PL205207B1 - N-tlenki pochodnych 4-fenylopirydyny środek leczniczy, sposób wytwarzania tych N-tlenków i ich zastosowanie - Google Patents
N-tlenki pochodnych 4-fenylopirydyny środek leczniczy, sposób wytwarzania tych N-tlenków i ich zastosowanieInfo
- Publication number
- PL205207B1 PL205207B1 PL365684A PL36568401A PL205207B1 PL 205207 B1 PL205207 B1 PL 205207B1 PL 365684 A PL365684 A PL 365684A PL 36568401 A PL36568401 A PL 36568401A PL 205207 B1 PL205207 B1 PL 205207B1
- Authority
- PL
- Poland
- Prior art keywords
- methyl
- oxides
- bis
- general formula
- compound
- Prior art date
Links
- 239000000651 prodrug Substances 0.000 title claims abstract description 21
- 229940002612 prodrug Drugs 0.000 title claims abstract description 21
- 150000001204 N-oxides Chemical class 0.000 title claims description 44
- 150000005362 4-phenylpyridines Chemical class 0.000 title claims description 6
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 title abstract description 8
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 title abstract description 8
- 239000002464 receptor antagonist Substances 0.000 title description 3
- 229940044551 receptor antagonist Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 91
- -1 cyclic tertiary amine Chemical class 0.000 claims abstract description 54
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 125000001424 substituent group Chemical group 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 9
- 238000011282 treatment Methods 0.000 claims abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 22
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 8
- 229940047889 isobutyramide Drugs 0.000 claims description 8
- VZOPVKZLLGMDDG-UHFFFAOYSA-N 1-oxido-4-phenylpyridin-1-ium Chemical class C1=C[N+]([O-])=CC=C1C1=CC=CC=C1 VZOPVKZLLGMDDG-UHFFFAOYSA-N 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 6
- 206010047700 Vomiting Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 4
- 230000036506 anxiety Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 150000004682 monohydrates Chemical class 0.000 claims description 4
- 230000008673 vomiting Effects 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 208000028017 Psychotic disease Diseases 0.000 claims description 3
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 3
- 208000015114 central nervous system disease Diseases 0.000 claims description 3
- 150000001860 citric acid derivatives Chemical class 0.000 claims description 3
- FFHWGQQFANVOHV-UHFFFAOYSA-N dimethyldioxirane Chemical compound CC1(C)OO1 FFHWGQQFANVOHV-UHFFFAOYSA-N 0.000 claims description 3
- 150000003840 hydrochlorides Chemical class 0.000 claims description 3
- 150000002688 maleic acid derivatives Chemical class 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 3
- 150000002823 nitrates Chemical class 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 150000003890 succinate salts Chemical class 0.000 claims description 3
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- 208000012902 Nervous system disease Diseases 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 239000012425 OXONE® Substances 0.000 claims 1
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- 150000002431 hydrogen Chemical group 0.000 abstract 5
- 125000003545 alkoxy group Chemical group 0.000 abstract 4
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- 239000000243 solution Substances 0.000 description 56
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 239000007787 solid Substances 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000000203 mixture Substances 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 23
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 18
- 229940079593 drug Drugs 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 238000001816 cooling Methods 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- FMQPGFVLWDLWPR-UHFFFAOYSA-N n-methyl-n-[(2-methylnaphthalen-1-yl)methyl]-4-(2-methylphenyl)-6-morpholin-4-ylpyridine-3-carboxamide Chemical compound CC=1C=CC2=CC=CC=C2C=1CN(C)C(=O)C1=CN=C(N2CCOCC2)C=C1C1=CC=CC=C1C FMQPGFVLWDLWPR-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- STBYRSZXHDPASK-UHFFFAOYSA-N 1-(chloromethyl)-2-methylnaphthalene Chemical compound C1=CC=CC2=C(CCl)C(C)=CC=C21 STBYRSZXHDPASK-UHFFFAOYSA-N 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
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- 235000019198 oils Nutrition 0.000 description 10
