JP2016512823A5 - - Google Patents
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- JP2016512823A5 JP2016512823A5 JP2016501067A JP2016501067A JP2016512823A5 JP 2016512823 A5 JP2016512823 A5 JP 2016512823A5 JP 2016501067 A JP2016501067 A JP 2016501067A JP 2016501067 A JP2016501067 A JP 2016501067A JP 2016512823 A5 JP2016512823 A5 JP 2016512823A5
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- JP
- Japan
- Prior art keywords
- optionally substituted
- alkyl
- pharmaceutically acceptable
- acceptable salt
- ring
- 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.)
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- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 16
- 239000011780 sodium chloride Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000005842 heteroatoms Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 5
- 208000007056 Sickle Cell Anemia Diseases 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 208000008445 Altitude Sickness Diseases 0.000 claims description 2
- 206010011985 Decubitus ulcer Diseases 0.000 claims description 2
- 208000009856 Lung Disease Diseases 0.000 claims description 2
- 208000004210 Pressure Ulcer Diseases 0.000 claims description 2
- 206010038683 Respiratory disease Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 206010068760 Ulcers Diseases 0.000 claims description 2
- 230000001154 acute Effects 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 231100000397 ulcer Toxicity 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 11
- 125000003545 alkoxy group Chemical group 0.000 claims 8
- 239000000651 prodrug Chemical group 0.000 claims 8
- 229940002612 prodrugs Drugs 0.000 claims 8
- 229910052760 oxygen Inorganic materials 0.000 claims 7
- 229910052717 sulfur Inorganic materials 0.000 claims 7
- 125000005843 halogen group Chemical group 0.000 claims 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 6
- 229910052757 nitrogen Inorganic materials 0.000 claims 4
- 239000003814 drug Substances 0.000 claims 3
- 229940079593 drugs Drugs 0.000 claims 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 3
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 239000001301 oxygen Substances 0.000 claims 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims 1
- 208000008425 Protein Deficiency Diseases 0.000 claims 1
- 108010016797 Sickle Hemoglobin Proteins 0.000 claims 1
- 125000004432 carbon atoms Chemical group C* 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- 125000004043 oxo group Chemical group O=* 0.000 claims 1
- 230000001575 pathological Effects 0.000 claims 1
- 239000000546 pharmaceutic aid Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical class ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- -1 heteroaryl ether analogs Chemical class 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- HUMNYLRZRPPJDN-UHFFFAOYSA-N Benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000010626 work up procedure Methods 0.000 description 4
- FJBFPHVGVWTDIP-UHFFFAOYSA-N Dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 3
- XWAWSFKKJSWXOV-JOYOIKCWSA-N FC1=C(C=C(C=C1)F)[C@@H]1CN(C[C@H]1CO)C(C)=O Chemical compound FC1=C(C=C(C=C1)F)[C@@H]1CN(C[C@H]1CO)C(C)=O XWAWSFKKJSWXOV-JOYOIKCWSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000007429 general method Methods 0.000 description 3
- 239000008079 hexane Substances 0.000 description 3
- 238000002953 preparative HPLC Methods 0.000 description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N Benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229940095076 benzaldehyde Drugs 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical class [H]O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Inorganic materials [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- RWQOGZHKBNANKP-UHFFFAOYSA-N (2-propan-2-ylpyrazol-3-yl)boronic acid Chemical compound CC(C)N1N=CC=C1B(O)O RWQOGZHKBNANKP-UHFFFAOYSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-Bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LHZFVHKQGVLJLN-UHFFFAOYSA-N 1-O-tert-butyl 4-O-ethyl 5-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1,4-dicarboxylate Chemical compound CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CN(C(=O)OC(C)(C)C)CC1 LHZFVHKQGVLJLN-UHFFFAOYSA-N 0.000 description 1
- DGXAGETVRDOQFP-UHFFFAOYSA-N 2,6-dihydroxybenzaldehyde Chemical compound OC1=CC=CC(O)=C1C=O DGXAGETVRDOQFP-UHFFFAOYSA-N 0.000 description 1
- PVIVWSKQVHYIEI-UHFFFAOYSA-N 2-(bromomethyl)benzaldehyde Chemical compound BrCC1=CC=CC=C1C=O PVIVWSKQVHYIEI-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 206010001897 Alzheimer's disease Diseases 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N Benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- QXXHVUCUNXUODF-UHFFFAOYSA-N CC(C)N1N=CC=C1C1=NC=CC=C1O Chemical compound CC(C)N1N=CC=C1C1=NC=CC=C1O QXXHVUCUNXUODF-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N Carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- STPLOYFTJQWYIW-XQRIHRDZSA-N [(3S,4R)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]methanol;hydrochloride Chemical compound Cl.OC[C@@H]1CNC[C@H]1C1=CC(F)=CC=C1F STPLOYFTJQWYIW-XQRIHRDZSA-N 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 1
- 125000005325 aryloxy aryl group Chemical group 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 230000003197 catalytic Effects 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N cdcl3 Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
Description
別の実施形態において、Rは
である(式中、
X3は、独立に、C1〜C6アルキル、C3〜C8シクロアルキル、C3〜C9ヘテロシクリル、C6〜C10アリール、又はC3〜C9ヘテロアリールであり;且つ
R42は、独立に、水素、又はC1〜C6アルキル、C3〜C8シクロアルキル、C3〜C9ヘテロシクリル、C6〜C10アリール、若しくはC3〜C9ヘテロアリールである)。
である(式中、
X3は、独立に、C1〜C6アルキル、C3〜C8シクロアルキル、C3〜C9ヘテロシクリル、C6〜C10アリール、又はC3〜C9ヘテロアリールであり;且つ
R42は、独立に、水素、又はC1〜C6アルキル、C3〜C8シクロアルキル、C3〜C9ヘテロシクリル、C6〜C10アリール、若しくはC3〜C9ヘテロアリールである)。
いくつかの実施形態において、Rは以下の構造により表される:
(式中、上記の例において、R43は、C10〜C22アルキル又はアルキレンであり、R44は、H又はC1〜C6アルキルであり、且つR45は、天然のαアミノ酸に存在する側鎖アルキル基を表す);
(式中、R46は(CH2)nであり、n=2−4、且つ、CO−R47−NH2はアミノアシル基を表す);又は
(式中、R46は(CH2)nであり、n=2−4、R47は(CH2)nであり、n=1−3、且つ、R49はO又はNMeである)。
(式中、上記の例において、R43は、C10〜C22アルキル又はアルキレンであり、R44は、H又はC1〜C6アルキルであり、且つR45は、天然のαアミノ酸に存在する側鎖アルキル基を表す);
(式中、R46は(CH2)nであり、n=2−4、且つ、CO−R47−NH2はアミノアシル基を表す);又は
(式中、R46は(CH2)nであり、n=2−4、R47は(CH2)nであり、n=1−3、且つ、R49はO又はNMeである)。
