TW202035399A - 螺唍衍生物 - Google Patents
螺唍衍生物 Download PDFInfo
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- TW202035399A TW202035399A TW108122548A TW108122548A TW202035399A TW 202035399 A TW202035399 A TW 202035399A TW 108122548 A TW108122548 A TW 108122548A TW 108122548 A TW108122548 A TW 108122548A TW 202035399 A TW202035399 A TW 202035399A
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Classifications
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Abstract
本發明關於螺𠳭唍衍生物,或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物,以及含有彼等之醫藥組成物及彼等用作為哺乳動物對象的α7菸鹼乙醯膽鹼受體活性的調節劑之用途。
Description
本發明關於藥理活性螺𠳭唍化合物、或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物,以及關於含有彼等之醫藥組成物及彼等作為哺乳動物對象之α7菸鹼乙醯膽鹼受體活性的調節劑之用途。
乙醯膽鹼(ACh)藉由與膽鹼能受體的結合而在哺乳動物中樞神經系統(CNS)中發揮其神經遞質的功能。根據毒蕈鹼和菸鹼的促效活性,哺乳動物CNS含有二種主要類型的ACh受體:分別為蕈毒(mAChR)和菸鹼(nAChR)受體。菸鹼乙醯膽鹼受體為由五個次單元組成的配體閘控離子通道 (Purves et al. Neuroscience 4th ed. (2008) 122-126)。菸鹼受體的次單元屬於多基因家族且根據彼等的胺基酸序列分成二組;一組含有α次單元,另一組含有β次單元。不同次單元組合的五聚體組合體導致大量具有各種藥理學性質的受體亞型。最廣泛表現之亞型的組合體包括肌型((α1)2
β1
δε)、神經節型((α3)2
(β4)3
)和CNS型(α4)2
(β2)3
或(α7)5
)nAChR亞型(Le Novère N et al. Journal of Molecular Evolution 40 (1995)155-172)。α7次單元已顯示當單獨表現時,形成功能性受體,並因此推測形成同源寡聚物(
homooligomeric)五聚體。
nAChR離子通道的活化主要由配體結合在習知促效劑之結合位置來控制,但也受負向或正向異位調節劑(positive allosteric modulator)(NAM和PAM)的調節。nAChR的異位過渡狀態模式至少涉及靜止狀態、活化狀態和“脫敏”封閉通道狀態、受體變得對促效劑不敏感的過程。不同的nAChR配體可穩定彼等優先結合的受體之構形狀態。例如,促效劑ACh和(-)-菸鹼分別穩定活化和脫敏狀態。菸鹼受體之活性的改變與許多疾病有關。菸鹼受體的減少已被假設可媒介疾病中所見的認知缺陷,諸如阿茲海默症和思覺失調症。來自煙草的菸鹼之作用也是由菸鹼受體媒介,並且因為菸鹼之作用係穩定在脫敏狀態下的受體,所以菸鹼受體的活性增加可能會降低吸煙的慾望。
然而,以作用於與Ach相同的位置之菸鹼受體促效劑治療是有問題的,因為ACh不僅活化,而且亦透過過程阻斷受體活性,其包括脫敏和非競爭性阻斷。此外,長時間的活化似乎會誘發持久的去活。因此,可預期ACh的促效劑在長期投予(chronic administration)後失去效用。
而α7 nAChR的特徵在於其相較於其他亞型的快速活化動力學及對Ca2+
的高滲透性(Delbono et al. J. Pharmacol. Exp. Ther. 280(1997) 428-438),其在暴露於正構(
orthosteric)位置上之促效劑後亦展現快速脫敏(Castro et al. Neurosci. Lett. 164 (1993) 137-140;Couturier et al. Neuron 5 (1990)847-856)。儘管近年來已進行經開發各種α7-選擇性促效劑和部分促效劑,但由於促效劑活化之後的此受體阻斷(脫敏),彼等臨床療效被證明是次優的。此問題可藉由用PAM治療,增強由內源促進劑媒介的α7 nAChR活化而克服。在各種臨床前模式中已證明α7 nAChRs的正調節具有認知效益(Thomsen et al. Curr Pharm Des 16 (2010)323-343;Lendvai et al. Brain Res Bull 93 (2013) 86-96)。
本發明之化合物可用於治療由α7 nAChR的正向異位調節媒介或與其相關的疾病和病況,包括但不限於精神病症,例如思覺失調症(Deutsch SI et al. Schizophr Res 148 (2013) 138-144)、類思覺失調症(Rowe AR et al. J
Psychopharmacol 29 (2015)197-211)、情感思覺失調症(Martin LF et al. Am J Med Genet B Neuropsychiatr Genet 144B (2007)611-614)、妄想症(Carson R et al.
Neuromolecular Med 10 (2008) 377-384)、短暫精神病症、一般醫學狀況誘發之精神病症、物質誘發之精神病症或未注明之精神病症)、認知損傷(包括例如治療認知功能損傷,以及由於中風引起的認知損傷)、阿茲海默症(Lewis AS et al. Prog Neuropsychopharmacol Biol Psychiatry 75 (2017)、亨汀頓氏症(Foucault-Fruchard L et al. Neural Regen Res 13 (2018)737-741)、匹克症(Fehér A et al. Dement Geriatr Cogn Disord 28 (2009) 56-62)、與HIV相關失智症(Capó-Vélez CM et al. Sci Rep 8 (2018) 1829)、額顳葉失智症(Minami SS et al. Biochem Pharmacol 97 (2015) 454-462)、路易氏體失智症(Perry EK et al. Neuroscience 64 (1995)385-395)、血管型失智症(Putignano S et al. Clin Interv Aging 7 (2012)113-118)、腦血管疾病(Si ML和Lee TJF Circ Res 91 (2002)62-69)或其他失智症狀態、及與其他退化型疾病(肌肉萎縮性脊髓側索硬化症)相關的失智症(Kawamata et al. Ther Adv Chronic Dis 2 (2011)197-208)、等等)、其他可引起認知衰退的急性或亞急性病況諸如譫妄(Sfera A et al. Front Med 2 (2015)56)、外傷性腦損傷(Shin SS et al. Neural Regen Res 10 (2015)1552-1554)、老年失智症(Whitehouse PJ et et al. Science 215 (1982)1237-1239)、輕度認知損傷(Ikonomovic MD et al. Arch Neurol 66 (2009)646-651)、唐氏症(Deutsch SI et al. Clin
Neuropharmacol 26 (2003) 277-283)、憂鬱和與其他疾病相關的認知缺陷)及運動障礙(Parameswaran N et al. Soc Neurosci Abstr (2007)(諸如帕金森氏病症(Quik M et al. Biochem Pharmacol 97 (2015)399-407)、以及精神抑制劑誘發之帕金森病、或遲發性運動障礙(Terry AV和Gearhart DA Eur J Pharmacol 571 (2007)29-32)、憂鬱和情感症,包括憂鬱和發作(Philip NS et al. Psychopharmacology 212 (2010)1-12)、躁鬱症(Leonard S和Freedman R. Biol
Psychiatry 60 (2006) 115-122)、循環型情感症(Ancín I et al. J Affect Disord 133 (2011)340-345)和未注明之躁鬱症、其他情感症(Shytle RD et al. Depression和Anxiety 16 (2002)89-92)、物質誘發之情感症和未注明之情感症、焦慮症(Picciotto MR et al. Neuropharmacology 96 (2015) 235-243)、恐慌症和恐慌發作(Zvolensky MJ et al. Clin Psychol Rev 25 (2005)761-789)、強迫症(Tizabi Y et al. Biol Psychiatry 51 (2002)164-171)、創傷後壓力症(Sun R et al. Neuroscience 344 (2017)243-254)、急性壓力症(Mineur YS et al. Neuropsychopharmacology 41 (2015)1579-1587)、廣泛性焦慮症(Cocores JA Prim Care Companion J Clin Psychiatry 10 (2008)253-254)、一般醫學狀況誘發之焦慮症、物質誘發之焦慮症、恐懼症和未注明之焦慮症)、與物質相關病症例如物質使用或物質誘發之病症,例如酒精-(de Fiebre NC和de Fiebre CM Alcohol 31 (2003)149-153;Diaper AM et al. Br J Clin Pharmacol 77 (2014)302-314)、菸鹼-(Leslie FM et al. Mol Pharmacol 83 (2013)753-758)、安非他命-(Pubill D et al. Pharmaceuticals 4 (2011)822-847)、苯環己哌啶-(Thomsen MS et al. Neuropharmacology 56 (2009)1001-1009)、類鴉片-(Zhang W, Int J Clin Exp Med 8 (2015)1871-1879)、大麻-(Solinas M et al. J Neurosci 27(2007)5615-5620)、古柯鹼-(Francis MM et al. Mol Pharmacol 60(2001)71-79)、咖啡因-、迷幻劑-、吸入劑-、鎮靜劑-、安眠藥-、抗焦慮藥-、多物質-或其他物質-相關疾病;睡眠障礙(McNamara JP et al. Psychol Health Med 19 (2014)410-419)諸如嗜睡症(Krahn et al J Clin Sleep Med 5 (2009)390)、睡眠異常、原發型嗜睡症、與呼吸相關的睡眠障礙、晝夜節律性睡眠障礙和未注明之睡眠異常;異睡症、睡眠驚恐障礙、夢遊症和未注明之異睡症(parasomnia);與另一種神精障礙相關的睡眠障礙(包括另一種神精神障礙相關的失眠症和另一種神精神障礙相關的嗜睡症)、一般醫學狀況誘發之睡眠障礙和物質誘發之睡眠障礙;代謝和飲食障礙(Somm E Arch Immunol Ther Exp 62 (2014)62:87-101),諸如神經性厭食症(Cuesto G et al. J Neurogenet 31 (2017)266-287)、神經性暴食症、肥胖症(Lakhan SE和Kirchgessner A J Transl Med 9 (2011)129-139)、強迫性飲食障礙、暴食症和未注明之飲食障礙;糖尿病(Marrero MB et al. J Pharmacol Exp Ther 332 (2010) 173-180)、潰瘍性結腸炎(Salaga et al. JPET 356 (2016) 157-169)、克隆氏病(Bencherif M et al. Cell Mol Life Sci 68 (2011)931-949)、腸躁症候群、(Keszthelyi D et al. Neurogastroenterol Motil 21 (2009)1239-1249)、泛自閉症障礙(Deutsch et al. Clin Neuropharmacol 33 (2010)114-120),包括自閉症、亞斯伯格症、雷特氏症、兒童期崩解症和其他未注明之廣泛性發展障礙;注意力缺陷過動症(Wilens TE和Decker MW Biochem Pharmacol 74 (2007) 1212-1223)、破壞性行為障礙、對立性反抗症和未注明之破壞性行為障礙;及抽動障礙諸如妥瑞症(Gotti C和Clementi F Prog Neurobiol 74 (2004)363-396)、人格障礙(Kamens HM et al. Behav Genet 46 (2016)693-704);性功能障礙諸如性慾障礙、性興奮障礙、性高潮障礙、性疼痛障礙、未注明之性功能障礙)、性倒錯、性別認同障礙、不孕症(Bray C et al. Biol Reprod 73 (2005) 807-814)、經前症候群(Gündisch D和Eibl C Expert Opin Ther Pat 21 (2011) 1867-1896)、和未注明之性功能障礙、呼吸系統之病症如咳嗽(Canning BJ Am J Respir Crit Care Med 195 (2017) A4498)、哮喘(Santana FPR et al. Eur Respir J 48 (2016) PA5066)、慢性阻塞性肺臟疾病(Maouche K et al. Proc Natl Acad Sci USA 110 (2013) 4099-4104)、肺部炎症(Enioutina EY et al. PLoS One 10 (2015) e0121128)、心血管系統之病症諸如心臟衰竭(Mai XK et al. J Immunol 200 (2018) 108.11)、心律不整(Mazloom R et al. PLoS One 8 (2013) e82251)、和高血壓(Chen JK et al. BMC Cardiovasc Disord 12 (2012)38)。
