JP4768010B2 - 嘔吐のためのnk−1アンタゴニストの代謝物 - Google Patents
嘔吐のためのnk−1アンタゴニストの代謝物 Download PDFInfo
- Publication number
- JP4768010B2 JP4768010B2 JP2008502283A JP2008502283A JP4768010B2 JP 4768010 B2 JP4768010 B2 JP 4768010B2 JP 2008502283 A JP2008502283 A JP 2008502283A JP 2008502283 A JP2008502283 A JP 2008502283A JP 4768010 B2 JP4768010 B2 JP 4768010B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- compound
- formula
- piperazin
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 206010047700 Vomiting Diseases 0.000 title claims description 9
- 230000008673 vomiting Effects 0.000 title claims description 5
- 239000005557 antagonist Substances 0.000 title description 3
- 239000002207 metabolite Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 56
- -1 4-methyl-piperazine- 1-yl Chemical group 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 8
- 229940047889 isobutyramide Drugs 0.000 claims description 7
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 5
- 208000019901 Anxiety disease Diseases 0.000 claims description 4
- 208000019695 Migraine disease Diseases 0.000 claims description 4
- 239000012425 OXONE® Substances 0.000 claims description 4
- 206010030113 Oedema Diseases 0.000 claims description 4
- 230000036506 anxiety Effects 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 206010027599 migraine Diseases 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 206010019233 Headaches Diseases 0.000 claims description 3
- 208000002193 Pain Diseases 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 208000028017 Psychotic disease Diseases 0.000 claims description 3
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 3
- 201000010105 allergic rhinitis Diseases 0.000 claims description 3
- 231100000869 headache Toxicity 0.000 claims description 3
- 230000004968 inflammatory condition Effects 0.000 claims description 3
- 229960005181 morphine Drugs 0.000 claims description 3
- 201000003152 motion sickness Diseases 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 claims description 2
- 239000000203 mixture Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 102100024304 Protachykinin-1 Human genes 0.000 description 10
- 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 8
- CUGOZHKFGSQBGD-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-n-[4-[2-(hydroxymethyl)phenyl]-6-(4-methylpiperazin-1-yl)pyridin-3-yl]-n,2-dimethylpropanamide Chemical compound C=1N=C(N2CCN(C)CC2)C=C(C=2C(=CC=CC=2)CO)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CUGOZHKFGSQBGD-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 101800003906 Substance P Proteins 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000000829 suppository Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000000370 acceptor Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 239000013543 active substance Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 description 4
