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
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- 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
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- Prior art keywords
- methyl
- compound
- formula
- piperazin
- phenyl
- Prior art date
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- 229930006000 Sucrose Natural products 0.000 description 1
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- 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
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- 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
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- 230000000994 depressogenic effect Effects 0.000 description 1
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 102000004196 processed proteins & peptides Human genes 0.000 description 1
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- 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
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- 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
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- 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
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Classifications
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- 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
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- 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
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- 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
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Landscapes
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- Pharmacology & Pharmacy (AREA)
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- Rheumatology (AREA)
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- Orthopedic Medicine & Surgery (AREA)
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- Cardiology (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。
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DE602005026669D1 (de) | 2004-07-06 | 2011-04-14 | Hoffmann La Roche | Herstellungsverfahren für carboxamid-pyridin-derivate als zwischenprodukte bei der synthese von nk-1-rezeptor-antagonisten |
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 |
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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 |
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AU2006226665A1 (en) | 2006-09-28 |
NO20074622L (no) | 2007-10-18 |
US20060217393A1 (en) | 2006-09-28 |
RU2404969C2 (ru) | 2010-11-27 |
CN101146775A (zh) | 2008-03-19 |
IL185689A (en) | 2012-05-31 |
WO2006099968A1 (en) | 2006-09-28 |
KR100903224B1 (ko) | 2009-06-17 |
EP1863767A1 (en) | 2007-12-12 |
CA2602445A1 (en) | 2006-09-28 |
TW200700390A (en) | 2007-01-01 |
DK1863767T3 (da) | 2009-05-04 |
ATE425144T1 (de) | 2009-03-15 |
MX2007011489A (es) | 2007-10-11 |
AR052949A1 (es) | 2007-04-11 |
ZA200708029B (en) | 2008-11-26 |
KR20070107146A (ko) | 2007-11-06 |
TWI316056B (en) | 2009-10-21 |
JP2008534454A (ja) | 2008-08-28 |
CN101146775B (zh) | 2012-07-18 |
BRPI0609699A2 (pt) | 2010-04-20 |
AU2006226665B2 (en) | 2011-01-27 |
IL185689A0 (en) | 2008-01-06 |
PT1863767E (pt) | 2009-03-27 |
ES2320590T3 (es) | 2009-05-25 |
PL1863767T3 (pl) | 2009-08-31 |
EP1863767B1 (en) | 2009-03-11 |
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US7211579B2 (en) | 2007-05-01 |
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