JP2018519351A - オキシステロールおよびそれらの使用の方法 - Google Patents
オキシステロールおよびそれらの使用の方法 Download PDFInfo
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- JP2018519351A JP2018519351A JP2018500417A JP2018500417A JP2018519351A JP 2018519351 A JP2018519351 A JP 2018519351A JP 2018500417 A JP2018500417 A JP 2018500417A JP 2018500417 A JP2018500417 A JP 2018500417A JP 2018519351 A JP2018519351 A JP 2018519351A
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000000453 second toe Anatomy 0.000 description 1
- 208000012201 sexual and gender identity disease Diseases 0.000 description 1
- 208000015891 sexual disease Diseases 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 210000001626 skin fibroblast Anatomy 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 230000003997 social interaction Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 201000009032 substance abuse Diseases 0.000 description 1
- 231100000736 substance abuse Toxicity 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000005156 substituted alkylene group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000003900 succinic acid esters Chemical class 0.000 description 1
- 125000004964 sulfoalkyl group Chemical group 0.000 description 1
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 229910052714 tellurium Inorganic materials 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000005305 thiadiazolinyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005458 thianyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000003777 thiepinyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000005296 thioaryloxy group Chemical group 0.000 description 1
- 125000005323 thioketone group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 210000000431 third toe Anatomy 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000005881 triazolinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
- C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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Abstract
に記載の化合物およびその薬学的に受容可能な塩ならびにその薬学的組成物が提供され;式中、R1、R2、R3、R6、R7、R8、およびnは、本明細書中で定義されるとおりである。本発明の化合物は、種々の症状の予防および処置に有用であると予想される。NMDA媒介性障害を含むがこれに限定されない広範囲の障害の予防および/または処置に有用な置換オキシステロールが本明細書中に提供される。これらの化合物は、他のオキシステロールと比べて、改善されたインビボ効力、薬物動態学的(PK)特性、経口バイオアベイラビリティ、製剤化適性、安定性および/または安全性を示すと予想される。本発明の化合物を含む薬学的組成物ならびにそれらの使用および処置の方法がさらに提供される。
Description
本願は、2015年7月6日に出願された米国仮出願第62/189,048号および2016年1月19日に出願された同第62/280,394号に対する優先権を主張し、これらの米国仮出願の各々の内容は、その全体が参照によって本明細書中に組み込まれる。
NMDAレセプターは、NR1、NR2および/またはNR3サブユニットを含むヘテロマー複合体であり、外来性リガンドおよび内在性リガンドに対して異なる認識部位を有する。これらの認識部位は、グリシンに対する結合部位ならびにグルタメートアゴニストおよび調節因子に対する結合部位を含む。NMDAレセプターは、末梢組織およびCNSにおいて発現され、それらにおいて興奮性シナプス伝達に関与する。これらのレセプターの活性化は、いくつかの状況ではシナプス可塑性に寄与し、他の状況では興奮毒性に寄与する。これらのレセプターは、グルタメートおよびグリシンの結合後にCa2+を受け入れるリガンド開口型(ligand−gated)イオンチャネルであり、興奮性神経伝達および正常なCNS機能に必須である。正の調節因子は、向知性薬として、およびグルタミン酸作動性の伝達が低下または欠損している精神障害の処置において潜在的な臨床用途を有する治療薬として有用であり得る(例えば、Horakら、J.of Neuroscience,2004,24(46),10318−10325を参照のこと)。対照的に、負の調節因子は、グルタミン酸作動性の伝達が病理学的に増加している精神障害(例えば、処置抵抗性うつ)の処置において潜在的な臨床用途を有する治療薬として有用であり得る。
オキシステロールは、コレステロールに由来し、NMDAレセプターの機能を強力かつ選択的に調節すると示されている。NMDAの発現および機能に関連する症状を予防および処置するための、NMDAレセプターを調節する新規のおよび改善されたオキシステロールが必要である。本明細書中に記載される化合物、組成物および方法は、この目的に向けられている。
NMDA媒介性障害を含むがこれに限定されない広範囲の障害の予防および/または処置に有用な置換オキシステロールが本明細書中に提供される。これらの化合物は、他のオキシステロールと比べて、改善されたインビボ効力、薬物動態学的(PK)特性、経口バイオアベイラビリティ、製剤化適性、安定性および/または安全性を示すと予想される。本発明の化合物を含む薬学的組成物ならびにそれらの使用および処置の方法がさらに提供される。
1つの局面において、式(I):
定義
化学的定義
他の定義
本明細書中に広く記載されるように、本発明は、NMDA媒介性障害を含むがこれに限定されない広範囲の障害の予防および/または処置に有用なオキシステロールを提供する。これらの化合物は、他のオキシステロールと比べて、改善されたインビボ効力、薬物動態学的(PK)特性、経口バイオアベイラビリティ、製剤化適性、安定性および/または安全性を示すと予想される。
化合物
処置方法および使用方法
疾患および障害
ステロール合成障害を処置する方法が本明細書中に記載される。例示的な障害は、本明細書中に記載される。その方法は、被験体、例えば、SLOSなどのステロール合成障害に罹患している被験体に、NMDAレセプター調節化合物を投与することを含む。例示的な化合物は、本明細書中に記載される。
ステロール合成障害
スミス・レムリ・オピッツ症候群
デスモステロローシス
シトステロール血症
脳腱黄色腫症(CTX)
