TW201819377A - 新穎萘啶酮衍生物及其於心律不整之治療的用途 - Google Patents
新穎萘啶酮衍生物及其於心律不整之治療的用途 Download PDFInfo
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- TW201819377A TW201819377A TW106135836A TW106135836A TW201819377A TW 201819377 A TW201819377 A TW 201819377A TW 106135836 A TW106135836 A TW 106135836A TW 106135836 A TW106135836 A TW 106135836A TW 201819377 A TW201819377 A TW 201819377A
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- chloro
- naphthyridin
- dichlorophenyl
- methyl
- alkyl
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000001515 vagal effect Effects 0.000 description 1
- 229960001254 vildagliptin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940019333 vitamin k antagonists Drugs 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229950000339 xinafoate Drugs 0.000 description 1
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Abstract
Description
本發明提供萘啶酮化合物、其用於抑制GIRK 1/4通道之用途及使用其治療疾病之方法。
正常心週期開始於竇房結,其產生在整個心房及心室心肌中以有序方式形式傳播之興奮性電刺激以誘導收縮(心收縮)。在細胞水準下,興奮性電脈衝觸發心臟動作電位。此特徵在於初始、迅速的膜去極化,接著為平台期且隨後再極化以返回至靜息膜電位。心臟動作電位控制貫穿心臟之信號傳播。舉例而言,初始細胞去極化之速率確定興奮性刺激傳播之速度。再極化期之持續時間確定動作電位持續時間(APD)及不反應期,或心肌細胞不能對另一電刺激起反應之時間。 心臟動作電位之異常與心律不整有關。舉例而言,動作電位持續時間及相關不反應期之過度降低可對所謂的重入快速性心律失常提供基底。在此情況下,心臟脈衝經由易興奮組織回饋於自身以形成凹腔電路,而非正常傳播(Waldo及Wit, 1993. Mechanism of cardiac arrhythmias. Lancet341
, 1189-1193)。認為現有III類抗心律不整藥物藉由延長APD及相關有效不反應期(ERP)來起作用,藉此最小化再興奮以及隨後形成顫動性再入電路之風險(Singh B.N.及Vaughan Williams, E.M., 1970. A third class of anti-arrhythmic action. Effects on atrial and ventricular intracellular potentials, and other pharmacological actions on cardiac muscle, of MJ 1999 and AH3474. British Journal of pharmacology 39, 675-687)。 某些III類抗心律不整藥物藥物(例如索他洛爾(sotalol))用於治療心房震顫(AF)。AF為人類中持續心律不整之最常見形式,且其特徵在於損害心房功能之顫動性收縮。AF與不利的心臟血管事件相關。特定言之,AF之存在係血栓栓塞中風、心臟衰竭及總死亡率之獨立風險因素(Estes等人, (2008). Journal of the American College of Cardiology51
