BG63969B1 - Пиперидиниламинометил трифлуорметил циклени етерни съединения като антагонисти на субстанция р - Google Patents

Пиперидиниламинометил трифлуорметил циклени етерни съединения като антагонисти на субстанция р Download PDF

Info

Publication number: BG63969B1
Authority: BG; Bulgaria
Prior art keywords: methoxy; disorders; trifluoromethyl; methyl; dihydroisobenzofuran
Prior art date: 1997-11-19

Application number

BG104437A

Other languages

Bulgarian (bg)

English (en)

Other versions

BG104437A (en

Inventor

Kunio Satake

Original Assignee

Pfizer Inc.

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.)

1997-11-19

Filing date

2000-05-15

Publication date

2003-08-29

2000-05-15 Application filed by Pfizer Inc. filed Critical Pfizer Inc.

2001-02-28 Publication of BG104437A publication Critical patent/BG104437A/xx

2003-08-29 Publication of BG63969B1 publication Critical patent/BG63969B1/bg

Links

-1 Piperidinylaminomethyl trifluoromethyl cyclic ether compounds Chemical class 0.000 title claims description 34
239000003890 substance P antagonist Substances 0.000 title description 6
150000001875 compounds Chemical class 0.000 claims abstract description 132
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 41
208000035475 disorder Diseases 0.000 claims abstract description 38
150000003839 salts Chemical class 0.000 claims abstract description 34
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 32
239000001257 hydrogen Substances 0.000 claims abstract description 30
238000002360 preparation method Methods 0.000 claims abstract description 25
206010047700 Vomiting Diseases 0.000 claims abstract description 19
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 11
208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 8
208000018522 Gastrointestinal disease Diseases 0.000 claims abstract description 7
230000000172 allergic effect Effects 0.000 claims abstract description 7
230000033115 angiogenesis Effects 0.000 claims abstract description 7
208000010668 atopic eczema Diseases 0.000 claims abstract description 7
241000590002 Helicobacter pylori Species 0.000 claims abstract description 6
230000002411 adverse Effects 0.000 claims abstract description 6
229940037467 helicobacter pylori Drugs 0.000 claims abstract description 6
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
206010046543 Urinary incontinence Diseases 0.000 claims abstract description 5
125000001475 halogen functional group Chemical group 0.000 claims abstract 8
239000000203 mixture Substances 0.000 claims description 55
QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 claims description 19
102100024304 Protachykinin-1 Human genes 0.000 claims description 19
101800003906 Substance P Proteins 0.000 claims description 19
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
230000008673 vomiting Effects 0.000 claims description 18
150000002431 hydrogen Chemical class 0.000 claims description 13
208000010877 cognitive disease Diseases 0.000 claims description 12
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
241000124008 Mammalia Species 0.000 claims description 11
208000024714 major depressive disease Diseases 0.000 claims description 11
208000002193 Pain Diseases 0.000 claims description 10
208000020925 Bipolar disease Diseases 0.000 claims description 8
208000019695 Migraine disease Diseases 0.000 claims description 8
201000000980 schizophrenia Diseases 0.000 claims description 7
AZXGYKQBRXSPHY-UHFFFAOYSA-N 6-methoxy-1-methyl-1-(trifluoromethyl)-3,4-dihydroisochromene Chemical compound C1COC(C(F)(F)F)(C)C=2C1=CC(OC)=CC=2 AZXGYKQBRXSPHY-UHFFFAOYSA-N 0.000 claims description 6
208000019901 Anxiety disease Diseases 0.000 claims description 6
208000016285 Movement disease Diseases 0.000 claims description 6
201000001880 Sexual dysfunction Diseases 0.000 claims description 6
206010041303 Solar dermatitis Diseases 0.000 claims description 6
239000003814 drug Substances 0.000 claims description 6