本發明之化合物也可用於治療炎症、炎性和神經性疼痛(Alsharari SD et al. Biochem Pharmacol 86 (2013)1201-1207)、類風濕性關節炎(van Maanen MA et al. Arthritis & Rheumatism 60 (2009)1272-1281)、骨關節炎(Lee SE Neurosci Lett 548 (2013)291-295)、過敏(Yamamoto T et al. PLoS One 9 (2014)e85888)、類肉瘤病(Nicotine Treatment for Pulmonary Sarcoidosis:A Clinical Trial Pilot Study Elliott Crouser MD, Principal Investigator, Ohio State University ClinicalTrials.gov Identifier:NCT02265874)、牛皮癬(Westman M et al. Scand J Immunol 70 (2009)136-140)、失調症(Taslim N et al. Behav Brain Res 217 (2011) 282-292)、肌肉緊張不足(Zimmerman CN et al. Front Syst Neurosci 11 (2017)43)、全身性紅斑狼瘡(Fairley AS和Mathis KW Physiol Rep 5 (2017)e13213)、躁狂症(Janowsky DS et al. Lancet 2 (1972)632-635)、不寧腿症候群(Buchfuhrer MJ Neurotherapeutics 9 (2012)776-790)、進行性核上性麻痺(Warren NM et al. Brain 128 (2005)239-245)、癲癇(Bertrand D Epilepsy Curr 2 (2002)191-193)、肌陣攣(Leppik IE Epilepsia 44 (2003)2-6)、偏頭痛(Liu Q et al. J Pain Res 11 (2018)1129-1140)、健忘症(Bali Zs K et al. Front Cell Neurosci 11 (2017)271)、慢性疲勞症候群(Shan ZY et al. J Magn Reson Imaging 44 (2016)1301-1311)、猝倒症(Ebben MR和Krieger AC J Clin Sleep Med 8 (2012)195-196)、腦缺血(Han Z et al. J Neurochem 131 (2014)498-508)、多發性硬化症(Di Bari M et al. Cent Nerv Syst Agents Med Chem 17 (2017)109-115)、腦脊髓炎(Hao J et al. Exp Neurol 227 (2011):110-119)、時差(Shi M et al. eLife 3 (2014)e01473)、大腦類澱粉血管病變(Clifford PM et al. Brain Res 1234 (2008)158-171)、敗血症(Ren C et al. Int J Biol Sci 14 (2018)748-759),且通常,可用於治療與nAChR之正向異位調節相關的所有類型之疾病和病症。
此外,此等化合物也可與包括但不限於下列之其他治療劑組合:乙醯膽鹼酯酶抑制劑(諸如加蘭他敏(
galantamine)、利斯的明(rivastigmine)、多奈派齊(donepezil)、他克林(tacrine)、吩色蘭(phenserine)、拉多替吉(ladostigil)和ABT-089);NMDA受體促效劑或拮抗劑(諸如美金剛胺(memantine)、奈拉美生(neramexane)、EVT101和AZD4282);抗類澱粉蛋白抗體,包括抗類澱粉蛋白人源化單株抗體(諸如巴匹珠單抗(bapineuzumab)、ACCOOl、CAD 106、AZD3102、H12A11V1);ß-(諸如維羅斯他(verubecestat)、和AZD3293)或γ-分泌酶抑制劑(諸如LY450139和TAK 070)或調節劑;tau 磷酸化抑制劑;ApoE4構形調節劑;p25/CDK5抑制劑;NK1/NK3受體拮抗劑;COX-2抑制劑(諸如塞來昔布(celecoxib)、羅非昔布(rofecoxib)、伐地昔布(valdecoxib)、406381和644784);LRRK2抑制劑;HMG-CoA還原酶抑制劑;NSAID(諸如伊布洛芬(ibuprofen));維生素E;甘胺酸運輸抑制劑;甘胺酸位置拮抗劑(諸如拉科醯胺(lacosamide));LXR β促效劑;雄性激素受體調節劑;Aβ寡聚物形成的阻斷劑;NR2B拮抗劑、抗發炎化合物(諸如(R)-氟比洛芬(flurbiprofen)、硝基氟比洛芬(nitroflurbiprofen)、ND-1251、VP-025、
HT-0712、和EHT-202);PPAR γ促效劑(諸如匹格列酮(pioglitazone)和羅格列酮(rosiglitazone));CB-1受體拮抗劑或逆促效劑(諸如AVE1625);CB-2促效劑(諸如842166和SAB378);VR-1拮抗劑(諸如AMG517、705498、782443、PAC20030、VI 14380和A425619);緩激肽Bl受體拮抗劑(諸如SSR240612和NVPSAA164);鈉通道阻斷劑和拮抗劑(諸如VX409和SPI860);NOS抑制劑(諸如SD6010和274150);抗生素;生長激素促泌素(諸如伊布莫崙(ibutamoren)、伊布莫侖甲磺酸鹽(ibutamoren mesylate)、和卡莫瑞林(capromorelin));鉀通道開放劑;AMPA促效劑或AMPA調節劑(諸如CX-717、LY 451395、LY404187和S-18986);GSK3抑制劑(諸如AZD1080、SAR502250和CEP16805);神經元菸鹼促效劑;MARK配體;M1
或M4
mAChR促效劑或PAM;mGluR2拮抗劑或NAM或PAM;mGluR5拮抗劑(諸如AZD9272);α-腎上腺素能促效劑;ADAM-10配體;鎮定劑、安眠藥、抗焦慮劑、抗精神病藥、環吡咯酮、咪唑并吡啶、吡唑并嘧啶、輕鎮靜劑、褪黑激素促效劑和拮抗劑、褪黑激素劑;食慾激素拮抗劑和促效劑;前動力蛋白(prokineticin)促效劑和拮抗劑;T型鈣通道拮抗劑;三唑并吡啶苯并二氮呯、巴比妥酸鹽;5-HT1A
拮抗劑(諸如列可左坦(lecozotan));5-HT2
拮抗劑;5-HT4
促效劑(諸如PRX-03140);5-HT6
拮抗劑(諸如GSK 742467、SGS-518、FK-962、SL-65.0155、SRA- 333和紮利羅登(xaliproden));組織胺H3
受體拮抗劑和逆促效劑(諸如S38093、ABT-834、ABT 829、GSK 189254和CEP16795);PDE4
抑制劑(諸如HT0712);PDE9
抑制劑(諸如BI40936);PDE10
抑制劑;HDAC抑制劑;KCNQ拮抗劑;GABAA
逆促效劑;GABA信號增強劑;GABA促效劑、GABAA
受體α5次單元NAM或PAM、抗精神病藥;MAO-B抑制劑;多巴胺轉運抑制劑;降腎上腺素轉運抑制劑;D2
促效劑和部分促效劑;抗膽鹼劑(諸如比哌立登(biperiden));COMT抑制劑(諸如恩他卡朋(entacapone));A2a腺苷受體拮抗劑;膽鹼能促效劑;來自精神抑制劑之啡噻𠯤、噻噸(thioxanthene)(諸如氯普噻噸(chlorprothixene)和替沃噻噸(thiothixene))、雜環二苯并氮呯(諸如氯氮平(clozapine))、丁醯苯(諸如氟派醇(haloperidol))、二苯基丁基哌啶(諸如匹莫齊特(pimozide))和吲哚酮(諸如嗎啉吲酮(molindolone))的類別之化合物;洛沙平(loxapine)、舒必利(sulpiride)和利培酮(risperidone
);左旋多巴;鈣通道阻斷劑(諸如齊考諾肽(ziconotide)和NMED160);MMP抑制劑;血栓溶解劑;類鴉片止痛劑(諸如可待因、芬太尼(fentanyl)、氫嗎啡酮(hydromorphone)、左啡諾(levorphanol)、嘜啶(meperidine)、美沙酮(
methadone)、嗎啡、羥考酮(oxycodone)、氧化嗎啡酮(
oxymorphone)、噴他佐辛(pentazocine)、丙氧芬(
propoxyphene);普拉克索(pramipexole);羅匹尼羅(ropinirole);嗜中性細胞抑制因子;SSRI或SSNRI;三環抗抑鬱藥;降腎上腺素調節劑;鋰;丙戊酸;加巴噴丁(
gabapentin);普瑞巴林(pregabaline);利紮曲坦(
rizatriptan);佐米曲坦(zolmitriptan);那拉曲坦(
naratriptan)、和舒馬曲坦(sumatriptan)或影響增加效力、安全性、方便性、或減少本發明化合物的不良副作用或毒性之受體或酶的其他藥物。
α7菸鹼乙醯膽鹼受體之已知正向異位調節劑包括2-苯胺-4-芳基噻唑衍生物(WO 2007/031440 A2,JANSSEN PHARMACEUTICA NV)、醯胺衍生物(WO 2009/100294 A2,ABBOT LAB.)、三取代之1,2,4-三唑(WO 2009/115547 A1,JANSSEN PHARMACEUTICA NV)、吲哚衍生物(
WO 2009/127678 A1,GLAXO GROUP LTD.)和
WO 2009/127679 A1,GLAXO GROUP LTD.)、四唑取代之芳基醯胺衍生物(WO 2009/043780 A1,HOFFMANN LA ROCHE)、環丙基芳基醯胺衍生物(WO 2009/043784 A1,HOFFMANN LA ROCHE)、經三取代之吡唑(
WO 2009/135944 A1,JANSSEN PHARMACEUTICA NV)、吡咯衍生物(WO 2014/141091 A1,LUPIN LTD)、環丙基苯衍生物(WO 2017/165256 A1,MERCK SHARP & DOHME CORP.)、和經取代之雙環雜芳基衍生物(WO 2018/085171 A1,MERCK SHARP & DOHME CORP.)。
本發明係關於一種呈現α7菸鹼乙醯膽鹼受體的正向異位調節之化合物的新穎類別。
發明概述
本發明關於式(I)化合物,
其中
A為五員或六員雜環;
B為六員碳環或雜環;
X為C或N;
Y為C或N;
Z為C或N;
W為O或S;
R1
為H、C1-6
烷基、鹵素或鹵C1-6
烷基;
R2
為H或O;
R3
為H、C1-6
烷基、鹵素、鹵C1-6
烷基或C1-6
烷氧基;
R4
為H或C1-6
烷基;
R5
為H或C1-6
烷基;
n和m獨立地為1或2;為單鍵或雙鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在另一態樣中,本發明關於式(II)化合物,
其中
V為C或S;
Z為C或N;
W為O或S;
R1a
為H、C1-6
烷基、或鹵C1-6
烷基;
R1b
為H、C1-6
烷基、鹵素、或鹵C1-6
烷基;
當V為碳時,R1c
為H、C1-6
烷基、鹵素、或鹵C1-6
烷基,或當V為硫時,R1c
不存在;
R2
為H或O;
R3
為H、C1-6
烷基、鹵素、鹵C1-6
烷基、或C1-6
烷氧基;
n和m獨立地為1或2;為單鍵或雙鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在另一態樣中,本發明提供一種用於治療或預防與α7菸鹼乙醯膽鹼受體活性相關的疾病之如上述所定義的式(I)或式(II)化合物。
在另一態樣中,本發明提供一種如上述所定義的式(I)或式(II)化合物之用途,其係用於製造供治療或預防與α7菸鹼乙醯膽鹼受體活性相關的疾病之藥物。
在另一態樣中,本發明提供一種治療或預防與α7菸鹼乙醯膽鹼受體活性相關的疾病之方法,其包含將有效量的至少一種如上述所定義的式(I)或式(II)化合物投予至需要該治療或預防的哺乳動物。
在另一態樣中,如上述所定義的式(I)或式(II)化合物可與用於治療或預防與α7菸鹼乙醯膽鹼受體活性相關的疾病之其他化合物組合投予。
在另一態樣中,本發明提供一種製造式(II)化合物之方法。
發明之詳細說明
本發明關於式(I)化合物,
其中:
A為五員或六員雜環;
B為六員碳環或雜環;
X為C或N;
Y為C或N;
Z為C或N;
W為O或S;
R1
為H、C1-6
烷基、鹵素或鹵C1-6
烷基;
R2
為H或O;
R3
為H、C1-6
烷基、鹵素、鹵C1-6
烷基或C1-6
烷氧基;
R4
為H或C1-6
烷基;
R5
為H或C1-6
烷基;
n和m獨立地為1或2;為單鍵或雙鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
術語“五員雜環”,如本文所用,係指隨意地經取代之具有五個原子且併入一個、二個、三個或四個雜原子(選自氮、氧或硫)的飽和、不飽和或芳族環系統。五員雜環(
heterocyclic)部分之實例包括但不限於吡咯啶基(
pyrrolydinyl)、吡咯基、四氫呋喃基、二氫呋喃基、呋喃基、四氫噻吩基、噻吩基、咪唑啶基、咪唑基、吡唑啶基、吡唑基、㗁唑啶基、異㗁唑啶基、㗁唑基、異㗁唑基、四氫噻唑基、四氫異噻唑基、噻唑基、異噻唑基、二氧環戊烷基、二硫環戊烷基、三唑基、㗁二唑基、噻二唑基、四唑基。
術語“六員雜環”,如本文所用,係指隨意地經取代之具有六個原子且併入一個、二個、三個或四個雜原子(選自氮、氧或硫)的飽和、不飽和或芳族環系統。六員雜環之實例包括但不限於哌啶基、吡啶基、嗒𠯤基、嘧啶基、二氫哌喃基、四氫哌喃基、哌喃基、硫哌喃基、哌𠯤基、高哌𠯤基、嗎啉基、硫嗎啉基。
術語“六員碳環”如本文所用,係指隨意地經取代之具有六個碳原子的飽和、不飽和或芳族環系統,包括環己基、環己烯基、環己二烯基、和苯基。
術語“鹵”或“鹵素”,如本文所用,原樣或作為另一基團的一部分,係指氟基、氯基、溴基或碘基。
術語“C1-6
烷基”,如本文所用,原樣或作為另一基團的一部分,係指具有一、二、三、四、五或六個碳原子的支鏈或直鏈飽和烴基,包括但不限於甲基、乙基、正丙基、異丙基、正丁基、二級丁基、和三級丁基。
術語“鹵C1-6
烷基”,如本文所用,係指透過如上述所定義的“C1-6
烷基”基團鍵結至母分子部分之至少一種如上述所定義的鹵素。當存在幾個鹵素時,鹵素可為相同或不同且鹵素可連接至不同的碳原子,或者幾個鹵素可連接至相同的碳原子。鹵C1-6
烷基基團包括但不限於二氟甲基、三氟甲基和2-氯乙基。
術語“C1-6
烷氧基”,如本文所用係指透過氧原子鍵結至母分子部分之如上述所定義的“C1-6
烷基”基團,包括但不限於甲氧基、乙氧基、正丙氧基、異丙氧基和三級丁氧基。
術語“醫藥上可接受的”描述可用於製備醫藥組成物的成分通常為安全無毒的且不是生物學上也不是其他方面不合適的,並包括彼等獸醫用途以及人類醫藥用途可以接受者。
術語“醫藥上可接受的鹽”係指習知酸加成鹽或鹼加成鹽,其保持式(I)或式(II)化合物的生物效力和性質且可與適當無毒有機或無機酸或有機或無機鹼形成。酸加成鹽之實例包括衍生自無機酸(諸如但不限於鹽酸、氫溴酸、氫碘酸、硫酸、胺磺酸、磷酸、硝酸和過氯酸)以及衍生自各種有機酸(諸如但不限於乙酸、丙酸、苯甲酸、乙醇酸、苯基乙酸、水楊酸、丙二酸、馬來酸、油酸、雙羥萘酸、棕櫚酸、苯磺酸、甲苯磺酸、甲烷磺酸、草酸、酒石酸、琥珀酸、檸檬酸、蘋果酸、乳酸、麩胺酸、富馬酸)等等之鹽。鹼加成鹽之實例為衍生自銨-、鉀-、鈉-和四級銨氫氧化物,諸如氫氧化四甲基銨。