, 865-884) (Fang等人, 2008. Comparison of risk stratification schemes to predict thromboembolism in people with nonvalvular atrial fibrillation. Journal of the American College of Cardiology51
, 810-815)。AF亦可藉由誘導心悸及減少運動耐量降低一些患者之生活品質(Thrall等人, 2006. Quality of life in patients with atrial fibrillation: a systematic review. The American journal of medicine119
, 448. e441-419)。針對AF之抗心律不整療法的目標為避免此等不利影響及最終結果。 現有III類抗心律不整藥物之缺點為其起作用而延長心房及心室兩者中之有效不反應期。心室組織中之過度延長使QTc間期延長且可為促心律不整的,且已知具有此作用機制之某些藥物(例如多非利特(dofetilide))誘導潛在危及生命之心室心律不整,諸如扭轉型心動過速(Torsades de Pointes) (Redfern等人, 2003. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovascular research58
, 32-45)。由此需要針對AF之新穎抗心律不整療法,其組織選擇性地靶向心房且不靶向心室。 在細胞水準下藉由多個不同的跨膜離子通道控制心臟動作電位之組態及持續時間。舉例而言,初始去極化期藉由經由心臟特異性Nav
1.5通道之鈉離子流入來介導。鉀通道負責之後的再極化期,且由此幫助調節動作電位之總持續時間。實際上,靶向鉀通道之III類抗心律不整藥物(例如多非利特)延長動作電位持續時間及有效不反應期兩者。存在數種不同種類之跨膜鉀通道(Schmitt等人, 2014. Cardiac potassium channel subtypes: new roles in repolarization and arrhythmia. Physiological reviews94
, 609-653;Tamargo等人, 2004. Pharmacology of cardiac potassium channels. Cardiovascular research62
, 9-33),包括: · 電壓閘控通道(Kv1-9) · 鈣活化通道(KCa1-2) · 串聯孔結構域通道(例如TASK) · 內向性整流通道(Kir1-6) 雖然大多數心臟鉀通道促進人類心房及心室組織兩者中之再極化,但認為兩者-Kv
1.5及GIRK1/4 (亦即經G蛋白調節之內向性整流鉀通道1/4)-僅表現於心室中(Gaborit等人, 2007. Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart. The Journal of physiology582
, 675-693)。此表現之心房特異性模式使此等通道為針對AF之新穎抗心律不整療法之尤其有吸引力的靶標,因為其不應具有現有III類藥物諸如多非利特之不利的心室作用。 哺乳動物表現四種不同的GIRK通道(GIRK 1、2、3及4;分別由KCNJ3 、 KCNJ6 、 KCNJ9
及KCNJ5
編碼)。此等跨膜蛋白以四聚體(同四聚體或雜四聚體)排列以形成功能性鉀通道(Krapivinsky等人, 1995. The G-protein-gated atrial K+channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins. Nature374
, 135-141)。此等通道係配體閘控的(亦即藉由配體與相同細胞膜中存在之Gi-蛋白偶聯受體之結合來調節)。舉例而言,GIRK1/4通道係很大程度上表現於竇房結及房室結以及心房心肌中之雜四聚體(兩個次單元各自為GIRK1及GIRK4) (Wickman等人, 1999. Structure, G protein activation, and functional relevance of the cardiac G protein-gated K+channel, IKACh. Annals of the New York Academy of Sciences868