本発明のさらなる態様において、鎌状赤血球症を治療する方法であって、その必要のある被験者に、治療上有効な量の、本明細書に記載されるいずれかの化合物又は組成物の化合物を投与することを含む方法が提供される。本発明のなおさらなる態様において、癌、肺疾患、脳卒中、高山病、潰瘍、褥瘡、アルツハイマー病、急性呼吸器疾患症候群、及び創傷を治療する方法であって、その必要のある被験者に、治療上有効な量の、本明細書に記載されるいずれかの化合物又は組成物の化合物を投与することを含む方法が提供される。
置換されたメチレンハライド(2)及びヒドロキシル(ヘテロ)アリールアルデヒド誘導体(3a/3b)から、アリールオキシ/ヘテロアリールエーテルアナログ(4a/4b)を調製する全般的方法B(スキーム1)。ヒドロキシル(ヘテロ)アリールアルデヒド誘導体(3a/3b)(0.1〜2mmol、1〜4当量)、置換された塩化メチレン又は臭化メチレン(2)(1当量)、及びK2CO3(2〜5当量)(触媒量のNaI又はBu4NIを加えてもよい)のDMF又はアセトニトリル(1から10mL)中の混合物を、室温で、又は120℃まで加熱して、0.5〜8時間、窒素雰囲気下で撹拌した。後処理Aにおいて、水を反応混合物に加え、沈殿した生成物を回収し、水で洗浄し、次いで、分取HPLC又はフラッシュシリカゲルクロマトグラフィー精製に付した。後処理B(沈殿しない生成物の場合)において、希HCl又はNH4Cl水溶液を0℃で加えて、pHをおよそ7に調整し、反応混合物を、酢酸エチル又はジクロロメタンと、塩化ナトリウム水溶液の間で分配し、有機層を分離し、乾燥させ、溶媒を真空下で除去すると粗生成物を与え、それを、適切な溶媒混合物(例えば、酢酸エチル/ヘキサン)を使用して自動化シリカゲルカラムクロマトグラフィーにより精製した。
全般的な方法工程2−N−アルキル化(14aから14bへ):カルボキシラート14a(R1=H)を、最初にアルキル化し、次いで還元してN−アルキルヒドロキシメチレンアナログ14b(R1=アルキル)を与えることができる。典型的な手順において、カルボキシラート14a(1〜10mmol)を最初にDMF(2〜20mL)に溶解させる。次いで、これに、NaH又はCs2CO3などの塩基(1〜1.2当量)を加え、それに続いてハロゲン化アルキル(例えば、BnBr)(0.9〜1.5当量)を加えた。反応を、室温で、40から115℃に加熱して、0.5から24時間進行させた。後処理Aにおいて、水を反応混合物に加え、沈殿した生成物を回収し、水で洗浄し、次いで分取HPLC又はフラッシュシリカゲルクロマトグラフィー精製に付した。後処理B(沈殿しない生成物の場合)において、希HCl又はNH4Cl水溶液を0℃で加えて、pHをおよそ7に調整し、反応混合物を、酢酸エチル又はジクロロメタンと、塩化ナトリウム水溶
液の間で分配し、有機層を分離し、乾燥させ、溶媒を真空下で除去すると粗生成物を与え、それを、適切な溶媒混合物(例えば、酢酸エチル/ヘキサン)を使用して自動化シリカゲルカラムクロマトグラフィーにより精製した。
液の間で分配し、有機層を分離し、乾燥させ、溶媒を真空下で除去すると粗生成物を与え、それを、適切な溶媒混合物(例えば、酢酸エチル/ヘキサン)を使用して自動化シリカゲルカラムクロマトグラフィーにより精製した。
工程2:1−tert−ブチル4−エチル3−(((トリフルオロメチル)スルホニル)オキシ)−5,6−ジヒドロピリジン−1,4(2H)−ジカルボキシラート(1.49g、3.7mmol)と(1−イソプロピル−1H−ピラゾール−5−イル)ボロン酸(0.57g、3.7mmol)のジオキサン(10mL)溶液に、Pd(dppf)Cl2(0.27g、0.37mmol)及び炭酸ナトリウム(1.18g、11.10mmol)の水(3ml)溶液を加え、混合物をN2で5分間脱気し、100℃で15時間加熱し、室温に冷却後、混合物をEtOAcで希釈し、飽和NaHCO3及びブラインで洗浄し、有機層を合わせ、乾燥させ、濃縮すると、粗生成物を与え、それをカラムクロマトグラフィー(ヘキサン/EtOAc=3:1)により精製すると、所望の生成物830mg(62%)を与えた。
GBT912
GBT912−2−(((3S,4R)−1−アセチル−4−(2,5−ジフルオロフェニル)ピロリジン−3−イル)メトキシ)−6−ヒドロキシベンズアルデヒド。化合物を、1−((3R,4S)−3−(2,5−ジフルオロフェニル)−4−(ヒドロキシメチル)ピロリジン−1−イル)エタン−1−オンと2,6−ジヒドロキシベンズアルデヒド(INT−7)から、全般的方法A(光延条件)を利用して調製した。1H NMR(400MHz,クロロホルム−d)δ11.90(s,1H),9.88(s,1H),7.37(dd,J=8.4,6.4Hz,1H),7.01(m,3H),6.53(t,J=8.6Hz,1H),6.27(dd,J=8.3,0.8Hz,1H),4.02(m,4H),3.55(m,3H),2.96(m,1H),2.11(s,3H).MS(M+H)+ C20H19F2NO4に対する実測値:376.3.
GBT912−2−(((3S,4R)−1−アセチル−4−(2,5−ジフルオロフェニル)ピロリジン−3−イル)メトキシ)−6−ヒドロキシベンズアルデヒド。化合物を、1−((3R,4S)−3−(2,5−ジフルオロフェニル)−4−(ヒドロキシメチル)ピロリジン−1−イル)エタン−1−オンと2,6−ジヒドロキシベンズアルデヒド(INT−7)から、全般的方法A(光延条件)を利用して調製した。1H NMR(400MHz,クロロホルム−d)δ11.90(s,1H),9.88(s,1H),7.37(dd,J=8.4,6.4Hz,1H),7.01(m,3H),6.53(t,J=8.6Hz,1H),6.27(dd,J=8.3,0.8Hz,1H),4.02(m,4H),3.55(m,3H),2.96(m,1H),2.11(s,3H).MS(M+H)+ C20H19F2NO4に対する実測値:376.3.
1−((3R,4S)−3−(2,5−ジフルオロフェニル)−4−(ヒドロキシメチル)ピロリジン−1−イル)エタン−1−オンの調製
((3S,4R)−4−(2,5−ジフルオロフェニル)ピロリジン−3−イル)メタノール塩酸塩(200mg、0.8mmol)の0℃のDCM(2mL)溶液に、DIPEA(0.3mL、1.68mmol)及びAc2O(90mg、0.84mmol)を加え、30分間撹拌した後、溶液をDCMで希釈し、有機層を、飽和NaHCO3、ブラインで洗浄し、MgSO4で乾燥させ、濃縮すると、1−((3R,4S)−3−(2,5−ジフルオロフェニル)−4−(ヒドロキシメチル)ピロリジン−1−イル)エタン−1−オンを粗生成物(175mg)として与えた。
((3S,4R)−4−(2,5−ジフルオロフェニル)ピロリジン−3−イル)メタノール塩酸塩(200mg、0.8mmol)の0℃のDCM(2mL)溶液に、DIPEA(0.3mL、1.68mmol)及びAc2O(90mg、0.84mmol)を加え、30分間撹拌した後、溶液をDCMで希釈し、有機層を、飽和NaHCO3、ブラインで洗浄し、MgSO4で乾燥させ、濃縮すると、1−((3R,4S)−3−(2,5−ジフルオロフェニル)−4−(ヒドロキシメチル)ピロリジン−1−イル)エタン−1−オンを粗生成物(175mg)として与えた。
GBT1133
GBT1133−2−(((2−(1−イソプロピル−1H−ピラゾール−5−イル)ピリジン−3−イル)オキシ)メチル)ベンズアルデヒド。化合物を、以下の反応スキームに従って、2−(ブロモメチル)ベンゾニトリルから2工程で調製した。
GBT1133−2−(((2−(1−イソプロピル−1H−ピラゾール−5−イル)ピリジン−3−イル)オキシ)メチル)ベンズアルデヒド。化合物を、以下の反応スキームに従って、2−(ブロモメチル)ベンゾニトリルから2工程で調製した。
工程2:50mL丸底フラスコに、2−(ブロモメチル)ベンズアルデヒド(150mg、0.75mmol、1.00当量)のCH3CN(25mL)溶液を入れた。2−[1−(プロパン−2−イル)−1H−ピラゾール−5−イル]ピリジン−3−オール(150mg、0.74mmol、1.00当量)、炭酸カリウム(210mg、1.52mmol、2.00当量)、及びKI(40mg、0.30当量)を反応物に加えた。生じた溶液を6時間還流加熱し、次いで、それを室温に冷却した。生じた溶液を20mLのH2Oで希釈し、次いで、それを3×20mLの酢酸エチルで抽出した。合わせた有機層を1×30mLのブラインで洗浄し、真空下で濃縮した。粗生成物(200mg)を、以下の条件で分取HPLCにより精製した(Prep−HPLC−010):カラム、SunFire Prep C18 OBDカラム、5μm、19×150mm;移動相、0.05%TFAを含む水及びMeCN(8分で38.0%MeCNから55.0%)。これにより、98.6mg(41%)の2−[([2−[1−(プロパン−2−イル)−1H−ピラゾール−5−イル]ピリジン−3−イル]オキシ)メチル]ベンズアルデヒドが薄黄色の固体として生じた;1HNMR(300MHz,CDCl3,ppm):10.01(s,1H),8.43(m,1H),7.88(m,1H),7.86(m,1H),7.61−7.79(m,6H),6.61(d,J=2.1Hz,1H),5.60(s,2H),4.69−4.78(m,1H),1.46(d,J=6.6Hz,6H);(ES,m/z):322[M+1]+
Claims (12)
- 式(X−I)の化合物:
若しくはその互変異性体、又はそのそれぞれの薬学的に許容できる塩
(式中、
環Aは、1〜3つのハロ及び/若しくはC 1 〜C 6 アルコキシにより任意選択で置換されているフェニルであるか、又は5つまでの環ヘテロ原子を含む4〜10員の複素環であり、前記ヘテロ原子は、O、N、S、並びにN及びSの酸化された形態からなる群から選択され、任意選択で置換されており、又は
環Bは、
からなる群から選択され、式中、R 8 は、C 1 〜C 6 アルキル、−CO−C 1 〜C 6 アルキル、又はプロドラッグ部分であり;
Xは、O、S、SO、又はSO 2 であり;
環Cは、フェニル又は6員の窒素含有ヘテロアリールであり、そのそれぞれは、1〜4つのハロ、オキソ、−OR 1 、C 1 〜C 6 アルキル、−COOR 1 、及び/又はC 1 〜C 6 アルコキシにより任意選択で置換されており、前記C 1 〜C 6 アルキルは、1〜5つのハロ、C 1 〜C 6 アルコキシ、及び/又は5つまでの環ヘテロ原子を含む4〜10員の複素環により任意選択で置換されており、前記ヘテロ原子は、O、N、S、並びにN及びSの酸化された形態からなる群から選択され;且つ
各R 1 は、水素又はプロドラッグ部分Rであり;
V 1 及びV 2 は、独立に、C 1 〜C 6 アルコキシであり;或いは、V 1 とV 2 は、それらが結合している炭素原子と共に以下の式の環を形成し:
R 80 は、任意選択で置換されているC 1 〜C 6 アルキルであり;
R 81 及びR 82 は、独立に、水素、任意選択で置換されているC 1 〜C 6 アルキル、COR 83 、又はCO 2 R 84 からなる群から選択され;
R 83 は、水素又は任意選択で置換されているC 1 〜C 6 アルキルであり;
R 84 は、任意選択で置換されているC 1 〜C 6 アルキルであり;
但し、環Cが、C 6 〜C 10 アリールであり;
且つ、環Bが、任意選択で置換されている4〜10員のヘテロシクリルである場合;
環Aが、任意選択で置換されている5〜10員のヘテロアリールを除外することを条件とする)。 - 以下の式の、請求項1に記載の化合物:
- 式(IIA)、(IIB)、及び(IIC)から選択される、請求項1に記載の化合物:
(式中、
R 9 は、水素、−OR 1 、1〜3つのC 1 〜C 6 アルコキシにより任意選択で置換されているC 1 〜C 6 アルコキシ、又はN、O、S、若しくはその酸化された形態から選択される5つまでの環ヘテロ原子を含む4〜10員の複素環であり;
R 10 は、水素、ハロ、ヒドロキシ、又はC 1 〜C 6 アルコキシであり;
R 11 は、水素又はC 1 〜C 6 アルキルであり;且つ
R 12 は、−OR 1 であり;
式中、R 1 は、水素又はプロドラッグ部分Rである)。 - 環Aが、1〜3つのハロ若しくはC 1 〜C 6 アルコキシにより置換されているフェニル又は1〜3つのヘテロ原子を含むC 3 〜C 8 ヘテロシクリルであり、前記複素環が1〜3つのハロにより任意選択で置換されている、請求項2に記載の化合物若しくはその互変異性体、又はそれぞれの薬学的に許容できる塩。
-
-
- 下記からなる群から選択される、請求項1に記載の化合物:
- 請求項1〜7のいずれか一項に記載の化合物、若しくはそのプロドラッグ、又はそのそれぞれの薬学的に許容できる塩、並びに少なくとも1種の薬学的に許容できる賦形剤を含む組成物。
- 請求項1〜7のいずれか一項に記載の化合物、若しくはそのプロドラッグ、又はそのそれぞれの薬学的に許容できる塩を含む、ヘモグロビンSの酸素親和性増加用の薬剤。
- 請求項1〜7のいずれか一項に記載の化合物、若しくはそのプロドラッグ、又はそのそれぞれの薬学的に許容できる塩を含む、酸素欠乏に関連する病態の治療用の薬剤。
- 請求項1〜7のいずれか一項に記載の化合物、若しくはそのプロドラッグ、又はそのそ
れぞれの薬学的に許容できる塩を含む、癌、肺疾患、脳卒中、高山病、潰瘍、褥瘡、急性呼吸器疾患症候群、及び鎌状赤血球症から選択される病態の治療用の薬剤。 - 前記病態が鎌状赤血球症である、請求項10に記載の薬剤。
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Families Citing this family (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2797597B1 (en) | 2011-12-28 | 2020-02-26 | Global Blood Therapeutics, Inc. | Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation |
PE20142454A1 (es) | 2011-12-28 | 2015-02-07 | Global Blood Therapeutics Inc | Compuestos de benzaldehido sustituidos y metodos para su uso en incrementar la oxigenacion del tejido |
EP2943485B1 (en) | 2013-01-14 | 2017-09-20 | Incyte Holdings Corporation | Bicyclic aromatic carboxamide compounds useful as pim kinase inhibitors |
SI2945939T1 (sl) | 2013-01-15 | 2020-08-31 | Incyte Holdings Corporation | Spojine tiazolkarboksamidov in piridinkarboksamida uporabne kot zaviralci PIM kinaze |
WO2014145040A1 (en) | 2013-03-15 | 2014-09-18 | Global Blood Therapeutics, Inc. | Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation |
WO2014150258A1 (en) | 2013-03-15 | 2014-09-25 | 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 |
US8952171B2 (en) | 2013-03-15 | 2015-02-10 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
EA034922B1 (ru) | 2013-03-15 | 2020-04-07 | Глобал Блад Терапьютикс, Инк. | Соединения и их применения для модуляции гемоглобина |
US9458139B2 (en) | 2013-03-15 | 2016-10-04 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
JP6401772B2 (ja) * | 2013-03-15 | 2018-10-10 | グローバル ブラッド セラピューティクス インコーポレイテッド | ヘモグロビンの修飾のための化合物及びその使用 |
KR20190041548A (ko) | 2013-03-15 | 2019-04-22 | 글로벌 블러드 테라퓨틱스, 인크. | 헤모글로빈 조정을 위한 화합물 및 이의 용도 |
US10266551B2 (en) | 2013-03-15 | 2019-04-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
MX2016002367A (es) | 2013-08-23 | 2016-10-28 | Incyte Corp | Compuestos de carboxamida de furo y tienopiridina utiles como inhibidores de cinasas pim. |
EA202092627A1 (ru) | 2013-11-18 | 2021-09-30 | Глобал Блад Терапьютикс, Инк. | Соединения и их применения для модуляции гемоглобина |
WO2015120133A1 (en) | 2014-02-07 | 2015-08-13 | 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 |
US9822124B2 (en) | 2014-07-14 | 2017-11-21 | Incyte Corporation | Bicyclic heteroaromatic carboxamide compounds useful as Pim kinase inhibitors |
US9580418B2 (en) | 2014-07-14 | 2017-02-28 | Incyte Corporation | Bicyclic aromatic carboxamide compounds useful as Pim kinase inhibitors |
MA41841A (fr) | 2015-03-30 | 2018-02-06 | Global Blood Therapeutics Inc | Composés aldéhyde pour le traitement de la fibrose pulmonaire, de l'hypoxie, et de maladies auto-immunes et des tissus conjonctifs |
WO2016196244A1 (en) | 2015-05-29 | 2016-12-08 | Incyte Corporation | Pyridineamine compounds useful as pim kinase inhibitors |
AR105967A1 (es) | 2015-09-09 | 2017-11-29 | Incyte Corp | Sales de un inhibidor de pim quinasa |
TW201718546A (zh) | 2015-10-02 | 2017-06-01 | 英塞特公司 | 適用作pim激酶抑制劑之雜環化合物 |
SG10201912511WA (en) | 2015-12-04 | 2020-02-27 | Global Blood Therapeutics Inc | Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
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 |
EP3472150A1 (en) * | 2016-06-17 | 2019-04-24 | Fronthera U.S. Pharmaceuticals LLC | Hemoglobin modifier compounds and uses thereof |
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 |
RS59306B1 (sr) | 2017-03-20 | 2019-10-31 | Forma Therapeutics Inc | Kompozicije pirolopirola kao aktivatori piruvat kinaze (pkr) |
AR113922A1 (es) | 2017-12-08 | 2020-07-01 | Incyte Corp | Terapia de combinación de dosis baja para el tratamiento de neoplasias mieloproliferativas |
MA53668A (fr) | 2018-09-19 | 2021-09-15 | Forma Therapeutics Inc | Traitement de la drépanocytose avec un composé activant la pyruvate kinase r |
JP7450610B2 (ja) | 2018-09-19 | 2024-03-15 | ノヴォ・ノルディスク・ヘルス・ケア・アーゲー | ピルビン酸キナーゼrの活性化 |
EP3860975B1 (en) | 2018-10-01 | 2023-10-18 | Global Blood Therapeutics, Inc. | Modulators of hemoglobin for the treatment of sickle cell disease |
EP3880654B1 (en) | 2018-11-19 | 2021-12-29 | Global Blood Therapeutics, Inc. | 2-formyl-3-hydroxyphenyloxymethyl compounds capable of modulating hemoglobin |
PE20211592A1 (es) | 2018-11-29 | 2021-08-18 | Pfizer | Pirazoles como moduladores de la hemoglobina |
BR112021012312A2 (pt) | 2018-12-21 | 2021-09-08 | Crystal Pharma, S.A.U. | Processo para preparar voxelotor e composto |
CN113365992B (zh) | 2018-12-21 | 2024-05-28 | 晶体制药独资有限公司 | 用于沃塞洛托的制备的方法和中间体 |
KR20220057629A (ko) * | 2019-09-12 | 2022-05-09 | 아심켐 래보러토리즈 (푸신) 컴퍼니, 리미티드 | 2,6-디히드록시벤즈알데히드의 연속 제조 장치 및 그 응용 |
CN112920160B (zh) * | 2019-12-06 | 2022-08-16 | 中国科学院宁波材料技术与工程研究所 | 基于环状缩醛结构的可降解单体、其合成方法及应用 |
IT202000009970A1 (it) * | 2020-05-05 | 2021-11-05 | Dipharma Francis Srl | Procedimento per la preparazione di un farmaco per il trattamento dell’anemia falciforme |
WO2021224280A1 (en) * | 2020-05-05 | 2021-11-11 | Dipharma Francis S.R.L. | Synthesis of a sickle cell disease agent and intermediates thereof |
CN112047924B (zh) * | 2020-10-10 | 2023-04-18 | 山东汇海医药化工有限公司 | 一种沃克洛多的制备方法 |
TW202233589A (zh) * | 2020-11-06 | 2022-09-01 | 美商全球血液治療公司 | 2-羥基-6-((2-(1-異丙基-1h-吡唑-5-基)吡啶-3-基)甲氧基)苯甲醛之製備方法 |
Family Cites Families (267)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE226590C (ja) | ||||
DE258226C (ja) | ||||
DE276479C (ja) | ||||
BE554933A (ja) | 1956-02-13 | 1900-01-01 | ||
BE787576A (fr) | 1971-08-13 | 1973-02-14 | Hoechst Ag | Derives de benzofuranne et leur utilisation comme azureurs optiques |
BE787580A (fr) | 1971-08-13 | 1973-02-14 | Hoechst Ag | Procede de preparation de derives du furanne |
GB1409865A (en) | 1973-02-13 | 1975-10-15 | Science Union & Cie | Dihydropyridines derivatives their preparation and pharmaceu tical compositions containing them |
US4062858A (en) | 1976-12-22 | 1977-12-13 | E. R. Squibb & Sons, Inc. | Derivatives of 5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-ones and 11(1H)-imines |
GB1593417A (en) | 1976-12-22 | 1981-07-15 | Squibb & Sons Inc | Carbocyclic-fused pyrazolopyridine derivatives |
DE2964427D1 (en) | 1978-10-04 | 1983-02-03 | Ciba Geigy Ag | Process for the preparation of furanyl-benzazoles |
DE2853765A1 (de) | 1978-12-13 | 1980-06-26 | Bayer Ag | Verfahren zur herstellung von benzimidazolylbenzofuranen |
DE2904829A1 (de) | 1979-02-08 | 1980-08-14 | Bayer Ag | Verfahren zur herstellung von benzimidazolylbenzofuran |
ZM5780A1 (en) | 1979-06-29 | 1983-11-21 | Wellcome Found | Pharmaceutical ethers,preparation,use and intermediates therefor and their preparation |
DE3175083D1 (en) | 1980-12-18 | 1986-09-11 | Wellcome Found | Pharmaceutical compounds, their preparation and use |
JPS5929667A (ja) | 1982-08-13 | 1984-02-16 | Otsuka Pharmaceut Co Ltd | カルボスチリル誘導体および強心剤 |