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000005540 biological transmission Effects 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000013149 parallel artificial membrane permeability assay Methods 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000003786 synthesis reaction Methods 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
- YLIRSRYWNHPZRS-UHFFFAOYSA-N 4-iodo-6-(4-methylpiperazin-1-yl)pyridin-3-amine Chemical compound C1CN(C)CCN1C1=CC(I)=C(N)C=N1 YLIRSRYWNHPZRS-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000002742 neurokinin 1 receptor antagonist Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- DGUWACLYDSWXRZ-UHFFFAOYSA-N (2-formylphenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1C=O DGUWACLYDSWXRZ-UHFFFAOYSA-N 0.000 description 2
- SFEVQUPISPQHOG-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl chloride Chemical compound ClC(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 SFEVQUPISPQHOG-UHFFFAOYSA-N 0.000 description 2
- YHHGTSDAOLXNKX-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-n-[4-(2-formylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl]-n,2-dimethylpropanamide Chemical compound C=1N=C(N2CCN(C)CC2)C=C(C=2C(=CC=CC=2)C=O)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 YHHGTSDAOLXNKX-UHFFFAOYSA-N 0.000 description 2
- BTXBMUKEYNBXAD-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-n-[4-iodo-6-(4-methylpiperazin-1-yl)pyridin-3-yl]-2-methylpropanamide Chemical compound C1CN(C)CCN1C(N=C1)=CC(I)=C1NC(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 BTXBMUKEYNBXAD-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- NUFBIAUZAMHTSP-UHFFFAOYSA-N 3-(n-morpholino)-2-hydroxypropanesulfonic acid Chemical compound OS(=O)(=O)CC(O)CN1CCOCC1 NUFBIAUZAMHTSP-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 102100021260 Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 1 Human genes 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 101000894906 Homo sapiens Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 1 Proteins 0.000 description 2
- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102000003141 Tachykinin Human genes 0.000 description 2
- 102000007124 Tachykinin Receptors Human genes 0.000 description 2
- 108010072901 Tachykinin Receptors Proteins 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- LHYWCVALBBMUPK-UHFFFAOYSA-N n-[4-iodo-6-(4-methylpiperazin-1-yl)pyridin-3-yl]-2,2-dimethylpropanamide Chemical compound C1CN(C)CCN1C1=CC(I)=C(NC(=O)C(C)(C)C)C=N1 LHYWCVALBBMUPK-UHFFFAOYSA-N 0.000 description 2
- WAXQNWCZJDTGBU-UHFFFAOYSA-N netupitant Chemical compound C=1N=C(N2CCN(C)CC2)C=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 WAXQNWCZJDTGBU-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 108060008037 tachykinin Proteins 0.000 description 2
- 239000002462 tachykinin receptor antagonist Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 238000002211 ultraviolet spectrum Methods 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- CVXOXWXUGAGXHJ-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-n-[4-iodo-6-(4-methylpiperazin-1-yl)pyridin-3-yl]-n,2-dimethylpropanamide Chemical compound C=1N=C(N2CCN(C)CC2)C=C(I)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CVXOXWXUGAGXHJ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010066091 Bronchial Hyperreactivity Diseases 0.000 description 1