術語“前驅藥”係指根據本發明之式(I)或式(II)化合物的衍生物,本身沒有治療效果但含有該等在活體內化學或代謝降解(生物轉化)後成為負責治療效果的“生物活性代謝物”之基團。與本發明之式(I)或式(II)化合物相關的該等分解基團,特別是適用於前藥的基團,為該項技術已知的且也可應用於本發明之化合物(Rautio et al., Nature Reviews -Drug Discovery 2008, 7:255-270)。
術語“水合物”表示水和溶質之間的非共價組合。
術語“溶劑合物”表示溶劑和溶質之間的非共價組合。溶劑包括但不限於乙醇、2-丙醇、乙腈和四氫呋喃。
“隨意的”或“隨意地”表示隨後描述的事件或狀況可能但不一定發生,且該說明包括事件或狀況發生的情況以及事件或狀況不發生的情況。
“隨意地經取代”表示未經取代或經一或多個如本文所述的取代基取代。在此,“一或多個”表示從一個到最高可能的取代數,即,從置換一個氫到置換所有的氫。給定原子上的一個、二個或三個取代基是較佳的。
疾病狀態的“治療(Treating或treatment)”包括:
a)預防疾病狀態,即在可能暴露於或易患疾病狀態,但尚未經歷或顯示疾病狀態的症狀之對像中不會發生導致疾病狀態的臨床症狀,
b)抑制疾病狀態,即阻止疾病狀態或其臨床症狀的發生,或
c)緩解疾病狀態,即導致疾病狀態或其臨床症狀的暫時或永久消退。
在一實施態樣中,本發明關於式(I)化合物,其中
A為五員雜環,其中該環的成員係選自由下列所組成之群組:碳、氮、氧和硫;
B為六員碳環或雜環,其中該環的成員係選自由下列所組成之群組:碳、氮、氧和硫;
X為C;
Y為C;
Z為C或N;
W為O或S;
R1
為H、C1-6
烷基、鹵素或鹵C1-6
烷基;
R2
為H或O;
R3
為H、C1-6
烷基、鹵素、鹵C1-6
烷基或C1-6
烷氧基;
R4
為H;
R5
為H;
n和m獨立地為1或2;為單鍵或雙鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在一實施態樣中,本發明關於式(II)化合物,
其中
V為C或S;
Z為C或N;
W為O或S;
R1a
為H、C1-6
烷基、或鹵C1-6
烷基;
R1b
為H、C1-6
烷基、鹵素、或鹵C1-6
烷基;
當V為C時,R1c
為H、C1-6
烷基、鹵素、或鹵C1-6
烷基;或當V為S時,R1c
不存在;
R2
為H或O;
R3
為H、C1-6
烷基、鹵素、鹵C1-6
烷基、或C1-6
烷氧基;
n和m獨立地為1或2;為單鍵或雙鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在一實施態樣中,本發明關於式(II)化合物,其中
V為C或S;
Z為C或N;
W為O或S;
R1a
為H、C1-4
烷基、或鹵C1-4
烷基;
R1b
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;
當V為C時,R1c
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;或當V為S時,R1c
不存在;
R2
為H;
R3
為H、C1-4
烷基、鹵素、鹵C1-4
烷基、或C1-4
烷氧基;
n和m獨立地為1或2;當其連接至R2
時,為單鍵,及在環內為單鍵或雙鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在一實施態樣中,本發明關於式(II)化合物,其中
V為C或S;
Z為C或N;
W為O或S;
R1a
為H、C1-4
烷基、或鹵C1-4
烷基;
R1b
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;
當V為C時,R1c
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;或當V為S時,R1c
不存在;
R2
為H;
R3
為H、C1-4
烷基、鹵素、鹵C1-4
烷基、或C1-4
烷氧基;
n和m為1;當其連接至R2
時,為單鍵,及在環內為單鍵或雙鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在一實施態樣中,本發明關於式(II)化合物,其中
V為C或S;
Z為C或N;
W為O或S;
R1a
為H、C1-4
烷基、或鹵C1-4
烷基;
R1b
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;
R1c
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基當V為C時;或R1c
不存在當V為S時;
R2
為H;
R3
為H、C1-4
烷基、鹵素、鹵C1-4
烷基、或C1-4
烷氧基;
n和m為2;當其連接至R2
時,為單鍵,及在環內為單鍵或雙鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在一實施態樣中,本發明關於式(II)化合物,其中
V為C或S;
Z為C或N;
W為O或S;
R1a
為H、C1-4
烷基、或鹵C1-4
烷基;
R1b
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;
當V為C時,R1c
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;或當V為S時,R1c
不存在;
R2
為H;
R3
為H、C1-4
烷基、鹵素、鹵C1-4
烷基、或C1-4
烷氧基;
n為1;
m為2;當其連接至R2
時,為單鍵,及在環內為單鍵或雙鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在一實施態樣中,本發明關於式(II)化合物,其中
V為C或S;
Z為C或N;
W為O或S;
R1a
為H、C1-4
烷基、或鹵C1-4
烷基;
R1b
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;
當V為C時,R1c
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;或當V為S時,R1c
不存在;
R2
為O;
R3
為H、C1-4
烷基、鹵素、鹵C1-4
烷基、或C1-4
烷氧基;
n和m獨立地為1或2;當其連接至R2
時,為雙鍵,及在環內為單鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在一實施態樣中,本發明關於式(II)化合物,其中
V為C或S;
Z為C或N;
W為O或S;
R1a
為H、C1-4
烷基、或鹵C1-4
烷基;
R1b
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;
當V為C時,R1c
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;或當V為S時,R1c
不存在;
R2
為O;
R3
為H、C1-4
烷基、鹵素、鹵C1-4
烷基、或C1-4
烷氧基;
n和m為1;當其連接至R2
時,為雙鍵,及在環內為單鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在一實施態樣中,本發明關於式(II)化合物,其中
V為C或S;
Z為C或N;
W為O或S;
R1a
為H、C1-4
烷基、或鹵C1-4
烷基;
R1b
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;
當V為C時,R1c
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;或當V為S時,R1c
不存在;
R2
為O;
R3
為H、C1-4
烷基、鹵素、鹵C1-4
烷基、或C1-4
烷氧基;
n和m為2;當其連接至R2
時,為雙鍵,及在環內為單鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在一實施態樣中,本發明關於式(II)化合物,其中
V為C或S;
Z為C或N;
W為O或S;
R1a
為H、C1-4
烷基、或鹵C1-4
烷基;
R1b
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;
當V為C時,R1c
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;或當V為S時,R1c
不存在;
R2
為O;
R3
為H、C1-4
烷基、鹵素、鹵C1-4
烷基、或C1-4
烷氧基;
n為1;
m為2;當其連接至R2
時,為雙鍵,及在環內為單鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在一實施態樣中,本發明關於式(II)化合物,其中
V為C;
Z為C或N;
W為O;
R1a
為H、C1-6
烷基、或鹵C1-6
烷基;
R1b
為H、C1-6
烷基、鹵素、或鹵C1-6
烷基;
R1c
為H、C1-6
烷基、鹵素、或鹵C1-6
烷基;
R2
為H或O;
R3
為H、C1-6
烷基、鹵素、或鹵C1-6
烷基;
n和m獨立地為1或2;為單鍵或雙鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在一實施態樣中,本發明關於式(II)化合物,其中
V為C;
Z為C或N;
W為O;
R1a
為H、C1-4
烷基、或鹵C1-4
烷基;
R1b
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;
R1c
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;
R2
為H或O;
R3
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;
n和m獨立地為1或2;為單鍵或雙鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在一實施態樣中,本發明關於式(II)化合物,其中
V為C;
Z為C或N;
W為O或S;
R1a
為H、C1-4
烷基、或鹵C1-4
烷基;
R1b
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;
R1c
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;
R2
為O;
R3
為H、C1-4
烷基、鹵素、鹵C1-4
烷基、或C1-4
烷氧基;
n和m為1;當其連接至R2
時,為雙鍵,及在環內為單鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在一實施態樣中,本發明關於式(II)化合物,其中
V為C;
Z為C或N;
W為O或S;
R1a
為H、C1-4
烷基、或鹵C1-4
烷基;
R1b
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;
R1c
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;
R2
為O;
R3
為H、C1-4
烷基、鹵素、鹵C1-4
烷基、或C1-4
烷氧基;
n和m為2;當其連接至R2
時,為雙鍵,及在環內為單鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在一實施態樣中,本發明關於式(II)化合物,其中
V為C;
Z為C或N;
W為O或S;
R1a
為H、C1-4
烷基、或鹵C1-4
烷基;
R1b
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基;
R1c
為H、C1-4
烷基、鹵素、或鹵C1-4
烷基
R2
為O;
R3
為H、C1-4
烷基、鹵素、鹵C1-4
烷基、或C1-4
烷氧基;
n為1;
m為2;當其連接至R2
時,為雙鍵,及在環內為單鍵;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在一實施態樣中,本發明關於選自下列群組之式(I)或式(II)化合物:
6'-氟-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
6-氯-N-[(1-甲基-1H-吲哚-5-基)甲基]-4-側氧基-3,4-二氫螺[1-苯并哌喃-2,4'-哌啶]-1'-甲醯胺;
6'-氯-N-[(1-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
7'-氟-N-[(1-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
N-[(1-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
6-氯-N-[(1-甲基-1H-吲哚-5-基)甲基]-3,4-二氫螺[1-苯并哌喃-2,4'-哌啶]-1'-甲醯胺;
N-[(3-氯-1-甲基-1H-吲哚-5-基)甲基]-6'-氟-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
6'-氯-N-[(1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
6'-氟-N-[(1-甲基-1H-吲哚-5-基)甲基]-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
6'-氟-N-[(1-甲基-1H-吲哚-5-基)甲基]螺[吖呾-3,2'-𠳭唏]-1-甲醯胺;
N-[(1-甲基-1H-吲哚-5-基)甲基]-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
6'-氯-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
6',8'-二氟-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
7'-氯-N-[(2-氯-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
7'-氯-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
7'-氟-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-6'-(三氟甲基)-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
N-[(1-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-7'-(三氟甲基)-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-7'-(三氟甲基)-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