, 386-398)。此通道之一個功能為介導心跳速率之自主調節。在對心臟迷走神經傳出神經元進行之副交感神經刺激時釋放之乙醯膽鹼與心臟中之Gi-偶聯M2蕈毒鹼受體結合。此釋放Gβγ次單元,其繼而打開GIRK1/4通道以允許鉀自心肌細胞流出且因此促進膜再極化。在竇房結之自發去極化起搏細胞中,此再極化之幅度規定再極化之間的時序,且從而規定心跳速率。由於其藉由乙醯膽鹼來調節,因此藉由GIRK1/4通道介導之電流稱為I KAch
(Wickman等人, 1999)。 數條證據指出GIRK1/4為針對AF之所需抗心律不整靶標。在動物中,迷走神經之神經刺激促進乙醯膽鹼自迷走神經傳入釋放及I KAch
增加。此繼而縮短心房(但非心室)動作電位持續時間及有效不反應期,且可經由再入機制誘導AF (Hashimoto等人, 2006. Tertiapin, a selective IKACh blocker, terminates atrial fibrillation with selective atrial effective refractory period prolongation. Pharmacological research: the official journal of the Italian Pharmacological Society54
, 136-141)。在來自患有持續AF之人類以及來自患有心房快速起搏(一種促進電重塑及對AF之易感性之公認模式)之動物的心房組織中,已顯示I KAch
為失調的。具體言之,通道傾向於甚至在不存在乙醯膽鹼之情況下組成性地打開(Cha等人, 2006. Kir3-based inward rectifier potassium current: potential role in atrial tachycardia remodeling effects on atrial repolarization and arrhythmias. Circulation113
, 1730-1737;Voigt等人, 2014. Constitutive activity of the acetylcholine-activated potassium current IK,ACh in cardiomyocytes. Advances in pharmacology (San Diego, Calif)70
, 393-409)。在此等研究中,在患者及動物中觀測到心房APD/ERP係短暫的。 由此,研發GIRK1/4阻斷劑將有益於治療諸如心房震顫之心律不整。
仍需要針對心律不整之新的治療及療法。本發明提供化合物、其醫藥學上可接受之鹽、其醫藥組合物及其組合,該等化合物為GIRK1/4通道阻斷劑。本發明進一步提供治療、預防或改善心律不整、心房震顫、原發性高醛固酮症、高血壓及/或心房腔失調症候群之方法,該等方法包含向有需要之個體投與有效量之GIRK1/4通道阻斷劑。 在本文中描述本發明之各種實施例。 在某些態樣內,本文提供式I化合物;其中:X2
為CR2
或N;X3
為CH或N;R1
為C1-4
烷基、-CH2
CN、-CN、C1-4
烷氧基C1-4
烷基、鹵基-C1-4
烷基、-CH=N-OH、-CH=N-O-C1-4
烷基、-CH=N-O-(羥基C1-4
烷基)、羥基-C1-4
烷基、-CH2
OP(O)(OH)2
或C3-5
環烷基;R3
為-ORa
;-NHRb
;-C(O)NH2
;-C(O)[羥基C1-4
烷基];視情況經一或多個獨立地選自OH及羥基C1-4
烷基之取代基取代之雜環基;視情況經一或多個C1-4
烷基取代之5員或6員環雜芳基;或R3
為經一或多個獨立地選自-C(O)[羥基C1-4
烷基]及-ORc
之取代基取代之C1-4
烷基;Ra
為經一或多個獨立地選自以下之取代基取代之-C1-6
烷基:-ORc
、-SO2
C1-4
烷基、-NHS(O)2
C1-4
烷基及進一步視情況經一或多個獨立地選自C1-4
烷基或羥基C1-4
烷基之取代基取代之雜環基;或Ra
為H、-[CH2
-CH2
-O]n
-H、-[CH2
-CH2
-O]m
-CH3
或視情況經一或多個C1-4
烷基取代之雜芳基;其中n為2-6且m為1-6;Rb
為經一或多個獨立地選自以下之取代基取代之-C1-6
烷基:-ORc
、-C(O)NH-C1-4
烷基、-C(O)NH-(羥基C1-4
烷基)、羥基C1-4
烷基、5員或6員雜芳基、雜環基、-SO2
C1-4
烷基及-NHS(O)2