US4478834A (en) | 1983-02-11 | 1984-10-23 | Usv Pharmaceutical Corporation | Dihydropyridines and their use in the treatment of asthma |
GB8402740D0 (en) | 1984-02-02 | 1984-03-07 | Scras | Furo-(3 4-c)-pyridine derivatives |
JPS6140236A (ja) | 1984-08-02 | 1986-02-26 | Yamanouchi Pharmaceut Co Ltd | ハイドロキノン誘導体 |
DE3431004A1 (de) | 1984-08-23 | 1986-03-06 | Hoechst Ag, 6230 Frankfurt | Neue 3-pyridylverbindungen und verfahren zu ihrer herstellung |
DD226590A1 (de) | 1984-09-07 | 1985-08-28 | Univ Leipzig | Mittel zur phagenhemmung in mikrobiellen produktionsprozessen |
GB8603475D0 (en) | 1986-02-12 | 1986-03-19 | Glaxo Group Ltd | Chemical compounds |
DK111387A (da) | 1986-03-05 | 1987-09-06 | Otsuka Pharma Co Ltd | Carbostyrilderivater og salte deraf, laegemiddel indeholdende saadanne derivater samt fremgangsmaade til fremstilling af derivaterne |
US4831041A (en) | 1986-11-26 | 1989-05-16 | Fujisawa Pharmaceutical Co., Ltd. | Imidazopyridine compounds and processes for preparation thereof |
AU598093B2 (en) | 1987-02-07 | 1990-06-14 | Wellcome Foundation Limited, The | Pyridopyrimidines, methods for their preparation and pharmaceutical formulations thereof |
DD258226A1 (de) | 1987-03-05 | 1988-07-13 | Fahlberg List Veb | Verfahren zur herstellung von aroxymethylchinoxalinen |
JPH07121937B2 (ja) | 1987-03-18 | 1995-12-25 | 大塚製薬株式会社 | カルボスチリル誘導体 |
JPS63258463A (ja) | 1987-04-14 | 1988-10-25 | Kumiai Chem Ind Co Ltd | 2−フエノキシピリミジン誘導体及び除草剤 |
GB8711802D0 (en) | 1987-05-19 | 1987-06-24 | Fujisawa Pharmaceutical Co | Dithioacetal compounds |
GB8718940D0 (en) | 1987-08-11 | 1987-09-16 | Glaxo Group Ltd | Chemical compounds |
US4920131A (en) | 1987-11-03 | 1990-04-24 | Rorer Pharmaceutical Corp. | Quinoline derivatives and use thereof as antagonists of leukotriene D4 |
JP2650038B2 (ja) | 1988-01-27 | 1997-09-03 | サントリー株式会社 | ピロリチジン化合物およびその用途 |
EP0336369A1 (en) | 1988-04-04 | 1989-10-11 | E.R. Squibb & Sons, Inc. | 3-Acylamino-1-[[[(substituted sulfonyl)amino]carbonyl]amino]2-azetidinones |
US4952574A (en) | 1988-09-26 | 1990-08-28 | Riker Laboratories, Inc. | Antiarrhythmic substituted N-(2-piperidylmethyl)benzamides |
IE81170B1 (en) | 1988-10-21 | 2000-05-31 | Zeneca Ltd | Pyridine derivatives |
DD276480A1 (de) | 1988-10-26 | 1990-02-28 | Fahlberg List Veb | Verfahren zur herstellung von naphtho/2,1-b/fur-2-ylchinoxalinen |
DD276479A1 (de) | 1988-10-26 | 1990-02-28 | Fahlberg List Veb | Verfahren zur herstellung von benzo/b/fur-2-ylchinoxalinen |
US5236917A (en) | 1989-05-04 | 1993-08-17 | Sterling Winthrop Inc. | Saccharin derivatives useful as proteolytic enzyme inhibitors and compositions and method of use thereof |
IT1230859B (it) | 1989-06-05 | 1991-11-08 | Corvi Camillo Spa | 2 alchinilfenoli sostituiti ad azione anti infiammatoria, procedimento per la loro preparazione e composizioni farmaceutiche che li contengono. |
EP0453210A3 (en) | 1990-04-19 | 1993-01-13 | Imperial Chemical Industries Plc | Pyridine derivatives |
IL98526A0 (en) | 1990-06-18 | 1992-07-15 | Merck & Co Inc | Pyridones,processes for their preparation and pharmaceutical compositions containing them |
WO1991019697A1 (en) | 1990-06-19 | 1991-12-26 | Meiji Seika Kabushiki Kaisha | Pyridine derivative with angiotensin ii antagonism |
NL9001752A (nl) | 1990-08-02 | 1992-03-02 | Cedona Pharm Bv | Nieuwe 1,4-dihydropyridinederivaten. |
IL99731A0 (en) | 1990-10-18 | 1992-08-18 | Merck & Co Inc | Hydroxylated pyridine derivatives,their preparation and pharmaceutical compositions containing them |
JPH05301872A (ja) | 1992-04-23 | 1993-11-16 | Kumiai Chem Ind Co Ltd | ピコリン酸誘導体及び除草剤 |
US5403816A (en) | 1990-10-25 | 1995-04-04 | Kumiai Chemical Industry Co., Ltd. | Picolinic acid derivative and herbicidal composition |
WO1992013841A1 (de) | 1991-02-08 | 1992-08-20 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Komplexbildner |
JPH0641118A (ja) | 1991-05-31 | 1994-02-15 | Kumiai Chem Ind Co Ltd | ピコリン酸誘導体及び除草剤 |
US5185251A (en) | 1991-06-07 | 1993-02-09 | Merck & Co., Inc. | Microbial transformation of a substituted pyridinone using actinoplanacete sp. MA 6559 |
JP2600644B2 (ja) | 1991-08-16 | 1997-04-16 | 藤沢薬品工業株式会社 | チアゾリルベンゾフラン誘導体 |
FR2680512B1 (fr) | 1991-08-20 | 1995-01-20 | Adir | Nouveaux derives de 2,4-thiazolidinedione, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
US5202243A (en) | 1991-10-04 | 1993-04-13 | Merck & Co., Inc. | Method of hydroxylating 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-2-(1H)-pyridinone by incubation with liver slices |
GB9203798D0 (en) | 1992-02-21 | 1992-04-08 | Fujisawa Pharmaceutical Co | Quinolylbenzofuran derivatives,processes for preparation thereof and pharmaceutical composition comprising the same |
EP0648209A1 (de) | 1992-07-01 | 1995-04-19 | Byk Gulden Lomberg Chemische Fabrik GmbH | Kontrastmittel für die mr diagnostik |
US5290941A (en) | 1992-10-14 | 1994-03-01 | Merck & Co., Inc. | Facile condensation of methylbenzoxazoles with aromatic aldehydes |
EP0645387A1 (en) | 1993-04-07 | 1995-03-29 | Taiho Pharmaceutical Co., Ltd. | Thiazolidine derivative and pharmaceutical composition containing the same |
DE4318550A1 (de) | 1993-06-04 | 1994-12-08 | Boehringer Mannheim Gmbh | Aryliden-4-oxo-2-thioxo-3- thiazolidincarbonsäuren, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel |
IL110151A (en) | 1993-06-30 | 1998-10-30 | Sankyo Co | Amid and urea histories and pharmaceutical preparations containing them |
JPH0725882A (ja) | 1993-07-07 | 1995-01-27 | Res Dev Corp Of Japan | アクロメリン酸bおよびeを製造するための中間体と、その製造方法 |
ES2132284T3 (es) | 1993-08-05 | 1999-08-16 | Hoechst Marion Roussel Inc | Derivados de carbamato de 2-(piperidin-4-il, piridin-4-il y tetrahidropiridin-4-il)-benzofurano-7, su preparacion y su uso como inhibidores de acetilcolinesterasa. |
EP0640609A1 (en) | 1993-08-24 | 1995-03-01 | Ono Pharmaceutical Co., Ltd. | Fused phenol derivatives having inhibitory activity on TXA2 synthetase, and 5-lipoxygenase and scavenging activity on oxygen species |
US5880131A (en) | 1993-10-20 | 1999-03-09 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US5965566A (en) | 1993-10-20 | 1999-10-12 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US5840900A (en) | 1993-10-20 | 1998-11-24 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US5605976A (en) | 1995-05-15 | 1997-02-25 | Enzon, Inc. | Method of preparing polyalkylene oxide carboxylic acids |