208000027866 inflammatory disease Diseases 0.000 claims description 6
206010027599 migraine Diseases 0.000 claims description 6
231100000872 sexual dysfunction Toxicity 0.000 claims description 6
NBUDNQJPOCYIIN-UHFFFAOYSA-N 5-methoxy-1-(trifluoromethyl)-1,3-dihydro-2-benzofuran Chemical compound COC1=CC=C2C(C(F)(F)F)OCC2=C1 NBUDNQJPOCYIIN-UHFFFAOYSA-N 0.000 claims description 5
FGGKIMGMRFUCLN-UHFFFAOYSA-N 6-methoxy-3-methyl-3-(trifluoromethyl)-1h-2-benzofuran Chemical compound COC1=CC=C2C(C(F)(F)F)(C)OCC2=C1 FGGKIMGMRFUCLN-UHFFFAOYSA-N 0.000 claims description 5
230000003042 antagnostic effect Effects 0.000 claims description 5
210000003169 central nervous system Anatomy 0.000 claims description 5
239000000126 substance Substances 0.000 claims description 5
AZXGYKQBRXSPHY-LLVKDONJSA-N (1r)-6-methoxy-1-methyl-1-(trifluoromethyl)-3,4-dihydroisochromene Chemical compound C=1([C@](OCC2)(C)C(F)(F)F)C2=CC(OC)=CC=1 AZXGYKQBRXSPHY-LLVKDONJSA-N 0.000 claims description 4
NASATCITWOQHEY-OGUPFJCYSA-N (2s,3s)-n-[[6-methoxy-3-phenyl-3-(trifluoromethyl)-1h-2-benzofuran-5-yl]methyl]-2-phenylpiperidin-3-amine Chemical compound C1([C@@H]2NCCC[C@@H]2NCC2=CC=3C(OCC=3C=C2OC)(C=2C=CC=CC=2)C(F)(F)F)=CC=CC=C1 NASATCITWOQHEY-OGUPFJCYSA-N 0.000 claims description 4
DOLRECVJKHHFSD-UHFFFAOYSA-N 1-[6-methoxy-3-methyl-3-(trifluoromethyl)-1h-2-benzofuran-5-yl]ethanone Chemical compound C1=C(C(C)=O)C(OC)=CC2=C1C(C)(C(F)(F)F)OC2 DOLRECVJKHHFSD-UHFFFAOYSA-N 0.000 claims description 4
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
239000003937 drug carrier Substances 0.000 claims description 4
229910052731 fluorine Inorganic materials 0.000 claims description 4
239000008194 pharmaceutical composition Substances 0.000 claims description 4
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
NITVFOGGUFSYNJ-NUEVNEFVSA-N (2S,3S)-3-[6-methoxy-3-methyl-3-(trifluoromethyl)-1H-2-benzofuran-5-yl]-N-methyl-2-phenylpiperidin-1-amine Chemical compound COC1=C(C=C2C(OCC2=C1)(C(F)(F)F)C)[C@H]1[C@H](N(CCC1)NC)C1=CC=CC=C1 NITVFOGGUFSYNJ-NUEVNEFVSA-N 0.000 claims description 3
RDOKLDFJIBLNAR-UHFFFAOYSA-N 6-methoxy-1-methyl-1-(trifluoromethyl)-3,4-dihydroisochromene-7-carbaldehyde Chemical compound C1COC(C)(C(F)(F)F)C2=C1C=C(OC)C(C=O)=C2 RDOKLDFJIBLNAR-UHFFFAOYSA-N 0.000 claims description 3
UTEFTKTYELSUJY-UHFFFAOYSA-N 6-methoxy-3-phenyl-3-(trifluoromethyl)-1h-2-benzofuran-5-carbaldehyde Chemical compound C1=2C=C(C=O)C(OC)=CC=2COC1(C(F)(F)F)C1=CC=CC=C1 UTEFTKTYELSUJY-UHFFFAOYSA-N 0.000 claims description 3
CZRCXUGPHJTJCZ-UHFFFAOYSA-N n-methyl-2-phenylpiperidin-1-amine Chemical compound CNN1CCCCC1C1=CC=CC=C1 CZRCXUGPHJTJCZ-UHFFFAOYSA-N 0.000 claims description 3
RDOKLDFJIBLNAR-GFCCVEGCSA-N (1r)-6-methoxy-1-methyl-1-(trifluoromethyl)-3,4-dihydroisochromene-7-carbaldehyde Chemical compound C1CO[C@@](C)(C(F)(F)F)C2=C1C=C(OC)C(C=O)=C2 RDOKLDFJIBLNAR-GFCCVEGCSA-N 0.000 claims description 2
NITVFOGGUFSYNJ-MTNREXPMSA-N (2S,3S)-3-[(3R)-6-methoxy-3-methyl-3-(trifluoromethyl)-1H-2-benzofuran-5-yl]-N-methyl-2-phenylpiperidin-1-amine Chemical compound COC1=C(C=C2[C@@](OCC2=C1)(C(F)(F)F)C)[C@H]1[C@H](N(CCC1)NC)C1=CC=CC=C1 NITVFOGGUFSYNJ-MTNREXPMSA-N 0.000 claims description 2
ARZVJUKNXGNLEF-UHFFFAOYSA-N 6-methoxy-3,3-bis(trifluoromethyl)-1h-2-benzofuran Chemical compound COC1=CC=C2C(C(F)(F)F)(C(F)(F)F)OCC2=C1 ARZVJUKNXGNLEF-UHFFFAOYSA-N 0.000 claims description 2
ZMSIXMWTEKXFEN-UHFFFAOYSA-N 6-methoxy-3,3-bis(trifluoromethyl)-1h-2-benzofuran-5-carbaldehyde Chemical compound C1=C(C=O)C(OC)=CC2=C1C(C(F)(F)F)(C(F)(F)F)OC2 ZMSIXMWTEKXFEN-UHFFFAOYSA-N 0.000 claims description 2
GPWGSWJZRDEAJI-UHFFFAOYSA-N 6-methoxy-3-(trifluoromethyl)-2,3-dihydro-1-benzofuran-5-carbaldehyde Chemical compound C1=C(C=O)C(OC)=CC2=C1C(C(F)(F)F)CO2 GPWGSWJZRDEAJI-UHFFFAOYSA-N 0.000 claims description 2
WKAUHBLYGCROEW-UHFFFAOYSA-N 6-methoxy-3-methyl-3-(trifluoromethyl)-1h-2-benzofuran-5-carbaldehyde Chemical compound C1=C(C=O)C(OC)=CC2=C1C(C)(C(F)(F)F)OC2 WKAUHBLYGCROEW-UHFFFAOYSA-N 0.000 claims description 2