6',8'-二氯-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
7'-氟-4'-側氧基-N-{[2-(三氟甲基)-1H-吲哚-5-基]甲基}-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
N-{[2-(二氟甲基)-1H-吲哚-5-基]甲基}-7'-氟-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺;
或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
在另一態樣中,本發明提供一種用於治療或預防與α7菸鹼乙醯膽鹼受體活性相關的疾病之如上述所定義的式(I)或式(II)化合物。
在另一態樣中,本發明提供一種如上述所定義的式(I)或式(II)化合物之用途,其係用於製造供治療或預防與α7菸鹼乙醯膽鹼受體活性相關的疾病之藥物。
在另一態樣中,本發明提供一種治療或預防與α7菸鹼乙醯膽鹼受體活性相關的疾病之方法,其包含將有效量的至少一種如上述所定義的式(I)或式(II)化合物投予至需要該治療或預防的哺乳動物。
在一實施態樣中,與α7菸鹼乙醯膽鹼受體活性相關的疾病係選自下列群組:精神病症(包括但不限於思覺失調症、類思覺失調症、情感思覺失調症、妄想症、短暫精神病症、一般醫學狀況誘發之精神病症、物質誘發之精神病症或未注明之精神病症);認知損傷(包括但不限於由於中風引起的認知損傷)、阿茲海默症、亨汀頓氏症、匹克症、與HIV相關失智症、額顳葉失智症、路易氏體失智症、血管型失智症、腦血管疾病或其他失智症狀態及與其他退化型疾病(包括但不限於肌肉萎縮性脊髓側索硬化症)相關的失智症、其他可引起認知衰退的急性或亞急性病況(包括但不限於譫妄、外傷性腦損傷、老年失智症、輕度認知損傷、唐氏症、憂鬱和與其他疾病相關的認知缺陷)、及運動障礙(包括但不限於帕金森氏病症、精神抑制劑誘發之帕金森病、或遲發性運動障礙)、憂鬱和情感症(包括但不限於憂鬱和發作、躁鬱症、循環型情感症和未注明之躁鬱症、其他情感症、物質誘發之情感症和未注明之情感症);焦慮症、恐慌症和恐慌發作、強迫症、創傷後壓力症、急性壓力症、廣泛性焦慮症、一般醫學狀況誘發之焦慮症、物質誘發之焦慮症、恐懼症和未注明之焦慮症);與物質相關病症(包括但不限於物質使用或物質誘發之病症,包括但不限於酒精-、菸鹼-、安非他命-、苯環己哌啶-、類鴉片-、大麻-、古柯鹼-、咖啡因-、迷幻劑-、吸入劑-、鎮靜劑-、安眠藥-、抗焦慮藥-、多物質-或其他物質-相關疾病);睡眠障礙(包括但不限於嗜睡症、睡眠異常、原發型嗜睡症、與呼吸相關的睡眠障礙、晝夜節律性睡眠障礙和未注明之睡眠異常;異睡症、睡眠驚恐障礙、夢遊症和未注明之異睡症(parasomnia);與另一種神精神障礙相關的睡眠障礙、一般醫學狀況誘發之睡眠障礙和物質誘發之睡眠障礙;代謝和飲食障礙(包括但不限於神經性厭食症、神經性暴食症、肥胖症、強迫性飲食障礙、暴食症和未注明之飲食障礙);糖尿病、潰瘍性結腸炎、克隆氏病、腸躁症候群、泛自閉症障礙(包括但不限於自閉症、亞斯伯格症、雷特氏症、兒童期崩解症和其他未注明之廣泛性發展障礙);注意力缺陷過動症、破壞性行為障礙、對立性反抗症和未注明之破壞性行為障礙;及抽動障礙(包括但不限於妥瑞症);人格障礙;性功能障礙(諸如性慾障礙、性興奮障礙、性高潮障礙、性疼痛障礙、未注明之性功能障礙)、性倒錯、性別認同障礙、不孕症、經前症候群和未注明之性功能障礙;呼吸系統之病症(如咳嗽、哮喘、慢性阻塞性肺臟疾病、肺部炎症)、心血管系統之病症(諸如心臟衰竭、心律不整、高血壓);炎症、炎性和神經性疼痛、類風濕性關節炎、骨關節炎、過敏、類肉瘤病、牛皮癬、失調症、肌肉緊張不足、全身性紅斑狼瘡、躁狂症、不寧腿症候群、進行性核上性麻痺、癲癇、肌陣攣、偏頭痛、健忘症、慢性疲勞症候群、猝倒症、腦缺血、多發性硬化症、腦脊髓炎、時差、大腦類澱粉血管病變和敗血症。
在一實施態樣中,與α7菸鹼乙醯膽鹼受體活性相關的疾病係選自下列群組:認知損傷、思覺失調症和自閉症。
本發明進一步關於組合治療,其中本發明化合物或包含本發明化合物之醫藥組成物或調配物係與另一種治療劑或治療劑等一起投予,用於治療前示一或多種病況。該等治療劑可選自:乙醯膽鹼酯酶抑制劑、NMDA受體促效劑或拮抗劑、抗類澱粉蛋白抗體(包括抗類澱粉蛋白人源化單株抗體)、β-或γ-分泌酶抑制劑或調節劑、tau磷酸化抑制劑、ApoE4構形調節劑、p25/CDK5抑制劑、NK1/NK3受體拮抗劑、COX-2抑制劑、LRRK2抑制劑、HMG-CoA還原酶抑制劑、NSAID、維生素E、甘胺酸運輸抑制劑、甘胺酸位置拮抗劑、LXR β促效劑、雄性激素受體調節劑、Aβ寡聚物形成的阻斷劑、NR2B拮抗劑、抗發炎化合物、PPAR γ促效劑、CB-1受體拮抗劑或逆促效劑、CB-2促效劑、VR-1拮抗劑、緩激肽Bl受體拮抗劑、鈉通道阻斷劑和拮抗劑、NOS抑制劑、抗生素、生長激素促泌素、鉀通道開放劑、AMPA促效劑或AMPA調節劑、GSK3抑制劑、神經元菸鹼促效劑、MARK配體、M1
或M4
mAChR促效劑或PAM、mGluR2拮抗劑或NAM或PAM、mGluR5拮抗劑、α-腎上腺素能促效劑、ADAM-10配體、鎮定劑、安眠藥、抗焦慮劑、抗精神病藥、環吡咯酮、咪唑并吡啶、吡唑并嘧啶、輕鎮靜劑、褪黑激素促效劑和拮抗劑、褪黑激素劑、食慾激素拮抗劑和促效劑、前動力蛋白(prokineticin)促效劑和拮抗劑、T型鈣通道拮抗劑、三唑并吡啶苯并二氮呯、巴比妥酸鹽、5-HT1A
拮抗劑、5-HT2
拮抗劑、5-HT4
促效劑、5-HT6
拮抗劑、組織胺H3
受體拮抗劑和逆促效劑、PDE4
抑制劑、PDE9
抑制劑、PDE10
抑制劑、HDAC抑制劑、KCNQ拮抗劑、GABAA
逆促效劑、GABA信號增強劑、GABA促效劑、GABAA
受體α5次單元NAM或PAM、抗精神病藥、MAO-B抑制劑、多巴胺轉運抑制劑、降腎上腺素轉運抑制劑、D2
促效劑和部分促效劑、抗膽鹼劑、COMT抑制劑、A2a腺苷受體拮抗劑、膽鹼能促效劑、精神抑制劑、洛沙平(loxapine)、舒必利(sulpiride)和利培酮(risperidone)、左旋多巴、鈣通道阻斷劑、MMP抑制劑、血栓溶解劑、類鴉片止痛劑、普拉克索(pramipexole)、羅匹尼羅(ropinirole)、嗜中性細胞抑制因子、SSRI或SSNRI、三環抗抑鬱藥、降腎上腺素調節劑、鋰、丙戊酸、加巴噴丁(gabapentin)、普瑞巴林(pregabaline)、利紮曲坦(rizatriptan)、佐米曲坦(zolmitriptan)、那拉曲坦(naratriptan)、和舒馬曲坦(sumatriptan)。
在一實施態樣中,治療劑係選自下列群組:乙醯膽鹼酯酶抑制劑、NMDA受體拮抗劑、β-分泌酶抑制劑、抗精神病藥、GABAA
受體α5次單元NAM或PAM、組織胺H3
受體拮抗劑、5-HT6
受體拮抗劑、M1或M4 mAChR促效劑或PAM、mGluR2拮抗劑或NAM或PAM、和左旋多巴。
在另一態樣中,本發明提供一種根據下列路徑製造式(II)化合物之方法:
根據本發明之化合物係根據下述合成路徑和流程合成。
在整個說明書中,通式係以羅馬數字(I)、(II)、(III)、等等表示。 流程 1
使一種式(III)之苯乙酮衍生物與一種式(IV)之含氮環脂族酮衍生物反應,該反應或以二步驟經由式(VII)或直接以一步驟進行以提供一種式(V)之螺𠳭唍酮化合物,
- 其中R3
的意義係如上對於式(II)化合物所述,
- 其中n和m的意義係如上對於式(II)化合物所述,
- 其中n和m的意義係如上對於式(II)化合物所述,
- 其中R3
、n和m的意義係如上對於式(II)所述,
接著使式(V)化合物與
a.)氯化氫反應以提供式(VI)之螺𠳭唍酮鹽衍生物,
- 其中R3
、n和m的意義係如上對於式(II)所述,或與
b.)錯合氫化物反應以提供適當式(VIII)之螺𠳭唍醇衍生物,
- 其中R3
、n和m的意義係如上對於式(II)所述,接著用三乙膦將式(VIII)化合物還原以提供式(IX)之3,4-二氫螺𠳭唏/螺𠳭唏衍生物,
- 其中R3
、n和m的意義係如上對於式(II)所述。流程 2
接著,使如此獲得之式(IX)或式(VI)衍生物與式(X)之雜環胺衍生物反應,所述而提供式(II)之脲/硫脲衍生物,
- 其中R1a
、R1b
、R1c
、V和Z的意義係如上對於式(II),
- 其中R1a
、R1b
、R1c
、R2
、R3
、V、Z、n、m、和W的意義係如上對於式(II)所述。
經保護的式(V)之螺𠳭唍-4-酮的合成可藉由不同的路徑進行:
a)式(III)之苯乙酮衍生物與式(IV)之含氮環脂族酮衍生物的縮合較佳在適當溶劑(例如甲醇)中進行,較佳在吡咯啶存在下進行。反應較佳在溶劑的沸點下進行。必要的反應時間為15-20小時。該等反應係以薄層層析法追踪。藉由蒸發溶劑淬滅反應混合物。藉由用適當有機溶劑萃取,或在除去有機溶劑後,藉由過濾,或藉由管柱層析分離式(V)之產物。
b)式(III)之苯乙酮衍生物與式(IV)之含氮環脂族酮衍生物的反應較佳在適當溶劑例如四氫呋喃中,較佳在強鹼(例如,二異丙基胺化鋰)存在下進行。反應在-20℃至室溫範圍的溫度下進行。必要的反應時間為3-4小時。該等反應的進展係以薄層層析法追踪。藉由添加飽和氯化銨溶液淬滅反應混合物。藉由用適當有機溶劑萃取,及在除去有機溶劑後,藉由過濾分離式(VII)之產物。
式(VII)之衍生物的脫氫環化較佳在適當溶劑中,在例如三氟乙酸酐和DBU(1,8-二吖雙環[5.4.0]十一-7-烯)的存在下進行。
除非另有說明,否則一般技術人士可容易地選擇溶劑、溫度和其他反應條件。實施例部分提供特定的程序。反應可以習知方式進一步處理,例如,從殘餘物中消除溶劑並藉由根據該項技術通常已知的方法(包括但不限於結晶、萃取、研磨和層析法)進一步純化。
使用與先前技術的不同方法,可獲得所需脫保護的式(VI)之螺𠳭唍-4-酮。較佳在EtOAc與鹽酸中於0℃至室溫的範圍下進行。必要的反應時間為2-3小時。該反應的進展係以薄層層析法追踪,並藉由過濾分離產物。
式(V)之衍生物(螺酮的羰基)的還原較佳適當溶劑(例如乙醇)中與NaBH4
進行。該反應的進展係以TLC追踪。藉由消除溶劑分離粗製螺唍-4-醇,接著將殘餘物分溶在DCM和水之間,並蒸發有機相以獲得標題化合物,其在未來的步驟中不經純化而使用。
式(VIII)之螺𠳭唍-4-醇衍生物的還原脫氧係藉由眾所周知稱為“離子氫化”的還原方法完成:藉由將羥基衍生物以Et3
SiH/CF3
COOH系統在90℃下處理6-18小時。該反應的進展係以薄層層析法追踪。蒸發反應混合物,將殘餘物用飽和NaHCO3
溶液處理,並藉由用適當有機溶劑萃取分離式(IX)之產物。
大多數的式(X)之一級胺衍生物為市售,或者可由熟習該項技術者使用與先前技術所述的不同方法從市售的起始材料和試劑合成。在實施例部分中描述一些新的式(X)之胺衍生物的合成。
上述式(II)化合物可藉由使用標準程序和試劑(例如,CDI(1,1'-羰基二咪唑)、氯甲酸酯、或1,1′-硫羰基二咪唑)在適當溶劑(例如,DCM)中在氬氛圍下活化式(X)之一級胺化合物,接著添加反應物(式(VI)或式(IX))來製備。反應在0℃至室溫範圍的溫度下進行。必要的反應時間為15-20小時。該等反應的進展係以薄層層析法追踪。反應混合物的後處理可藉由不同的方法進行,通常藉由加水來淬滅。藉由用適當有機溶劑萃取來分離產物,並藉由結晶或管柱層析法來純化。
本揭示內容在其範圍內包括化合物的所有可能同位素標記形式。
本發明之化合物可以口服、腸胃外(例如、肌內、腹膜內、靜脈內、關節內、鞘內、腹膜內、直接心室內、腦室內、髓內注射、腦池內注射或輸注、皮下注射或植入)、眼、鼻、陰道、直腸、舌下和局部之投予路徑且可單獨或與以包含適用於各投予路徑的醫藥上可接受的賦形劑之適當劑量單元調配物一起投予。
或者,吾人可以局部而非全身方式,例如經由將化合物直接注射至腎臟或心臟區域中,經常以改良釋放調配物來投予化合物。此外,吾人可以靶向藥物遞送系統,例如以組織特異性抗體塗佈之脂質體來投予藥物。脂質體被靶向組織選擇性吸收。
本發明之醫藥組成物通常在單一劑量單元中含有0.01至500 mg的活性成分。然而,一些組成物中的活性成分之量可能超過上述定義的上限或下限。
化合物可以每天1至4次,較佳每天一次或二次的方案投予。
可調整此劑量含量和方案以提供最佳治療反應。然而,應該理解,任何特定患者的特定劑量含量和劑量頻率可改變,且取決於各種因素包括所用特定化合物的活性、代謝穩定性和該化合物的作用長度、年齡、體重、一般健康、性別、飲食、投予的模式和時間、排泄率、藥物組合、特定病況的嚴重性和接受治療的宿主。
作為本發明的另一態樣,提供含有式(I)或式(II)化合物或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物的藥物之醫藥製造。
本發明之醫藥組成物可調配成不同的醫藥劑型,包括但不限於固體口服劑型如錠劑(例如,頰、舌下、發泡性、咀嚼性、口腔分散性、冷凍乾燥)、膠囊、口含錠、錠劑、丸劑、口腔分散膜、顆粒、粉末;液體口服劑型,包括但不限於溶液、乳液、懸浮液、糖漿、酏劑、口服滴劑;腸胃外劑型,包括但不限於靜脈注射、肌內注射、皮下注射;其他劑型,包括但不限於滴眼液、半固體眼製劑、滴鼻液或噴霧劑、透皮劑型、栓劑、直腸膠囊、直腸溶液、乳液和懸浮液、等等。
本發明之醫藥組成物可以任何習知方式製造,例如,藉由混合、溶解、乳化、懸浮、包埋、冷凍乾燥、擠出、層壓、薄膜鑄造、製粒、研磨、包封、糖衣錠製造或壓片方法製造。
根據本發明使用的醫藥組成物因此可以任何習知方式使用一或多種生理學上可接受的賦形劑調配。如適合且如該項技術理解可使用任何眾所周知的技術和賦形劑。
用於製備劑型之適當賦形劑可選自下列類別,包括但不限於錠劑和膠囊填充劑、錠劑和膠囊黏合劑、釋放改良劑、崩散劑、助滑劑、潤滑劑、甜味劑、味道掩蓋劑、調味劑、塗佈劑、界面活性劑、抗氧化劑、緩衝劑、錯合劑、乳化劑、凍乾助劑、微包封劑、軟膏基劑、滲透增強劑、助溶劑、溶劑、栓劑基劑、和懸浮劑。
在一實施態樣中,本發明關於特定賦形劑的使用,其能夠改良活性成分的溶解性、溶解、滲透性、吸收性及/或生體可用率,包括但不限於親水聚合物、熱熔擠出賦形劑、界面活性劑、緩衝劑、錯合劑、乳化劑、凍乾助劑、超崩散劑、微包封劑、滲透增強劑、助溶劑、共溶劑、和懸浮劑。
上述成分和製造之不同路徑僅僅是代表性的。也可使用該項技術中眾所周知的其他材料和加工技術等等。
實施例
本發明進一步定義於下列實施例中。應了解,實施例僅以說明的方式給出。從上述討論及實例,熟習該項技術者可確定本發明之必要特徵,且在不悖離其精神和範疇下,可進行各種改變和修飾以使其適應各種用途及條件。因此,本發明不受以下本文所闡述之說明性實施例限制,而是由其隨附之申請專利範圍限定。
通常,式(I)和式(II)化合物可根據熟習該項技術者的一般知識及/或使用接著的實施例及/或中間物部分中所述的方法製備。一般技藝人士可容易地選擇溶劑、溫度、壓力和其他反應條件。起始材料為市售的及/或由熟習該項技術者容易地製備。
現將以下列非限制性實施例說明本發明。