メバロン酸キナーゼ欠損症症候群(MKD)
SC4MOL遺伝子変異(SMO欠損症)
ニーマン・ピック病
自閉症
フェニルケトン尿症に関連する障害
省略形
工程2。トルエン(10mL)中のBHT(2.29g,10.4mmol)の溶液に、AlMe3(2.61mL,5.22mmol)の溶液(トルエン中2M)を25℃において添加した。得られた混合物を25℃で1時間撹拌し、その後、トルエン(5mL)中のA2(700mg,1.74mmol)の溶液を窒素下、−78℃において添加した。この混合物をさらに30分間撹拌し、その後、MeMgBr(Et2O中3.0M、1.74mL,5.22mmol)を−78℃において滴下により添加した。この反応混合物をこの温度で3時間撹拌し、次いで、−78℃の飽和NH4Cl水溶液(30mL)でクエンチした。得られた懸濁液を濾過し、濾過ケーキをEtOAcで洗浄した(2×50mL)。合わせた有機相をNa2SO4で乾燥させ、濃縮し、シリカゲル(PE/EtOAc=10/1〜8/1)により精製して、化合物1(120mg,17%)をオフホワイトの固体として得た。1H NMR (400 MHz, CDCl3) δ 5.30 (d, J = 3.6 Hz, 1H), 2.40-2.30 (m, 1H), 1.99-1.98(m, 3H), 1.70-1.57 (m, 4H), 1.46-1.17 (m, 28H), 1.11-0.92 (m, 8H), 0.67 (s,3H). LCMS Rt=1.503分(2分間のクロマトグラフィー、10−80AB)、C28H49O2[M+H]+のMS ESI計算値417、C28H45[M−2H2O+H]+の実測値381。
工程2。MeOH(15mL)中のB2(8.5g,56.3mmol)の懸濁液に、98%H2SO4(2.80g,28.1mmol)を添加した。この混合物を25℃で24時間撹拌した。この反応混合物を減圧中でエバポレートした。蒸留物を水(20mL)で洗浄した。有機層を分離し、Na2SO4で乾燥させて、B3(7g,75%)を無色油状物として得た。1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 14.0Hz, 1H), 6.53 (d, J = 14.0 Hz, 1H), 3.76 (s, 3H)。
工程3。N2下の無水THF(300mL)中のPh3PMeBr(67.5g,189mmol)の懸濁液に、t−BuOK(21.2g,189mmol)を添加した。60℃で30分間撹拌した後、A3(20g,63.1mmol)を添加した。得られた混合物を60℃で4時間撹拌した。この反応混合物を氷水(500mL)に注ぎ、EtOAcで抽出した(2×500mL)。合わせた有機層をNa2SO4で乾燥させ、濾過し、濃縮した。その残渣をシリカゲルでのカラムクロマトグラフィー(PE/EtOAc=15/1)により精製して、A4(18g,91%)をオフホワイトの固体として得た。1H NMR (400 MHz, CDCl3) δ 5.39-5.32 (m, 1H), 4.85(s, 1H), 4.71 (s, 1H), 3.59-3.47 (m, 1H), 2.36-2.17 (m, 2H), 2.07-1.94 (m, 2H),1.89-1.65 (m, 9H), 1.60-1.39 (m, 6H), 1.26-0.92 (m, 8H), 0.59 (s, 3H)。
工程4。無水DCM(150mL)中のA4(18g,57.2mmol)の溶液に、Ac2O(8.75g,85.8mmol)およびDMAP(13.9g,114mmol)を添加した。この混合物を25℃で2時間撹拌した。この反応混合物を水(200mL)で希釈し、DCMで抽出した(3×150mL)。合わせた有機層を飽和NaHCO3(150mL)およびブライン(150mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、濃縮して、A5(20g,99%)をオフホワイトの固体として得た。
工程5。窒素雰囲気下、30℃の無水THF(150mL)中のA5(30g,84.1mmol)の溶液に、9−BBN(THF中0.5M,185mL,92.5mmol)を添加した。この混合物を75℃で3時間撹拌した。この反応混合物を30℃に冷却し、(E)−メチル3−ブロモアクリレート(15.2g,92.5mmol)、CsF(25.5g,168mmol)およびPd(t−Bu3P)2(4.55g,8.40mmol)を添加した。得られた混合物を75℃で16時間撹拌した。この反応物を冷却し、水(300mL)でクエンチし、EtOAcで抽出した(3×300mL)。合わせた有機層をNa2SO4で乾燥させ、シリカゲルパッドで濾過し、濃縮した。その残渣をMeOHから磨砕して(triturated)、A6(20g,54%)をオフホワイトの固体として得た。1H NMR (400 MHz, CDCl3) δ 7.00-6.90 (m, 1H), 5.81(d, J = 15.6 Hz, 1H), 5.37 (d, J = 4.5 Hz, 1H), 4.66-4.53 (m,1H), 3.73 (s, 3H), 2.36-2.24 (m, 3H), 2.03 (s, 3H), 2.00-1.79 (m, 6H),1.65-1.38 (m, 8H), 1.34-1.05 (m, 6H), 1.01 (s, 3H), 0.95 (d, J = 6.5 Hz,3H), 0.69 (s, 3H)。
工程6。無水MeOH(250mL)中のA6(20g,45.1mmol)の懸濁液に、AcCl(2.82g,36.0mmol)を添加した。この混合物を25℃で16時間撹拌した。この反応混合物を濃縮して、MeOHの大部分を除去し、EtOAc(500mL)で希釈し、飽和NaHCO3(500mL)、ブライン(300mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、濃縮した。その残渣をシリカゲルでのカラムクロマトグラフィー(PE/EtOAc/DCM=8/1/1)により精製して、A7(12g,67%)をオフホワイトの固体として得た。
工程7。THF(150mL)中のA7(12g,29.9mmol)の溶液に、5%Pt/C(2g)を添加した。この混合物を脱気およびH2でパージすることを数回行い、H2バルーン下、25℃で4時間撹拌した。この反応混合物をセライトパッドで濾過し、濾液を濃縮して、A8(12g,100%)をオフホワイトの固体として得た。1H NMR (400 MHz, CDCl3) δ 5.34 (d, J = 5.0Hz, 1H), 3.66 (s, 3H), 3.57-3.45 (m, 1H), 2.33-2.21 (m, 4H), 2.05-1.65 (m, 7H),1.48-1.32 (m, 6H), 1.31-0.88 (m, 17H), 0.67 (s, 3H)。
工程8。DCM(300mL)中のA8(27g,67.0mmol)の溶液に、DMP(85.2g,201mmol)を25℃において添加した。この反応物を25℃で1時間撹拌した。この反応物を25℃で1時間撹拌した。この混合物を0℃の飽和Na2S2O3(400ml)に注ぎ、EtOAcで抽出した(3×300mL)。合わせた有機層を飽和NaHCO3(2×250mL)、ブライン(200mL)で洗浄し、Na2SO4で乾燥させ、濾過し、減圧中で濃縮して、A9(27g,粗)を油状物として得、これをさらに精製せずに次の工程のために直接使用した。
工程9。トルエン(250mL)中のBHT(88.8g,403mmol)の溶液に、AlMe3(100mL,201mmol,トルエン中2M)を25℃未満において滴下により添加した。この溶液を25℃で1時間撹拌した。トルエン(250mL)中のA9(27g,67.3mmol)の溶液を−78℃において滴下により添加した。−78℃で1時間撹拌した後、MeMgBr(67.0mL,201mmol,エチルエーテル中3M)を−78℃において滴下により添加した。得られた溶液を−78℃〜−50℃で3時間撹拌した。この反応を−78℃の飽和クエン酸溶液(400mL)によってクエンチした。25℃で0.5時間撹拌した後、得られた混合物を濾過し、濾液をEtOAcで抽出した(3×300mL)。合わせた有機層をNa2SO4で乾燥させ、濾過し、減圧中で濃縮した。この粗生成物をシリカゲルカラム(PE/EtOAc=5/1)により精製して、生成物(18.5g,66%)を得て、その生成物の70mgを再結晶して(PE/EtOAc=10mL/2mL)、A27(67mg)をオフホワイトの固体として得た。A27:1H NMR(400 MHz, CDCl3) δ 5.30-5.28 (m, 1H), 3.65(s, 3H), 2.40-0.91 (m, 37H), 0.66 (s, 3H). LCMS Rt=1.562分(2分間のクロマトグラフィー、10−80AB)、C27H43O2[M+H−H2O]+のMS ESI計算値399、実測値399。