XIRBHTNKLIOEGN-UHFFFAOYSA-N 6-methoxy-3-phenyl-3-(trifluoromethyl)-1h-2-benzofuran Chemical compound C=1C(OC)=CC=C2C=1COC2(C(F)(F)F)C1=CC=CC=C1 XIRBHTNKLIOEGN-UHFFFAOYSA-N 0.000 claims description 2
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
206010021639 Incontinence Diseases 0.000 claims description 2
125000000217 alkyl group Chemical group 0.000 claims description 2
229910052799 carbon Inorganic materials 0.000 claims description 2
239000011737 fluorine Substances 0.000 claims description 2
RDOKLDFJIBLNAR-LBPRGKRZSA-N (1s)-6-methoxy-1-methyl-1-(trifluoromethyl)-3,4-dihydroisochromene-7-carbaldehyde Chemical compound C1CO[C@](C)(C(F)(F)F)C2=C1C=C(OC)C(C=O)=C2 RDOKLDFJIBLNAR-LBPRGKRZSA-N 0.000 claims 1
NAWOVAZMDQTKQU-ICTUGDKOSA-N (2S,3S)-3-[6-methoxy-3-(trifluoromethyl)-1,3-dihydro-2-benzofuran-5-yl]-N-methyl-2-phenylpiperidin-1-amine Chemical compound COC1=C(C=C2C(OCC2=C1)C(F)(F)F)[C@H]1[C@H](N(CCC1)NC)C1=CC=CC=C1 NAWOVAZMDQTKQU-ICTUGDKOSA-N 0.000 claims 1
208000015114 central nervous system disease Diseases 0.000 abstract description 6
239000000543 intermediate Substances 0.000 abstract description 5
239000002260 anti-inflammatory agent Substances 0.000 abstract description 2
229940121363 anti-inflammatory agent Drugs 0.000 abstract description 2
125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 3
229940035676 analgesics Drugs 0.000 abstract 1
239000000730 antalgic agent Substances 0.000 abstract 1
208000014001 urinary system disease Diseases 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 70
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 69
239000000243 solution Substances 0.000 description 55
238000000034 method Methods 0.000 description 39
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 36
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
238000005481 NMR spectroscopy Methods 0.000 description 36
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
238000006243 chemical reaction Methods 0.000 description 30
239000011541 reaction mixture Substances 0.000 description 26
235000019439 ethyl acetate Nutrition 0.000 description 24
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
239000012043 crude product Substances 0.000 description 18
229910052943 magnesium sulfate Inorganic materials 0.000 description 18
235000019341 magnesium sulphate Nutrition 0.000 description 18
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
239000000284 extract Substances 0.000 description 17
239000012299 nitrogen atmosphere Substances 0.000 description 16
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 13
239000000741 silica gel Substances 0.000 description 13
229910002027 silica gel Inorganic materials 0.000 description 13
239000012267 brine Substances 0.000 description 12
125000005843 halogen group Chemical group 0.000 description 12
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
239000002253 acid Substances 0.000 description 11
238000004440 column chromatography Methods 0.000 description 11
239000007787 solid Substances 0.000 description 11
239000002904 solvent Substances 0.000 description 11
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
239000012230 colorless oil Substances 0.000 description 10
239000013078 crystal Substances 0.000 description 10
239000003921 oil Substances 0.000 description 10
235000019198 oils Nutrition 0.000 description 10
229920006395 saturated elastomer Polymers 0.000 description 10
ICFIBYSBLHRUNG-QJCCHNLGSA-N (2s,3s)-n-[1-[6-methoxy-3-methyl-3-(trifluoromethyl)-1h-2-benzofuran-5-yl]ethyl]-2-phenylpiperidin-3-amine;dihydrochloride Chemical compound Cl.Cl.C1([C@@H]2NCCC[C@@H]2NC(C)C2=CC=3C(C)(OCC=3C=C2OC)C(F)(F)F)=CC=CC=C1 ICFIBYSBLHRUNG-QJCCHNLGSA-N 0.000 description 9
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
150000001412 amines Chemical class 0.000 description 9
230000008569 process Effects 0.000 description 9
125000006239 protecting group Chemical group 0.000 description 9
238000005160 1H NMR spectroscopy Methods 0.000 description 8
YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 8
