methyl]piperidin-4-yl]-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide;dihydrochloride Chemical compound Cl.Cl.CC1=CC(N)=CC(CN2CCC(CC2)NC(=O)[C@@](O)([C@H]2CC(F)(F)CC2)C=2C=CC=CC=2)=C1 OOUXONCUYKIRLQ-SNGUCQNNSA-N 0.000 claims description 2
XJSISMNRMMJNLY-CLOONOSVSA-N (2r)-n-[1-[(5-amino-2-fluorophenyl)methyl]piperidin-4-yl]-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide Chemical compound NC1=CC=C(F)C(CN2CCC(CC2)NC(=O)[C@@](O)([C@H]2CC(F)(F)CC2)C=2C=CC=CC=2)=C1 XJSISMNRMMJNLY-CLOONOSVSA-N 0.000 claims description 2
125000003342 alkenyl group Chemical group 0.000 claims description 2
125000005357 cycloalkylalkynyl group Chemical group 0.000 claims description 2
230000006806 disease prevention Effects 0.000 claims description 2
125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 claims description 2
125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 2
BEOVVFGGIFGFLM-IBVKSMDESA-N (2r)-n-[1-[(3-amino-5-methoxyphenyl)methyl]piperidin-4-yl]-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide Chemical compound COC1=CC(N)=CC(CN2CCC(CC2)NC(=O)[C@@](O)([C@H]2CC(F)(F)CC2)C=2C=CC=CC=2)=C1 BEOVVFGGIFGFLM-IBVKSMDESA-N 0.000 claims 2
YRRVEDQQANFYHX-NLFFAJNJSA-N (2r)-n-[1-[(3-aminophenyl)methyl]piperidin-4-yl]-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide Chemical compound NC1=CC=CC(CN2CCC(CC2)NC(=O)[C@@](O)([C@H]2CC(F)(F)CC2)C=2C=CC=CC=2)=C1 YRRVEDQQANFYHX-NLFFAJNJSA-N 0.000 claims 2
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 2
206010009887 colitis Diseases 0.000 claims 2
LXYVNUSGHHMEDG-UHFFFAOYSA-N tert-butyl n-[6-(chloromethyl)pyridin-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CC(CCl)=N1 LXYVNUSGHHMEDG-UHFFFAOYSA-N 0.000 claims 2
PGZXMKKKPMGNSP-NLFFAJNJSA-N (2r)-n-[1-[(2-aminophenyl)methyl]piperidin-4-yl]-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide Chemical compound NC1=CC=CC=C1CN1CCC(NC(=O)[C@@](O)([C@H]2CC(F)(F)CC2)C=2C=CC=CC=2)CC1 PGZXMKKKPMGNSP-NLFFAJNJSA-N 0.000 claims 1
IGPWDRYGBFEYFG-RLWLMLJZSA-N (2r)-n-[1-[(3-amino-5-methylphenyl)methyl]piperidin-4-yl]-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide Chemical compound CC1=CC(N)=CC(CN2CCC(CC2)NC(=O)[C@@](O)([C@H]2CC(F)(F)CC2)C=2C=CC=CC=2)=C1 IGPWDRYGBFEYFG-RLWLMLJZSA-N 0.000 claims 1
NHMQQTIJAYTYLB-IBVKSMDESA-N (2r)-n-[1-[(4-amino-3-methoxyphenyl)methyl]piperidin-4-yl]-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide Chemical compound C1=C(N)C(OC)=CC(CN2CCC(CC2)NC(=O)[C@@](O)([C@H]2CC(F)(F)CC2)C=2C=CC=CC=2)=C1 NHMQQTIJAYTYLB-IBVKSMDESA-N 0.000 claims 1
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 1
125000001544 thienyl group Chemical group 0.000 claims 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 80
239000000243 solution Substances 0.000 description 80
230000015572 biosynthetic process Effects 0.000 description 78
238000003786 synthesis reaction Methods 0.000 description 77
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 76
239000002904 solvent Substances 0.000 description 76
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 68
230000002829 reductive effect Effects 0.000 description 56
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
238000003756 stirring Methods 0.000 description 46
238000005160 1H NMR spectroscopy Methods 0.000 description 45
238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 42
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 38
239000011541 reaction mixture Substances 0.000 description 37
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
239000000203 mixture Substances 0.000 description 23
239000012266 salt solution Substances 0.000 description 23
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
238000004821 distillation Methods 0.000 description 18
239000007787 solid Substances 0.000 description 18
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
238000010898 silica gel chromatography Methods 0.000 description 15
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 14
OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 14
102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 13
108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 13
239000012267 brine Substances 0.000 description 13