工程10。THF(135mL)中のLiAlH4(6.11g,161mmol)の溶液に、0℃のTHF(135mL)中のA27(27g,64.8mmol)の溶液を滴下により添加した。この混合物を25℃で1時間撹拌した。H2O(100mL)を0℃において添加した。この反応混合物を濾過し、THFで洗浄した(2×100mL)。濾液を減圧中で濃縮して、粗生成物を得、これをEtOAc(100mL)で洗浄して、化合物4(25g,100%)を得て、その生成物の30mgを再結晶して(EtOAc,3mL)、化合物4(27mg)をオフホワイトの固体として得た。
化合物4:1H NMR (400 MHz, CDCl3) δ 5.31-5.29 (m, 1H),3.70-3.60 (m, 2H), 2.43-2.40 (m, 1H), 2.20-0.90 (m, 37H), 0.67 (s, 3H). LCMS Rt=1.402分(2分間のクロマトグラフィー、10−80AB)、C26H45O2[M+H]+のMS ESI計算値389、C26H43O[M+H−H2O]の実測値371。
工程11。DCM(180mL)中の化合物4(18g,46.3mmol)の溶液に、DMP(58.5g,138mmol)を0℃において添加した。この反応物を25℃で1時間撹拌した。この混合物を0℃の飽和Na2S2O3(100mL)に注いだ。この混合物をEtOAcで抽出した(3×100mL)。合わせた有機層を飽和NaHCO3(2×150mL)、ブライン(100mL)で洗浄し、Na2SO4で乾燥させ、濾過し、減圧中で濃縮して、粗生成物を得、これをシリカゲルカラム(PE/EtOAc=5/1)により精製して、A10(13g,73%)をオフホワイトの固体として得た。1H NMR(400 MHz, CDCl3) δ 9.76 (t, J = 1.8Hz, 1H), 5.33-5.27 (m, 1H), 2.46-2.31 (m, 3H), 2.10-0.72 (m, 34H), 0.67 (s, 3H)。
工程12。THF(100mL)中のA10(10g,25.8mmol)の溶液に、MeMgBr(51mL,154mmol)をN2下、0℃において添加した。この反応物を25℃で1時間撹拌した。この反応を飽和NH4Cl(30mL)によりクエンチし、EtOAcで抽出した(3×100mL)。合わせた有機層をブライン(50mL)で洗浄し、Na2SO4で乾燥させ、濾過し、減圧中で濃縮して、粗生成物を得、これをシリカゲルカラム(PE/EtOAc=10/1)により精製して、A11(4.1g,40%)をオフホワイトの固体として得た。1H NMR(400 MHz, CDCl3) δ 5.30-5.29 (m, 1H),3.81-3.77 (m, 1H), 2.43-2.39 (m, 1H), 1.99-0.76 (m, 40H), 0.67 (s, 3H)。
工程13。A11(400mg,0.993mmol)の混合物をSFC分離(カラム:Chiralpak AD 250×30mm I.D.,5μm;移動相:超臨界CO2/MeOH+NH3H2O=55/45;流速:60ml/分;波長:220nm)により精製して、化合物5(ピーク1,120mg,30%)をオフホワイトの固体として、および化合物6(ピーク2,150mg,38%)をオフホワイトの固体として得た。化合物5:1H NMR(400 MHz, CDCl3) δ 5.32-5.27 (m, 1H),3.85-3.72 (m, 1H), 2.45-2.40 (m, 1H), 2.06-1.91 (m, 3H), 1.88-1.65 (m, 3H),1.54-1.33 (m, 12H), 1.32-0.87 (m, 22H), 0.68 (s, 3H). LCMS Rt=1.267分(2分間のクロマトグラフィー、30−90AB)、C27H47O2[M+H]+のMS ESI計算値403、C27H45O[M−H2O+H]+の実測値385。
化合物6:1H NMR (400 MHz, CDCl3) δ 5.33-5.27 (m, 1H),3.84-3.75 (m, 1H), 2.45-2.40 (m, 1H), 2.06-1.92 (m, 3H), 1.89-1.64 (m, 3H),1.56-0.79 (m, 34H), 0.67 (s, 3H). LCMS Rt=1.262分(2分間のクロマトグラフィー、30−90AB)、C27H47O2[M+H]+のMS ESI計算値403、C27H45O[M−H2O+H]+の実測値385。
工程2。N2下、−10℃の無水THF(10mL)中のA13(288mg,0.718mmol)の溶液に、EtMgBr(ジエチルエーテル中3M,1.43mL,4.30mmol)を滴下により添加した。この混合物を25℃で3時間撹拌した。この混合物を飽和NH4Cl(10mL)でクエンチし、EtOAcで抽出した(3×10mL)。合わせた有機層をNa2SO4で乾燥させ、濾過し、濃縮した。その残渣を、DCMで溶出するシリカゲルカラムクロマトグラフィーにより精製して、A14(105mg,34%)をオフホワイトの固体として得た。
工程3。A14(105mg,0.244mmol)をSFC(カラム:Chiralpak AD 250×30mm I.D.,5μm;移動相:超臨界CO2/EtOH+NH3H2O=70/30;流速:60ml/分;波長:220nm)により分離して、化合物7(ピーク1,21.4mg,28%)をオフホワイトの固体として、および化合物8(ピーク2,12.4mg,16%)をオフホワイトの固体として得た。
化合物7:1H NMR (400 MHz, CDCl3) δ 5.32-5.28 (m, 1H), 2.45-2.40 (m, 1H),2.04-1.93 (m, 3H), 1.81-1.65 (m, 3H), 1.52-0.79 (m, 39H), 0.68 (s, 3H). LCMS Rt=1.378分(2分間のクロマトグラフィー、30−90AB)、C29H51O2[M+H]+のMS ESI計算値431、C29H47[M+H−2H2O]+の実測値395。
化合物8:1H NMR (400 MHz, CDCl3) δ 5.32-5.28 (m, 1H), 2.45-2.40 (m, 1H),2.05-1.94 (m, 3H), 1.88-1.63 (m, 4H), 1.52-0.83 (m, 38H), 0.68 (s, 3H). LCMS Rt=1.374分(2分間のクロマトグラフィー、30−90AB)、C29H51O2[M+H]+のMS ESI計算値431、C29H47[M+H−2H2O]+の実測値395。
工程2。A16(100mg,0.224mmol)をSFC(カラム:Chiralpak AD 250×30mm I.D.,5um;移動相:超臨界CO2/EtOH+NH3H2O=65/35;流速:60ml/分;波長:220nm)により分離して、化合物9(ピーク1,26.2mg,26%)をオフホワイトの固体として、および化合物10(ピーク2,18.8mg,19%)をオフホワイトの固体として得た。
化合物9:1H NMR (400 MHz, CDCl3) δ 5.33-5.27 (m, 1H), 2.45-2.40 (m,1H), 2.06-1.92 (m, 3H), 1.88-1.64 (m, 5H), 1.52-0.78 (m, 39H), 0.68 (s, 3H). LCMS Rt=1.444分(2分間のクロマトグラフィー、30−90AB)、C30H53O2[M+H]+のMS ESI計算値445、C30H49[M+H−2H2O]+の実測値409。
化合物10:1HNMR (400 MHz, CDCl3) δ 5.32-5.28 (m, 1H), 2.45-2.40 (m, 1H),2.05-1.93 (m, 3H), 1.88-1.65 (m, 5H), 0.84-1.52 (m, 39H), 0.68 (s, 3H). LCMS Rt=1.442分(2分間のクロマトグラフィー、30−90AB)、C30H53O2[M+H]+のMS ESI計算値445、C30H49[M+H−2H2O]+実測値409。
工程2。A18(100mg.212μmol)をSFC分離(カラム:Chiralpak AD 250×30mm I.D.,5μm;移動相:超臨界CO2/MeOH+NH3H2O=70/30;流速:60ml/分;波長:220nm)により精製して、化合物11(ピーク1,25.6mg,26%)および化合物12(ピーク2,30mg,30%)をオフホワイトの固体として得た。