在下列實施例中,“室溫”表示範圍從20℃至25℃之溫度。
具體實施例中所使用的縮寫具有下列意義:
AcOH 乙酸
abs. 絕對
aq. 水性
atm 大氣壓
Boc2
O 二碳酸二-三級丁酯
BH3
.THF 硼烷四氫呋喃錯合物溶液
CDI 1,1'-羰基二咪唑
DBU 1,8-二吖雙環[5.4.0]十一-7-烯
DCE 1,2-二氯乙烷
DCM 二氯甲烷
DIPEA N,N-二異丙基乙胺
DMF N,N'-二甲基甲醯胺
DMSO 二甲亞碸
EtOAc 乙酸乙酯
Et3
SiH 三乙基矽烷
ESI 電噴霧離子化
HEPES (4-(2-羥乙基)-1-哌𠯤乙磺酸)
HPLC 高效液相層析法
LC-MS 液相層析法結合質譜法
MeOH 甲醇
n-BuLi 正丁基鋰溶液
NMP N-甲基-2-吡咯啶酮
PCC 氯鉻酸吡啶鎓
sat. 飽和
TEA 三乙胺
TFA 三氟乙酸
THF 四氫呋喃
TLC 薄層層析法
中間物1
6'-氯-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-4'-酮鹽酸鹽
步驟1:6'-氯-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲酸三級丁酯
將3.42 g(20 mmol)3-側氧基吖呾-1-甲酸三級丁酯、3.41 g(20 mmol)的1-(5-氯-2-羥苯基)乙-1-酮和1.42 g(1.67 mL,20 mmol)的吡咯啶在甲醇(20 mL)中之溶液回流20小時。在真空中蒸發反應混合物,將棕色殘餘物溶解於二氯甲烷(120 mL)中,並用1N HCl分溶,接著將有機層用水(2×50 mL)和鹽水(50 mL)洗滌,用無水硫酸鈉乾燥,過濾及在真空中濃縮。在矽凝膠上用DCM:MeOH溶析將粗製產物層析以產生3.02 g(46%)的標題化合物。
步驟2:6'-氯-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-4'-酮鹽酸鹽
在0℃下在10分鐘內將在EtOAc中之20%鹽酸(30 mL)加至3.0 g(8.9 mmol)的6'-氯-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲酸三級丁酯(來自上一步驟)在EtOAc(30 mL)中之溶液。添加後,使混合物加熱至室溫並在此溫度下攪拌2小時。接著將反應混合物在真空中濃縮至約15 mL,並用乙醚(20 mL)稀釋。將沉澱的淺棕色晶體濾出,用乙醚洗滌及乾燥以產生2.0 g(90%)的標題化合物。
根據關於中間物1所述的方法在吡咯啶存在下從適當的苯乙酮和含氮環脂族酮製備表1之化合物。
中間物18
3',4'-二氫螺[吖呾-3,2'-哌喃并[3,2-b]吡啶]-4'-酮鹽酸鹽
步驟1:4'-側氧基-3',4'-二氫螺[吖呾-3,2'-哌喃并[3,2-b]吡啶]-1-甲酸三級丁酯
將1-(3-羥基吡啶-2-基)乙酮(160 mg;1.17 mmol)、N-三級丁氧羰基-3-吖呾酮(azetidinon)(205 mg,1.2 mmol)和吡咯啶(0.1 mL,1.2 mmol)在甲苯(4 mL)中之溶液在回流下攪拌28小時。一旦反應完成(以TLC監測),在真空下濃縮混合物,並將所得將深棕色殘餘物分溶在EtOAc(30 mL)和1 N鹽酸(10 mL)之間。分離各層。將水層用EtOAc(2×20 mL)萃取。將合併的有機萃取液依次用水(2×20 mL)、飽和NaHCO3
溶液(20 mL)和鹽水(20 mL)洗滌。藉由快速矽膠管柱層析法使用在EtOAc中之30%正己烷作為溶析液將溶劑蒸發後所得之殘餘物純化,以產生100 mg(29%)的標題化合物。
步驟2:3',4'-二氫螺[吖呾-3,2'-哌喃并[3,2-b]吡啶]-4'-酮鹽酸鹽
在10分鐘內在0℃下將在EtOAc之20%鹽酸(2 mL)中加至113 mg (0.389 mmol)的4'-側氧基-3',4'-二氫螺[吖呾-3,2'-哌喃并[3,2-b]吡啶]-1-甲酸三級丁酯(來自上一步驟)在EtOAc(2 mL)中之溶液。添加後,使混合物加熱至室溫,並在此溫度下攪拌2小時。接著將反應混合物在真空中濃縮至約15 mL,並用乙醚(3 mL)稀釋。將沉澱的淺棕色晶體濾出,用乙醚洗滌,及乾燥以產生80 mg(91%)的標題化合物。
中間物19
7'-氟-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-4'-酮鹽酸鹽
步驟1:3-[2-(4-氟-2-羥苯基)-2-側氧基乙基]-3-羥基吖呾-1-甲酸三級丁酯
將二異丙胺(17.7 mL,125 mmol)在THF(50 mL)中之溶液冷卻至-15℃,在氮氛圍下滴加在己烷中之2.5 M n-BuLi(50 mL),及將混合物在-15℃下攪拌30分鐘。接著滴加8.96 g(58.14 mmol)的4'-氟-2'-羥基苯乙酮在THF(50 mL)中之溶液,並將混合物在-15℃下攪拌1小時,及接著用3-側氧基吖呾-1-甲酸三級丁酯(12.9 g,75.6 mmol)在THF(50 mL)中之溶液逐滴處理20分鐘,使加熱至室溫並在此溫度下攪拌1小時。藉由添加飽和NH4
Cl溶液(100 mL)將反應混合物淬滅。將反應混合物用乙酸乙酯(2×90 mL)萃取,將合併的有機層用鹽水(120 mL)洗滌,用無水Na2
SO4
乾燥,過濾及在真空中濃縮。將殘餘物與異丙醚(50 mL)一起研磨,將沉澱的白色晶體濾出,用二異丙醚洗滌,及乾燥以產生16.79 g(89%)的標題化合物。
步驟2:7'-氟-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲酸三級丁酯
在氮氛圍下於-10℃將14.48 g(9.58 mL,68.12 mmol)的三氟乙酸酐滴加至14.2 g(43.6 mmol)的3-[2-(4-氟-2-羥苯基)-2-側氧基乙基]-3-羥基吖呾-1-甲酸三級丁酯在乾燥吡啶(35 mL)中之溶液。添加後,使混合物加熱至室溫並在此溫度下攪拌1至2小時。接著將反應混合物用乙醇(80 mL)稀釋,及用49 g(48 mL)的1,8-二吖雙環[5.4.0]十一-7-烯處理。在添加期間,將混合物的溫度升至50℃並在此溫度下保持1小時。在真空中濃縮混合物,並將殘餘物溶解在EtOAc(160 mL)中,並用水(2×80 mL)、1 N HCl(80 mL)、1 M NaHCO3
溶液(80 mL)和鹽水(40 mL)洗滌。將有機層經無水Na2
SO4
乾燥,過濾及在真空中濃縮。將殘餘物與乙醚和正己烷(1:1,40 mL)之混合物一起研磨,將沉澱的白色晶體濾出,用乙醚洗滌及乾燥以產生4.9 g(36%)的標題化合物。
將蒸發的母液在矽凝膠上用CH2
Cl2
溶析進行層析以產生另外2.05 g(15%)的標題化合物。
步驟3:7'-氟-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-4'-酮鹽酸鹽
在0℃下 經10分鐘將在EtOAc中之20% HCl(60 mL)加至6.05 g(19.7 mmol)的7'-氟-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲酸三級丁酯(來自上一步驟)在EtOAc(60 mL)中之溶液。添加後,使混合物加熱至室溫,並在此溫度下攪拌2小時。接著將反應混合物的體積在真空中減至15-20 mL,並用乙醚(30 mL)稀釋。將沉澱的白色晶體濾出,用乙醚洗滌,及乾燥以產生4.53 g(94%)的標題化合物。
中間物20
3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃
步驟1. 4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲酸三級丁酯
此中間物係根據關於中間物1所述的方法從適當的2-羥基-苯乙酮和3-側氧基吖呾-1-甲酸三級丁酯與吡咯啶製備。
步驟2. 4'-羥基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲酸三級丁酯
至在冰水冷卻下將NaBH4
(52.3 mg,1.38 mmol)分批加400 mg(1.38 mmol)的4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲酸三級丁酯在MeOH(5 mL)中之溶液。添加後,使混合物加熱至室溫,並在此溫度下攪拌4小時。接著在真空中濃縮反應混合物,及將殘餘物溶解在EtOAc(15 mL)中,用水和鹽水洗滌。將有機層經無水Na2
SO4
乾燥,過濾及在真空中濃縮,以產生320 mg(79%)的標題化合物。將所得粗製螺𠳭唍-4-醇使用於下一步驟而無需任何純化。
步驟3. 3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃
將Et3
SiH(450 mg,4 mmol)加至4'-羥基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲酸三級丁酯(292 mg,1 mmol)在三氟乙酸(4 mL)中之溶液,並將混合物在90℃下攪拌16小時。接著在真空中濃縮反應混合物,並將殘餘物溶解在水中,及藉由添加1.5N NaOH溶液將pH調節至9。用CH2
Cl2
(3x)萃取混合物,將合併的萃取液用無水Na2
SO4
乾燥,過濾並在真空中濃縮,以產生80 mg(50%)的標題化合物。所得粗製3,4-二氫螺𠳭唏衍生物在未經任何純化下用於下一步驟。
藉由中間物20所述的方法從適當螺𠳭唍-4-酮、螺𠳭唍-4-醇、3,4-二氫螺𠳭唏反應順序製備表2之化合物。
將源自6'-氟-4'-羥基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲酸三級丁酯的還原脫氧反應之中間物24和25使用於下一步驟而不分離。
中間物26
(1H-吲哚-5-基)甲胺
該化合物是可商購自Sigma Aldrich(目錄編號:
655864)。
中間物27
(1-甲基-1H-吲哚-5-基)甲胺
該化合物是可商購自Maybridge(目錄編號:
CC41413DA)。
中間物28
(2-甲基-1H-吲哚-5-基)甲胺
該化合物是可商購自Enamine (目錄編號:EN300-209649)。
中間物29
(2-氯-1H-吲哚-5-基)甲胺
步驟1:3,3-二溴-2-側氧基-2,3-二氫-1H-吲哚-5-甲腈
在25℃下將溴(42.5 g;13.5 mL,275 mmol)滴加(20 min)至1H-吲哚-5-甲腈(7.10 g;50 mmol,Combi-Blocks)在三級丁醇(250 mL)中之攪拌溶液,並攪拌1.5小時。完成後,將反應混合物在真空下濃縮。將此殘餘物用EtOAc (400 mL)稀釋,並添加水(75 mL)。將有機層用水(2×100 mL)、鹽水(100 mL)洗滌,用無水Na2
SO4
乾燥,過濾及在減壓下濃縮。將粗製殘餘物與異丙醚(100 mL)一起攪拌30分鐘。將沉澱的晶體濾出,用異丙醚洗滌,並乾燥以產生12.89 g(81%)的呈紅棕色固體之標題化合物。
步驟2:2-側氧基-2,3-二氫-1H-吲哚-5-甲腈
將鋅粉(16.3 g;250 mmol)分批(各約2克)加至3,3-二溴-2-側氧基-2,3-二氫-1H- 吲哚-5-甲腈(12.89 g;40.8 mmol)在AcOH(270 mL)中之懸浮液。不允許混合物的溫度升高到35℃以上並在30℃下攪拌2小時。完成後,將反應混合物在真空下濃縮。將此殘餘物懸浮在EtOAc(300 mL)中,濾出,再次將固體與EtOAc(150 mL)一起攪拌,接著濾出。將合併的有機層在真空中濃縮。將殘餘物與1 N HCl溶液(100 mL)一起攪拌1小時,濾出,用水(2×5 mL)洗滌,及乾燥以產生3.86 g(60%)的標題化合物。
步驟3:2-氯-1H-吲哚-5-甲腈
在0℃下將POCl3
(11.5 g,6.95 mL;74.79 mmol)加至2-側氧基吲哚啉-5-甲腈(5.8 g;36.9 mmol)在DCE(23 ml)中之攪拌懸浮液。將反應混合物在90℃下回流30分鐘。冷卻反應後,添加咪唑(2.75 g,44.55 mmol)並在90℃下進一步加熱2小時。完成後,將反應混合物濃縮並將殘餘物溶解在EtOAc(110 mL)中並用飽和NaHCO3
溶液(30 mL)、鹽水(50 mL)洗滌,用無水Na2
SO4
乾燥,過濾及在真空中濃縮。藉由管柱層析法在矽凝膠上用THF:正己烷9:1溶析將該產物純化以產生4.58 g(70%)的呈黃色固體之標題化合物。
步驟4:(2-氯-1H-吲哚-5-基)甲胺
在氮氛圍下於0℃下將LiAlH4
(在THF中之1 M;45 mL;45 mol)加至2-氯-1H-吲哚-5-甲腈(4.48 g;25.3 mmol)在乾燥THF(23 mL)中之攪拌溶液。將反應混合物在65℃下回流2小時。TLC顯示產物形成。將反應混合物在0℃下用EtOAc(20 mL)淬滅並滴加飽和Na2
SO4
水溶液(15 mL)。將反應混合物通過矽藻土墊過濾並用乙酸乙酯(100 mL)徹底洗滌。將濾液用鹽水(50 mL)洗滌,用無水Na2
SO4
乾燥,過濾及在真空中濃縮。將粗製產物從EtOAc(50 mL)結晶純化以產生3.9 g(85%)的呈灰白色固體之標題化合物。
中間物30
(3-氯-1-甲基-1H-吲哚-5-基)甲胺
步驟1:N-[(1-甲基-1H-吲哚-5-基)甲基]胺甲酸三級丁酯
在氮氛圍下於0℃將二碳酸二-三級丁酯(Boc2
O)(1.74 g;7.97 mmol)在CH2
Cl2
(10 mL)中之溶液加至(1-甲基-1H-吲哚-5-基)甲胺(640 mg;3.995 mmol)和DIPEA(1.03g;1.39 mL,7.98 mmol)在CH2
Cl2
(40 mL)中之攪拌溶液。將反應混合物在室溫下攪拌過夜。TLC顯示產物形成。將反應混合物用CH2
Cl2
(20 mL)稀釋並用水(50 mL)洗滌。將有機相用鹽水(50 mL)洗滌,用無水Na2
SO4
乾燥,過濾及在真空中濃縮。藉由急速層析法純化粗製產物以產生786 mg (76%)的呈白色固體之標題化合物。
步驟2:N-[(3-氯-1-甲基-1H-吲哚-5-基)甲基]胺甲酸三級丁酯
在氬氛圍下於0℃將 N-氯琥珀醯亞胺(82 mg;0.61 mmol)加至N-[(1-甲基-1H-吲哚-5-基)甲基]胺甲酸三級丁酯(160 mg;0.615 mmol)在CH2
Cl2
(4 mL)中之攪拌溶液。將反應混合物在室溫下攪拌3.5小時。TLC顯示產物形成。將反應混合物用CH2
Cl2
(20 mL)稀釋,並用水洗滌(20 mL)。將有機相用鹽水(15 mL)洗滌,用無水Na2
SO4
乾燥,過濾及在真空中濃縮。藉由急速層析法純化粗製產物以產生145 mg(80%)的呈油之標題化合物。
步驟3:(3-氯-1-甲基-1H-吲哚-5-基)甲胺
在氬氛圍下於0-2℃將CF3
COOH (300 mg;0.2 mL,3 mmol)加至N-[(3-氯-1-甲基-1H-吲哚-5-基)甲基]胺甲酸三級丁酯(72 mg,0.244 mmol)在乾燥CH2