WO1995014015A1 (en) | 1993-11-19 | 1995-05-26 | Ciba-Geigy Ag | Benzothiophene derivatives possessing a methoxyimino substituent as microbicides |
EP0658559A1 (de) | 1993-12-14 | 1995-06-21 | Chemisch Pharmazeutische Forschungsgesellschaft m.b.H. | Thienothiazinderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als 5-dipoxygenase und Cyclooxygenaseinhibitoren |
AU691243B2 (en) | 1994-02-14 | 1998-05-14 | Aventisub Ii Inc. | Novel mercaptoacetylamido 1,3,4,5-tetrahydro-benzo(c)azepin-3-one disulfide derivatives useful as inhibitors of enkephalinase and ace |
GB9420557D0 (en) | 1994-10-12 | 1994-11-30 | Zeneca Ltd | Aromatic compounds |
DE4442050A1 (de) | 1994-11-25 | 1996-05-30 | Hoechst Ag | Heterospiroverbindungen und ihre Verwendung als Elektrolumineszenzmaterialien |
US5650408A (en) | 1995-06-07 | 1997-07-22 | Karanewsky; Donald S. | Thiazolo benzazepine containing dual action inhibitors |
TW434240B (en) | 1995-06-20 | 2001-05-16 | Zeneca Ltd | Aromatic compounds, preparation thereof and pharmaceutical composition comprising same |
JP3895404B2 (ja) | 1996-05-17 | 2007-03-22 | 興和株式会社 | カルコン誘導体及びこれを含有する医薬 |
CN1221417A (zh) | 1996-07-26 | 1999-06-30 | 雷迪博士研究基金会 | 具有抗糖尿病、降低血脂、抗高血压性能的噻唑烷二酮化合物,其制备方法及其药物组合物 |
CA2264020A1 (en) | 1996-08-26 | 1998-03-05 | Jean Bemis | Inhibitors of phospholipase enzymes |
US6630496B1 (en) | 1996-08-26 | 2003-10-07 | Genetics Institute Llc | Inhibitors of phospholipase enzymes |
WO1998009967A1 (fr) | 1996-09-09 | 1998-03-12 | Kyowa Hakko Kogyo Co., Ltd. | Derives de pyrrolocarbazole |
CN1237166A (zh) | 1996-11-12 | 1999-12-01 | 诺瓦提斯公司 | 可用作除草剂的吡唑衍生物 |
US6043389A (en) | 1997-03-11 | 2000-03-28 | Mor Research Applications, Ltd. | Hydroxy and ether-containing oxyalkylene esters and uses thereof |
US5760232A (en) | 1997-06-16 | 1998-06-02 | Schering Corporation | Synthesis of intermediates useful in preparing bromo-substituted tricyclic compounds |
US6214817B1 (en) | 1997-06-20 | 2001-04-10 | Monsanto Company | Substituted pyridino pentaazamacrocyle complexes having superoxide dismutase activity |
US6011042A (en) | 1997-10-10 | 2000-01-04 | Enzon, Inc. | Acyl polymeric derivatives of aromatic hydroxyl-containing compounds |
US6111107A (en) | 1997-11-20 | 2000-08-29 | Enzon, Inc. | High yield method for stereoselective acylation of tertiary alcohols |
GB2346878B (en) | 1997-12-12 | 2002-12-04 | Euro Celtique Sa | Preparation of 3-substituted adenines |
AU3297099A (en) | 1998-02-25 | 1999-09-15 | Genetics Institute Inc. | Inhibitors of phospholipase a2 |
WO1999047529A1 (en) | 1998-03-18 | 1999-09-23 | Ariad Pharmaceuticals, Inc. | Heterocyclic signal transduction inhibitors, compositions containing them |
US6214879B1 (en) | 1998-03-24 | 2001-04-10 | Virginia Commonwealth University | Allosteric inhibitors of pyruvate kinase |
US6153655A (en) | 1998-04-17 | 2000-11-28 | Enzon, Inc. | Terminally-branched polymeric linkers and polymeric conjugates containing the same |
GB9810860D0 (en) | 1998-05-20 | 1998-07-22 | Hoechst Schering Agrevo Gmbh | Substituted pyridine and pyrimidines, processes for their preparation and their use as pesticides |
US6232320B1 (en) | 1998-06-04 | 2001-05-15 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
KR20010052570A (ko) | 1998-06-04 | 2001-06-25 | 스티븐 에프. 웨인스톡 | 세포 유착을 억제하는 소염성 화합물 |
GB9818627D0 (en) | 1998-08-26 | 1998-10-21 | Glaxo Group Ltd | Improvements in dva vaccination |
GB9823871D0 (en) | 1998-10-30 | 1998-12-23 | Pharmacia & Upjohn Spa | 2-Amino-thiazole derivatives, process for their preparation, and their use as antitumour agents |
US20030060425A1 (en) | 1998-11-24 | 2003-03-27 | Ahlem Clarence N. | Immune modulation method using steroid compounds |
TR200101744T2 (tr) | 1998-12-14 | 2001-12-21 | F. Hoffmann-La Roche Ag | Fenilglisin türevleri. |
US6544980B2 (en) | 1998-12-31 | 2003-04-08 | Aventis Pharmaceuticals Inc. | N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase |
WO2000040564A1 (en) | 1998-12-31 | 2000-07-13 | Aventis Pharmaceuticals Inc. | N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase |
BR0009410A (pt) | 1999-03-31 | 2002-02-13 | Basf Ag | Piridina-2,3-dicarboxamida, composto, uso de uma piridina-2,3-dicarboxamida, composição herbicida, composição para a dessecação e/ou desfolhação de vegetais, e, processo para controlar vegetação não desejável |
US6251927B1 (en) | 1999-04-20 | 2001-06-26 | Medinox, Inc. | Methods for treatment of sickle cell anemia |
CA2370245A1 (en) | 1999-05-14 | 2000-11-23 | Boehringer Ingelheim Pharmaceuticals, Inc. | Enzyme-activated anti-tumor prodrug compounds |
US6184228B1 (en) | 1999-05-25 | 2001-02-06 | Anadys Pharmaceuticals, Inc. | Anti-sickling agents: selection methods and effective compounds |
WO2000075145A1 (en) | 1999-06-03 | 2000-12-14 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
AUPQ105499A0 (en) | 1999-06-18 | 1999-07-08 | Biota Scientific Management Pty Ltd | Antiviral agents |
ES2215683T3 (es) | 1999-06-28 | 2004-10-16 | Janssen Pharmaceutica N.V. | Inhibidores de la replicacion del virus sincitial respiratorio. |
ATE312100T1 (de) | 1999-09-28 | 2005-12-15 | Eisai Co Ltd | Chinuclidin-verbindungen und medikamente die diese als aktive wirkstoffe enthalten |
IL149336A0 (en) | 1999-11-05 | 2002-11-10 | Emisphere Tech Inc | Phenyl amine carboxylic acid compounds and compositions for delivering active agents |
AUPQ407699A0 (en) | 1999-11-16 | 1999-12-09 | Fujisawa Pharmaceutical Co., Ltd. | Aminoalcohol derivatives |
ATE253561T1 (de) | 1999-11-29 | 2003-11-15 | Hoffmann La Roche | 2-(3,5-bis-trifluoromethyl-phenyl)-n-methyl-n-( - morpholin-4-yl-4-o-tolyl-pyridin-3-yl)- isobutyramid |
CA2396079A1 (en) | 2000-01-07 | 2001-07-19 | Transform Pharmaceuticals, Inc. | High-throughput formation, identification, and analysis of diverse solid-forms |
AU2001230537A1 (en) | 2000-02-01 | 2001-08-14 | Daiichi Pharmaceutical Co., Ltd. | Pyridoxazine derivatives |
US6506755B2 (en) | 2000-02-03 | 2003-01-14 | Hoffmann-La Roche Inc. | Thiazolidinecarboxyl acids |
AUPQ585000A0 (en) | 2000-02-28 | 2000-03-16 | Fujisawa Pharmaceutical Co., Ltd. | Aminoalcohol derivatives |
CA2403553A1 (en) | 2000-03-17 | 2001-09-27 | David Johnson | Novel amphipathic aldehydes and their use as adjuvants and immunoeffectors |