239000003814 drug Substances 0.000 description 13
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
230000008485 antagonism Effects 0.000 description 12
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YXQLGYVHODRFHA-UHFFFAOYSA-N ethyl 2-cyclopentyl-2-hydroxy-2-phenylacetate Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC)C1CCCC1 YXQLGYVHODRFHA-UHFFFAOYSA-N 0.000 description 1
BBWMASBANDIFMV-UHFFFAOYSA-N ethyl 4-phenylpiperidine-4-carboxylate;hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C1(C(=O)OCC)CC[NH2+]CC1 BBWMASBANDIFMV-UHFFFAOYSA-N 0.000 description 1
CDFOARSBQKJGNL-UHFFFAOYSA-N ethyl 6-(hydroxymethyl)pyridine-2-carboxylate Chemical compound CCOC(=O)C1=CC=CC(CO)=N1 CDFOARSBQKJGNL-UHFFFAOYSA-N 0.000 description 1
RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
QKLCQKPAECHXCQ-UHFFFAOYSA-N ethyl phenylglyoxylate Chemical compound CCOC(=O)C(=O)C1=CC=CC=C1 QKLCQKPAECHXCQ-UHFFFAOYSA-N 0.000 description 1
238000002474 experimental method Methods 0.000 description 1
238000000605 extraction Methods 0.000 description 1
239000012025 fluorinating agent Substances 0.000 description 1
235000019253 formic acid Nutrition 0.000 description 1
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
238000001640 fractional crystallisation Methods 0.000 description 1
239000012458 free base Substances 0.000 description 1
VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
125000000524 functional group Chemical group 0.000 description 1
HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 1
239000008273 gelatin Substances 0.000 description 1
229920000159 gelatin Polymers 0.000 description 1
235000019322 gelatine Nutrition 0.000 description 1
235000011852 gelatine desserts Nutrition 0.000 description 1
230000000762 glandular Effects 0.000 description 1
239000011521 glass Substances 0.000 description 1
ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
239000008187 granular material Substances 0.000 description 1
125000005843 halogen group Chemical group 0.000 description 1
125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
150000002430 hydrocarbons Chemical group 0.000 description 1
150000003840 hydrochlorides Chemical class 0.000 description 1
229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
238000007327 hydrogenolysis reaction Methods 0.000 description 1
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
239000001863 hydroxypropyl cellulose Substances 0.000 description 1
235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 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
125000005932 isopentyloxycarbonyl group Chemical group 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
210000004731 jugular vein Anatomy 0.000 description 1
239000008101 lactose Substances 0.000 description 1
230000000670 limiting effect Effects 0.000 description 1
238000004811 liquid chromatography Methods 0.000 description 1
239000012280 lithium aluminium hydride Substances 0.000 description 1
229910001629 magnesium chloride Inorganic materials 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
150000002688 maleic acid derivatives Chemical class 0.000 description 1
MAGPZHKLEZXLNU-UHFFFAOYSA-N mandelamide Chemical compound NC(=O)C(O)C1=CC=CC=C1 MAGPZHKLEZXLNU-UHFFFAOYSA-N 0.000 description 1
JHPHVAVFUYTVCL-UHFFFAOYSA-M methacholine chloride Chemical compound [Cl-].C[N+](C)(C)CC(C)OC(C)=O JHPHVAVFUYTVCL-UHFFFAOYSA-M 0.000 description 1
229960002931 methacholine chloride Drugs 0.000 description 1
AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
LZCOQTDXKCNBEE-IKIFYQGPSA-N methscopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)C)=CC=CC=C1 LZCOQTDXKCNBEE-IKIFYQGPSA-N 0.000 description 1
ZXUQEPZWVQIOJE-UHFFFAOYSA-N methyl 2-chloro-2-oxoacetate Chemical compound COC(=O)C(Cl)=O ZXUQEPZWVQIOJE-UHFFFAOYSA-N 0.000 description 1
CWOQXQKTGNVYCV-UHFFFAOYSA-N methyl 3-methoxy-5-[(2-methylpropan-2-yl)oxycarbonylamino]benzoate Chemical compound COC(=O)C1=CC(NC(=O)OC(C)(C)C)=CC(OC)=C1 CWOQXQKTGNVYCV-UHFFFAOYSA-N 0.000 description 1
OSTVXCVLGHROLX-UHFFFAOYSA-N methyl 3-methoxy-5-nitrobenzoate Chemical compound COC(=O)C1=CC(OC)=CC([N+]([O-])=O)=C1 OSTVXCVLGHROLX-UHFFFAOYSA-N 0.000 description 1