Cl2
(3 mL)中之溶液。將反應混合物在室溫下攪拌3小時。反應完成後(以TLC監測),在真空中濃縮混合物。將殘餘物溶於CH2
Cl2
(20 mL)中,藉由添加1 N NaOH溶液將pH調節至10(在冷卻下),用CH2
Cl2
(3×15 mL)萃取水相,將有機相用無水Na2
SO4
乾燥,過濾及在真空中濃縮。藉由急速層析法在矽石上,以在CH2
Cl2
中之10%MeOH溶析,將粗製產物純化,以產生49 mg的呈黃色固體之標題化合物。
中間物31
(3-氟-1-甲基-1H-吲哚-5-基)甲胺
步驟1:1-甲基-1H-吲哚-5-甲腈
在氬氛圍下於0℃將NaH(840 mg,在油中的60%,21 mmol)加至lH-吲哚-5-甲腈(2.09 g,14.7 mmol)在DMF(16 mL)中之溶液並激烈攪拌。將溶液攪拌30分鐘,接著添加碘甲烷(9.12 g,4 mL,63 mmol)。將反應混合物在室溫下攪拌4小時。將反應物用水(50 mL)淬滅,並用EtOAc(3×120 mL)萃取。將有機層合併,用水(2×50 mL)洗滌,用無水Na2
SO4
乾燥,過濾及在真空中濃縮,及從殘餘物中蒸發乾燥甲苯以產生2.3 g的呈灰白色固體之標題化合物,使用於下一步驟而無需任何純化。
步驟2:1-甲基-2,3-二側氧基-2,3-二氫-1H-吲哚-5-甲腈
將PCC(7.6 g,35.2 mmol)加至1-甲基-1H-吲哚-5-甲腈(1.38 g,8.83 mmol)在乙腈(40 mL)中之溶液,並將混合物回流7小時。反應完成後(以TLC監測),在真空中濃縮反應混合物,並將殘餘物分溶在H2
O和EtOAc之間。將不溶部分濾出,將有機層用鹽水洗滌,用無水Na2
SO4
乾燥,並將溶劑蒸發至乾。藉由急驟層析法在矽石上以CH2
Cl2
溶析將粗製殘餘物純化以產生760 mg的呈橙色固體之標題化合物。
步驟3:3,3-二氟-1-甲基-2-側氧基-2,3-二氫-1H-吲哚-5-甲腈
在氬氛圍下將1-甲基-2,3-二側氧基-2,3-二氫-1H-吲哚-5-甲腈(502 mg,2.7 mmol)加至雙(2-甲氧基乙基)胺基三氟化硫之溶液(Deoxofluor,在甲苯中之50%,5 mL,10 mmol),接著添加25 μL abs. EtOH,及將混合物在90℃下加熱1小時。
以MeOH(1 mL)將反應物淬滅並用CH2
Cl2
(100 mL)稀釋,接著將混合物倒入冷飽和Na2
SO4
溶液,並將產物用二氯甲烷萃取。將萃取物用鹽水洗滌,用無水Na2
SO4
乾燥,並將溶劑蒸發至乾。藉由急速層析法在矽石上以0-20% EtOAc/己烷的梯度溶析將粗製殘餘物純化以產生322 mg的呈黃色固體之標題化合物。
步驟4:(3-氟-1-甲基-1H-吲哚-5-基)甲胺
在氬氛圍下於0-2℃將BH3
.THF(在THF中之1 M)(7.5 mL,7.5 mmol)加至3,3-二氟-1-甲基-2-側氧基-2,3-二氫-1H-吲哚-5-甲腈(510 mg,2.45 mmol)在乾燥THF(10 mL)中之溶液。將反應混合物在室溫下攪拌3小時。反應完成後(以TLC監測),在冷卻下添加MeOH(10 mL),及在真空中濃縮混合物。將殘餘物溶解在EtOAc(50 mL)中,用飽和NaHCO3
水溶液(25 mL),接著用鹽水(25 mL)洗滌,用無水Na2
SO4
乾燥,過濾及在真空中濃縮。藉由急速層析法在矽石上以在CH2
Cl2
中之10% MeOH溶析將粗製產物純化以產生70 mg的呈淺黃色固體之標題化合物。
中間物32
{1-甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺
化合物5-溴-1H-吡咯並[2,3-b]吡啶可商購自Combi Blocks(目錄編號:IN-0206),且所需的氮雜吲哚衍生物以如上所示之一系列步驟製備。
步驟1:1H-吡咯并[2,3-b]吡啶-5-甲腈
如EP1782811 A1(EISAI R&D MAN CO LTD)中所述製備中間物。
步驟2:1-甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈
如WO 2009/155017 A2(MERCK & CO INC)中所述製備中間物。
步驟3:{1-甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺
如WO 2012/042915 A1 (RAQUALIA PHARMA INC)中所述製備中間物。
中間物33
{3-氯-1-甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺
化合物5-溴-1H-吡咯並[2,3-b]吡啶可可商購自Combi Blocks(目錄編號:IN-0206),且所需的3-氯氮雜吲哚衍生物以如上所示之一系列步驟製備。
步驟1:1H-吡咯并[2,3-b]吡啶-5-甲腈
如EP 1782811 A1(EISAI R&D MAN CO LTD)中所述製備中間物。
步驟2:1-甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈
如WO 2009/155017 A2(MERCK & CO INC)中所述製備中間物。
步驟3:3-氯-1-甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈
在氬氛圍下於室溫將N-氯琥珀醯亞胺(502 mg,3.76 mmol)加至1-甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈(600 mg,3.69 mmol)在DMF(14 mL)中之溶液並激烈攪拌。將溶液在室溫下攪拌過夜。反應完成後(以TLC監測),在真空中濃縮混合物(從殘餘物中蒸發乾燥甲苯數次)。將殘餘物溶於乙醚-EtOAc之混合物(1:1,40 mL)中,並用水(3×15 mL)洗滌。將有機層經無水Na2
SO4
乾燥,過濾及在真空中濃縮以產生670 mg的標題化合物,使用於下一步驟而無需任何純化。
步驟4:{3-氯-1-甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺
如WO 2012/042915 A1(RAQUALIA PHARMA INC)中所述製備中間物。
中間物34
{3-溴-1-甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺
步驟1-2:
藉由與EP 1782811 A1(EISAI R&D MAN CO LTD)和WO 2009/155017 A2(MERCK & CO INC)中所述相同的方法以中間物33所述步驟之一系列步驟製備中間物。
步驟3:3-溴-1-甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈
在氬氛圍下於室溫將N-溴琥珀醯亞胺(446 mg,2.51 mmol)加至1-甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈(358 mg,2.28 mmol)在CH2
Cl2
(6.5 mL)中之溶液並激烈攪拌。將溶液在下攪拌室溫過夜。反應完成後(以TLC監測),將混合物用CH2
Cl2
(25 mL)稀釋並用水(3×20 mL)洗滌。將有機層經無水Na2
SO4
乾燥,過濾及在真空中濃縮以產生670 mg的標題化合物,使用於下一步驟而無需任何純化。
步驟4:{3-溴-1-甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺
如WO 2012/042915 A1(RAQUALIA PHARMA INC)中所述製備中間物。
中間物35
{1,2-二甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺
步驟1:6-胺基-5-碘吡啶-3-甲腈
將三氟乙酸(574 mg,386 uL,1.2 mol當量)加至2-胺基-5-氰吡啶(500 mg,4.2 mmol)在DMF(5 mL)中之溶液。在室溫下添加N-碘琥珀醯亞胺(1.04 g,4.62 mmol,1.1 mol當量)並將反應混合物在50℃下加熱3小時。以TLC指示完全轉化。將反應混合物冷卻至室溫後,藉由將反應混合物加至水中使產物沉澱。用Na2
S2
O3
和1N NaOH中和後,藉由過濾收集呈棕色固體之標題化合物(660 mg)。將其使用於下一步驟而無需任何純化。
步驟2:6-胺基-5-(丙-1-炔-1-基)吡啶-3-甲腈
在0-5℃下經由隔膜將丙炔(propyn)溶液(在THF中之3-4%;13.2 mL)加至6-胺基-5-(丙-1-炔-1-基)吡啶-3-甲腈(329 mg,1.34 mmol)、雙'(三苯膦)二氯鈀(0)(95 mg,0.134 mmol)、碘化銅(I)(128 mg,0.671 mmol)和三乙胺(976 mg,1.34 mL,9.64 mmol)在abs. THF(18 mL)中之脫氣混合物。將混合物在0-5℃下攪拌30分鐘,接著在室溫下攪拌18小時。藉由添加NH4
Cl溶液將反應物淬滅。藉由過濾除去固體並將濾餅用CH2
Cl2
洗滌。將合併的有機層用無水Na2
SO4
乾燥,過濾及在真空中濃縮。藉由急速層析法在矽石上以在環己烷中之40% EtOAc溶析將粗製產物純化以產生150 mg的呈黃色固體之標題化合物(71%)。
步驟3:2-甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈
將三級丁醇鉀(428 mg,3.82 mmol,2 mol當量)加至6-胺基-5-(丙-1-炔-1-基)吡啶-3-甲腈(300 mg,1.91 mmol)在DMF(5 mL)中之溶液。將反應混合物在90℃下加熱5.5小時。以TLC指示完全轉化。將反應混合物冷卻至室溫後,將混合物倒入水中並用CH2
Cl2
萃取。將合併的有機層用無水Na2
SO4
乾燥,過濾及在真空中濃縮以產生279 mg(93%)的呈黃色固體之標題化合物。將其使用於下一步驟而無需任何純化。
步驟4:1,2-二甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈
在0℃下將氫化鈉(在礦物油中之60%)(92 mg,2.31 mmol,1.3 mol當量)加至2-甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈(279 mg,1.78 mmol)在DMF (7.5 mL)中之溶液。將反應混合物在此溫度下攪拌30分鐘,接著滴加在DMF(1.5 mL)中之碘甲烷(380 mg,167 uL)。將混合物在下攪拌室溫過夜。以TLC指示完全轉化。將混合物倒入水中並用CH2
Cl2
(3×20 mL)萃取。將合併的有機層用無水Na2
SO4
乾燥,過濾及在真空中濃縮,以產生298 mg(98%)的呈黃色固體之標題化合物。將其使用於下一步驟而無需任何純化。
步驟5:1-(1,2-二甲基-1H-吡咯并[2,3-b]吡啶-5-基)甲胺
將雷氏鎳(200 mg)加至1,2-二甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈(297 mg,1.73 mmol)在MeOH(100 mL)和25%氨溶液在水(25 mL)中的混合物中之溶液並將混合物在1 atm的H2
下於室溫攪拌16小時。將反應混合物通過矽藻土墊過濾,並將濾液在減壓下濃縮以產生226 mg(74%)的呈黃色固體之標題化合物。
中間物36
[2-(三氟甲基)-1H-吲哚-5-基]甲胺
如WO 2009/127678 A1(GLAXO GROUP LTD)中所述製備中間物。
中間物37
[2-(二氟甲基)-1H-吲哚-5-基]甲胺
化合物5-溴-1H-吲哚-2-甲酸乙酯可商購自Aldrich(目錄編號:724718)及所需的2-二氟烷基吲哚-胺以如下所示之一系列步驟製備。
步驟1:(5-溴-1H-吲哚-2-基)甲醇
在氬氛圍下於0-2℃將LiAlH4
溶液(在THF中之1M)(7.0 mL,7.0 mmol)加至5-溴-1H-吲哚-2-甲酸酯(2.08 g,7.77 mmol)在乾燥THF(30 mL)中之溶液,接著將反應混合物在室溫下攪拌4小時。反應完成後(以TLC監測),在冷卻下添加NH4
Cl溶液(20 mL),並用EtOAc(2×50 mL)萃取混合物。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾及在真空中濃縮,以產生1.73 g的呈淺棕色固體之粗製化合物。將其使用於下一步驟而無需任何純化。
步驟2:5-溴-1H-吲哚-2-甲醛
將MnO2
(1.92 g,22.1 mmol)加至(5-溴-1H-吲哚-2-基)甲醇(1.0 g,4.42 mmol)在乾燥乙腈(20 mL)中之溶液,並將反應混合物在室溫下攪拌過夜。反應完成後(以TLC監測),將懸浮物濾出,並用EtOAc(5×15 mL)洗滌。將合併的有機層用鹽水洗滌,用無水Na2
SO4
乾燥,過濾及在真空中濃縮。從丙酮中結晶粗製棕色固體以產生656 mg(66%)的標題化合物。
步驟3:5-溴-2-甲醯基-1H-吲哚-1-甲酸三級丁酯
在氮氛圍下於0℃將Boc2
O(965 mg;4.4 mmol)加至5-溴-1H-吲哚-2-甲醛(518 mg;2.2 mmol)和4-(二甲基胺基)吡啶(27 mg;0.22 mmol)在乙腈(20 mL)中之攪拌溶液。將反應混合物在室溫下攪拌過夜。TLC顯示產物形成。將反應混合物蒸發至乾燥,並藉由急速層析法純化粗製產物以產生664 mg(93%)的呈黃色固體之標題化合物。
步驟4:5-溴-2-(二氟甲基)-1H-吲哚-1-甲酸三級丁酯
將在THF(6.28 g,14.2 mmol)中Deoxo-Fluor®(雙(2-甲氧基乙基)(三氟硫基)胺)溶液50%加至5-溴-2-甲醯基-1H-吲哚-1-甲酸三級丁酯(657 mg,2.027 mmol)在乾燥二氯甲烷(20 mL)中之溶液,並將反應混合物在室溫下攪拌過夜。反應完成後(以TLC監測),將混合物用CH2
Cl2
稀釋,用飽和NaHCO3
溶液和鹽水洗滌。將有機相用無水Na2
SO4
乾燥,過濾及在真空中濃縮。藉由急速層析法純化粗製產物以產生642 mg(91%)的呈黃色油之標題化合物。
步驟5:2-(二氟甲基)-1H-吲哚-5-甲腈
在氬氛圍下將氰化鋅(326 mg,2.77 mmol)和肆(三苯膦)鈀(0)(214 mg,0.184 mmol)加至5-溴-2-(二氟甲基)-1H-吲哚-1-甲酸三級丁酯(639 mg,1.848 mmol)在NMP(15 mL)中之溶液並將反應混合物在70℃下攪拌3小時,接著在90℃下經3小時。藉由TLC追踪反應進程。將混合物倒入水(100 mL)中,並用EtOAc(3×30 mL)萃取。將合併的有機相用水(4×50 mL)和鹽水洗滌。將有機相用無水Na2
SO4
乾燥,過濾及在真空中濃縮。藉由急速層析法純化粗製產物以產生241 mg(68%)的呈白色固體之標題化合物。
步驟6:[2-(二氟甲基)-1H-吲哚-5-基]甲胺