化合物11:1H NMR (400 MHz, CDCl3) δ 5.33-5.28 (m, 1H),2.45-2.40 (m, 1H), 2.06-1.93 (m, 3H), 1.90-1.61 (m, 6H), 1.56-1.38 (m, 9H),1.35 (s, 3H), 1.32-0.82 (m, 19H), 0.68 (s, 3H).LCMS Rt=1.327分(2分間のクロマトグラフィー、30−90AB)、C28H44F3O[M−H2O+H]+のMS ESI計算値453、実測値453。化合物12:1H NMR (400 MHz, CDCl3) δ 5.34 - 5.28 (m, 1H),2.45 - 2.40 (m, 1H), 2.06 - 1.92 (m, 3H), 1.90 - 1.66 (m, 5H), 1.56 - 1.33 (m,13H), 1.31 - 0.87 (m, 19H), 0.68 (s, 3H). LCMS Rt=1.320分(2分間のクロマトグラフィー、30−90AB)、C28H44F3O[M−H2O+H]+のMS ESI計算値453、実測値453。
工程2。A20(190mg,0.416mmol)を25℃においてSFC(カラム:Chiralpak AD 250×30mm I.D.,5um;移動相:超臨界CO2/MeOH+NH3H2O=65/35;流速:60ml/分;波長:220nm)により精製して、化合物13(ピーク1,38.4mg,20%)および化合物14(ピーク2,47.6mg,25%)をオフホワイトの固体として得た。
化合物13:1H NMR (400 MHz, CDCl3) δ 5.34 - 5.27 (m, 1H),3.98 - 3.84 (m, 1H), 2.45-2.40 (m, 1H), 2.08 - 1.92 (m, 4H), 1.89 - 1.64 (m,6H), 1.53 - 1.36 (m, 7H), 1.33 - 1.21 (m, 3H), 1.21 - 1.08 (m, 7H), 1.07 - 0.90(m, 10H), 0.68 (s, 3H). LCMS Rt=1.302分(2分間のクロマトグラフィー、30−90AB)、C27H44F3O2[M+H]+のMS ESI計算値457、C27H42F3O[M+H−H2O]+の実測値439。化合物14:1HNMR (400 MHz,CDCl3) δ 5.34-5.28 (m, 1H), 3.95-3.89 (m, 1H), 2.45-2.40 (m, 1H), 2.06-1.92(m, 4H), 1.89-1.59 (m, 7H), 1.54-1.34 (m, 8H), 1.32-1.21 (m, 2H), 1.20-1.05 (m,8H), 1.04-0.90 (m, 8H), 0.68 (s, 3H). LCMS Rt=1.299分(2分間のクロマトグラフィー、30−90AB)、C27H44F3O2[M+H]+のMS ESI計算値457、C27H42F3O[M+H−H2O]+の実測値439。
工程2。トルエン(20mL)中のBHT(4.93g,22.4mmol)の溶液に、0℃のAlMe3(5.60mL,トルエン中2M,11.2mmol)を滴下により添加した。この反応混合物を25℃で1.5時間撹拌した。トルエン(20mL)中のA9(1.5g,3.74mmol)の溶液を−70℃において添加した。得られた混合物を−70℃で1時間撹拌した。−70℃のEtMgBr(3.73mL,ジエチルエーテル中3.0M,11.2mmol)を添加した。この反応混合物を−70℃でさらに1時間撹拌した。この反応をNH4Cl(100mL)でクエンチし、EtOAcで抽出した(2×100mL)。合わせた有機層をブライン(100mL)で洗浄した。有機層をNa2SO4で乾燥させ、濾過し、減圧下で濃縮して、粗生成物を得、これをPE/EtOAc=10/1で溶出するシリカゲルクロマトグラフィーにより精製して、A30(600mg,35%)を白色固体として得た。1H NMR (400 MHz, CDCl3) δ 5.31-5.26 (m, 1H), 3.67(s, 3H), 2.41-2.19 (m, 3H), 2.07-1.91 (m, 3H), 1.88-1.61 (m, 5H), 1.55-1.33 (m,11H), 1.31-1.01 (m, 10H), 1.00-0.80 (m, 7H), 0.67 (s, 3H)。
工程3。THF(5mL)中のA30(550mg,1.27mmol)の溶液に、−70℃のMeLi(3.17mL,5.08mmol)を添加した。この混合物を−70℃で10分間撹拌した。この反応を飽和NH4Cl(20mL)でクエンチし、EtOAcで抽出した(2×20mL)。合わせた有機層をブライン(30mL)で洗浄し、Na2SO4で乾燥させ、濾過し、減圧下で濃縮した。この混合物を、50mgの出発物質から合成された別のバッチと合わせた。その残渣をシリカゲルクロマトグラフィー(PE/EtOAc=10/1)により精製して、化合物18(270mg,49%収率)を白色固体として得た。1H NMR (400 MHz, CDCl3) δ 5.28 (d, J = 5.0 Hz, 1H), 2.36 (d, J= 13.1 Hz, 1H), 2.08-1.91 (m, 3H), 1.89-1.69 (m, 3H), 1.65-1.60 (m, 3H),1.51-1.32 (m, 8H), 1.30-1.17 (m, 11H), 1.15-1.01 (m, 8H), 0.99-0.81 (m, 9H),0.68 (s, 3H).
LCMS Rt=1.372分(2分間のクロマトグラフィー、30−90AB)、C29H51O2[M+H]+のMS ESI計算値431、C29H47[M+H−2H2O]+の実測値395。
工程4。EtOAc(10mL)中の化合物18(200mg,0.464mmol)の溶液に、Pd/C(100mg)を25℃において添加した。この混合物をH2下、55℃で12時間撹拌した。この反応混合物を濾過し、濾過ケーキをEtOAcで洗浄した(2×40mL)。この混合物を減圧下で濃縮して、粗生成物を得、これをPE/EtOAc=10/1で溶出するシリカゲルクロマトグラフィーにより精製して、化合物19(6.6mg)および化合物20(10.2mg)をオフホワイトの固体として得た。
化合物19:1H NMR (400 MHz, CDCl3) δ 2.02-1.95 (m, 1H), 1.94-1.72 (m, 4H),1.52-1.31 (m, 14H), 1.27-1.16 (m, 14H), 1.14-0.99 (m, 7H), 0.97 (s, 3H),0.95-0.89 (m, 6H), 0.65 (s, 3H).LCMS Rt=1.432分(2分間のクロマトグラフィー、30−90AB)、C29H53O2[M+H]+のMS ESI計算値433、C29H49[M+H−2H2O]+の実測値397。
化合物20:1H NMR (400 MHz, CDCl3) δ 1.96 (d, J = 12.5 Hz, 1H), 1.86-1.75(m, 1H), 1.58-1.50 (m, 5H), 1.49-1.29 (m, 10H), 1.21 (s, 13H), 1.13-0.95 (m,8H), 0.94-0.84 (m, 7H), 0.82 (s, 3H), 0.64 (s, 4H). LCMS Rt=1.431分(2分間のクロマトグラフィー、30−90AB)、C29H53O2[M+H]+のMS ESI計算値433、C29H49[M+H−2H2O]+の実測値397。
工程2。DCM(30mL)中のA32(3g,7.41mmol)の溶液に、PCC(3.19g,14.8mmol)およびシリカゲル(4g,66.6mmol)を25℃において添加した。この混合物を25℃で1.5時間撹拌した。この混合物を濾過した。濾液を減圧中で濃縮し、シリカゲルでのカラムクロマトグラフィー(PE/EtOAc=50/1〜10/1)により精製して、A33(2.4g)をオフホワイトの固体として得た。1H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 2.44-2.19(m, 5H), 2.13-1.94 (m, 3H), 1.89-1.64 (m, 3H), 1.53-0.82 (m, 24H), 0.76-0.66(m, 4H)。