C1-4
烷基;或Rb
為-S(O)2
雜芳基;或Rb
為視情況經一或多個羥基取代之4員至7員雜環基;或Rb
為H、-ORc
、-[CH2
-CH2
-O]n
-H、-[CH2
-CH2
-O]m
-CH3
或視情況經一或多個C1-4
烷基取代之雜芳基;其中n及m如先前所定義;Rc
為H或羥基C1-4
烷基;R2
為H、C1-4
烷氧基、鹵基-C1-4
烷氧基、鹵基、C1-4
烷基、-S-C1-4
烷基或-NH-C1-4
烷基;R4
為H、鹵基、鹵基-C1-4
烷基、C1-4
烷基、C3-5
環烷基;R5
為H、鹵基、CN、C1-4
烷氧基、羥基-C1-4
烷氧基、C1-4
烷氧基-C1-4
烷氧基、-CH=NH-O-C1-4
烷基、-CH=NH-O(羥基C1-4
烷基);或R5
為視情況經OH或NRg
Rh
取代之C2-6
炔基,其中Rg
及Rh
獨立地為H或C1-4
烷基;或Rg
及Rh
與其所連接之氮一起形成視情況含有選自O、S或N之額外雜原子的4員至7員雜環基,其中該雜原子可呈其氧化形式;且其中該雜環基視情況經C1-4
烷基取代;R6
為鹵基、C1-4
烷基或CN;或其醫藥學上可接受之鹽。 在另一實施例中,本發明提供一種醫藥組合物,其包含治療有效量之根據式(I)定義之化合物、或其醫藥學上可接受之鹽、或其子式II或III及一或多種醫藥學上可接受之載劑。 在另一實施例中,本發明提供一種組合,尤其一種醫藥組合,其包含治療有效量之根據式(I)定義之化合物、或其醫藥學上可接受之鹽、或其子式II或III及一或多種治療活性劑。
在實施例1中,本發明因此提供式(I)化合物:其中:X2
為CR2
或N;X3
為CH或N;R1
為C1-4
烷基、-CH2
CN、-CN、C1-4
烷氧基C1-4
烷基、鹵基-C1-4
烷基、-CH=N-OH、-CH=N-O-C1-4
烷基、-CH=N-O-(羥基C1-4
烷基)、羥基-C1-4
烷基、-CH2
OP(O)(OH)2
或C3-5
環烷基;R3
為-ORa
;-NHRb
;-C(O)NH2
;-C(O)[羥基C1-4
烷基];視情況經一或多個獨立地選自OH及羥基C1-4
烷基之取代基取代之雜環基;視情況經一或多個C1-4
烷基取代之5員或6員環雜芳基;或R3
為經一或多個獨立地選自-C(O)[羥基C1-4
烷基]及-ORc
之取代基取代之C1-4
烷基;Ra
為經一或多個獨立地選自以下之取代基取代之-C1-6
烷基:-ORc
、-SO2
C1-4
烷基、-NHS(O)2
C1-4
烷基及進一步視情況經一或多個獨立地選自C1-4
烷基或羥基C1-4
烷基之取代基取代之雜環基;或Ra
為H、-[CH2
-CH2
-O]n
-H、-[CH2
-CH2
-O]m
-CH3
或視情況經一或多個C1-4
烷基取代之雜芳基;其中n為2-6且m為1-6;Rb
為經一或多個獨立地選自以下之取代基取代之-C1-6
烷基:-ORc
、-C(O)NH-C1-4
烷基、-C(O)NH-(羥基C1-4
烷基)、羥基C1-4
烷基、5員或6員雜芳基、雜環基、-SO2
C1-4
烷基及-NHS(O)2
C1-4
烷基;或Rb
為-S(O)2
雜芳基;或Rb
為視情況經一或多個羥基取代之4員至7員雜環基;或Rb
為H、-ORc
、-[CH2
-CH2
-O]n
-H、-[CH2
-CH2
-O]m
-CH3
或視情況經一或多個C1-4
烷基取代之雜芳基;其中n及m如先前所定義;Rc
為H或羥基C1-4
烷基;R2
為H、C1-4
烷氧基、鹵基-C1-4
烷氧基、鹵基、C1-4
烷基、-S-C1-4
烷基或-NH-C1-4
烷基;R4
為H、鹵基、鹵基-C1-4
烷基、C1-4
烷基、C3-5
環烷基;R5
為H、鹵基、CN、C1-4
烷氧基、羥基-C1-4
烷氧基、C1-4
烷氧基-C1-4
烷氧基、-CH=NH-O-C1-4
烷基、-CH=NH-O(羥基C1-4
烷基);或R5
為視情況經OH或NRg
Rh
取代之C2-6
炔基,其中Rg
及Rh
獨立地為H或C1-4
烷基;或Rg
及Rh
與其所連接之氮一起形成視情況含有選自O、S或N之額外雜原子的4員至7員雜環基,其中該雜原子可呈其氧化形式;且其中該雜環基視情況經C1-4
烷基取代;R6
為鹵基、C1-4