- KQBQHPKRWZRQPH-UHFFFAOYSA-N CC(C)(C(N(C)c(cnc(N1CCN(C)CC1)c1)c1-c1c(CO)cccc1)=O)c1cc(C=C)cc(C(F)(F)F)c1 Chemical compound CC(C)(C(N(C)c(cnc(N1CCN(C)CC1)c1)c1-c1c(CO)cccc1)=O)c1cc(C=C)cc(C(F)(F)F)c1 KQBQHPKRWZRQPH-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010007979 Glycocholic Acid Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
- 208000000501 Lipidoses Diseases 0.000 description 1
- 206010024585 Lipidosis Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 102000028517 Neuropeptide receptor Human genes 0.000 description 1
- 108070000018 Neuropeptide receptor Proteins 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZPHBZEQOLSRPAK-UHFFFAOYSA-N Phosphoramidon Natural products C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O ZPHBZEQOLSRPAK-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 241001062472 Stokellia anisodon Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000008344 egg yolk phospholipid Substances 0.000 description 1
- 239000002895 emetic Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 231100000040 eye damage Toxicity 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000008011 inorganic excipient Substances 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 210000001630 jejunum Anatomy 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000008012 organic excipient Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- HJKYXKSLRZKNSI-UHFFFAOYSA-I pentapotassium;hydrogen sulfate;oxido sulfate;sulfuric acid Chemical compound [K+].[K+].[K+].[K+].[K+].OS([O-])(=O)=O.[O-]S([O-])(=O)=O.OS(=O)(=O)O[O-].OS(=O)(=O)O[O-] HJKYXKSLRZKNSI-UHFFFAOYSA-I 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 108010072906 phosphoramidon Proteins 0.000 description 1
- BWSDNRQVTFZQQD-AYVHNPTNSA-N phosphoramidon Chemical compound O([P@@](O)(=O)N[C@H](CC(C)C)C(=O)N[C@H](CC=1[C]2C=CC=CC2=NC=1)C(O)=O)[C@H]1O[C@@H](C)[C@H](O)[C@@H](O)[C@@H]1O BWSDNRQVTFZQQD-AYVHNPTNSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 210000003594 spinal ganglia Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000002466 tachykinin receptor agonist Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—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
- C07D213/02—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
- 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- 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
- A61P11/02—Nasal agents, e.g. decongestants
-
- 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
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Psychiatry (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Otolaryngology (AREA)
- Rheumatology (AREA)
- Addiction (AREA)
- Hospice & Palliative Care (AREA)
- Cardiology (AREA)
- Psychology (AREA)