工程3。トルエン(25mL)中のBHT(7.88g,35.7mmol)の溶液に、N2下、0℃のAlMe3(8.9mL,17.8mmol,トルエン中2M)を添加した。この混合物を25℃で1時間撹拌した。−70℃のトルエン(5mL)中のA33(2.4g,5.96mmol)の溶液を添加した。この混合物を−78℃で1時間撹拌した。MeMgBr(5.93mL,17.8mmol,ジエチルエーテル中3M)を−78℃において添加した。この混合物を−78℃で1時間撹拌した。この反応混合物を飽和クエン酸(100mL)でクエンチした。この混合物をEtOAcで抽出し(3×100mL)、ブラインで洗浄し(3×300mL)、Na2SO4で乾燥させ、減圧中で濃縮して、粗生成物を得、これをシリカゲルでのカラムクロマトグラフィー(PE/EtOAc=30/1〜10/1)により精製して、A34(2g)を黄色固体として得た。A34:1H NMR (400 MHz, CDCl3) δ 3.67 (s, 3H), 2.36-2.18 (m, 2H), 2.01-1.92 (m, 1H), 1.86-1.77(m, 1H), 1.72-1.61 (m, 3H), 1.55-1.46 (m, 4H), 1.40-1.21 (m, 13H), 1.18-0.99(m, 7H), 0.95-0.86 (m, 5H), 0.81 (s, 3H), 0.70-0.60 (m, 4H). LCMS Rt=1.372分(2分間のクロマトグラフィー、30−90AB)、C27H47O2[M+H]+のMS ESI計算値418.3、[M+H−H2O]+の実測値401。
工程4。THF(10ml)中の、A34(300mg,0.716mmol)およびTi(i−PrO)4(203mg,0.716mmol)の溶液に、EtMgBr(ジエチルエーテル中3M,713μL,2.14mmol)を添加した。この混合物を25℃で16時間撹拌した。この反応混合物を飽和NH4Cl(5mL)でクエンチした。この混合物をセライトパッドで濾過した。濾液をEtOAcで抽出した(2×20mL)。合わせた有機層をNa2SO4で乾燥させ、濾過し、濃縮した。その残渣をシリカゲルでのカラムクロマトグラフィー(PE/EtOAc=20/1〜10/1)により精製して、化合物22(77mg,26%)をオフホワイトの固体として得た。1H NMR (400 MHz, CDCl3) δ 2.00-1.92 (m, 1H), 1.84-1.61 (m, 6H),1.53-0.83 (m, 30H), 0.80 (s, 3H), 0.76-0.71 (m, 2H), 0.69-0.60 (m, 4H),0.47-0.40 (m, 2H). LCMS Rt=1.317分(2分間のクロマトグラフィー、30−90AB)、C28H49O2[M+H]+のMS ESI計算値417、C28H47O[M+H−H2O]+の実測値399。
化合物24:1HNMR (400 MHz, CDCl3) δ 3.80-3.75 (m, 1H), 2.00-1.90 (m, 1H),1.90-1.75 (m, 1H), 1.75-0.70 (m, 38H), 0.80 (s, 3H), 0.70-0.60 (m, 4H).LCMS Rt=1.282分(2.0分間のクロマトグラフィー、30−90AB)、C27H49O2[M+H]+のMS ESI計算値405、C27H45[M−2H2O+H]+の実測値369。
工程2。THF(5mL)中のA36(800mg,2mmol)の溶液に、0℃の9−BBN(40mL,20.0mmol)を添加した。この混合物を25℃で1時間撹拌した。NaOH(13.3mL,40mmol,3M)およびH2O2(1.2mL,40mmol)を0℃において添加した。この混合物を25℃で2時間撹拌した。この反応物を水に注いだ。この混合物をEtOAcで抽出した(2×50mL)。合わせた有機層を飽和Na2S2O3(2×50mL)、ブライン(50mL)で洗浄し、Na2SO4で乾燥させ、濾過し、減圧中で濃縮して、A37(400mg)をオフホワイトの固体として得た。1H NMR (400 MHz, CDCl3) δ 5.35-5.27 (m, 1H),4.00-3.90 (m, 1H), 3.90-3.80 (m, 1H), 2.45-2.40 (m, 1H), 2.04-1.91 (m, 3H),1.88-1.66 (m, 5H), 1.53-1.21 (m, 10H), 1.20-0.87 (m, 23H), 0.68 (s, 3H).工程3。DCM(10mL)中のA37(500mg,1.19mmol)の溶液に、TEA(240mg,2.38mmol)およびAc2O(181mg,1.78mmol)を25℃において添加した。この反応物を25℃で2時間撹拌した。この反応を飽和NaHCO3(10mL)によってクエンチした。この混合物をDCMで抽出し(2×10mL)、ブラインで洗浄し(2×10mL)、Na2SO4で乾燥させ、濃縮して、A38(450mg,82%)をオフホワイトの固体として得た。1H NMR (400 MHz, CDCl3) δ 5.35-5.25 (m, 1H),3.56-3.38 (m, 2H), 2.45-2.40 (m, 1H), 2.07-1.91 (m, 3H), 1.89-1.67 (m, 3H),1.65-1.53 (m, 5H), 1.49-1.32 (m, 8H), 1.32-1.09 (m, 10H), 1.09-0.97 (m, 7H),0.97-0.87 (m, 7H), 0.68 (s, 3H)。
工程4。A38(450mg)をSFC(カラム:Chiralpak AD 250×30mm I.D.,5μm;移動相:超臨界CO2/MeOH+NH3H2O=60/40;流速:60ml/分;波長:220nm)により精製して、A39(200mg)およびA40(150mg)をオフホワイトの固体として得た。
工程5。MeOH(10mL)中のA39(200mg,0.435mmol)の溶液に、AcCl(17.0mg,0.217mmol)を25℃において添加した。この混合物を25℃で2時間撹拌した。この反応物を水(10mL)に注ぎ、THFで抽出した(2×20mL)。有機層をブライン(30mL)で洗浄し、Na2SO4で乾燥させ、濃縮して、化合物25(100mg,55%)をオフホワイトの固体として得た。1H NMR (400 MHz, CDCl3) δ 5.33-5.28 (m, 1H), 3.57-3.36 (m, 2H), 2.46-2.38 (m, 1H),2.05-1.92 (m, 3H), 1.87-1.57 (m, 6H), 1.52-1.34 (m, 7H), 1.28-1.20 (m, 3H),1.18-0.89 (m, 22H), 0.68 (s, 3H). LCMS Rt=1.328分(2分間のクロマトグラフィー、30−90AB_E)、C28H49O2[M+H]+のMS ESI計算値417、C28H47O[M+H−H2O]+の実測値399。
工程6。MeOH(10mL)中のA40(150mg,0.326mmol)の溶液に、AcCl(12.7mg,0.163mmol)を25℃において添加した。この混合物を25℃で2時間撹拌した。この反応物を水(10mL)に注ぎ、THFで抽出した(2×20mL)。有機層をブライン(30mL)で洗浄し、Na2SO4で乾燥させ、濃縮して、粗生成物を得、これをシリカゲルでのカラムクロマトグラフィー(PE/EtOAc=20/1〜8/1)により精製して、化合物26(90mg,66%)をオフホワイトの固体として得た。1H NMR (400 MHz, CDCl3) δ 5.33-5.28 (m, 1H), 3.55-3.38 (m, 2H), 2.46-2.38 (m, 1H),2.05-1.93 (m, 3H), 1.87-1.58 (m, 5H), 1.51-0.89 (m, 33H), 0.68 (s, 3H). LCMS Rt=1.320分(2分間のクロマトグラフィー、30−90AB_E)、C28H49O2[M+H]+のMS ESI計算値417、C28H47O[M+H−H2O]+の実測値399。
工程2。N2下、0℃のTHF(50mL)中のA41(2g,4.62mmol)の溶液に、LiAlH4(263mg,6.93mmol)を小分けにして添加した。この反応物を0℃で30分間撹拌した。この反応を0℃の1M HCl(30mL)でクエンチし、EtOAcで抽出した(3×30mL)。合わせた有機相をブライン(100mL)で洗浄し、Na2SO4で乾燥させ、濾過し、濃縮して、粗化合物33(1.3g,70%)をオフホワイトの固体として得た。100mgの粗化合物33をMeCN/DCM(10mL/10mL)から再結晶して、化合物33(30mg)をオフホワイトの固体として得た。1H NMR (400 MHz, CDCl3) δ 3.68-3.60 (m, 2H),2.00-1.91 (m, 1H), 1.86-1.74 (m, 1H), 1.70-1.58 (m, 4H), 1.56-1.44 (m, 6H),1.42-1.31 (m, 6H), 1.30-1.18 (m, 7H), 1.14-0.95 (m, 7H), 0.93-0.81 (m, 9H),0.93-0.79 (m, 1H), 0.68-0.58 (m, 4H). LCMS Rt=1.279分(2.0分間のクロマトグラフィー、30−90AB)、C27H47O[M+H−H2O]+のMS ESI計算値387、実測値387。