AUPQ841300A0 (en) | 2000-06-27 | 2000-07-20 | Fujisawa Pharmaceutical Co., Ltd. | New aminoalcohol derivatives |
CZ303639B6 (cs) * | 2000-07-14 | 2013-01-23 | F. Hoffmann-La Roche Ag | N-Oxid derivátu 4-fenylpyridinu, zpusob jeho prípravy a lécivo s jeho obsahem |
WO2002009723A2 (en) | 2000-08-01 | 2002-02-07 | Gmp Companies, Inc. | Ammonium salts of hemoglobin allosteric effectors, and uses thereof |
US6653313B2 (en) | 2000-08-10 | 2003-11-25 | Warner-Lambert Company Llc | 1,4-dihydropyridine compounds as bradykinin antagonists |
JP4272338B2 (ja) | 2000-09-22 | 2009-06-03 | バイエル アクチェンゲゼルシャフト | ピリジン誘導体 |
AUPR034000A0 (en) | 2000-09-25 | 2000-10-19 | Fujisawa Pharmaceutical Co., Ltd. | Aminoalcohol derivatives |
AU2426602A (en) | 2000-11-20 | 2002-05-27 | Biovitrum Ab | Piperazinylpyrazine compounds as agonist or antagonist of serotonin 5ht-2 receptor |
WO2002051849A1 (fr) | 2000-12-26 | 2002-07-04 | Daiichi Pharmaceutical Co., Ltd. | Inhibiteurs cdk4 |
WO2002053547A1 (fr) | 2000-12-28 | 2002-07-11 | Takeda Chemical Industries, Ltd. | Derives d'acide alcanoique, procede de production et utilisation correspondants |
US20030022923A1 (en) | 2001-03-01 | 2003-01-30 | Medinox, Inc. | Methods for treatment of sickle cell anemia |
US6627646B2 (en) | 2001-07-17 | 2003-09-30 | Sepracor Inc. | Norastemizole polymorphs |
WO2003009807A2 (en) | 2001-07-23 | 2003-02-06 | Galileo Laboratories, Inc. | Cytoprotective compounds, pharmaceutical and cosmetic formulations, and methods |
JP2003075970A (ja) | 2001-08-31 | 2003-03-12 | Konica Corp | ハロゲン化銀カラー写真感光材料、カラー写真感光材料、その画像形成方法及びデジタル画像情報作製方法 |
KR100467313B1 (ko) | 2001-11-22 | 2005-01-24 | 한국전자통신연구원 | 적색 유기 전기발광 화합물 및 그 제조 방법과 전기발광소자 |
GB0128499D0 (en) | 2001-11-28 | 2002-01-23 | Merck Sharp & Dohme | Therapeutic agents |
US20030187026A1 (en) | 2001-12-13 | 2003-10-02 | Qun Li | Kinase inhibitors |
AU2002360763A1 (en) | 2001-12-19 | 2003-07-09 | Atherogenics, Inc. | Chalcone derivatives and their use to treat diseases |
US20030190333A1 (en) | 2002-02-04 | 2003-10-09 | Corixa Corporation | Immunostimulant compositions comprising aminoalkyl glucosaminide phosphates and saponins |
WO2003088980A1 (en) | 2002-04-18 | 2003-10-30 | Embury Stephen H | Method and composition for preventing pain in sickle cell patients |
US6608076B1 (en) | 2002-05-16 | 2003-08-19 | Enzon, Inc. | Camptothecin derivatives and polymeric conjugates thereof |
GB0212785D0 (en) | 2002-05-31 | 2002-07-10 | Glaxo Group Ltd | Compounds |
NZ538134A (en) | 2002-08-08 | 2006-03-31 | Smithkline Beecham Corp | Thiophene compounds |
KR100942073B1 (ko) | 2002-08-23 | 2010-02-12 | 기린 홀딩스 가부시키가이샤 | TGF β 저해 활성을 갖는 화합물 및 그것을 포함하여 이루어지는 의약 조성물 |
WO2004024705A1 (ja) | 2002-09-10 | 2004-03-25 | Takeda Pharmaceutical Company Limited | 5員複素環化合物 |
CA2507545C (en) | 2002-12-04 | 2011-06-21 | Virginia Commonwealth University | Use of furfural derivatives as anti-sickling agents |
WO2004056727A2 (en) | 2002-12-19 | 2004-07-08 | Atherogenics, Inc. | Process of making chalcone derivatives |
EP1577317A4 (en) | 2002-12-25 | 2007-05-09 | Kissei Pharmaceutical | NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVES, MEDICINAL COMPOSITIONS COMPRISING SAID DERIVATIVES AND MEDICAL USE OF SAID DERIVATIVES |
WO2004073675A1 (de) | 2003-02-24 | 2004-09-02 | Randolph Riemschneider | Kosmetische zusammensetzung mit whitening-effekt, verfahren zu ihrer herstellung und ihre verwendung |
US20040186077A1 (en) | 2003-03-17 | 2004-09-23 | Medicure International Inc. | Novel heteroaryl phosphonates as cardioprotective agents |
ZA200507752B (en) | 2003-03-28 | 2007-01-31 | Threshold Pharmaceuticals Inc | Compositions and methods for treating cancer |
US7291631B2 (en) | 2003-04-11 | 2007-11-06 | Genzyme Corporation | CXCR4 chemokine receptor binding compounds |
KR20060017791A (ko) | 2003-06-12 | 2006-02-27 | 노보 노르디스크 에이/에스 | 호르몬-민감성 리파제 억제제로서의 피리디닐 카르바메이트 |
WO2005019220A2 (en) | 2003-08-11 | 2005-03-03 | Cellular Genomics Inc. | Substituted imidazo[1,2-a]pyrazines as modulators of kinase activity |
US7411083B2 (en) | 2003-09-25 | 2008-08-12 | Wyeth | Substituted acetic acid derivatives |
AU2004291262C1 (en) | 2003-11-05 | 2011-08-11 | F. Hoffmann-La Roche Ag | Phenyl derivatives as PPAR agonists |
KR20060123292A (ko) | 2003-11-10 | 2006-12-01 | 쉐링 악티엔게젤샤프트 | Ccr-5 길항제로서 유용한 벤질에테르 아민 화합물 |
NZ548049A (en) | 2003-12-02 | 2009-01-31 | Celgene Corp | Methods and compositions for the treatment and management of hemoglobinopathy and anemia |
US7378439B2 (en) | 2004-01-20 | 2008-05-27 | Usv, Ltd. | Process for the preparation of 4-(2-dipropylaminoethyl)-1,3-dihydro-2H-indol-2-one hydrochloride |
AU2005211349A1 (en) | 2004-01-30 | 2005-08-18 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | N-benzyl-3,4-dihyroxypyridine-2-carboxamide and N-benzyl-2,3-dihydroxypyridine-4-carboxamide compounds useful as HIV integrase inhibitors |
GB0403038D0 (en) | 2004-02-11 | 2004-03-17 | Novartis Ag | Organic compounds |
CN1930161A (zh) | 2004-03-09 | 2007-03-14 | P·安杰莱蒂分子生物学研究所 | Hiv整合酶抑制剂 |
US20080132458A1 (en) | 2004-03-10 | 2008-06-05 | Threshold Pharmaceuticals, Inc. | Hypoxia-Activated Anti-Cancer Agents |
DE102004015226B3 (de) | 2004-03-24 | 2005-08-25 | Siemens Ag | Verfahren zum Plasmareinigen eines Werkstücks und zu dessen Durchführung geeignete Vorrichtung |
US20070293698A1 (en) | 2004-04-22 | 2007-12-20 | Allos Therapeutics, Inc. | Compositions of Allosteric Hemoglobin Modifiers and Methods of Making the Same |
WO2006003923A1 (ja) | 2004-06-30 | 2006-01-12 | Sankyo Company, Limited | 置換ベンゼン化合物 |
TW200606129A (en) | 2004-07-26 | 2006-02-16 | Chugai Pharmaceutical Co Ltd | Novel cyclohexane derivative, its prodrug, its salt and diabetic therapeutic agent containing the same |
GB0420722D0 (en) | 2004-09-17 | 2004-10-20 | Addex Pharmaceuticals Sa | Novel allosteric modulators |
AU2005304220A1 (en) | 2004-10-28 | 2006-05-18 | Medicure International Inc. | Dual antiplatelet/anticoagulant pyridoxine analogs |
JP2008523139A (ja) | 2004-12-14 | 2008-07-03 | アストラゼネカ・アクチエボラーグ | 置換アミノピリジン類及びその使用 |
US7968574B2 (en) | 2004-12-28 | 2011-06-28 | Kinex Pharmaceuticals, Llc | Biaryl compositions and methods for modulating a kinase cascade |
US7858788B2 (en) | 2005-02-21 | 2010-12-28 | Shionogi & Co., Ltd. | Bicyclic carbamoylpyridone derivative having HIV integrase inhibitory activity |
CA2601871A1 (en) | 2005-03-19 | 2006-09-28 | Amorepacific Corporation | Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same |
WO2006106711A1 (ja) | 2005-03-30 | 2006-10-12 | Eisai R & D Management Co., Ltd. | ピリジン誘導体を含有する抗真菌剤 |
GB0506677D0 (en) | 2005-04-01 | 2005-05-11 | Btg Int Ltd | Iron modulators |
DK3187225T3 (da) | 2005-04-28 | 2022-02-28 | Viiv Healthcare Co | Polycyklisk carbamoylpyridonderivat med hiv-integrasehæmmende aktivitet |
DE102005025989A1 (de) | 2005-06-07 | 2007-01-11 | Bayer Cropscience Ag | Carboxamide |
JP2006342115A (ja) | 2005-06-10 | 2006-12-21 | Shionogi & Co Ltd | Hivインテグラーゼ阻害活性を有する多環性化合物 |
AU2006264649A1 (en) | 2005-06-30 | 2007-01-11 | Prosidion Limited | GPCR agonists |
CN100562514C (zh) | 2005-07-22 | 2009-11-25 | 中国科学院上海药物研究所 | 一类取代丙酰胺衍生物、其制备方法和用途 |
GB0516270D0 (en) | 2005-08-08 | 2005-09-14 | Glaxo Group Ltd | Novel compounds |
PT1945622E (pt) | 2005-10-11 | 2012-04-09 | Univ Pittsburgh | Compostos de benzofurano marcados isotopicamente enquanto agentes de imagiologia para proteínas amilóides |
JP5131689B2 (ja) | 2005-10-27 | 2013-01-30 | 塩野義製薬株式会社 | Hivインテグラーゼ阻害活性を有する多環性カルバモイルピリドン誘導体 |
JP2009515997A (ja) | 2005-11-18 | 2009-04-16 | タケダ サン ディエゴ インコーポレイテッド | グルコキナーゼ活性剤 |
WO2007084914A2 (en) | 2006-01-17 | 2007-07-26 | Neurocrine Biosciences, Inc. | Phenoxy-substituted pyrimidines as adenosine receptor antagonists |
WO2007095495A2 (en) | 2006-02-13 | 2007-08-23 | Pharmacopeia, Inc. | Benzodiazepine gcnf modulators for stem cell modulation |
RU2318818C1 (ru) | 2006-04-12 | 2008-03-10 | Общество С Ограниченной Ответственностью "Исследовательский Институт Химического Разнообразия" | Азагетероциклы, комбинаторная библиотека, фокусированная библиотека, фармацевтическая композиция и способ получения (варианты) |
DE102006062417A1 (de) | 2006-07-07 | 2008-01-10 | Dieter Prof. Greif | Verfahren zur Biodieselherstellung aus Altölen und Altfetten |
GB0614586D0 (en) | 2006-07-22 | 2006-08-30 | Pliva Istrazivacki Inst D O O | Pharmaceutical Formulation |
CN101113148A (zh) | 2006-07-26 | 2008-01-30 | 中国海洋大学 | 二氧哌嗪类化合物及其制备方法和用途 |
KR101410318B1 (ko) | 2006-07-27 | 2014-06-27 | (주)아모레퍼시픽 | 바닐로이드 수용체 길항제로서의 신규 화합물, 그의 이성질체, 또는 약제학적으로 허용가능한 그의 염, 및 이를함유하는 약제학적 조성물 |
TW200817424A (en) | 2006-08-04 | 2008-04-16 | Daiichi Sankyo Co Ltd | Benzylphenyl glucopyranoside derivatives |
TWI389895B (zh) | 2006-08-21 | 2013-03-21 | Infinity Discovery Inc | 抑制bcl蛋白質與結合夥伴間之交互作用的化合物及方法 |
ES2670407T3 (es) | 2006-09-03 | 2018-05-30 | Techfields Biochem Co. Ltd | Profármacos de acetaminofén solubles en agua cargados positivamente y compuestos relacionados con una tasa de penetración de la piel muy rápida |
JP2010505811A (ja) | 2006-10-04 | 2010-02-25 | ファイザー・プロダクツ・インク | カルシウム受容体アンタゴニストとしてのピリド[4,3−d]ピリミジン−4(3H)−オン誘導体 |
CA2667007A1 (en) | 2006-10-23 | 2008-05-02 | Merck & Co., Inc. | 2-[1-phenyl-5-hydroxy or methoxy-4alpha-methyl-hexahydrocyclopenta[f]indazol-5-yl]ethyl phenyl derivatives as glucocorticoid receptor ligands |
WO2008066145A1 (fr) | 2006-11-30 | 2008-06-05 | R-Tech Ueno, Ltd. | Dérivé de thiazole et son utilisation en tant qu'inhibiteur de la vap-1 |
FR2909379B1 (fr) | 2006-11-30 | 2009-01-16 | Servier Lab | Nouveaux derives heterocycliques,leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
CA2670984A1 (en) | 2006-11-30 | 2008-06-05 | Tokyo Institute Of Technology | Novel curcumin derivative |
WO2008101682A2 (en) | 2007-02-22 | 2008-08-28 | Syngenta Participations Ag | Iminipyridine derivatives and their uses as microbiocides |
TWI407960B (zh) | 2007-03-23 | 2013-09-11 | Jerini Ag | 小分子緩激肽b2受體調節劑 |
CN101679172B (zh) | 2007-05-22 | 2013-05-29 | 住友化学株式会社 | 苯甲醛化合物的制造方法 |
WO2009001214A2 (en) | 2007-06-28 | 2008-12-31 | Pfizer Products Inc. | Thieno[2,3-d]pyrimidin-4(3h)-one, isoxazolo[5,4-d]pyrimidin-4(5h)-one and isothiazolo[5,4-d]pyrimidin-4(5h)-one derivatives as calcium receptor antagonists |
US20090069288A1 (en) | 2007-07-16 | 2009-03-12 | Breinlinger Eric C | Novel therapeutic compounds |
WO2009010416A2 (en) | 2007-07-17 | 2009-01-22 | F. Hoffmann-La Roche Ag | Inhibitors of 11b-hydroxysteroid dehydrogenase |
JP5090528B2 (ja) | 2007-07-26 | 2012-12-05 | ノバルティス アーゲー | ALK4またはALK5が介在する疾患を処置するための2、3、7位置換イミダゾ[1,2−b]ピリダジン類 |
TW200918521A (en) * | 2007-08-31 | 2009-05-01 | Astrazeneca Ab | Heterocyclic amides and methods of use thereof |
AU2008313773B2 (en) | 2007-10-17 | 2012-04-12 | Novartis Ag | Imidazo [1, 2-A] pyridine derivatives useful as ALK inhibitors |
DK2227467T3 (en) * | 2007-12-04 | 2015-01-19 | Hoffmann La Roche | Isoxazolo-pyridine derivatives |
US7776875B2 (en) | 2007-12-19 | 2010-08-17 | Hoffman-La Roche Inc. | Spiroindolinone derivatives |
JP2009203230A (ja) | 2008-01-31 | 2009-09-10 | Daiichi Sankyo Co Ltd | ベンジルフェニルグルコピラノシド誘導体を含有する医薬組成物 |
US8258349B2 (en) | 2008-02-14 | 2012-09-04 | Suitomo Chemical Company, Limited | Process for production of benzaldehyde compound |
US8633245B2 (en) | 2008-04-11 | 2014-01-21 | Institute Of Medicinal Molecular Design, Inc. | PAI-1 inhibitor |
KR20100132073A (ko) | 2008-04-11 | 2010-12-16 | 가부시키가이샤 이야쿠 분지 셋케이 겐쿠쇼 | Pai―1 저해제 |
JP2011136906A (ja) | 2008-04-18 | 2011-07-14 | Otsuka Pharmaceut Co Ltd | 複素環化合物 |
US8119647B2 (en) | 2008-04-23 | 2012-02-21 | Glenmark Pharmaceuticals S.A. | Fused pyrimidineone compounds as TRPV3 modulators |
ES2599002T3 (es) | 2008-05-08 | 2017-01-31 | Nova Southeastern University | Inhibidores específicos para receptores del factor de crecimiento endotelial vascular |
JP5514810B2 (ja) | 2008-06-04 | 2014-06-04 | タイメッド バイオロジクス インコーポレイテッド | ピリドキシンに由来するhivインテグラーゼ阻害剤 |
DE102008027574A1 (de) | 2008-06-10 | 2009-12-17 | Merck Patent Gmbh | Neue Pyrrolidinderivate als MetAP-2 Inhibitoren |
JP5314330B2 (ja) | 2008-06-16 | 2013-10-16 | 住友化学株式会社 | 2−(アリールオキシメチル)ベンズアルデヒドの製造方法およびその中間体 |
GB0811451D0 (en) | 2008-06-20 | 2008-07-30 | Syngenta Participations Ag | Novel microbiocides |
AR073304A1 (es) | 2008-09-22 | 2010-10-28 | Jerini Ag | Moduladores del receptor de bradiquinina b2 de molecula pequena |
WO2010056631A1 (en) | 2008-11-12 | 2010-05-20 | Schering Corporation | Inhibitors of fatty acid binding protein (fabp) |
TW201033201A (en) | 2009-02-19 | 2010-09-16 | Hoffmann La Roche | Isoxazole-isoxazole and isoxazole-isothiazole derivatives |
ES2811342T3 (es) | 2009-03-31 | 2021-03-11 | Ligand Pharm Inc | Antagonista de receptores de endotelina y angiotensina II de bifenilsulfonamida para tratar glomeruloesclerosis y nefropatía inducida por IgA |
ES2440000T3 (es) | 2009-05-08 | 2014-01-27 | Tetraphase Pharmaceuticals, Inc. | Compuestos de 8-aza-tetraciclina |
EP2471789B9 (en) | 2009-08-26 | 2015-03-25 | Takeda Pharmaceutical Company Limited | Fused heterocyclic ring derivative and use thereof |
EP2474540A4 (en) | 2009-08-31 | 2013-03-13 | Nippon Chemiphar Co | GPR119 AGONIST |
JP2013505218A (ja) | 2009-09-21 | 2013-02-14 | エフ.ホフマン−ラ ロシュ アーゲー | 複素環式抗ウイルス化合物 |
PT2498756T (pt) | 2009-11-09 | 2019-11-26 | Wyeth Llc | Formulações de comprimidos de maleato de neratinib |
TW201139406A (en) | 2010-01-14 | 2011-11-16 | Glaxo Group Ltd | Voltage-gated sodium channel blockers |
KR101698153B1 (ko) | 2010-04-26 | 2017-01-23 | 광주과학기술원 | P2x1 및 p2x3 수용체 길항제로 사용되는 신규한 피리딘 카르복실산계 화합물, 이의 제조방법 및 이를 포함하는 조성물 |
CN102232949A (zh) | 2010-04-27 | 2011-11-09 | 孙远 | 提高药物溶出度的组合物及其制备方法 |
TWI535442B (zh) | 2010-05-10 | 2016-06-01 | Kyowa Hakko Kirin Co Ltd | A nitrogen-containing heterocyclic compound having an action of inhibiting the production of canine erythritine |
US20120122928A1 (en) | 2010-08-11 | 2012-05-17 | Bayer Cropscience Ag | Heteroarylpiperidine and -Piperazine Derivatives as Fungicides |
CN102116772B (zh) | 2010-09-28 | 2013-08-28 | 上海大学 | 二氢查尔酮化合物的筛选方法 |
EP2658530A2 (en) | 2010-12-27 | 2013-11-06 | Takeda Pharmaceutical Company Limited | Orally disintegrating tablet |
WO2012138981A2 (en) | 2011-04-06 | 2012-10-11 | Teva Pharmaceutical Industries Ltd. | New intermediates and processes for preparing ticagrelor |
US9399635B2 (en) | 2011-04-11 | 2016-07-26 | Green Tech Co., Ltd. | Pyrazole derivative |
AU2012308274B2 (en) | 2011-09-15 | 2017-08-17 | Demerx, Inc. | Noribogaine salt ansolvates |
US20140308260A1 (en) | 2011-10-07 | 2014-10-16 | Radiorx, Inc. | Methods and compositions comprising a nitrite-reductase promoter for treatment of medical disorders and preservation of blood products |
EP2797597B1 (en) | 2011-12-28 | 2020-02-26 | Global Blood Therapeutics, Inc. | Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation |
PE20142454A1 (es) | 2011-12-28 | 2015-02-07 | Global Blood Therapeutics Inc | Compuestos de benzaldehido sustituidos y metodos para su uso en incrementar la oxigenacion del tejido |
EP2940012B1 (en) | 2012-12-27 | 2019-01-30 | Sumitomo Chemical Company Limited | Tetrazolinone compound and applications thereof |
US9422279B2 (en) | 2013-03-15 | 2016-08-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US20140271591A1 (en) | 2013-03-15 | 2014-09-18 | Global Blood Therapeutics, Inc. | Compositions and methods for the modulation of hemoglobin (s) |
US9604999B2 (en) | 2013-03-15 | 2017-03-28 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US20150057251A1 (en) | 2013-08-26 | 2015-02-26 | 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 |
JP6401772B2 (ja) | 2013-03-15 | 2018-10-10 | グローバル ブラッド セラピューティクス インコーポレイテッド | ヘモグロビンの修飾のための化合物及びその使用 |
US9802900B2 (en) | 2013-03-15 | 2017-10-31 | Global Blood Therapeutics, Inc. | Bicyclic heteroaryl 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 |
WO2014150258A1 (en) | 2013-03-15 | 2014-09-25 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
CA2902874C (en) | 2013-03-15 | 2021-04-20 | Global Blood Therapeutics, Inc. | Substituted pyridinyl-6-methoxy-benzaldehyde derivatives and pharmaceutical compositions thereof useful for the modulation of hemoglobin |
KR20190041548A (ko) | 2013-03-15 | 2019-04-22 | 글로벌 블러드 테라퓨틱스, 인크. | 헤모글로빈 조정을 위한 화합물 및 이의 용도 |
JP2016512821A (ja) | 2013-03-15 | 2016-05-09 | グローバル ブラッド セラピューティクス インコーポレイテッド | ヘモグロビンの修飾のための組成物及び方法 |
EA034922B1 (ru) | 2013-03-15 | 2020-04-07 | Глобал Блад Терапьютикс, Инк. | Соединения и их применения для модуляции гемоглобина |
US20140274961A1 (en) | 2013-03-15 | 2014-09-18 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US8952171B2 (en) | 2013-03-15 | 2015-02-10 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
WO2014145040A1 (en) | 2013-03-15 | 2014-09-18 | Global Blood Therapeutics, Inc. | Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation |
WO2015031284A1 (en) | 2013-08-26 | 2015-03-05 | Global Blood Therapeutics, Inc. | Formulations comprising wetting agents and compounds for the modulation of hemoglobin (s) |
WO2015031285A1 (en) | 2013-08-27 | 2015-03-05 | Global Blood Therapeutics, Inc. | Crystalline 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde ansolvate salts |
US20160207904A1 (en) | 2013-08-27 | 2016-07-21 | Global Blood Therapeutics, Inc. | Crystalline 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde ansolvate salts |
EA202092627A1 (ru) | 2013-11-18 | 2021-09-30 | Глобал Блад Терапьютикс, Инк. | Соединения и их применения для модуляции гемоглобина |
US20150141465A1 (en) | 2013-11-18 | 2015-05-21 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
WO2015116061A1 (en) | 2014-01-29 | 2015-08-06 | Global Blood Therapeutics, Inc. | 1:1 adducts of sickle hemoglobin |
US9248199B2 (en) | 2014-01-29 | 2016-02-02 | Global Blood Therapeutics, Inc. | 1:1 adducts of sickle hemoglobin |
WO2015120133A1 (en) | 2014-02-07 | 2015-08-13 | 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 |
WO2016043849A2 (en) | 2014-07-24 | 2016-03-24 | Global Blood Therapeutics, Inc. | Compounds for treating acute respiratory distress syndrome or a negative effect thereof |
TWI544395B (zh) | 2014-09-26 | 2016-08-01 | 義隆電子股份有限公司 | 單層電容式觸控面板之掃描方法及裝置 |
MA41841A (fr) | 2015-03-30 | 2018-02-06 | Global Blood Therapeutics Inc | Composés aldéhyde pour le traitement de la fibrose pulmonaire, de l'hypoxie, et de maladies auto-immunes et des tissus conjonctifs |
SG10201912511WA (en) | 2015-12-04 | 2020-02-27 | Global Blood Therapeutics Inc | Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
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 |
EP3860975B1 (en) | 2018-10-01 | 2023-10-18 | Global Blood Therapeutics, Inc. | Modulators of hemoglobin for the treatment of sickle cell disease |
EP3880654B1 (en) | 2018-11-19 | 2021-12-29 | Global Blood Therapeutics, Inc. | 2-formyl-3-hydroxyphenyloxymethyl compounds capable of modulating hemoglobin |
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