將雷氏鎳(100 mg)加至2-(二氟甲基)-1H-吲哚-5-甲腈(211 mg,1.08 mmol)在MeOH(24 mL)和在水(6 mL)中之25%氨溶液的混合物中並將混合物在1 atm的H2
下於室溫攪拌3小時。將反應混合物通過矽藻土墊過濾,接著用MeOH (3×10 mL)洗滌,接著將濾液在減壓下濃縮以產生218 mg (約100%)的呈淺棕色固體之標題化合物。
中間物38
1-(1,3-苯并噻唑-6-基)甲胺
如WO 2011/079804 A1(HUTCHISON MEDIPHARMA LTD)或US 20100298314 A1(SCHERING CORP)中所述製備中間物。
中間物39
1-(1-甲基-1,2,3,4-四氫喹啉-6-基)甲胺
該化合物是可商購自Enamine(目錄編號:EN300-
57206)。
實施例1
6'-氟-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺
在氬氛圍下於0℃將氯甲酸4-硝苯酯(1020 mg,5.06 mmol)加至800 mg(5.0 mmol)的2-(甲基-1H-吲哚-5-基)甲胺(中間物26)和1.295 g(1.75 mL,10 mmol)的DIPEA在120 mL的二氯甲烷(CH2
Cl2
)之混合物。在此條件下將淺黃色懸浮液攪拌1小時。活化期後,添加6'-氟-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-4'-酮鹽酸鹽(1.22 g,5 mmol,中間物6)和1.75 mL DIPEA(7.75 mmol)在30 mL CH2
Cl2
中之混合物。添加後,使混合物加熱至室溫並在此溫度下攪拌22小時。反應完成後(以TLC監測),將混合物用水(2×40 mL),接著用鹽水洗滌。將有機層經無水Na2
SO4
乾燥,過濾及在真空中濃縮,以產生1.8 g的粗製化合物。將殘餘物在矽凝膠上,用CH2
Cl2
和MeOH(10:1)之混合物溶析進行層析以產生1.02 g(50%)的標題化合物。LC-MS(ESI) m/z[M+H]+
= 394.1。
根據關於實施例1所述之程序合成下列表3中之實施例。
實施例66b
6'‐氯‐N‐[(2‐甲基‐1H‐吲哚-5-基)甲基]‐4'‐側氧基-3',4'‐二氫螺[吖呾‐3,2'‐[1]苯并哌喃]‐1‐硫代甲醯胺(carbothioamide)
在氬氛圍下於室溫將1,1'-硫羰基-二咪唑(98 mg,0.55 mmol)加至80.1 mg(0.5 mmol)的2-(甲基-1H-吲哚-5-基)甲胺(中間物28)在2 mL的DMF中之溶液。將棕黃色溶液在該條件下攪拌1小時。活化期後,添加6'-氯-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-4'-酮鹽酸鹽(130 mg,0.5 mmol,中間物1)和0.131 mL的DIPEA(0.75 mmol)在2 mL DMF中之混合物,並將混合物在此溫度下攪拌20小時。反應完成後(以TLC監測),將混合物倒入水(8 mL)中並用EtOAc(2×15 mL)萃取。將有機層經無水Na2
SO4
乾燥,過濾及在真空中濃縮。將殘餘物在矽凝膠上,用CH2
Cl2
和MeOH(10:1)之混合物溶析進行層析以產生100 mg(47%)的標題化合物。LC-MS (ESI) m/z [M+H]+
= 426.2
實施例71c
7'‐氟-N‐[(1‐甲基‐1,2,3,4‐四氫喹啉‐6-基)甲基]‐4'‐側氧基-3',4'‐二氫螺[吖呾‐3,2'‐[1]苯并哌喃]‐1‐甲醯胺
在氬氛圍下於0℃將氯甲酸4-硝苯酯(111 mg,0.55 mmol)加至88 mg(0.5 mmol)的1‐(1‐甲基‐1,2,3,4‐四氫喹啉‐6-基)甲胺(中間物39)和175 µL(1.0 mmol)的DIPEA在20 mL的二氯甲烷(CH2
Cl2
)中之混合物。將淡黃色懸浮液在此條件下攪拌1.5小時。活化期後,添加7'-氟-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-4'-酮鹽酸鹽(122 mg,0.5 mmol,中間物19)和131 µL DIPEA(0.75 mmol)在5 mL CH2
Cl2
中之混合物。添加後,使混合物加熱至室溫,並在此溫度下攪拌24小時。反應完成後(以TLC監測),將混合物用水(2×20 mL),接著用鹽水洗滌。將有機層經無水Na2
SO4
乾燥,過濾及在真空中濃縮以產生300 mg的粗製化合物。將殘餘物在矽凝膠上,用CH2
Cl2
和MeOH(99:1)之混合物溶析進行層析,以產生30 mg(15%)的標題化合物。LC-MS(ESI) m/z [M+H]+
= 410.2
實施例72d
N-[(3-氯-2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺
在氬氛圍下於室溫將N-氯琥珀醯亞胺(36 mg,0.266 mmol)加至N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺(實施例31) (100 mg,0.266 mmol)在DCM(2 mL)中之溶液,並激烈攪拌。將溶液在室溫下攪拌過夜。反應完成後(以TLC監測),將混合物用DCM(20 mL)稀釋,並用水(3×15 mL)洗滌。將有機層經無水硫酸鈉乾燥,過濾及在真空中濃縮。藉由管柱層析法將粗製產物純化以產生35 mg的標題化合物。LC-MS(ESI) m/z [M+H]+
=410.1
實施例74e
N‐[(1‐甲基‐1H‐吲哚-5-基)甲基]‐4'‐側氧基-3',4'‐二氫螺[吖呾‐3,2'‐哌喃并[3,2‐b]吡啶]‐1‐甲醯胺
在氬氛圍下於0℃將氯甲酸4-硝苯酯(71 mg,0.35 mmol)加至56 mg(0.35 mmol)的(1-甲基-1H-吲哚-5-基)甲胺(中間物27)和122 µL(0.7 mmol)的N,N-二異丙基乙胺(DIPEA)在10 mL的二氯甲烷(CH2
Cl2
)中之混合物。將淺黃色懸浮液在此條件下攪拌1小時。活化期後,添加3',4'‐二氫螺[吖呾‐3,2'‐哌喃并[3,2‐b]吡啶]‐4'-酮鹽酸鹽(80 mg,0.35 mmol,中間物18)和92 µL DIPEA(0.53 mmol)在2 mL CH2
Cl2
中之混合物。添加後,使混合物加熱至室溫,並在此溫度下攪拌24小時。反應完成後(以TLC監測),將混合物用水(2×10 mL),接著用鹽水洗滌。將有機層經無水Na2
SO4
乾燥,過濾及在真空中濃縮,以產生60 mg的粗製化合物。將殘餘物在矽凝膠上用CH2
Cl2
和MeOH(99:1)之混合物溶析進行層析:以產生7 mg(5%)的標題化合物。LC-MS (ESI) m/z [M+H]+
= 377.2
醫藥組成物的製備
下列調配物實施例說明本發明的代表性醫藥組成物。然而,本發明不限於下列醫藥組成物。
A) 固體口服劑型
I.,錠劑
活性成分 0.01-90%
填充劑 1-99.9%
黏合劑 0-20%
崩散劑 0-20%
潤滑劑 0-10%
其他特定賦形劑 0-50%
II.,口腔分散膜
活性成分 0.01-90%
成膜劑 1-99.9%
塑化劑 0-40%
其他特定賦形劑 0-50%
B) 液體口服劑型
III.,口服懸浮液
活性成分 0.01-50%
液體媒液 10-99.9%
潤濕劑 0-50%
增稠劑 0-50%
緩衝劑 適量
滲透劑 0-50%
防腐劑 適量
IV.,糖漿
活性成分 0.01-50%
溶劑 10-99.9%
糖組分 1-20%
矯味劑 0-10%
C) 腸胃外劑型
V.,靜脈注射
活性成分 0.01-50%
溶劑 10-99.9%
共溶劑 0-99.9%
滲透劑 0-50%
緩衝劑 適量
D) 其他劑型
VI.,栓劑
活性成分 0.01-50%
栓劑基劑 1-99.9%
界面活性劑 0-20%
潤滑劑 0-20%
防腐劑 適量
VII.,滴鼻液或鼻噴霧劑
活性成分 0.01-50%
水 0-99.9%
溶劑 0-99.9%
共溶劑 0-99.9%
滲透劑 0-20%
黏度增強劑 0-20%
緩衝劑 適量
防腐劑 適量
生物活性
人類α7菸鹼乙醯膽鹼受體[Ca2+]i分析
細胞:Flp-In 293細胞穩定地表現人類α7 nAchR和人類RIC-3(α7細胞,機構內部產生)。
材料:塗佈PDL(Falcon)之96孔盤、培養基、分析緩衝液、DMSO、FLIPR鈣5套件(Molecular Devices)、丙磺舒、促效劑和PAM試驗化合物。
該方法(Ca2+
螢光測定法)的簡要說明
在以上詳述的培養基中培養穩定地表現人類α7 nAchR之α7細胞,每週分離二次。關於細胞溶質Ca2+
離子濃度([Ca2+
]i
)之螢光測量,將細胞以60000細胞/孔的密度接種在96孔微量培養盤中,並在組織培養培養器中在95%空氣/ 5% CO2
的氛圍下於37℃保持過夜。平板接種培養基與培養基相同。用細胞洗滌器(BioTek Elx405UCVWS)吸出50 µl生長培養基。接著使用8通道移液器手動添加2倍稀釋於分析緩衝液中之50 μl/孔鈣5套件。培養期(20分鐘,37℃)之後,手動添加50 μl/孔含媒液(DMSO,4%添加)或參考α7 PAM(4倍的最終濃度)之分析緩衝液及將細胞在37℃下培養另外10分鐘。使用FlexStation II(Molecular Devices, Sunnyvale,CA),具有集成的8通道流體添加性能之盤式讀數器螢光計,監測基線和促效劑誘發之[Ca2+
]i
改變。螢光測量在37℃下進行。染料於485 nm激發,以1.4s間隔於525 nm取樣發射。記錄基線20秒,接著進行促效劑刺激。使用FlexStation II的移液器將50 µl 4×濃縮促效劑溶液加至細胞中,並監測螢光另外40秒。所有處理的最終DMSO濃度為1%。為此,從所有試驗化合物製備一系列DMSO儲備溶液。將這些儲備溶液儲存在0℃下,並進一步稀釋於分析緩衝液中,以在測量前立即獲得所需的最終濃度。分別在飽和濃度的PAM(主要是PNU-120596,5 µM)和促效劑(主要是PNU-282987,1 µM)存在下進行促進劑和PAM濃度-反應研究。使用SoftMax Pro軟體(Molecular Devices)將結果表示為ΔF/F值,其中F為促效劑應用之前的靜止螢光,ΔF為於給定時間的螢光增加(ΔF=刺激後的最大螢光強度值減去刺激前的平均螢光強度值)。在所有實驗中,所有處理在多個孔中平行測量,並且平均ΔF/F值用於分析。
表4顯示在[Ca2+
]i
分析中之PAM EC50
值:
活體內藥理學(位置識別試驗)
動物:雄性NMRI小鼠(Toxicoop,Hungary)
物質:將莨菪鹼溶解於鹽水中並以1 mg/kg劑量i.p.投予。試驗化合物在習得試驗(acquisition trial)(T1)之前30分鐘投予及習得試驗(acquisition trial)之後以0.1 ml/10 g的體積投予莨菪鹼。
程序:在透明塑膠玻璃Y形迷宮(每臂具有40 cm的長度,11 cm的內部寬度,30 cm的高度)進行作業。在臂周圍放置許多目視提示,並且在實驗期間保持不變。試驗由二個間隔30分鐘的試驗間隔之試驗(T1和T2)組成。在每次試驗開始時將小鼠置於迷宮的起始臂中。在T1中,關閉迷宮的對稱臂中之一(在T2中其為新奇的)且允許動物探索迷宮5分鐘(習得期)。在T2中,小鼠可自由進入所有三個臂2分鐘(檢索期)(retrieval phase)。測量在T2期間花在新奇和熟悉臂探索的時間。藉由MANOVA評估各組花在迷宮的熟悉對新奇臂的探索時間之間的差異,接著Duncan事後試驗(post hoct test)。
表5顯示小鼠位置識別分析中莨菪鹼誘發的健忘症之逆轉:
花在迷宮的新奇對熟悉臂的探索時間之間觀察到顯著差異(+
p<0.05;++
p<0.01;+++
p<0.001)。
培養基: | 分析緩衝液: |
- DMEM(杜貝卡氏改良依格培養基(Dulbecco's modified Eagle medium),Gibco) | -140 mM NaCl |
- 10% FBS (胎牛血清,Gibco) | - 5 mM KCl |
- 1% 麩醯胺酸(Sigma G) | - 10 mM HEPES |
- 50 μg/ml潮黴素B | - 2 mM MgCl2 |
- 800 μg/ml G418 | - 2 mM CaCl2 |
- 1% 青黴素-鏈黴素-抗黴溶液 | - 10 mM 葡萄糖 |
(PSA,Sigma) | - 2 mM 丙磺舒, |
pH=7.4 |
本發明之一示例性實施態樣以舉例的方式示出於附圖中,其中相同的參考編號表示相同或相似的元件(element)且其中:
圖1說明化合物實施例1之位置識別試驗的結果。描述花在Y形迷宮的新奇[N]對熟悉[O]臂之探索時間)。Scop:莨菪鹼(1 mg/kg,ip.)。+
p<0.05;++
p<0.01;+++
p<0.001。
圖2說明化合物實施例6之位置識別試驗的結果。描述花在Y形迷宮的新奇[N]對熟悉[O]臂之探索時間)。Scop:莨菪鹼(1 mg/kg,ip.)。+
p<0.05;++
p<0.01;+++
p<0.001。
圖3說明化合物實施例7之位置識別試驗的結果。描述花在Y形迷宮的新奇[N]對熟悉[O]臂之探索時間)。Scop:莨菪鹼(1 mg/kg,ip.)。+
p<0.05;++
p<0.01;+++
p<0.001。
圖4說明化合物實施例26之位置識別試驗的結果。描述花在Y形迷宮的新奇[N]對熟悉[O]臂之探索時間)。Scop:莨菪鹼(1 mg/kg,ip.)。+
p<0.05;++
p<0.01;+++
p<0.001。
圖5說明化合物實施例41之位置識別試驗的結果。描述花在Y形迷宮的新奇[N]對熟悉[O]臂之探索時間)。Scop:莨菪鹼(1 mg/kg,ip.)。+
p<0.05;++
p<0.01;+++
p<0.001。
圖6說明化合物實施例43之位置識別試驗的結果。描述花在Y形迷宮的新奇[N]對熟悉[O]臂之探索時間)。Scop:莨菪鹼(1 mg/kg,ip.)。+
p<0.05;++
p<0.01;+++
p<0.001。
圖7說明化合物實施例52之位置識別試驗的結果。描述花在Y形迷宮的新奇[N]對熟悉[O]臂之探索時間)。Scop:莨菪鹼(1 mg/kg,ip.)。+
p<0.05;++
p<0.01;+++
p<0.001。
圖8說明化合物實施例61之位置識別試驗的結果。描述花在Y形迷宮的新奇[N]對熟悉[O]臂之探索時間)。Scop:莨菪鹼(1 mg/kg,ip.)。+
p<0.05;++
p<0.01;+++
p<0.001。
Claims (24)