SFLGSKRGOWRGBR-UHFFFAOYSA-N phthalane Chemical compound C1=CC=C2COCC2=C1 SFLGSKRGOWRGBR-UHFFFAOYSA-N 0.000 description 8
238000000746 purification Methods 0.000 description 8
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
230000027455 binding Effects 0.000 description 7
230000000694 effects Effects 0.000 description 7
239000010410 layer Substances 0.000 description 7
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
239000012442 inert solvent Substances 0.000 description 6
239000012044 organic layer Substances 0.000 description 6
238000010898 silica gel chromatography Methods 0.000 description 6
238000012360 testing method Methods 0.000 description 6
WAYCQEPIQNTRDJ-UHFFFAOYSA-N 1,3-dihydro-2-benzofuran-5-carbaldehyde Chemical compound O=CC1=CC=C2COCC2=C1 WAYCQEPIQNTRDJ-UHFFFAOYSA-N 0.000 description 5
FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 5
241001465754 Metazoa Species 0.000 description 5
241000283984 Rodentia Species 0.000 description 5
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
229910052794 bromium Inorganic materials 0.000 description 5
239000003153 chemical reaction reagent Substances 0.000 description 5
239000003795 chemical substances by application Substances 0.000 description 5
238000004128 high performance liquid chromatography Methods 0.000 description 5
238000011534 incubation Methods 0.000 description 5
229910052757 nitrogen Inorganic materials 0.000 description 5
230000002829 reductive effect Effects 0.000 description 5
239000012258 stirred mixture Substances 0.000 description 5
238000003786 synthesis reaction Methods 0.000 description 5
BGKYIHZTAGIZDV-UHFFFAOYSA-N 2-[(2-bromo-5-methoxyphenyl)methoxy]oxane Chemical compound COC1=CC=C(Br)C(COC2OCCCC2)=C1 BGKYIHZTAGIZDV-UHFFFAOYSA-N 0.000 description 4
ZNMHZQWMFDNCIM-UHFFFAOYSA-N 6-methoxy-3-(trifluoromethyl)-1,3-dihydro-2-benzofuran-5-carbaldehyde Chemical compound C1=C(C=O)C(OC)=CC2=C1C(C(F)(F)F)OC2 ZNMHZQWMFDNCIM-UHFFFAOYSA-N 0.000 description 4
241000282412 Homo Species 0.000 description 4
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
208000013200 Stress disease Diseases 0.000 description 4
RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 4
239000012298 atmosphere Substances 0.000 description 4
235000017663 capsaicin Nutrition 0.000 description 4
229960002504 capsaicin Drugs 0.000 description 4
210000004027 cell Anatomy 0.000 description 4
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239000003085 diluting agent Substances 0.000 description 4
150000002009 diols Chemical class 0.000 description 4
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 4
238000001704 evaporation Methods 0.000 description 4
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238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
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BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
238000001953 recrystallisation Methods 0.000 description 4
235000017557 sodium bicarbonate Nutrition 0.000 description 4
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208000011117 substance-related disease Diseases 0.000 description 4
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NUIFQGHCIGDPNY-GXBCDIMNSA-N tert-butyl (2s,3s)-3-[[6-methoxy-3-(trifluoromethyl)-1,3-dihydro-2-benzofuran-5-yl]methylamino]-2-phenylpiperidine-1-carboxylate Chemical compound C1([C@@H]2N(CCC[C@@H]2NCC2=CC=3C(OCC=3C=C2OC)C(F)(F)F)C(=O)OC(C)(C)C)=CC=CC=C1 NUIFQGHCIGDPNY-GXBCDIMNSA-N 0.000 description 4
210000001519 tissue Anatomy 0.000 description 4
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
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 4
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GQOAORJRRSLOQA-KBPBESRZSA-N tert-butyl (2s,3s)-3-amino-2-phenylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1C1=CC=CC=C1 GQOAORJRRSLOQA-KBPBESRZSA-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
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Classifications