- Heart & Thoracic Surgery (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Description
(式中、
Rは、メチルであり;そして
R1は、4−メチル−4−オキシ−ピペラジン−1−イルであるか;又は
Rは、CH2OHであり、そして
R1は、4−メチル−ピペラジン−1−イル又は4−メチル−4−オキシ−ピペラジン−1−イルである)
の化合物及びその薬学的に許容される酸付加塩に関する。
2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(2−ヒドロキシメチル−フェニル)−6−(4−メチル−ピペラジン−1−イル)−ピリジン−3−イル]−N−メチル−イソブチルアミド(化合物I−2)及び、
2−(3,5−ジメチル−フェニル)−N−[4−(2−ヒドロキシメチル−フェニル)−6−(4−メチル−4−オキシ−ピペラジン−1−イル)−ピリジン−3−イル]−N−メチル−イソブチルアミド(1−3)、
を含む式Iの化合物及びその薬学的に許容される塩、上記化合物の製造、それらを含有する医薬及びその製造、並びに、疾病、特に、前記で言及された種類の疾病及び障害の抑制若しくは予防における又は対応する薬剤の製造における上記化合物の使用である。
a)式
b)式
DIPEA N−エチルジイソプロピル−アミン
KHMDS カリウム ヘキサメチルジシラジド
平衡溶解度の方法説明
方法説明:
浸透度を、96ウェルマイクロプレートに基づくPAMPA PSR4pアッセイにより調査した。浸透度を「サンドイッチ」構造を用いて測定する。フィルタープレートをリン脂質(膜)でコーティングし、薬物/緩衝溶液を含むドナープレート中に配置する。最後に、フィルタープレートに緩衝溶液(アクセプタ)を充填する。ドナー濃度を、t−start時(参考)に測定し、特定時間のt−end後のドナー及びアクセプタ濃度と比較する。以下のセットアップをPAMPA PSR4pアッセイに使用する:
膜:ドデカン中、10%(w/v)卵レシチン+0.5%(w/v)コレステロール
アクセプタ:pH6.5の0.05 MOPSO緩衝液
以下の組成の錠剤を常法により製造する:
mg/錠剤
活性物質 5
乳糖 45
トウモロコシデンプン 15
微晶質セルロース 34
ステアリン酸マグネシウム 1
錠剤重量 100
以下の組成のカプセル剤を常法により製造する:
mg/カプセル剤
活性物質 10
乳糖 155
トウモロコシデンプン 30
タルク 5
カプセル充填重量 200
以下の組成の座剤を製造する:
mg/座剤
活性物質 15
座薬用錬剤 1285
総量 1300
2−(3,5−ビス−トリフルオロメチル−フェニル)−N−メチル−N−[6−(4−メチル−4−オキシ−ピペラジン−1−イル)−4−o−トリル−ピリジン−3−イル]−イソブチルアミド(化合物I−1)
MS m/e(%):595(M+H+、100)
2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(2−ヒドロキシメチル−フェニル)−6−(4−メチル−ピペラジン−1−イル)−ピリジン−3−イル]−N−メチル−イソブチルアミド(化合物I−2)
3N塩酸50ml中のN−[4−ヨード−6−(4−メチル−ピペラジン−1−イル)−ピリジン−3−イル]−2,2−ジメチル−プロピオンアミド(合成はDE10008042に記載されている)2.20g(5.47mmol)の混合物を、100℃で18時間撹拌した。0℃まで冷却した後、反応混合物をエーテル(50ml)で2回洗浄した。水相をジクロロメタン50mlで処理し、炭酸ナトリウムの1M溶液で塩基性化した。有機相を分離し、水相をジクロロメタン50mlで4回抽出した。合わせた有機層を硫酸ナトリウムで乾燥し、真空下で濃縮して、標記化合物1.60g(92%)をオフホワイトの固体として得た。
MS m/e(%):319(M+H+、100)
ジクロロメタン16ml中の、4−ヨード−6−(4−メチル−ピペラジン−1−イル)−ピリジン−3−イルアミン1.60g(5.03mmol)及びN,N−ジイソプロピルエチルアミン975mg(7.54mmol)の懸濁液に、2−(3,5−ビス−トリフルオロメチル−フェニル)−2−メチル−プロピオニル クロライド1.76g(5.53mmol)を0℃で滴下した。反応混合物を室温で2時間及び還流温度で2時間撹拌した。室温まで冷却した後、反応混合物を1M炭酸ナトリウム水溶液20ml及び水20mlで洗浄した。合わせた有機層を硫酸ナトリウムで乾燥し、真空下で濃縮して、粗標記化合物3.39g(100%)を褐色の油状物として得た。
MS m/e(%):601(M+H+、100)
N,N−ジメチルホルムアミド30ml中の2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−ヨード−6−(4−メチル−ピペラジン−1−イル)−ピリジン−3−イル]−イソブチルアミド3.09g(5.15mmol)の溶液に、テトラヒドロフラン中のカリウム ビス(トリメチルシリル)アミドの0.91M溶液6.8ml(6.2mmol)を0℃で加えた。0℃で40分間撹拌した後、ヨードメタン0.352ml(5.66mmol)を加えた。混合物を密閉したフラスコ内で2日間撹拌した。反応混合物を真空下で濃縮し、フラッシュクロマトグラフィーにより精製して、標記化合物980mg(31%)を褐色の油状物として得た。
MS m/e(%):615(M+H+、100)
ジメトキシエタン5ml中の、2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−ヨード−6−(4−メチル−ピペラジン−1−イル)−ピリジン−3−イル]−N−メチル−イソブチルアミド900mg(1.47mmol)、1M炭酸ナトリウム水溶液2.8ml、酢酸パラジウム(II)33mg(0.15mmol)、トリフェニルホスフィン77mg(0.29mmol)及び2−ホルミルフェニルボロン酸242mg(1.61mmol)の混合物を排気させ、アルゴンを充填し、80℃で2時間撹拌した。室温まで冷却した後、反応混合物を酢酸エチル20mlで希釈し、ブライン20mlで洗浄した。合わせた有機層を硫酸ナトリウムで乾燥し、濃縮し、フラッシュクロマトグラフィーにより精製して、標記化合物584mg(67%)を淡褐色の固体として得た。
MS m/e(%):593(M+H+、100)
メタノール2ml中の水素化ホウ素ナトリウム15mg(0.41mmol)の混合物に、2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(2−ホルミル−フェニル)−6−(4−メチル−ピペラジン−1−イル)−ピリジン−3−イル]−N−メチル−イソブチルアミド200mg(0.338mmol)を0℃で加えた。0℃で1時間撹拌した後、ブライン1mlを0℃で加えた。混合物を30分間撹拌した。メタノールを留去し、残渣を酢酸エチル20mlで希釈し、ブライン20mlで洗浄した。有機層を硫酸ナトリウムで乾燥し、濃縮し、フラッシュクロマトグラフィーにより精製して、標記化合物137mg(68%)を淡褐色の固体として得た。