- 根據申請專利範圍第1或4項中任一項之化合物,其係選自下列群組: 6'-氟-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; 6-氯-N-[(1-甲基-1H-吲哚-5-基)甲基]-4-側氧基-3,4-二氫螺[1-苯并哌喃-2,4'-哌啶]-1'-甲醯胺; 6'-氯-N-[(1-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; 7'-氟-N-[(1-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; N-[(1-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; 6-氯-N-[(1-甲基-1H-吲哚-5-基)甲基]-3,4-二氫螺[1]-苯并哌喃-2,4'-哌啶]-1'-甲醯胺; N-[(3-氯-1-甲基-1H-吲哚-5-基)甲基]-6'-氟-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; 6'-氯-N-[(1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; 6'-氟-N-[(1-甲基-1H-吲哚-5-基)甲基]-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; 6'-氟-N-[(1-甲基-1H-吲哚-5-基)甲基]螺[吖呾-3,2'-𠳭唏]-1-甲醯胺; N-[(1-甲基-1H-吲哚-5-基)甲基]-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; 6'-氯-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; 6',8'-二氟-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; 7'-氯-N-[(2-氯-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; 7'-氯-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; 7'-氟-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-6'-(三氟甲基)-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; N-[(1-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-7'-(三氟甲基)-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-7'-(三氟甲基)-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; 6',8'-二氯-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; 7'-氟-4'-側氧基-N-{[2-(三氟甲基)-1H-吲哚-5-基]甲基}-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; N-{[2-(二氟甲基)-1H-吲哚-5-基]甲基}-7'-氟-4'-側氧基-3',4'-二氫螺[吖呾-3,2'-[1]苯并哌喃]-1-甲醯胺; 或其醫藥上可接受的鹽、生物活性代謝物、前驅藥、外消旋物、鏡像異構物、非鏡像異構物、溶劑合物和水合物。
- 根據申請專利範圍第1至5項中任一項之化合物,其用於治療或預防與α7菸鹼乙醯膽鹼受體活性相關的疾病。
- 根據申請專利範圍第6項之化合物,其中該疾病係選自下列群組:精神病症(包括但不限於思覺失調症、類思覺失調症、情感思覺失調症、妄想症、短暫精神病症、一般醫學狀況誘發之精神病症、物質誘發之精神病症或未注明之精神病症)、認知損傷(包括但不限於由於下列引起的認知損傷:中風、阿茲海默症、亨汀頓氏症、匹克症、與HIV相關失智症、額顳葉失智症、路易氏體失智症、血管型失智症、腦血管疾病或其他失智症狀態及與其他退化型疾病(包括但不限於肌肉萎縮性脊髓側索硬化症)相關的失智症、其他可引起認知衰退的急性或亞急性病況(包括但不限於譫妄、外傷性腦損傷、老年失智症、輕度認知損傷、唐氏症、憂鬱和與其他疾病相關的認知缺陷)、及運動障礙(包括但不限於帕金森氏病症、精神抑制劑誘發之帕金森病、或遲發性運動障礙)、憂鬱和情感症(包括但不限於憂鬱和發作、躁鬱症、循環型情感症和未注明之躁鬱症、其他情感症、物質誘發之情感症和未注明之情感症、焦慮症、恐慌症和恐慌發作、強迫症、創傷後壓力症、急性壓力症、廣泛性焦慮症、一般醫學狀況誘發之焦慮症、物質誘發之焦慮症、恐懼症和未注明之焦慮症)、與物質相關病症(包括但不限於物質使用或物質誘發之病症(包括但不限於酒精-、菸鹼-、安非他命-、苯環己哌啶-、類鴉片-、大麻-、古柯鹼-、咖啡因-、迷幻劑-、吸入劑-、鎮靜劑-、安眠藥-、抗焦慮藥-、多物質-或其他物質-相關疾病)、睡眠障礙(包括但不限於嗜睡症、睡眠異常、原發型嗜睡症、與呼吸相關的睡眠障礙、晝夜節律性睡眠障礙和未注明之睡眠異常、異睡症、睡眠驚恐障礙、夢遊症和未注明之異睡症(parasomnia)、與另一種神精神障礙相關的睡眠障礙、一般醫學狀況誘發之睡眠障礙和物質誘發之睡眠障礙)、代謝和飲食障礙(包括但不限於神經性厭食症、神經性暴食症、肥胖症、強迫性飲食障礙、暴食症和未注明之飲食障礙)、糖尿病、潰瘍性結腸炎、克隆氏病、腸躁症候群、泛自閉症障礙(包括但不限於自閉症、亞斯伯格症、雷特氏症、兒童期崩解症和其他未注明之廣泛性發展障礙)、注意力缺陷過動症、破壞性行為障礙、對立性反抗症和未注明之破壞性行為障礙、及抽動障礙(包括但不限於妥瑞症)、人格障礙、性功能障礙(諸如性慾障礙、性興奮障礙、性高潮障礙、性疼痛障礙、未注明之性功能障礙)、性倒錯、性別認同障礙、不孕症、經前症候群和未注明之性功能障礙、呼吸系統之病症(如咳嗽、哮喘、慢性阻塞性肺臟疾病、肺部炎症)、心血管系統之病症(諸如心臟衰竭、心律不整、高血壓)、炎症、炎性和神經性疼痛、類風濕性關節炎、骨關節炎、過敏、類肉瘤病、牛皮癬、失調症、肌肉緊張不足、全身性紅斑狼瘡、躁狂症、不寧腿症候群、進行性核上性麻痺、癲癇、肌陣攣、偏頭痛、健忘症、慢性疲勞症候群、猝倒症、腦缺血、多發性硬化症、腦脊髓炎、時差、大腦類澱粉血管病變和敗血症。
- 根據申請專利範圍第7項之化合物,其中該疾病係選自下列群組:認知損傷、思覺失調症、和自閉症。
- 一種根據申請專利範圍第1至5項中任一項之化合物之用途,其係用於製造供治療或預防與α7菸鹼乙醯膽鹼受體活性相關的疾病之藥物。
- 根據申請專利範圍第9項之用途,其中該疾病係選自下列群組:精神病症(包括但不限於思覺失調症、類思覺失調症、情感思覺失調症、妄想症、短暫精神病症、一般醫學狀況誘發之精神病症、物質誘發之精神病症或未注明之精神病症)、認知損傷(包括但不限於由於下列引起的認知損傷:中風、阿茲海默症、亨汀頓氏症、匹克症、與HIV相關失智症、額顳葉失智症、路易氏體失智症、血管型失智症、腦血管疾病或其他失智症狀態及與其他退化型疾病(包括但不限於肌肉萎縮性脊髓側索硬化症)相關的失智症、其他可引起認知衰退的急性或亞急性病況(包括但不限於譫妄、外傷性腦損傷、老年失智症、輕度認知損傷、唐氏症、憂鬱和與其他疾病相關的認知缺陷)、及運動障礙(包括但不限於帕金森氏病症、精神抑制劑誘發之帕金森病、或遲發性運動障礙)、憂鬱和情感症(包括但不限於憂鬱和發作、躁鬱症、循環型情感症和未注明之躁鬱症、其他情感症、物質誘發之情感症和未注明之情感症、焦慮症、恐慌症和恐慌發作、強迫症、創傷後壓力症、急性壓力症、廣泛性焦慮症、一般醫學狀況誘發之焦慮症、物質誘發之焦慮症、恐懼症和未注明之焦慮症)、與物質相關病症(包括但不限於物質使用或物質誘發之病症(包括但不限於酒精-、菸鹼-、安非他命-、苯環己哌啶-、類鴉片-、大麻-、古柯鹼-、咖啡因-、迷幻劑-、吸入劑-、鎮靜劑-、安眠藥-、抗焦慮藥-、多物質-或其他物質-相關疾病)、睡眠障礙(包括但不限於嗜睡症、睡眠異常、原發型嗜睡症、與呼吸相關的睡眠障礙、晝夜節律性睡眠障礙和未注明之睡眠異常、異睡症、睡眠驚恐障礙、夢遊症和未注明之異睡症(parasomnia)、與另一種神精神障礙相關的睡眠障礙、一般醫學狀況誘發之睡眠障礙和物質誘發之睡眠障礙)、代謝和飲食障礙(包括但不限於神經性厭食症、神經性暴食症、肥胖症、強迫性飲食障礙、暴食症和未注明之飲食障礙)、糖尿病、潰瘍性結腸炎、克隆氏病、腸躁症候群、泛自閉症障礙(包括但不限於自閉症、亞斯伯格症、雷特氏症、兒童期崩解症和其他未注明之廣泛性發展障礙)、注意力缺陷過動症、破壞性行為障礙、對立性反抗症和未注明之破壞性行為障礙、及抽動障礙(包括但不限於妥瑞症)、人格障礙、性功能障礙(諸如性慾障礙、性興奮障礙、性高潮障礙、性疼痛障礙、未注明之性功能障礙)、性倒錯、性別認同障礙、不孕症、經前症候群和未注明之性功能障礙、呼吸系統之病症(如咳嗽、哮喘、慢性阻塞性肺臟疾病、肺部炎症)、心血管系統之病症(諸如心臟衰竭、心律不整、高血壓)、炎症、炎性和神經性疼痛、類風濕性關節炎、骨關節炎、過敏、類肉瘤病、牛皮癬、失調症、肌肉緊張不足、全身性紅斑狼瘡、躁狂症、不寧腿症候群、進行性核上性麻痺、癲癇、肌陣攣、偏頭痛、健忘症、慢性疲勞症候群、猝倒症、腦缺血、多發性硬化症、腦脊髓炎、時差、大腦類澱粉血管病變和敗血症。
- 根據申請專利範圍第10項之用途,其中疾病為認知損傷、思覺失調症、或自閉症。
- 一種治療或預防與α7菸鹼乙醯膽鹼受體活性相關的疾病之方法,其包含將有效量的至少一種根據申請專利範圍第1至5項中任一項之化合物投予至需要該治療或預防的哺乳動物。
- 根據申請專利範圍第12項之方法,其中該疾病係選自下列群組:精神病症(包括但不限於思覺失調症、類思覺失調症、情感思覺失調症、妄想症、短暫精神病症、一般醫學狀況誘發之精神病症、物質誘發之精神病症或未注明之精神病症)、認知損傷(包括但不限於由於下列引起的認知損傷:中風、阿茲海默症、亨汀頓氏症、匹克症、與HIV相關失智症、額顳葉失智症、路易氏體失智症、血管型失智症、腦血管疾病或其他失智症狀態及與其他退化型疾病(包括但不限於肌肉萎縮性脊髓側索硬化症)相關的失智症、其他可引起認知衰退的急性或亞急性病況(包括但不限於譫妄、外傷性腦損傷、老年失智症、輕度認知損傷、唐氏症、憂鬱和與其他疾病相關的認知缺陷)、及運動障礙(包括但不限於帕金森氏病症、精神抑制劑誘發之帕金森病、或遲發性運動障礙)、憂鬱和情感症(包括但不限於憂鬱和發作、躁鬱症、循環型情感症和未注明之躁鬱症、其他情感症、物質誘發之情感症和未注明之情感症、焦慮症、恐慌症和恐慌發作、強迫症、創傷後壓力症、急性壓力症、廣泛性焦慮症、一般醫學狀況誘發之焦慮症、物質誘發之焦慮症、恐懼症和未注明之焦慮症)、與物質相關病症(包括但不限於物質使用或物質誘發之病症(包括但不限於酒精-、菸鹼-、安非他命-、苯環己哌啶-、類鴉片-、大麻-、古柯鹼-、咖啡因-、迷幻劑-、吸入劑-、鎮靜劑-、安眠藥-、抗焦慮藥-、多物質-或其他物質-相關疾病)、睡眠障礙(包括但不限於嗜睡症、睡眠異常、原發型嗜睡症、與呼吸相關的睡眠障礙、晝夜節律性睡眠障礙和未注明之睡眠異常、異睡症、睡眠驚恐障礙、夢遊症和未注明之異睡症(parasomnia)、與另一種神精神障礙相關的睡眠障礙、一般醫學狀況誘發之睡眠障礙和物質誘發之睡眠障礙)、代謝和飲食障礙(包括但不限於神經性厭食症、神經性暴食症、肥胖症、強迫性飲食障礙、暴食症和未注明之飲食障礙)、糖尿病、潰瘍性結腸炎、克隆氏病、腸躁症候群、泛自閉症障礙(包括但不限於自閉症、亞斯伯格症、雷特氏症、兒童期崩解症和其他未注明之廣泛性發展障礙)、注意力缺陷過動症、破壞性行為障礙、對立性反抗症和未注明之破壞性行為障礙、及抽動障礙(包括但不限於妥瑞症)、人格障礙、性功能障礙(諸如性慾障礙、性興奮障礙、性高潮障礙、性疼痛障礙、未注明之性功能障礙)、性倒錯、性別認同障礙、不孕症、經前症候群和未注明之性功能障礙、呼吸系統之病症(如咳嗽、哮喘、慢性阻塞性肺臟疾病、肺部炎症)、心血管系統之病症(諸如心臟衰竭、心律不整、高血壓)、炎症、炎性和神經性疼痛、類風濕性關節炎、骨關節炎、過敏、類肉瘤病、牛皮癬、失調症、肌肉緊張不足、全身性紅斑狼瘡、躁狂症、不寧腿症候群、進行性核上性麻痺、癲癇、肌陣攣、偏頭痛、健忘症、慢性疲勞症候群、猝倒症、腦缺血、多發性硬化症、腦脊髓炎、時差、大腦類澱粉血管病變和敗血症。
- 根據申請專利範圍第13項之方法,其中該疾病係選自下列群組:認知損傷、思覺失調症、和自閉症。
- 一種醫藥組成物,其包含作為活性成分之根據申請專利範圍第1至5項中任一項之化合物和至少一種醫藥上可接受的賦形劑。
- 根據申請專利範圍第15項之醫藥組成物,其中該組成物另外包含至少一種其他活性成分。
- 根據申請專利範圍第16項之醫藥組成物,其中該其他活性成分係選自下列群組:乙醯膽鹼酯酶抑制劑、NMDA受體拮抗劑、β-分泌酶抑制劑、抗精神病藥、GABAA 受體α5次單元NAM或PAM、組織胺H3 受體拮抗劑、5-HT6 受體拮抗劑、M1或M4 mAChR促效劑或PAM、mGluR2拮抗劑或NAM或PAM、和左旋多巴。
- 一種根據申請專利範圍第1至5項中任一項之化合物與至少一種其他活性成分的組合,其用於治療或預防與α7菸鹼乙醯膽鹼受體活性相關的疾病。
- 根據申請專利範圍第18項之組合,其中該其他活性成分係選自下列群組:乙醯膽鹼酯酶抑制劑、NMDA受體拮抗劑、β-分泌酶抑制劑、抗精神病藥、GABAA 受體α5次單元NAM或PAM、組織胺H3 受體拮抗劑、5-HT6 受體拮抗劑、M1或M4 mAChR促效劑或PAM、mGluR2拮抗劑或NAM或PAM、和左旋多巴。
- 一種製備根據申請專利範圍第3項之式(II)化合物之方法,其特徵在於使一種式(III)化合物與一種式(IV)化合物反應,該反應或以二步驟經由式(VII)或直接以一步驟進行以提供一種式(V)化合物, - 其中R3 的意義係如上對於式(II)化合物所述, - 其中n和m的意義係如上對於式(II)化合物所述, - 其中n和m的意義係如上對於式(II)化合物所述, - 其中R3 、n和m的意義係如上對於式(II)所述, 接著使式(V)化合物與 a.) 氯化氫反應以提供式(VI), - 其中R3 、n和m的意義係如上對於式(II)所述,或與 b.) 錯合氫化物反應以提供式(VIII), - 其中R3 、n和m的意義係如上對於式(II)所述,接著用三乙膦將式(VIII)化合物還原以提供式(IX), - 其中R3 、n和m的意義係如上對於式(II)所述, 接著使所得式(IX)或式(VI)衍生物與式(X)反應,而提供式(II), - 其中R1a 、R1b 、R1c 、V和Z的意義係如上對於式(II)所述, - 其中R1a 、R1b 、R1c 、R2 、R3 、V、Z、n、m、和W的意義係如上對於式(II)所述。
- 一種{1,2-二甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺之化合物。
- 一種{3-氯-1-甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺之化合物。
- 一種{3-溴-1-甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺之化合物。
- 一種3',4'-二氫螺[吖呾-3,2'-哌喃并[3,2-b]吡啶]-4'-酮鹽酸鹽之化合物。
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