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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
- 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
- C07D405/12—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 chain containing hetero atoms as chain links

Landscapes

Health & Medical Sciences (AREA)
Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Chemical Kinetics & Catalysis (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Neurosurgery (AREA)
Neurology (AREA)
Biomedical Technology (AREA)
Pulmonology (AREA)
Pain & Pain Management (AREA)
Immunology (AREA)
Urology & Nephrology (AREA)
Psychiatry (AREA)
Hospice & Palliative Care (AREA)
Dermatology (AREA)
Heart & Thoracic Surgery (AREA)
Rheumatology (AREA)
Reproductive Health (AREA)
Cardiology (AREA)
Endocrinology (AREA)
Oncology (AREA)
Physical Education & Sports Medicine (AREA)
Orthopedic Medicine & Surgery (AREA)
Gynecology & Obstetrics (AREA)
Vascular Medicine (AREA)
Communicable Diseases (AREA)
Otolaryngology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Hydrogenated Pyridines (AREA)
Plural Heterocyclic Compounds (AREA)

BG104437A 1997-11-19 2000-05-15 Пиперидиниламинометил трифлуорметил циклени етерни съединения като антагонисти на субстанция р BG63969B1 (bg)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
IB9701466		1997-11-19
PCT/IB1998/001704 WO1999025714A1 (en)	1997-11-19	1998-10-26	Piperidinylaminomethyl trifluoromethyl cyclic ether compounds as substance p antagonists

Publications (2)

Publication Number	Publication Date
BG104437A BG104437A (en)	2001-02-28
BG63969B1 true BG63969B1 (bg)	2003-08-29

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ID=11004634

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BG104437A BG63969B1 (bg)	1997-11-19	2000-05-15	Пиперидиниламинометил трифлуорметил циклени етерни съединения като антагонисти на субстанция р

Country Status (40)

Country	Link
US (2)	US20030208079A1 (zh)
EP (1)	EP1032571B1 (zh)
JP (2)	JP3394239B2 (zh)
KR (1)	KR100366902B1 (zh)
CN (1)	CN1173974C (zh)
AP (1)	AP909A (zh)
AR (1)	AR016422A1 (zh)
AT (1)	ATE219078T1 (zh)
AU (1)	AU734218B2 (zh)
BG (1)	BG63969B1 (zh)
CA (1)	CA2310627C (zh)
CO (1)	CO4771153A1 (zh)
CZ (1)	CZ297315B6 (zh)
DE (1)	DE69806045T2 (zh)
DK (1)	DK1032571T3 (zh)
DZ (1)	DZ2655A1 (zh)
EA (1)	EA002621B1 (zh)
ES (1)	ES2177058T3 (zh)
HK (1)	HK1033313A1 (zh)
HR (1)	HRP20000313B1 (zh)
HU (1)	HUP0101112A3 (zh)
ID (1)	ID24240A (zh)
IL (1)	IL135631A0 (zh)
IS (1)	IS2202B (zh)
MA (1)	MA26567A1 (zh)
MY (1)	MY120558A (zh)
NO (2)	NO20002544L (zh)
NZ (1)	NZ503912A (zh)
OA (1)	OA11380A (zh)
PA (1)	PA8463001A1 (zh)
PE (1)	PE20000021A1 (zh)
PL (1)	PL193484B1 (zh)
PT (1)	PT1032571E (zh)
RS (1)	RS49792B (zh)
SK (1)	SK283460B6 (zh)
TN (1)	TNSN98210A1 (zh)
TR (1)	TR200001463T2 (zh)
TW (1)	TW426667B (zh)
UA (1)	UA59417C2 (zh)
WO (1)	WO1999025714A1 (zh)