工程2。DCM(150mL)中のA42(1.7g,4.22mmol)の溶液に、DMP(3.2g,7.6mmol)を30℃において添加した。この混合物を30℃で30分間撹拌した。水(100mL)を添加した後、NaHCO3(4g,固体)を添加した。有機相を分離し、飽和Na2S2O3(2×200mL)、ブライン(2×200mL)で洗浄し、Na2SO4で乾燥させ、濾過し、減圧中で濃縮して、粗生成物A43(2.1g)を黄色固体として得た。
1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 5.35-5.25 (m, 1H), 2.45-2.30 (m, 3H), 2.05-1.90(m, 4H), 1.85-0.90 (m, 28H), 0.85-0.75 (m, 4H), 0.68(s, 3H)。
工程3。THF(20mL)中のA43(1g,粗)の溶液に、N2下、−70℃の臭化メチルマグネシウム(2.5mL,7.5mmol,エーテル中3M)を添加した。この混合物を20℃で1時間撹拌した。この混合物に、飽和NH4Cl(20mL)、EtOAc(20mL)およびH2O(10mL)を添加した。この混合物をEtOAcで抽出し(3×20mL)、飽和NaClで洗浄し(2×60mL)、Na2SO4で乾燥させ、濾過し、減圧中で濃縮して、粗生成物を得、これをシリカゲルでのカラムクロマトグラフィー(PE:EtOAc=100:1〜12:1)により精製して、化合物34(520mg,不純)をオフホワイトの固体として得た。化合物34(520mg,不純)を、80℃のCH3CN(50mL)で磨砕して、27mgの純粋な化合物34をオフホワイトの固体として得、400mgの不純な化合物34をSFCに使用した。
1H NMR (400 MHz, CDCl3) δ 5.35-5.25 (m, 1H), 3.85-3.75 (m, 1H), 2.40-2.30 (m, 1H),2.05-1.90 (m, 3H), 1.85-1.55 (m, 6H), 1.55-1.30 (m, 10H), 1.25-0.90 (m, 20H),0.85-0.75 (m, 3H), 0.67 (s, 3H). LCMS Rt=1.295分(2分間のクロマトグラフィー、30−90AB_E)、C28H47O[M−H2O+H]+のMS ESI計算値399、実測値399。
工程3。化合物35(400mg,不純)をSFC(カラム:AD(250mm*30mm,5um);条件:0.1%NH3H2O MeOH、40%B;流速(ml/分):60)により精製して、化合物35(79mg)および化合物36(59mg)をオフホワイトの固体として得た。
化合物35:1H NMR (400 MHz, CDCl3) δ 5.30-5.25 (m, 1H), 3.85-3.75 (m, 1H), 2.40-2.30 (m, 1H),2.10-1.95 (m, 3H), 1.90-1.60 (m, 4H), 1.45-1.28 (m, 11H), 1.25-0.90 (m, 17H),0.88-0.82 (m, 4H) , 0.78 (t, J = 7.2 Hz, 3H), 0.67 (s, 3H). LCMS Rt=1.295分(2分間のクロマトグラフィー、30−90AB_E)、[M−H2O+H]+のMS ESI計算値399、実測値399。
化合物36:1H NMR (400 MHz, CDCl3) δ 5.30-5.25 (m, 1H), 3.85-3.75 (m, 1H), 2.40-2.30 (m, 1H),2.10-1.95 (m, 3H), 1.90-1.60 (m, 4H), 1.50-1.17 (m, 11H), 1.14-0.90 (m, 17H),0.88-0.82 (m, 4H) , 0.78 (t, J = 7.2 Hz, 3H), 0.67 (s, 3H). LCMS Rt=1.295分(2分間のクロマトグラフィー、30−90AB_E)、C28H47O[M−H2O+H]+のMS ESI計算値399、実測値399。
工程2。N2下のTHF(20mL)中のA44(500mg,1.24mmol)の溶液に、0℃のMeMgBr(2.06mL,3.0M,6.19mmol)を一度に添加した。20℃で30分間撹拌した後、この混合物を50mLの飽和NH4Clによってクエンチし、50mLのEtOAcで抽出した。分離した有機相を100mLのブラインで洗浄し、Na2SO4で乾燥させ、濾過し、濃縮した。その残渣をコンビフラッシュ(PE中のEtOAc、0%〜40%)により精製して、化合物37(350mg,67%)をオフホワイトの固体として得た。27mgを供給した。1H NMR (400 MHz, CDCl3) δ 3.85-3.72 (m, 1H),1.99-1.91 (m, 1H), 1.86-1.74 (m, 1H), 1.69-1.59 (m, 3H), 1.56-1.50 (m, 3H),1.50-1.27 (m, 11H), 1.26-1.16 (m, 8H), 1.14-0.95 (m, 7H), 0.93-0.79 (m, 11H),0.67-0.59 (m, 4H). LCMS Rt=1.297分(2.0分間のクロマトグラフィー、30−90AB)、C28H47[M+H−2H2O]+のMS ESI計算値383、実測値383。
工程3。ピリジン(10mL)中の化合物37(300mg,0.716mmol)の溶液に、塩化ベンゾイル(501mg,3.57mmol)を添加した。この反応物を20℃で2時間撹拌した。この反応物をH2O(50mL)で希釈し、EtOAcで抽出した(3×20mL)。合わせた有機相を1N HCl(100mL)、ブライン(100mL)で洗浄し、Na2SO4で乾燥させ、濾過し、濃縮した。その残渣をコンビフラッシュ(PE中の0%〜15%のEtOAc)により精製して、A45(270mg,72%)を透明油状物として得た。1H NMR (400 MHz, CDCl3) δ 8.10-8.00 (m, 2H), 7.60-7.50 (m, 1H), 7.50-7.40 (m,2H),5.70-5.55 (m, 1H), 2.00-1.90 (m, 1H), 1.85-1.15 (m, 23H), 1.10-0.75 (m, 20H),0.70-0.50 (m, 4H)。
工程4。A45(270mg,0.516mmol)をSFC(カラム:AD(250mm*30mm,5um);条件:0.1%NH3.H2O EtOH;勾配35%B;勾配時間(分):30;流速(ml/分):60)により精製して、A46(ピーク1,90mg)を白色固体として、およびA47(ピーク2,100mg)を白色固体として得た。
A46:1H NMR (400 MHz, CDCl3) δ 8.10-8.00 (m, 2H), 7.60-7.50 (m, 1H), 7.50-7.40 (m,2H),5.70-5.55 (m, 1H), 2.00-1.60 (m, 6H), 1.55-1.25 (m, 14H), 1.20-1.10 (m, 7H),1.10-0.75 (m, 17H), 0.70-0.50 (m, 4H).
A47:1HNMR (400 MHz,CDCl3) δ 8.10-8.00 (m, 2H), 7.60-7.50(m, 1H), 7.50-7.40 (m,2H), 5.70-5.55 (m, 1H), 2.00-1.60 (m, 7H), 1.55-1.20 (m,20H), 1.20-0.80 (m, 17H), 0.70-0.50 (m, 4H)。
工程5。THF(5mL)中のA46(90mg,0.17mmol)の溶液に、MeOH(2mL)およびLiOH.H2O(72mg,1.72mmol)の溶液を25℃において添加した。この混合物を25℃で17時間撹拌した。水(5mL)を添加した。この混合物をEtOAcで抽出し(2×8mL)、ブラインで洗浄し(2×10mL)、Na2SO4で乾燥させ、濾過し、減圧中で濃縮して、粗生成物を得、これをフラッシュカラム(PE中の0〜30%のEtOAc,50分)により精製して、化合物37−A(28mg,39%)を白色固体として得た。1H NMR (400 MHz, CDCl3) δ 3.90-3.70 (m, 1H), 2.00-1.60 (m, 5H), 1.55-1.40 (m, 5H),1.35-1.20 (m, 17H), 1.20-0.80 (m, 18H), 0.70-0.50 (m, 4H). HPLC Rt=6.82分(8分間のクロマトグラフィー、30−90_AB_1.2ml_E)、C28H47[M+H−2H2O]+のMS MS ESI計算値383、実測値383。