烷基或CN;或其醫藥學上可接受之鹽。 除非另外規定,否則術語「本發明化合物(compounds of the present invention/compounds of the invention)」係指式(I)及其子式II或III之化合物及其鹽以及所有立體異構體(包括非對映異構體及對映異構體)、旋轉異構體、互變異構體及同位素標記化合物(包括氘取代物)以及固有形成部分。 出於解釋本說明書之目的,除非另外規定且在適當情況下,否則以下定義將適用,以單數形式使用之術語亦將包括複數且反之亦然。 必須注意,除非上下文另外明確說明,否則如本文及隨附申請專利範圍所使用,單數形式「一(a/an)」及「該(the)」包括複數個參照物。因此,舉例而言,提及「該化合物」包括提及一或多種化合物;等等。 術語「烷基」係指完全飽和分支鏈或非分支鏈(或直鏈或線性)烴部分,其包含1至6個碳原子。較佳地,烷基包含1至4個碳原子。C1-4
烷基係指包含1至4個碳之烷基鏈。C1-6
烷基係指包含1至6個碳之烷基鏈。 如本文所使用,術語「鹵烷基」(亦即鹵基-C1-4
烷基)係指經一或多個如本文所定義之鹵基取代之如本文所定義之烷基(亦即C1-4
烷基)。較佳地,鹵烷基可為單鹵烷基、二鹵烷基或多鹵烷基,包括全鹵烷基。單鹵烷基可在烷基內具有一個碘基、溴基、氯基或氟基。二鹵烷基及多鹵烷基可在烷基內具有兩個或更多個相同鹵原子或不同鹵基之組合。較佳地,多鹵烷基含有至多12個,或10個,或8個,或6個,或4個,或3個,或2個鹵基。鹵烷基之的代表性實例為氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基及二氯丙基。術語「鹵基-C1-4
烷基」係指具有一至四個碳原子且經一或多個鹵基取代之烴。 如本文所使用,術語「羥基烷基」(亦即羥基-C1-4
烷基)係指經如本文所定義之一或多個羥基取代之如本文所定義之烷基(亦即C1-4
烷基)。 如本文所使用,術語「烷氧基烷基」(亦即C1-4
烷氧基C1-4
烷基)係指經一或多個如本文所定義之烷氧基(亦即C1-4
烷氧基)取代之本文所定義之烷基(亦即C1-4
烷基)其。 如本文所使用,術語「烷氧基」(亦即係指基團烷基-O-,其中烷基為上文所定義。烷氧基之代表性實例包括(但不限於)甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、第三丁氧基、戊氧基、己氧基、環丙氧基-、環己氧基-及其類似基團。較佳地,烷氧基具有約1-8個、更佳約1-4個碳。 如本文所使用,術語「鹵代烷氧基」(亦即鹵基-C1-4
烷氧基)係指經一或多個如本文所定義之鹵基取代之如本文所定義之烷氧基。 如本文所使用,術語「C3-5
環烷基」係指3-5個碳原子之飽和或不飽和(但非芳族)單環烴基。示例性的單環烴基包括環丙基、環丁基、環戊基或環戊烯基。 術語雜芳基包括單環雜芳基,其含有5或6個選自碳原子及1至4個雜原子之環成員,且各雜原子獨立地選自O、N或S,其中S及N可經氧化至各種氧化態。雜芳基可經由碳原子或雜原子(例如經由N)鍵結。典型單環雜芳基包括噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、異噻唑基、噁-2,3-二唑基、噁-2,4-二唑基、噁-2,5-二唑基、噁-3,4-二唑基、噻-2,3-二唑基、噻-2,4-二唑基、噻-2,5-二唑基、噻-3,4-二唑基、3-、4-或5-異噻唑基、2-、4-或5-噁唑基、3-、4-或5-異噁唑基、3-或5-1,2,4-三唑基、4-或5-1,2,3-三唑基、四唑基、2-、3-或4-吡啶基、3-或4-噠嗪基、3-、4-或5-吡嗪基、2-吡嗪基、2-、4-或5-嘧啶基。 如本文所使用且除非另外規定,否則術語「雜環基」係指視情況經取代之飽和或不飽和非芳族(部分不飽和)環,其為4員、5員、6員或7員單環且含有至少一個選自O、S及N之雜原子,其中N及S亦可視情況經氧化至各種氧化態。雜環基可經由碳原子或雜原子(例如N)鍵結。在一個實施例中,雜環基部分表示含有4至7個環原子及視情況含有另一選自O、S或N之雜原子的飽和單環。雜環基可連接雜原子或碳原子。雜環之實例包括二氫呋喃基、二氧戊環基、二氧雜環己烷基、二噻烷基、哌嗪基、吡咯啶、二氫哌喃基、氧硫雜環戊烷基、二硫雜環戊烷、氧硫雜環己烷基、硫代嗎啉基、環氧乙烷基、氮丙啶基、氧雜環丁烷基、氧雜環庚烷基、氮雜環丁烷基、四氫呋喃基、四氫噻吩基、吡咯啶基、四氫哌喃基、哌啶基、嗎啉基、哌嗪基、氮雜卓基(azepinyl)、氧雜卓基(oxapinyl)、氧氮雜環庚烷基、氧硫雜環己烷基、硫雜環庚基、氮雜環庚烷基、二氧雜環庚烷基及二氮雜環庚烷基。 本文描述本發明之各種(所列舉的)實施例。應認識到在各實施例中指定之特徵可與其他指定特徵組合,以提供本發明之其他實施例。 在實施例2中,本發明係關於如實施例2之化合物,其具有式II:; 或其醫藥學上可接受之鹽,其中R1