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GB9812662D0 (en) *	1998-06-11	1998-08-12	Merck Sharp & Dohme	Therapeutic use
GB9812617D0 (en) *	1998-06-11	1998-08-12	Merck Sharp & Dohme	Therapeutic use
AU3572800A (en) *	1999-05-06	2000-11-21	Pfizer Products Inc.	Substituted benzolactam compounds
RS49964B (sr)	1999-05-17	2008-09-29	Pfizer Products Inc.,	Postupak za dobijanje 2-fenil-3-aminopiridina,njegovih supstituisanih fenil derivata, i njegovih soli
PT1178984E (pt) *	1999-05-21	2003-06-30	Pfizer Prod Inc	Derivados de 1-trifluorometil-4-hidroxi-7-piperidinilamimometilcromano
EP1219619B1 (en) *	1999-10-07	2004-08-11	Hisamitsu Pharmaceutical Co. Inc.	3-amino-2-phenylpiperidine derivatives as substance p antagonists
DK1095939T3 (da) *	1999-10-18	2004-04-13	Pfizer Prod Inc	Fremgangsmåde til fremstilling af cykliske piperidinylaminomethyltrifluormethyletherforbindelser
JP2001172178A (ja) *	1999-10-25	2001-06-26	Pfizer Prod Inc	偏頭痛治療用のｎｋ−１レセプターアンタゴニスト及びエレトリプタン
IL142810A0 (en) *	2000-05-03	2002-03-10	Pfizer Prod Inc	Pharmaceutical uses for fluoroalkoxybenzylamino derivatives of nitrogen containing heterocycles
US20020049211A1 (en) *	2000-09-06	2002-04-25	Sobolov-Jaynes Susan Beth	Combination treatment for depression and anxiety
EP1192952A3 (en) *	2000-09-28	2003-03-26	Pfizer Products Inc.	Combination, for treating depression and anxiety, containing an NK-3 receptor antagonist and a CNS penetrant NK-1 receptor antagonist
US6555581B1 (en)	2001-02-15	2003-04-29	Jones Pharma, Inc.	Levothyroxine compositions and methods
EP1365745A2 (en)	2001-02-15	2003-12-03	King Pharmaceuticals, Inc.	Stabilized pharmaceutical and thyroid hormone compositions and method of preparation
US7101569B2 (en)	2001-08-14	2006-09-05	Franz G Andrew	Methods of administering levothyroxine pharmaceutical compositions
DE60213043T2 (de)	2001-08-30	2007-01-04	Pfizer Products Inc., Groton	Verfahren zur Herstellung von 2-(4-Alkyl-1-Piperazinyl)-Benzaldehyd und -Benzylidenyl-Derivaten durch Nucleophile Substitution von 2-Fluorobenzaldehyd mit 4-Alkyl-1-Piperazinen in Wasser als Lösungsmittel
US20040001895A1 (en) *	2002-06-17	2004-01-01	Pfizer Inc.	Combination treatment for depression and anxiety
US20070207123A1 (en) *	2002-08-27	2007-09-06	Witten Mark L	Amelioration of effects of cigarette smoke
US6911544B2 (en) *	2002-10-23	2005-06-28	Pfizer Inc.	Process for the preparation of (S,S)-cis-2-phenyl-3-aminopiperidine
US7122700B2 (en)	2004-07-30	2006-10-17	Xerox Corporation	Arylamine processes
DE102008000891A1 (de)	2008-03-31	2009-10-01	Robert Bosch Gmbh	Schutzsystem für Werkzeugmaschinen
EP2729147B1 (en)	2011-07-04	2017-09-06	IRBM - Science Park S.p.A.	Nk-1 receptor antagonists for treating corneal neovascularisation
RU2020131446A (ru)	2018-02-26	2022-03-28	Оспедале Сан Раффаэле С.Р.Л.	Антагонисты nk-1 для применения в лечении глазной боли
EP4117673A1 (en)	2020-03-11	2023-01-18	Ospedale San Raffaele S.r.l.	Treatment of stem cell deficiency

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GB9317987D0 (en) *	1993-08-26	1993-10-13	Glaxo Group Ltd	Chemical compounds
KR19980703354A (ko) *	1995-03-27	1998-10-15	나카토미히로타카	피페리딘 유도체
TW475930B (en) *	1995-04-24	2002-02-11	Novartis Ag	Novel compound, its use and pharmaceutical composition comprising it
CA2226292C (en) *	1995-07-07	2001-12-11	Pfizer Inc.	Substituted benzolactam compounds as substance p antagonists
TW340842B (en) *	1995-08-24	1998-09-21	Pfizer	Substituted benzylaminopiperidine compounds
US6329396B1 (en) *	1996-06-10	2001-12-11	Pfizer Inc.	Substituted benzylaminopiperidine compounds
PT1178984E (pt) *	1999-05-21	2003-06-30	Pfizer Prod Inc	Derivados de 1-trifluorometil-4-hidroxi-7-piperidinilamimometilcromano
DK1095939T3 (da) *	1999-10-18	2004-04-13	Pfizer Prod Inc	Fremgangsmåde til fremstilling af cykliske piperidinylaminomethyltrifluormethyletherforbindelser

1998
- 1998-10-21 TW TW087117444A patent/TW426667B/zh not_active IP Right Cessation
- 1998-10-26 NZ NZ503912A patent/NZ503912A/xx unknown
- 1998-10-26 TR TR2000/01463T patent/TR200001463T2/xx unknown
- 1998-10-26 AT AT98947726T patent/ATE219078T1/de not_active IP Right Cessation
- 1998-10-26 EP EP98947726A patent/EP1032571B1/en not_active Expired - Lifetime
- 1998-10-26 UA UA2000042374A patent/UA59417C2/uk unknown
- 1998-10-26 CN CNB988112930A patent/CN1173974C/zh not_active Expired - Fee Related
- 1998-10-26 JP JP2000521096A patent/JP3394239B2/ja not_active Expired - Fee Related
- 1998-10-26 CZ CZ20001834A patent/CZ297315B6/cs not_active IP Right Cessation
- 1998-10-26 RS YUP-294/00A patent/RS49792B/sr unknown
- 1998-10-26 EA EA200000432A patent/EA002621B1/ru not_active IP Right Cessation
- 1998-10-26 AU AU94549/98A patent/AU734218B2/en not_active Ceased
- 1998-10-26 DK DK98947726T patent/DK1032571T3/da active
- 1998-10-26 ES ES98947726T patent/ES2177058T3/es not_active Expired - Lifetime
- 1998-10-26 SK SK723-2000A patent/SK283460B6/sk unknown
- 1998-10-26 IL IL13563198A patent/IL135631A0/xx not_active IP Right Cessation
- 1998-10-26 WO PCT/IB1998/001704 patent/WO1999025714A1/en active IP Right Grant
- 1998-10-26 HU HU0101112A patent/HUP0101112A3/hu unknown
- 1998-10-26 DE DE69806045T patent/DE69806045T2/de not_active Expired - Fee Related
- 1998-10-26 PT PT98947726T patent/PT1032571E/pt unknown
- 1998-10-26 CA CA002310627A patent/CA2310627C/en not_active Expired - Fee Related
- 1998-10-26 ID IDW20000926A patent/ID24240A/id unknown
- 1998-11-11 PA PA19988463001A patent/PA8463001A1/es unknown
- 1998-11-16 PE PE1998001112A patent/PE20000021A1/es not_active Application Discontinuation
- 1998-11-17 AR ARP980105829A patent/AR016422A1/es unknown
- 1998-11-17 MY MYPI98005209A patent/MY120558A/en unknown
- 1998-11-17 MA MA25354A patent/MA26567A1/fr unknown
- 1998-11-18 TN TNTNSN98210A patent/TNSN98210A1/fr unknown
- 1998-11-18 CO CO98067902A patent/CO4771153A1/es unknown
- 1998-11-18 DZ DZ980265A patent/DZ2655A1/xx active
- 1998-11-19 AP APAP/P/1998/001402A patent/AP909A/en active
2000
- 2000-04-26 IS IS5470A patent/IS2202B/is unknown
- 2000-05-12 OA OA1200000138A patent/OA11380A/en unknown
- 2000-05-15 BG BG104437A patent/BG63969B1/bg unknown
- 2000-05-17 HR HR960576A patent/HRP20000313B1/xx not_active IP Right Cessation
- 2000-05-18 NO NO20002544A patent/NO20002544L/no not_active Application Discontinuation
- 2000-05-18 PL PL98340642A patent/PL193484B1/pl unknown
- 2000-05-18 KR KR10-2000-7005431A patent/KR100366902B1/ko not_active IP Right Cessation
2001
- 2001-06-08 HK HK01103947A patent/HK1033313A1/xx not_active IP Right Cessation
2002
- 2002-06-18 JP JP2002177452A patent/JP2003040777A/ja active Pending
2003
- 2003-04-21 US US10/419,425 patent/US20030208079A1/en not_active Abandoned
2004
- 2004-07-07 NO NO20042879A patent/NO20042879L/no not_active Application Discontinuation
- 2004-11-18 US US10/991,977 patent/US20050171354A1/en not_active Abandoned

Also Published As

Publication number	Publication date
TR200001463T2 (tr)	2000-12-21
MA26567A1 (fr)	2004-12-20
CZ20001834A3 (cs)	2001-07-11
PA8463001A1 (es)	2000-09-29
JP2001523680A (ja)	2001-11-27
CN1173974C (zh)	2004-11-03
ID24240A (id)	2000-07-13
SK283460B6 (sk)	2003-08-05
HUP0101112A3 (en)	2002-06-28
ATE219078T1 (de)	2002-06-15
OA11380A (en)	2004-01-27
UA59417C2 (uk)	2003-09-15
IS2202B (is)	2007-02-15
RS49792B (sr)	2008-06-05
TNSN98210A1 (fr)	2005-03-15
SK7232000A3 (en)	2001-09-11
YU29400A (sh)	2003-02-28
AP9801402A0 (en)	1998-12-31
CZ297315B6 (cs)	2006-11-15
NO20002544L (no)	2000-07-17
IL135631A0 (en)	2001-05-20
AU9454998A (en)	1999-06-07
KR100366902B1 (ko)	2003-01-09
AP909A (en)	2000-12-04
BG104437A (en)	2001-02-28
US20030208079A1 (en)	2003-11-06
JP2003040777A (ja)	2003-02-13
AR016422A1 (es)	2001-07-04
CN1279681A (zh)	2001-01-10
PT1032571E (pt)	2002-09-30
HUP0101112A2 (hu)	2002-05-29
HRP20000313A2 (en)	2000-12-31
EA200000432A1 (ru)	2000-12-25
JP3394239B2 (ja)	2003-04-07
DK1032571T3 (da)	2002-07-15
PL340642A1 (en)	2001-02-12
HK1033313A1 (en)	2001-08-24
DZ2655A1 (fr)	2003-03-22
TW426667B (en)	2001-03-21
PE20000021A1 (es)	2000-02-25
US20050171354A1 (en)	2005-08-04
EA002621B1 (ru)	2002-06-27
NZ503912A (en)	2002-09-27
CO4771153A1 (es)	1999-04-30
WO1999025714A1 (en)	1999-05-27
NO20002544D0 (no)	2000-05-18
HRP20000313B1 (en)	2002-04-30
EP1032571A1 (en)	2000-09-06
ES2177058T3 (es)	2002-12-01
DE69806045D1 (en)	2002-07-18
DE69806045T2 (de)	2002-11-14
CA2310627C (en)	2005-08-09
AU734218B2 (en)	2001-06-07
CA2310627A1 (en)	1999-05-27
MY120558A (en)	2005-11-30
PL193484B1 (pl)	2007-02-28
IS5470A (is)	2000-04-26
NO20042879L (no)	2000-07-17
EP1032571B1 (en)	2002-06-12

Publication	Publication Date	Title
BG63969B1 (bg)	2003-08-29	Пиперидиниламинометил трифлуорметил циклени етерни съединения като антагонисти на субстанция р
US6239147B1 (en)	2001-05-29	1-trifluoromethyl-4-hydroxy-7-piperidinyl-aminomethylchroman derivatives
DE69524388T2 (de)	2002-08-14	4-amino-6-substituierte mycophenolsäurederivate mit immunsuppressiver wirkung
MXPA00004889A (en)	2001-07-09	Piperidinylaminomethyl trifluoromethyl cyclic ether compounds as substance p antagonists
Yanagi et al.	1999	Synthesis and pharmacological activity of 4-amino-5-chloro-2-methoxy-N-[(2S, 4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl] benzamide (TKS159) and its optical isomers
JPH11140052A (ja)	1999-05-25	サブスタンスｐアンタゴニストとしての３−［（５−置換ベンジル）アミノ］−２−フェニルピペリジン