工程6。THF(5mL)中のA47(100mg,0.19mmol)の溶液に、MeOH(2mL)およびLiOH.H2O(80mg,1.91mmol)の溶液を25℃において添加した。この混合物を25℃で17時間撹拌した。水(5mL)を添加した。この混合物をEtOAcで抽出し(2×8mL)、ブラインで洗浄し(2×10mL)、Na2SO4で乾燥させ、濾過し、減圧中で濃縮して、粗生成物を得、これをフラッシュカラム(PE中の0〜30%のEtOAc,50分)により精製して、化合物37−B(57mg,71%)を白色固体として得た。1H NMR (400 MHz, CDCl3) δ 3.90-3.70 (m, 1H), 2.00-1.60 (m, 7H), 1.55-1.30 (m, 11H),1.25-1.15 (m, 9H), 1.10-0.75 (m, 18H), 0.70-0.50 (m, 4H). HPLC Rt=6.78分(8分間のクロマトグラフィー、30−90_AB_1.2ml_E)、C28H47[M+H−2H2O]+のMS MS ESI計算値383、実測値383。
1H NMR (400 MHz, CDCl3) δ 5.32-5.25 (m, 1H), 3.95-3.85 (m, 1H), 2.40-2.30 (m, 1H),2.10-1.60 (m, 10H), 1.55-1.30 (m, 9H), 1.25-0.90 (m, 17H), 0.85 (t, J =7.6 Hz, 3H), 0.67 (s, 3H).LCMS Rt=1.308分(2分間のクロマトグラフィー、30−90AB_E)、C28H44F3O[M−H2O+H]+のMS ESI計算値453、実測値453。
工程2。化合物38(300mg)をSFC(カラム:AD(250mm*30mm,5um;条件:0.1%NH3H2O IPA、35%B;流速(ml/分):60;)により精製して、化合物39(68mg,23%)および化合物40(39mg,13%)をオフホワイトの固体として得た。
化合物39:1H NMR (400 MHz, CDCl3) δ 5.32-5.25 (m, 1H), 3.95-3.85 (m, 1H), 2.40-2.30 (m, 1H),2.10-1.60 (m, 10H), 1.55-1.30 (m, 10H), 1.25-0.90 (m, 16H), 0.85 (t, J =7.6 Hz, 3H), 0.68 (s, 3H). LCMS Rt=1.307分(2分間のクロマトグラフィー、30−90AB_E)、C28H44F3O[M−H2O+H]+のMS ESI計算値453、実測値453。
化合物40:1H NMR (400 MHz, CDCl3) δ 5.32-5.25 (m, 1H), 3.95-3.85 (m, 1H), 2.40-2.30 (m, 1H),2.10-1.60 (m, 10H), 1.55-1.25 (m, 13H), 1.20-0.90 (m, 13H), 0.85 (t, J =7.2 Hz, 3H), 0.68 (s, 3H). LCMS Rt=1.302分(2分間のクロマトグラフィー、30−90AB_E)、C28H44F3O[M−H2O+H]+のMS ESI計算値453、実測値453。
工程2。ピリジン(10mL)中の化合物43(350mg,0.740mmol)の溶液に、塩化ベンゾイル(416mg,2.96mmol)を添加した。この反応物を50℃で48時間撹拌した。この反応物をH2O(50mL)で希釈し、EtOAcで抽出した(3×20mL)。合わせた有機相を1N HCl(100mL)、ブライン(100mL)で洗浄し、Na2SO4で乾燥させ、濾過し、濃縮した。その残渣をコンビフラッシュ(PE中の0%〜20%のEtOAc)により精製して、A48(200mg,47%)を透明油状物として得た。1H NMR (400 MHz, CDCl3) δ 8.20-8.05 (m, 2H), 7.15-7.05 (m, 1H), 7.50-7.40 (m, 2H),5.60-5.50 (m, 1H), 2.00-1.70 (m, 3H), 1.55-1.40 (m, 12H), 1.35-1.15 (m, 9H),1.10-0.90 (m, 8H), 0.90-0.75 (m, 9H), 0.70-0.50 (m, 4H).
工程3。A48(200mg)をSFC(カラム:AD(250mm*30mm,5um);条件:0.1%NH3H2O MeOH、40%B;流速(ml/分):60)により精製して、A49(40mg,20%)を油状物として、およびA50(70mg,35%)をオフホワイトの固体として得た。
工程4。THF(2mL)中のA49(40mg)の溶液に、MeOH(1mL)、およびH2O(1mL)中のLiOH.H2O(16.6mg,0.69mmol)の溶液を25℃において添加した。この混合物を25℃で17時間撹拌した。この混合物をEtOAcで抽出し(2×5mL)、ブラインで洗浄し(2×10mL)、Na2SO4で乾燥させ、濾過し、フラッシュカラム(PE中の0〜30%のEtOAc)により精製して、43−A(20mg,不純)をオフホワイトの固体として得、これを25℃のCH3CN(2mL)で磨砕し、次いで、濾過ケーキを80℃のCH3CN(20mL)に溶解した。この溶液を減圧中で濃縮して、43−A(6mg,31%)をオフホワイトの固体として得た。1H NMR (400 MHz, CDCl3) δ 4.00-3.85 (m, 1H), 2.10-1.75 (m, 3H), 1.70-1.60 (m, 5H),1.55-1.20 (m, 16H), 1.15-0.75 (m, 18H), 0.70-0.55 (m,4H). LCMS Rt=1.319分(2分間のクロマトグラフィー、30−90AB_E)、C28H46F3O[M+H−H2O]+のMS ESI計算値455、実測値455。
工程5。THF(3mL)中のA50(70mg)の溶液に、MeOH(2mL)、およびH2O(2mL)中のLiOH.H2O(50.7mg,1.2mmol)の溶液を25℃において添加した。この混合物を25℃で17時間撹拌した。この混合物をEAで抽出し(2×6mL)、ブラインで洗浄し(2×10mL)、Na2SO4で乾燥させ、濾過し、フラッシュカラム(PE中の0〜30%EtOAc,1時間)により精製して、43−B(40mg,不純)を油状物として得、これを80℃の4mLのCH3CNから再結晶して、43−B(23mg,58%)をオフホワイトの固体として得た。1H NMR (400 MHz, CDCl3) δ 4.00-3.85 (m, 1H), 2.10-1.75 (m, 3H), 1.70-1.60 (m, 5H),1.55-1.20 (m, 16H), 1.15-0.75 (m, 18H), 0.70-0.55 (m,4H). LCMS Rt=1.315分(2分間のクロマトグラフィー、30−90AB_E)、C28H46F3O[M+H−H2O]+のMS ESI計算値455、実測値455。
材料および方法
NMDA増強
哺乳動物細胞のホールセルパッチクランプ(Ionworks Barracuda(IWB))
ホールセルパッチクランプ法を用いて、哺乳動物細胞において発現されたGlunN1/GluN2Aグルタメートレセプターに対する化合物の作用を調べた。結果を表1に示す。
HEK293細胞をアデノウイルス5DNAで形質転換し、ヒトGRIN1/GRIN2A遺伝子をコードするcDNAでトランスフェクトした。安定したトランスフェクタントを、発現プラスミドに組み込まれたG418遺伝子およびゼオシン耐性遺伝子ならびに培地中のG418およびゼオシンで維持される選択圧を用いて選択した。細胞を、10%ウシ胎児血清、100μg/mlペニシリンGナトリウム、100μg/ml硫酸ストレプトマイシン、100μg/mlゼオシン、5μg/mlブラストサイジンおよび500μg/ml G418が補充されたダルベッコ改変イーグル培地/栄養分混合物(D−MEM/F−12)中で培養した。
被験物質の効果を、8点の濃度反応形式(4連ウェル/濃度)で評価した。すべての試験溶液およびコントロール溶液が、0.3%DMSOおよび0.01%Kolliphor(登録商標)EL(C5135,Sigma)を含んだ。被験物質製剤を、自動化された液体ハンドリングシステム(SciClone ALH3000,Caliper LifeScienses)を用いて384ウェル化合物プレートに充填した。この手順に従ってIon Works Barracudaプラットフォームを用いて測定を行った:
電気生理学的手順:
a)細胞内溶液(mM):50mM CsCl、90mM CsF、2mM MgCl2、5mM EGTA、10mM HEPES。CsOHでpH7.2に調整する。
b)細胞外溶液、HB−PS(mMを単位とする組成):NaCl、137;KCl、1.0;CaCl2、5;HEPES、10;グルコース、10;pHをNaOHで7.4に調整する(使用するまで冷蔵する)。
c)保持電位:−70mV、アゴニスト/PAM適用中の電位:−40mV。
記録手順:
a)細胞外緩衝液をPPCプレートのウェルに充填する(1ウェルあたり11μL)。細胞懸濁液を、PPC平坦電極のウェルにピペットで添加する(1ウェルあたり9μL)。b)ホールセル記録の設定をパッチ穿孔によって確立し、膜電流を内蔵のパッチクランプ増幅器によって記録する。
c)2回の記録(走査)を行う。1回目は被験物質のみの事前適用中(事前適用の持続時間、5分)、2回目は被験物質およびアゴニスト(EC20L−グルタメートおよび30μMグリシン)の同時適用中に記録を行って、被験物質の正の調節作用を検出する。
被験物質の投与:1回目の事前適用は、10μL/s(2秒間の総適用時間)での、20μLの2×濃縮被験物質溶液の添加からなり、2回目は、20μLの1×濃縮被験物質およびアゴニストの添加からなる。
他の実施形態
Claims (57)
- 式(I):
R1は、C1〜6アルキルであり;
R2およびR3の各々は、独立して、水素、ハロゲン、C1〜6アルキルまたはカルボシクリルであるか;あるいは
R2およびR3は、それらが結合している炭素原子と一緒になって、3〜8員環を形成し;
R6は、存在しないか、または水素であり;
R7およびR8の各々は、独立して、水素、ハロゲン、C1〜6アルキルまたはカルボシクリルであるか;あるいは
R7およびR8の各々は、それらが結合している炭素原子と一緒になって、3〜8員環を形成するか;または
R2およびR7は、それらが結合している炭素原子と一緒になって、3〜8員環を形成し;
nは、1、2または3であり;
化合物またはその薬学的に受容可能な塩。 - R1が、メチル(例えば、−CHF2、−CF3、−CH2OCH3または−CH2OCH2CH3)、エチルまたはイソプロピルである、請求項1に記載の化合物。
- R1が、メチルまたはエチルである、請求項3に記載の化合物。
- R2およびR3の各々が、独立して、水素、C1〜6アルキルまたはカルボシクリルであるか、あるいはR2およびR3は、それらが結合している炭素原子と一緒になって、3〜8員環を形成する、請求項1に記載の化合物。
- 前記3〜8員環が、カルボシクリル環(例えば、シクロプロピル)である、請求項5に記載の化合物。
- R2およびR3の各々が、独立して、水素、C1〜6アルキルまたはカルボシクリルである、請求項5に記載の化合物。
- R2およびR3の各々が、独立して、水素、メチル(例えば、−CH3、−CF3)、エチル(例えば、−CH2CH3、−CH2CF3)、プロピル、イソプロピル、シクロプロピルまたはブチルである、請求項7に記載の化合物。
- R2が、水素、メチル(例えば、−CH3、−CF3)またはエチルである、請求項7に記載の化合物。
- R3が、メチル(例えば、−CH3、−CF3)、エチル(例えば、−CH2CH3、CH2CF3)、プロピル、イソプロピル、シクロプロピルまたはブチルである、請求項7に記載の化合物。
- R2が、水素であり、R3が、C1〜6アルキルである、請求項7に記載の化合物。
- R2が、C1〜6アルキルであり、R3が、C1〜6アルキルである、請求項7に記載の化合物。
- R7およびR8が、水素である、請求項1に記載の化合物。
- nが、1である、請求項1に記載の化合物。
- nが、1であり、R7およびR8が、水素である、請求項1に記載の化合物。
- R1が、メチル(例えば、−CHF2、−CF3、−CH2OCH3または−CH2OCH2CH3)、エチルまたはイソプロピルである、請求項25に記載の化合物。
- R2およびR3の各々が、独立して、水素、C1〜6アルキルまたはカルボシクリルであるか、あるいはR2およびR3が、それらが結合している炭素原子と一緒になって、3〜8員環を形成する、請求項21に記載の化合物。
- R2およびR3の各々が、独立して、水素、C1〜6アルキルまたはカルボシクリルである、請求項27に記載の化合物。
- R2およびR3の各々が、独立して、水素、メチル(例えば、−CH3、−CF3)、エチル(例えば、−CH2CH3、−CH2CF3)、プロピル、イソプロピル、シクロプロピルまたはブチルである、請求項28に記載の化合物。
- R2が、水素、メチル(例えば、−CH3、−CF3)またはエチルである、請求項29に記載の化合物。
- R3が、メチル(例えば、−CH3、−CF3)、エチル(例えば、−CH2CH3、−CH2CF3)、プロピル、イソプロピル、シクロプロピルまたはブチルである、請求項27に記載の化合物。
- R1が、メチル(例えば、−CHF2、−CF3、−CH2OCH3または−CH2OCH2CH3)、エチルまたはイソプロピルである、請求項33に記載の化合物。
- R2およびR3の各々が、独立して、水素、C1〜6アルキルまたはカルボシクリルであるか、あるいはR2およびR3が、それらが結合している炭素原子と一緒になって、3〜8員環を形成する、請求項33に記載の化合物。
- R2およびR3の各々が、独立して、水素、C1〜6アルキルまたはカルボシクリルである、請求項35に記載の化合物。
- R2およびR3の各々が、独立して、水素、メチル(例えば、−CH3、−CF3)、エチル(例えば、−CH2CH3、CH2CF3)、プロピル、イソプロピル、シクロプロピルまたはブチルである、請求項36に記載の化合物。
- R2が、水素、メチル(例えば、−CH3、−CF3)またはエチルである、請求項37に記載の化合物。
- R3が、メチル(例えば、−CH3、−CF3)、エチル(例えば、−CH2CH3、−CH2CF3)、プロピル、イソプロピル、シクロプロピル、ブチルである、請求項36に記載の化合物。
- 請求項1に記載の化合物またはその薬学的に受容可能な塩および薬学的に受容可能なキャリアを含む、薬学的組成物。
- 鎮静または麻酔を誘導する方法であって、有効量の請求項1に記載の化合物またはその薬学的に受容可能な塩あるいはその薬学的組成物を被験体に投与することを含む、方法。
- 本明細書中に記載される障害を処置するためまたは予防するための方法であって、該処置または予防を必要とする被験体に有効量の請求項1に記載の化合物またはその薬学的に受容可能な塩あるいはその薬学的組成物を投与する工程を含む、方法。
- 前記障害が、胃腸(GI)障害、例えば、便秘、過敏性腸症候群(IBS)、炎症性腸疾患(IBD)(例えば、潰瘍性大腸炎、クローン病)、GIに影響する構造障害、肛門障害(例えば、痔、内痔核、外痔核、肛門裂傷、肛門周囲膿瘍、痔瘻)、結腸ポリープ、がん、大腸炎である、請求項50に記載の方法。
- 前記障害が、炎症性腸疾患である、請求項50に記載の方法。
- 前記障害が、がん、糖尿病またはステロール合成障害である、請求項50に記載の方法。
- 前記障害が、代謝障害である、請求項50に記載の方法。
- CNS関連症状を処置するためまたは予防するための方法であって、該処置または予防を必要とする被験体に有効量の請求項1に記載の化合物またはその薬学的に受容可能な塩あるいはその薬学的組成物を投与する工程を含む、方法。
- 前記CNS関連症状が、適応障害、不安障害(強迫性障害、心的外傷後ストレス障害および社会恐怖を含む)、認知障害(アルツハイマー病および他の形態の認知症を含む)、解離性障害、摂食障害、気分障害(うつ(例えば、産後うつ)、双極性障害、気分変調性障害、自殺念慮を含む)、統合失調症または他の精神病性障害(統合失調感情障害を含む)、睡眠障害(不眠を含む)、物質関連障害、人格障害(強迫性人格障害を含む)、自閉症スペクトラム障害(Shank群のタンパク質(例えば、Shank3)に対する変異を伴うものを含む)、神経発達障害(レット症候群、結節性硬化症症候群を含む)、多発性硬化症、ステロール合成障害、疼痛(急性および慢性疼痛を含む)、ある病状に続発する脳症(肝性脳症および抗NMDAレセプター脳炎を含む)、発作性障害(てんかん発作重積状態および一遺伝子型のてんかん、例えばドラベ病を含む)、脳卒中、外傷性脳損傷、運動障害(ハンチントン病およびパーキンソン病を含む)、視覚障害、聴力損失および耳鳴である、請求項55に記載の方法。
- 前記障害が、ステロール合成障害である、請求項55に記載の方法。
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