MS m/e(%):595(M+H+、100)
Claims (8)
- 2−(3,5−ビス−トリフルオロメチル−フェニル)−N−メチル−N−[6−(4−メチル−4−オキシ−ピペラジン−1−イル)−4−o−トリル−ピリジン−3−イル]−イソブチルアミド(化合物I−1)又は、
2−(3,5−ビス−トリフルオロメチル−フェニル)−N−[4−(2−ヒドロキシメチル−フェニル)−6−(4−メチル−ピペラジン−1−イル)−ピリジン−3−イル]−N−メチル−イソブチルアミド(化合物I−2)である、請求項1記載の化合物。 - 請求項1又は2記載の一種以上の化合物及び薬学的に許容される賦形剤を含む医薬。
- 片頭痛、関節リウマチ及び喘息を含む炎症状態、嘔吐、パーキンソン病、疼痛、頭痛、アルツハイマー病、不安、鬱病、多発性硬化症、モルヒネ禁断の減衰、浮腫、アレルギー性鼻炎、クローン病、精神病、乗り物酔い及び嘔吐を処置するための、請求項3記載の医薬。
- 片頭痛、関節リウマチ及び喘息を含む炎症状態、嘔吐、パーキンソン病、疼痛、頭痛、アルツハイマー病、不安、鬱病、多発性硬化症、モルヒネ禁断の減衰、浮腫、アレルギー性鼻炎、クローン病、精神病、乗り物酔い及び嘔吐を処置する医薬を製造するための、請求項1又は2記載の化合物の使用。
- 嘔吐を処置する医薬を製造するための、請求項1又は2記載の化合物の使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05102359 | 2005-03-23 | ||
EP05102359.6 | 2005-03-23 | ||
PCT/EP2006/002313 WO2006099968A1 (en) | 2005-03-23 | 2006-03-14 | Metabolites for nk-i antagonists for emesis |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2008534454A JP2008534454A (ja) | 2008-08-28 |
JP4768010B2 true JP4768010B2 (ja) | 2011-09-07 |
Family
ID=36587133
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008502283A Expired - Fee Related JP4768010B2 (ja) | 2005-03-23 | 2006-03-14 | 嘔吐のためのnk−1アンタゴニストの代謝物 |
Country Status (22)
Country | Link |
---|---|
US (1) | US7211579B2 (ja) |
EP (1) | EP1863767B1 (ja) |
JP (1) | JP4768010B2 (ja) |
KR (1) | KR100903224B1 (ja) |
CN (1) | CN101146775B (ja) |
AR (1) | AR052949A1 (ja) |
AT (1) | ATE425144T1 (ja) |
AU (1) | AU2006226665B2 (ja) |
BR (1) | BRPI0609699A2 (ja) |
CA (1) | CA2602445C (ja) |
DE (1) | DE602006005624D1 (ja) |
DK (1) | DK1863767T3 (ja) |
ES (1) | ES2320590T3 (ja) |
IL (1) | IL185689A (ja) |
MX (1) | MX2007011489A (ja) |
NO (1) | NO20074622L (ja) |
PL (1) | PL1863767T3 (ja) |
PT (1) | PT1863767E (ja) |
RU (1) | RU2404969C2 (ja) |
TW (1) | TWI316056B (ja) |
WO (1) | WO2006099968A1 (ja) |
ZA (1) | ZA200708029B (ja) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4580426B2 (ja) | 2004-07-06 | 2010-11-10 | エフ.ホフマン−ラ ロシュ アーゲー | Nk−1受容体拮抗薬の合成において中間体として使用されるカルボキサミド誘導体の製造方法 |
US9403772B2 (en) | 2011-11-29 | 2016-08-02 | Helsinn Healthcare Sa | 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium as a neurokinin receptor modulator |
US8426450B1 (en) * | 2011-11-29 | 2013-04-23 | Helsinn Healthcare Sa | Substituted 4-phenyl pyridines having anti-emetic effect |
KR20160078997A (ko) | 2013-11-08 | 2016-07-05 | 깃세이 야쿠힌 고교 가부시키가이샤 | 카복시메틸피페리딘 유도체 |
EP3140007A1 (en) * | 2014-05-05 | 2017-03-15 | Apicore US LLC | Methods of making netupitant and intermediates thereof |
TWI649307B (zh) | 2014-05-07 | 2019-02-01 | 日商橘生藥品工業股份有限公司 | Cyclohexylpyridine derivative |
CN112174881B (zh) * | 2019-07-04 | 2022-06-21 | 上海森辉医药有限公司 | 一种奈妥匹坦的衍生物及其制备方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1035115A1 (en) * | 1999-02-24 | 2000-09-13 | F. Hoffmann-La Roche Ag | 4-Phenylpyridine derivatives and their use as NK-1 receptor antagonists |