及R3
-R6
如實施例1中所定義。 在實施例3中,本發明係關於如實施例1之化合物,其具有式III:; 或其醫藥學上可接受之鹽,其中R1
-R6
如實施例1中所定義。 在實施例4中,本發明係關於如實施例1至3中任一項之化合物,其中R1
為CH3
、環丙基-CH2
OH或CH=NH-OH;或其醫藥學上可接受之鹽。 在實施例4A中,本發明係關於如實施例4之化合物,其中R1
為CH3
或-CH2
OH;或其醫藥學上可接受之鹽。 在實施例4B中,本發明係關於如實施例4之化合物,其中R1
為-CH2
OH;或其醫藥學上可接受之鹽。 在實施例5中,本發明係關於如實施例1、3、4、4A及4B中任一項之化合物,其中R2
為H或-NH-CH3
;或其醫藥學上可接受之鹽。 在實施例5A中,本發明係關於如實施例5之化合物,其中R2
為H;或其醫藥學上可接受之鹽。 在實施例6中,本發明係關於如實施例1至5、4A、4B及5A中任一項之化合物,其中R4
為H或鹵基;或其醫藥學上可接受之鹽。 在實施例6A中,本發明係關於如實施例6之化合物,其中R4
為Cl;或其醫藥學上可接受之鹽。 在實施例7中,本發明係關於如實施例1至6、4A、4B、5A及6A中任一項之化合物,其中R5
為H、F、CN、經OH或硫代嗎啉取代之C2-4
炔基;或其醫藥學上可接受之鹽。 在實施例7A中,本發明係關於如實施例7之化合物,其中R5
為H、F或CN;或其醫藥學上可接受之鹽。 在實施例8中,本發明係關於如實施例1至7、4A、4B、5A、6A及7A中任一項之化合物,其中R6
為Cl或CN;或其醫藥學上可接受之鹽。 在實施例8A中,本發明係關於如實施例7之化合物,其中R6
為Cl;或其醫藥學上可接受之鹽。 在實施例9中,本發明係關於如實施例1至8、4A、4B、5A、6A、7A及8A中任一項之化合物,其中R3
為羥基C1-6
烷基、羥基C1-6
烷氧基、-O-(CH2
CH2
-O)n
H、-O-(CH2
CH2
-O)m
CH3
、-NH-(CH2
CH2
O)n
H、-NH-(CH2
CH2
-O)m
CH3
、經羥基取代之氮雜環丁烷、經一或多個獨立地選自羥基及羥基C1-4
烷基之取代基取代之吡咯啶、或經羥基C1-4
烷基取代之哌嗪;或其醫藥學上可接受之鹽。 在實施例10中,本發明係關於如實施例1至8、4A、4B、5A、6A、7A及8A中任一項之化合物,其中R3
選自以下基團: ;或其醫藥學上可接受之鹽。 在實施例10A中,本發明係關於如實施例10之化合物,其中R3
選自以下基團:;或其醫藥學上可接受之鹽。 在實施例11中,本發明係關於如實施例10之化合物,其中R3
係選自:。 在實施例12中,本發明係關於式III化合物,其中R1
為CH3
或CH2
OH,R2
為H,R3
為-ORa
或-NHRb
,R4
為Cl,R5
為H或F且R6
為Cl;或其醫藥學上可接受之鹽。 在實施例13中,本發明係關於一種化合物,其選自由描述於下文實例1至93中之特定化合物組成之群;或其醫藥學上可接受之鹽。 在實施例13A中,本發明係關於一種化合物,其選自由以下各者組成之群: 8-氯-1-(2,6-二氯苯基)-2-(羥甲基)-5-((3-(羥甲基)氧雜環丁-3-基)甲氧基)-1,6-萘啶-4(1H)-酮; N-(2-((8-氯-1-(2,6-二氯苯基)-2-(羥甲基)-4-側氧基-1,4-二氫-1,6-萘啶-5-基)氧基)乙基)甲磺醯胺; 8-氯-1-(2,6-二氯苯基)-5-(3-羥基-2-(羥甲基)丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-2-(羥甲基)-5-((2-(甲基磺醯基)乙基)胺基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-4-側氧基-1,4-二氫-1,6-萘啶-2-甲腈; 8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基-3-甲基丁氧基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥丙基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(1,2-二羥乙基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮;及 8-氯-1-(2,6-二氯苯基)-5-(3,4-二羥丁基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮;或其醫藥學上可接受之鹽。 