229960001383 methylscopolamine Drugs 0.000 description 1
239000004200 microcrystalline wax Substances 0.000 description 1
235000019808 microcrystalline wax Nutrition 0.000 description 1
239000002808 molecular sieve Substances 0.000 description 1
125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
IAJZDSFAYCRLGY-UHFFFAOYSA-N n-[6-(chloromethyl)-4-methylpyridin-2-yl]acetamide Chemical compound CC(=O)NC1=CC(C)=CC(CCl)=N1 IAJZDSFAYCRLGY-UHFFFAOYSA-N 0.000 description 1
ADLBAYRCTYUMAI-UHFFFAOYSA-N n-[6-(hydroxymethyl)-4-methylpyridin-2-yl]acetamide Chemical compound CC(=O)NC1=CC(C)=CC(CO)=N1 ADLBAYRCTYUMAI-UHFFFAOYSA-N 0.000 description 1
125000001624 naphthyl group Chemical group 0.000 description 1
230000010807 negative regulation of binding Effects 0.000 description 1
125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
150000002823 nitrates Chemical class 0.000 description 1
125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 1
230000009871 nonspecific binding Effects 0.000 description 1
125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
125000005071 nonynyl group Chemical group C(#CCCCCCCC)* 0.000 description 1
125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
150000002926 oxygen Chemical class 0.000 description 1
KGCNHWXDPDPSBV-UHFFFAOYSA-N p-nitrobenzyl chloride Chemical compound [O-][N+](=O)C1=CC=C(CCl)C=C1 KGCNHWXDPDPSBV-UHFFFAOYSA-N 0.000 description 1
125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
229960001412 pentobarbital Drugs 0.000 description 1
125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
235000019271 petrolatum Nutrition 0.000 description 1
239000008194 pharmaceutical composition Substances 0.000 description 1
150000002989 phenols Chemical class 0.000 description 1
WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
235000021317 phosphate Nutrition 0.000 description 1
150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
GJQNVZVOTKFLIU-UHFFFAOYSA-N piperidin-1-ium-4-one;chloride Chemical compound Cl.O=C1CCNCC1 GJQNVZVOTKFLIU-UHFFFAOYSA-N 0.000 description 1
150000003053 piperidines Chemical class 0.000 description 1
229910003446 platinum oxide Inorganic materials 0.000 description 1
239000002798 polar solvent Substances 0.000 description 1
229920001515 polyalkylene glycol Polymers 0.000 description 1
239000001267 polyvinylpyrrolidone Substances 0.000 description 1
229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
235000015497 potassium bicarbonate Nutrition 0.000 description 1
229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
239000011736 potassium bicarbonate Substances 0.000 description 1
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
230000000069 prophylactic effect Effects 0.000 description 1
238000011321 prophylaxis Methods 0.000 description 1
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
235000013772 propylene glycol Nutrition 0.000 description 1
125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
230000002685 pulmonary effect Effects 0.000 description 1
125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
102000005962 receptors Human genes 0.000 description 1
108020003175 receptors Proteins 0.000 description 1
238000001953 recrystallisation Methods 0.000 description 1
238000001226 reprecipitation Methods 0.000 description 1
239000011347 resin Substances 0.000 description 1
229920005989 resin Polymers 0.000 description 1
230000000241 respiratory effect Effects 0.000 description 1
210000002345 respiratory system Anatomy 0.000 description 1
230000000284 resting effect Effects 0.000 description 1
125000006413 ring segment Chemical group 0.000 description 1
HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 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
125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
230000028327 secretion Effects 0.000 description 1
230000035945 sensitivity Effects 0.000 description 1
SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
239000001509 sodium citrate Substances 0.000 description 1
235000009518 sodium iodide Nutrition 0.000 description 1
AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