JP2001151754A (ja) * | 1999-11-29 | 2001-06-05 | F Hoffmann La Roche Ag | 2−(3,5−ビス−トリフルオロメチル−フェニル)−N−メチル−N−(6−モルホリン−4−イル−4−o−トリル−ピリジン−3−イル)−イソブチルアミド |
JP2004504301A (ja) * | 2000-07-14 | 2004-02-12 | エフ.ホフマン−ラ ロシュ アーゲー | Nk1受容体拮抗物質プロドラッグとしての4−フェニル−ピリジン誘導体のn−オキシド |
JP2004536119A (ja) * | 2001-07-10 | 2004-12-02 | エフ.ホフマン−ラ ロシュ アーゲー | 脳、脊髄又は神経損傷の処置のためのnk−1レセプターアンタゴニストの使用 |
WO2005002577A1 (en) * | 2003-07-03 | 2005-01-13 | F. Hoffmann-La Roche Ag | Dual nk1/nk3 antagonists for treating schizophrenia |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4745123A (en) | 1986-02-18 | 1988-05-17 | Warner-Lambert Company | Substituted tetrahydro-3-pyridine-carboxylic acid, ester, and amide cholinergic agents |
IL111960A (en) | 1993-12-17 | 1999-12-22 | Merck & Co Inc | Morpholines and thiomorpholines their preparation and pharmaceutical compositions containing them |
BR9408442A (pt) | 1993-12-29 | 1997-08-05 | Merck Sharp & Dohme | Composto composição farmacêutica processos para tratamento ou prevenção de distúrbios fisiológicos associados com um excesso de taquiquininas e para a preparação do composto e de uso do composto |
TW385308B (en) | 1994-03-04 | 2000-03-21 | Merck & Co Inc | Prodrugs of morpholine tachykinin receptor antagonists |
US5972938A (en) | 1997-12-01 | 1999-10-26 | Merck & Co., Inc. | Method for treating or preventing psychoimmunological disorders |
WO2001085173A1 (en) * | 2000-05-10 | 2001-11-15 | Bristol-Myers Squibb Company | Alkylamine derivatives of dihydropyridine npy antagonists |
-
2006
- 2006-03-14 PL PL06707550T patent/PL1863767T3/pl unknown
- 2006-03-14 CA CA2602445A patent/CA2602445C/en not_active Expired - Fee Related
- 2006-03-14 ES ES06707550T patent/ES2320590T3/es active Active
- 2006-03-14 DK DK06707550T patent/DK1863767T3/da active
- 2006-03-14 MX MX2007011489A patent/MX2007011489A/es active IP Right Grant
- 2006-03-14 PT PT06707550T patent/PT1863767E/pt unknown
- 2006-03-14 CN CN2006800094426A patent/CN101146775B/zh active Active
- 2006-03-14 JP JP2008502283A patent/JP4768010B2/ja not_active Expired - Fee Related
- 2006-03-14 DE DE602006005624T patent/DE602006005624D1/de active Active
- 2006-03-14 WO PCT/EP2006/002313 patent/WO2006099968A1/en active Application Filing
- 2006-03-14 EP EP06707550A patent/EP1863767B1/en active Active
- 2006-03-14 AT AT06707550T patent/ATE425144T1/de active
- 2006-03-14 KR KR1020077021748A patent/KR100903224B1/ko active IP Right Grant
- 2006-03-14 RU RU2007134901/04A patent/RU2404969C2/ru not_active IP Right Cessation
- 2006-03-14 BR BRPI0609699-9A patent/BRPI0609699A2/pt not_active IP Right Cessation
- 2006-03-14 AU AU2006226665A patent/AU2006226665B2/en not_active Ceased
- 2006-03-15 US US11/376,042 patent/US7211579B2/en active Active
- 2006-03-20 TW TW095109514A patent/TWI316056B/zh not_active IP Right Cessation
- 2006-03-21 AR ARP060101093A patent/AR052949A1/es unknown
-
2007
- 2007-09-03 IL IL185689A patent/IL185689A/en not_active IP Right Cessation
- 2007-09-12 NO NO20074622A patent/NO20074622L/no not_active Application Discontinuation