- 239000006260 foam Substances 0.000 description 9
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- 102100024304 Protachykinin-1 Human genes 0.000 description 8
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- 238000012360 testing method Methods 0.000 description 8
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 101800003906 Substance P Proteins 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 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 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 5
- NSJVYHOPHZMZPN-UHFFFAOYSA-N (2-methylphenyl)boronic acid Chemical compound CC1=CC=CC=C1B(O)O NSJVYHOPHZMZPN-UHFFFAOYSA-N 0.000 description 4
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 4
- GXMHAZCHUPKETI-UHFFFAOYSA-N 6-chloro-n-methyl-4-(2-methylphenyl)pyridine-3-carboxamide Chemical compound CNC(=O)C1=CN=C(Cl)C=C1C1=CC=CC=C1C GXMHAZCHUPKETI-UHFFFAOYSA-N 0.000 description 4
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- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 description 1
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- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
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- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
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- 239000008117 stearic acid Substances 0.000 description 1
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- 235000020357 syrup Nutrition 0.000 description 1
- 108060008037 tachykinin Proteins 0.000 description 1
- 239000002466 tachykinin receptor agonist Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-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
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- 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
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- 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
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Landscapes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Applications Claiming Priority (2)
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| EP00115287 | 2000-07-14 | ||
| PCT/EP2001/007850 WO2002006236A1 (en) | 2000-07-14 | 2001-07-09 | N-oxides as nk1 receptor antagonist prodrugs of 4-phenyl-pyridine derivatives |
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| PL365684A1 PL365684A1 (en) | 2005-01-10 |
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| TWI287003B (en) * | 2000-07-24 | 2007-09-21 | Hoffmann La Roche | 4-phenyl-pyridine derivatives |
| MXPA03009720A (es) * | 2001-04-23 | 2004-01-29 | Hoffmann La Roche | USO DE ANTAGONISTAS DEL RECEPTOR DE NK-1 PARA TRATAMIENTO O PREVENCIoN DE HIPERPLASIA PROSTATICA BENIGNA. |
| JP4490421B2 (ja) | 2003-07-03 | 2010-06-23 | エフ．ホフマン−ラ ロシュ アーゲー | 統合失調症を処置するデュアルｎｋ１／ｎｋ３アンタゴニスト |
| EP1776342B1 (en) | 2004-07-06 | 2011-03-02 | F. Hoffmann-La Roche AG | Process for preparing carboxamide pyridine derivatives used as intermediates in the synthesis of nk-1 receptor antagonists |
| US20060030600A1 (en) * | 2004-08-06 | 2006-02-09 | Patrick Schnider | Dual NK1/NK3 receptor antagonists for the treatment of schizophrenia |
| CN101128189A (zh) | 2005-02-25 | 2008-02-20 | 弗·哈夫曼-拉罗切有限公司 | 药物物质分散性改善的片剂 |
| RU2404969C2 (ru) * | 2005-03-23 | 2010-11-27 | Ф. Хоффманн-Ля Рош Аг | Метаболиты антагонистов nk-1 против рвоты |
| JP2008280248A (ja) * | 2005-11-02 | 2008-11-20 | Eisai R & D Management Co Ltd | アルツハイマー型痴呆症治療薬塩酸ドネペジルのプロドラッグ |
| JP2010516734A (ja) | 2007-01-24 | 2010-05-20 | グラクソ グループ リミテッド | ３，５−ジアミノ−６−（２，３−ジクロロフェニル）−１，２，４−トリアジンまたはｒ（−）−２，４−ジアミノ−５−（２，３−ジクロロフェニル）−６−フルオロメチルピリミジンを含む医薬組成物 |
| GB0808747D0 (en) | 2008-05-14 | 2008-06-18 | Glaxo Wellcome Mfg Pte Ltd | Novel compounds |
| US8966414B2 (en) | 2009-05-29 | 2015-02-24 | Cypress Semiconductor Corporation | Implementing a circuit using an integrated circuit including parametric analog elements |
| US9858367B1 (en) | 2009-08-31 | 2018-01-02 | Cypress Semiconductor Corporation | Integrated circuit including parametric analog elements |
| EP2722045B1 (en) | 2009-11-18 | 2016-07-06 | Helsinn Healthcare SA | Compositions for treating centrally mediated nausea and vomiting |
| HRP20140759T1 (hr) | 2009-11-18 | 2014-10-24 | Helsinn Healthcare S.A. | Kompozicije za lijeäśenje središnje posredovane muäśnine i povraä†anja |
| ES2579616T3 (es) | 2011-10-18 | 2016-08-12 | Helsinn Healthcare Sa | Combinaciones terapéuticas de netupitant y palonosetrón |