235000019345 sodium thiosulphate Nutrition 0.000 description 1
238000000638 solvent extraction Methods 0.000 description 1
239000000600 sorbitol Substances 0.000 description 1
235000013599 spices Nutrition 0.000 description 1
230000002269 spontaneous effect Effects 0.000 description 1
238000013222 sprague-dawley male rat Methods 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000007858 starting material Substances 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
150000003900 succinic acid esters Chemical class 0.000 description 1
AXOIZCJOOAYSMI-UHFFFAOYSA-N succinylcholine Chemical compound C[N+](C)(C)CCOC(=O)CCC(=O)OCC[N+](C)(C)C AXOIZCJOOAYSMI-UHFFFAOYSA-N 0.000 description 1
229940032712 succinylcholine Drugs 0.000 description 1
150000003460 sulfonic acids Chemical class 0.000 description 1
QHMQWEPBXSHHLH-UHFFFAOYSA-N sulfur tetrafluoride Chemical compound FS(F)(F)F QHMQWEPBXSHHLH-UHFFFAOYSA-N 0.000 description 1
150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
239000000829 suppository Substances 0.000 description 1
208000024891 symptom Diseases 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
239000006188 syrup Substances 0.000 description 1
150000003892 tartrate salts Chemical class 0.000 description 1
KLOQZAJAQQKCNC-UHFFFAOYSA-N tert-butyl 4-aminopiperidine-1-carboxylate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)N1CCC(N)CC1 KLOQZAJAQQKCNC-UHFFFAOYSA-N 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
BAVHEGHNTHMHDU-UHFFFAOYSA-N tert-butyl n-[1-[(5-methylfuran-2-yl)methyl]piperidin-4-yl]carbamate Chemical compound O1C(C)=CC=C1CN1CCC(NC(=O)OC(C)(C)C)CC1 BAVHEGHNTHMHDU-UHFFFAOYSA-N 0.000 description 1
KNWPJBSPIHDARE-PBBNMVCDSA-N tert-butyl n-[6-[[4-[[(2r)-2-[(1r)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetyl]amino]piperidin-1-yl]methyl]pyridin-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CC(CN2CCC(CC2)NC(=O)[C@@](O)([C@H]2CC(F)(F)CC2)C=2C=CC=CC=2)=N1 KNWPJBSPIHDARE-PBBNMVCDSA-N 0.000 description 1
VTORJPDWMOIOIQ-UHFFFAOYSA-N tert-butyl(diphenyl)silane Chemical compound C=1C=CC=CC=1[SiH](C(C)(C)C)C1=CC=CC=C1 VTORJPDWMOIOIQ-UHFFFAOYSA-N 0.000 description 1
CXZADJGNQCDZGX-YWQXDYITSA-N tert-butyl-[tert-butyl-phenyl-[2-[(Z)-5,5,5-trifluoro-4-methylpent-3-enyl]phenyl]silyl]oxy-phenyl-[2-[(Z)-5,5,5-trifluoro-4-methylpent-3-enyl]phenyl]silane Chemical compound FC(\C(=C/CCC1=C([Si](C2=CC=CC=C2)(C(C)(C)C)O[Si](C2=C(C=CC=C2)CC\C=C(\C)/C(F)(F)F)(C2=CC=CC=C2)C(C)(C)C)C=CC=C1)\C)(F)F CXZADJGNQCDZGX-YWQXDYITSA-N 0.000 description 1
BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
150000003510 tertiary aliphatic amines Chemical class 0.000 description 1
125000005063 tetradecenyl group Chemical group C(=CCCCCCCCCCCCC)* 0.000 description 1
125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 description 1
238000004809 thin layer chromatography Methods 0.000 description 1
210000001519 tissue Anatomy 0.000 description 1
OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
125000005040 tridecenyl group Chemical group C(=CCCCCCCCCCCC)* 0.000 description 1
125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
229940038773 trisodium citrate Drugs 0.000 description 1
235000019263 trisodium citrate Nutrition 0.000 description 1
125000005065 undecenyl group Chemical group C(=CCCCCCCCCC)* 0.000 description 1
125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
238000009423 ventilation Methods 0.000 description 1
230000002861 ventricular Effects 0.000 description 1
230000008673 vomiting Effects 0.000 description 1
239000003871 white petrolatum Substances 0.000 description 1
239000008096 xylene Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
General Health & Medical Sciences (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Bioinformatics & Cheminformatics (AREA)
Pharmacology & Pharmacy (AREA)
Engineering & Computer Science (AREA)
Animal Behavior & Ethology (AREA)
Chemical Kinetics & Catalysis (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pulmonology (AREA)
Urology & Nephrology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Hydrogenated Pyridines (AREA)
Plural Heterocyclic Compounds (AREA)
Pyridine Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

HR53,979/97A 1996-08-01 1997-07-30 Fluorine containing 1,4-disubstituted piperidine derivatives HRP970426A2 (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
JP21943696		1996-08-01
JP5397997		1997-02-21

Publications (1)

Publication Number	Publication Date
HRP970426A2 true HRP970426A2 (en)	1998-08-31

Family

ID=26394715

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
HR53,979/97A HRP970426A2 (en)	1996-08-01	1997-07-30	Fluorine containing 1,4-disubstituted piperidine derivatives

Country Status (29)

Country	Link
US (2)	US5948792A (de)
EP (1)	EP0930298B1 (de)
JP (1)	JP3063164B2 (de)
KR (1)	KR20000022214A (de)
CN (1)	CN1226888A (de)
AR (3)	AR008272A1 (de)
AT (1)	ATE229941T1 (de)
AU (1)	AU716050B2 (de)
BG (1)	BG103114A (de)
BR (1)	BR9711108A (de)
CA (1)	CA2261680C (de)
CO (1)	CO4960641A1 (de)
CZ (1)	CZ33199A3 (de)
DE (1)	DE69718026T2 (de)
EE (1)	EE9900038A (de)
ES (1)	ES2188961T3 (de)
HR (1)	HRP970426A2 (de)
HU (1)	HUP9902381A3 (de)
ID (1)	ID17259A (de)
IL (1)	IL127685A0 (de)
IS (1)	IS4960A (de)
NO (1)	NO990472D0 (de)
NZ (1)	NZ333842A (de)
PE (1)	PE92198A1 (de)
PL (1)	PL331431A1 (de)
SK (1)	SK12299A3 (de)
TR (2)	TR200001482T2 (de)
WO (1)	WO1998005641A1 (de)
YU (1)	YU1299A (de)

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1997
- 1997-07-24 PE PE1997000659A patent/PE92198A1/es not_active Application Discontinuation
- 1997-07-28 DE DE69718026T patent/DE69718026T2/de not_active Expired - Lifetime
- 1997-07-28 BR BR9711108A patent/BR9711108A/pt not_active IP Right Cessation
- 1997-07-28 CZ CZ99331A patent/CZ33199A3/cs unknown
- 1997-07-28 AU AU36351/97A patent/AU716050B2/en not_active Ceased
- 1997-07-28 TR TR2000/01482T patent/TR200001482T2/xx unknown
- 1997-07-28 IL IL12768597A patent/IL127685A0/xx unknown
- 1997-07-28 HU HU9902381A patent/HUP9902381A3/hu unknown
- 1997-07-28 EP EP97933037A patent/EP0930298B1/de not_active Expired - Lifetime
- 1997-07-28 PL PL97331431A patent/PL331431A1/xx unknown
- 1997-07-28 CN CN97196911A patent/CN1226888A/zh active Pending
- 1997-07-28 ES ES97933037T patent/ES2188961T3/es not_active Expired - Lifetime
- 1997-07-28 KR KR1019980710633A patent/KR20000022214A/ko not_active Application Discontinuation
- 1997-07-28 YU YU1299A patent/YU1299A/sh unknown
- 1997-07-28 SK SK122-99A patent/SK12299A3/sk unknown
- 1997-07-28 WO PCT/JP1997/002600 patent/WO1998005641A1/ja not_active Application Discontinuation
- 1997-07-28 AT AT97933037T patent/ATE229941T1/de not_active IP Right Cessation
- 1997-07-28 CA CA002261680A patent/CA2261680C/en not_active Expired - Fee Related
- 1997-07-28 JP JP10507794A patent/JP3063164B2/ja not_active Expired - Fee Related
- 1997-07-28 TR TR1999/00204T patent/TR199900204T2/xx unknown
- 1997-07-28 EE EEP199900038A patent/EE9900038A/xx unknown
- 1997-07-30 HR HR53,979/97A patent/HRP970426A2/hr not_active Application Discontinuation
- 1997-07-31 US US08/903,768 patent/US5948792A/en not_active Expired - Lifetime
- 1997-07-31 ID IDP972666A patent/ID17259A/id unknown
- 1997-08-01 CO CO97044382A patent/CO4960641A1/es unknown
- 1997-08-01 AR ARP970103516A patent/AR008272A1/es not_active Application Discontinuation
1998
- 1998-08-25 AR ARP980104218A patent/AR016877A2/es unknown
- 1998-08-25 AR ARP980104219A patent/AR017021A1/es unknown
1999
- 1999-01-25 BG BG103114A patent/BG103114A/xx unknown
- 1999-01-28 NZ NZ333842A patent/NZ333842A/en unknown
- 1999-01-29 IS IS4960A patent/IS4960A/is unknown
- 1999-02-01 NO NO990472A patent/NO990472D0/no not_active Application Discontinuation
- 1999-04-13 US US09/290,607 patent/US6040449A/en not_active Expired - Fee Related

Also Published As

Publication number	Publication date
CO4960641A1 (es)	2000-09-25
WO1998005641A1 (fr)	1998-02-12
SK12299A3 (en)	2000-05-16
DE69718026D1 (de)	2003-01-30
EE9900038A (et)	1999-08-16
BG103114A (en)	1999-11-30
TR199900204T2 (xx)	2000-01-21
BR9711108A (pt)	1999-08-17
US6040449A (en)	2000-03-21
CA2261680A1 (en)	1998-02-12
DE69718026T2 (de)	2003-07-10
AR017021A1 (es)	2001-08-22
AR016877A2 (es)	2001-08-01
ATE229941T1 (de)	2003-01-15
YU1299A (sh)	2002-03-18
KR20000022214A (ko)	2000-04-25
ID17259A (id)	1997-12-11
ES2188961T3 (es)	2003-07-01
PL331431A1 (en)	1999-07-19
PE92198A1 (es)	1999-01-09
CN1226888A (zh)	1999-08-25
AU716050B2 (en)	2000-02-17
EP0930298A1 (de)	1999-07-21
AU3635197A (en)	1998-02-25
HUP9902381A3 (en)	2000-06-28
CA2261680C (en)	2005-03-08
NZ333842A (en)	2001-05-25
IL127685A0 (en)	1999-10-28
EP0930298B1 (de)	2002-12-18
NO990472L (no)	1999-02-01
NO990472D0 (no)	1999-02-01
IS4960A (is)	1999-01-29
US5948792A (en)	1999-09-07
HUP9902381A2 (hu)	1999-11-29
JP3063164B2 (ja)	2000-07-12
AR008272A1 (es)	1999-12-29
EP0930298A4 (de)	2000-06-07
CZ33199A3 (cs)	1999-07-14
TR200001482T2 (tr)	2000-11-21

Publication	Publication Date	Title
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CA2218479C (en)	2008-01-15	1,4-di-substituted piperidine derivatives
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EP0863141B1 (de)	2001-09-12	Substituierte heteroaromatische derivate
DE69634806T2 (de)	2006-04-27	Substituierte heterocyclische Verbindungen, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen
RU2083574C1 (ru)	1997-07-10	Полициклические аминосодержащие соединения или их соли, их оптически чистые изомеры, способ получения полициклических аминосодержащих соединений, циклические аминосодержащие соединения или их соли, их оптически чистые изомеры и фармацевтическая композиция, обладающая антагонистической активностью к рецепторам нейрокинина
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JP2993124B2 (ja)	1999-12-20	１，４−ジ置換ピペリジン誘導体
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