- 2007-09-18 ZA ZA200708029A patent/ZA200708029B/xx unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1035115A1 (en) * | 1999-02-24 | 2000-09-13 | F. Hoffmann-La Roche Ag | 4-Phenylpyridine derivatives and their use as NK-1 receptor antagonists |
JP2001151754A (ja) * | 1999-11-29 | 2001-06-05 | F Hoffmann La Roche Ag | 2−(3,5−ビス−トリフルオロメチル−フェニル)−N−メチル−N−(6−モルホリン−4−イル−4−o−トリル−ピリジン−3−イル)−イソブチルアミド |
JP2004504301A (ja) * | 2000-07-14 | 2004-02-12 | エフ.ホフマン−ラ ロシュ アーゲー | Nk1受容体拮抗物質プロドラッグとしての4−フェニル−ピリジン誘導体のn−オキシド |
JP2004536119A (ja) * | 2001-07-10 | 2004-12-02 | エフ.ホフマン−ラ ロシュ アーゲー | 脳、脊髄又は神経損傷の処置のためのnk−1レセプターアンタゴニストの使用 |
WO2005002577A1 (en) * | 2003-07-03 | 2005-01-13 | F. Hoffmann-La Roche Ag | Dual nk1/nk3 antagonists for treating schizophrenia |
Also Published As
Publication number | Publication date |
---|---|
US20060217393A1 (en) | 2006-09-28 |
AU2006226665B2 (en) | 2011-01-27 |
NO20074622L (no) | 2007-10-18 |
ATE425144T1 (de) | 2009-03-15 |
EP1863767B1 (en) | 2009-03-11 |
DE602006005624D1 (de) | 2009-04-23 |
TWI316056B (en) | 2009-10-21 |
AR052949A1 (es) | 2007-04-11 |
TW200700390A (en) | 2007-01-01 |
AU2006226665A1 (en) | 2006-09-28 |
KR20070107146A (ko) | 2007-11-06 |
BRPI0609699A2 (pt) | 2010-04-20 |
WO2006099968A1 (en) | 2006-09-28 |
EP1863767A1 (en) | 2007-12-12 |
CN101146775B (zh) | 2012-07-18 |
PL1863767T3 (pl) | 2009-08-31 |
US7211579B2 (en) | 2007-05-01 |
RU2007134901A (ru) | 2009-04-27 |
PT1863767E (pt) | 2009-03-27 |
DK1863767T3 (da) | 2009-05-04 |
ZA200708029B (en) | 2008-11-26 |
CA2602445A1 (en) | 2006-09-28 |
RU2404969C2 (ru) | 2010-11-27 |
ES2320590T3 (es) | 2009-05-25 |
IL185689A (en) | 2012-05-31 |
MX2007011489A (es) | 2007-10-11 |
IL185689A0 (en) | 2008-01-06 |
CA2602445C (en) | 2013-08-20 |
CN101146775A (zh) | 2008-03-19 |
JP2008534454A (ja) | 2008-08-28 |
KR100903224B1 (ko) | 2009-06-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP3399900B2 (ja) | 4−フェニル−ピリジン誘導体 | |
JP3950044B2 (ja) | Nk1受容体拮抗物質プロドラッグとしての4−フェニル−ピリジン誘導体のn−オキシド | |
JP4768010B2 (ja) | 嘔吐のためのnk−1アンタゴニストの代謝物 | |
EP1305319B1 (en) | 4-phenyl-pyridine derivatives as neurokinin-1 receptor antagonists | |
JP3480835B2 (ja) | 2−(3,5−ビス−トリフルオロメチル−フェニル)−N−メチル−N−(6−モルホリン−4−イル−4−o−トリル−ピリジン−3−イル)−イソブチルアミド | |
AU2001282005A1 (en) | 4-phenyl-pyridine derivatives as neurokinin-1 receptor antagonists | |
JP4700908B2 (ja) | 2−(3,5−ビス−トリフルオロメチル−フェニル)−N−〔6−(1,1−ジオキソ−1λ6−チオモルホリン−4−イル)−4−(2−メチル又は4−フルオロ−2−メチル置換)フェニル−ピリジン−3−イル〕−N−メチル−イソブチルアミド | |
JP4767973B2 (ja) | Nk1アンタゴニスト |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20101207 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20110307 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20110308 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20110314 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20110531 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20110615 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 4768010 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140624 Year of fee payment: 3 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |