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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