| US8426450B1 (en) | 2011-11-29 | 2013-04-23 | Helsinn Healthcare Sa | Substituted 4-phenyl pyridines having anti-emetic effect |
| CA3142817A1 (en) | 2011-12-28 | 2013-07-04 | Global Blood Therapeutics, Inc. | Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation |
| ES2790358T3 (es) | 2011-12-28 | 2020-10-27 | Global Blood Therapeutics Inc | Compuestos de heteroaril aldehído sustituido y métodos para su uso en el aumento de la oxigenación tisular |
| US8952171B2 (en) | 2013-03-15 | 2015-02-10 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
| US10100043B2 (en) | 2013-03-15 | 2018-10-16 | Global Blood Therapeutics, Inc. | Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation |
| EP3919056B1 (en) | 2013-03-15 | 2024-08-28 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
| CN112500338A (zh) | 2013-03-15 | 2021-03-16 | 全球血液疗法股份有限公司 | 化合物及其用于调节血红蛋白的用途 |
| US9604999B2 (en) | 2013-03-15 | 2017-03-28 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
| EP2968299B1 (en) | 2013-03-15 | 2021-01-20 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
| US9458139B2 (en) | 2013-03-15 | 2016-10-04 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
| US10266551B2 (en) | 2013-03-15 | 2019-04-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
| US9422279B2 (en) | 2013-03-15 | 2016-08-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
| US9802900B2 (en) | 2013-03-15 | 2017-10-31 | Global Blood Therapeutics, Inc. | Bicyclic heteroaryl compounds and uses thereof for the modulation of hemoglobin |
| CA2930008A1 (en) | 2013-11-08 | 2015-05-14 | Kissei Pharmaceutical Co., Ltd. | Carboxymethyl piperidine derivative |
| EA202092627A1 (ru) | 2013-11-18 | 2021-09-30 | Глобал Блад Терапьютикс, Инк. | Соединения и их применения для модуляции гемоглобина |
| US10350098B2 (en) * | 2013-12-20 | 2019-07-16 | Volcano Corporation | Devices and methods for controlled endoluminal filter deployment |
| SG10201911662YA (en) | 2014-02-07 | 2020-02-27 | Global Blood Therapeutics Inc | Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
| TWI649307B (zh) | 2014-05-07 | 2019-02-01 | 日商橘生藥品工業股份有限公司 | Cyclohexylpyridine derivative |
| CN106588899B (zh) * | 2015-10-15 | 2019-11-15 | 江苏恒瑞医药股份有限公司 | 吡啶基取代的6-氧杂螺[4.5]癸烷类衍生物、其制备方法及其在医药上的应用 |
| HUE072191T2 (hu) | 2015-12-04 | 2025-10-28 | Global Blood Therapeutics Inc | A 2-hidoxi-6-((2-(1-izopropil-1H-pirazol-5-il)piridin-3-il)metoxi)benzaldehid adagolási rendje |
| TWI825524B (zh) | 2016-05-12 | 2023-12-11 | 美商全球血液治療公司 | 用於合成2-羥基-6-((2-(1-異丙基-1h-吡唑-5-基)-吡啶-3-基)甲氧基)苯甲醛之方法 |
| TWI778983B (zh) | 2016-10-12 | 2022-10-01 | 美商全球血液治療公司 | 包含2-羥基-6-((2-(1-異丙基-1h-吡唑-5-基)吡啶-3-基)甲氧基)-苯甲醛之片劑 |
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| JP7158425B2 (ja) | 2017-06-30 | 2022-10-21 | チェイス セラピューティクス コーポレイション | Ｎｋ－１アンタゴニスト組成物およびうつ病の処置における使用法 |
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| JPS56106286A (en) | 1980-01-28 | 1981-08-24 | Nippon Musical Instruments Mfg | Electronic musical instrument |
| EP0103545A3 (en) | 1982-09-13 | 1984-10-03 | Arc Technologies Systems, Ltd. | Electrode for arc furnaces |
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| DE69428913T2 (de) | 1993-12-29 | 2002-05-29 | Merck Sharp & Dohme Ltd., Hoddesdon | Substituierte morpholinderivate und ihre verwendung als arzneimittel |
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| DE19627431A1 (de) * | 1996-07-08 | 1998-01-15 | Bayer Ag | Heterocyclisch kondensierte Pyridine |
| AR008789A1 (es) * | 1996-07-31 | 2000-02-23 | Bayer Corp | Piridinas y bifenilos substituidos |
| US5972938A (en) | 1997-12-01 | 1999-10-26 | Merck & Co., Inc. | Method for treating or preventing psychoimmunological disorders |
| CN1131212C (zh) * | 1999-02-24 | 2003-12-17 | 弗·哈夫曼-拉罗切有限公司 | 苯基－和吡啶基衍生物 |
| CN1134417C (zh) * | 1999-02-24 | 2004-01-14 | 弗·哈夫曼-拉罗切有限公司 | 3-苯基吡啶衍生物及其作为nk-1受体拮抗剂的应用 |
| DE60045564D1 (de) * | 1999-02-24 | 2011-03-03 | Hoffmann La Roche | 4-Phenylpyridinderivate und deren Verwendung als NK-1 Rezeptorantagonisten |
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| CA2415890C (en) * | 2000-07-14 | 2009-04-07 | F. Hoffmann-La Roche Ag | N-oxides as nk1 receptor antagonist prodrugs of 4-phenyl-pyridine derivatives |
| US20030083345A1 (en) * | 2001-07-10 | 2003-05-01 | Torsten Hoffmann | Method of treatment and/or prevention of brain, spinal or nerve injury |
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