在實施例13B中,本發明係關於一種化合物,其選自由以下各者組成之群: (R)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基-3-甲基丁氧基)-2-甲基-1,6-萘啶-4(1H)-酮; (S)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基-3-甲基丁氧基)-2-甲基-1,6-萘啶-4(1H)-酮;及 8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基-3-甲基丁氧基)-2-甲基-1,6-萘啶-4(1H)-酮;或其醫藥學上可接受之鹽。 在實施例13C中,本發明係關於一種化合物,其選自由以下各者組成之群: (S)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; (R)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮;或其醫藥學上可接受之鹽。 在實施例13D中,本發明係關於一種化合物,其選自由以下各者組成之群: (R)-8-氯-1-(2,6-二氯苯基)-5-(3,4-二羥丁基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; (S)-8-氯-1-(2,6-二氯苯基)-5-(3,4-二羥丁基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮;及 8-氯-1-(2,6-二氯苯基)-5-(3,4-二羥丁基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮;或其醫藥學上可接受之鹽。 在實施例13E中,本發明係關於一種化合物,其選自由以下各者組成之群: (R)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥丙基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; (S)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥丙基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮;及 8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥丙基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮;或其醫藥學上可接受之鹽。 在實施例13F中,本發明係關於一種化合物,其選自由以下各者組成之群: (R)-8-氯-1-(2,6-二氯苯基)-5-(1,2-二羥乙基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; (S)-8-氯-1-(2,6-二氯苯基)-5-(1,2-二羥乙基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮;及 8-氯-1-(2,6-二氯苯基)-5-(1,2-二羥乙基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮;或其醫藥學上可接受之鹽。 在實施例14中,本發明為實例1之水合結晶形式B。 在實施例15中,本發明為實例1之水合結晶形式B,該水合結晶形式B藉由包含四個或更多個2θ值(CuKα λ=1.5418 Å)之x射線粉末繞射圖案表徵,該等值選自由以下各者組成之群:14.294±0.2°、18.666±0.2°、22.353±0.2°、24.878±0.2°、26.163±0.2°、27.106±0.2°、27.744±0.2°及28.228±0.2°,其在約22℃之溫度下且x射線波長λ為1.5418 Å下測量。 在實施例16中,本發明為實例1之水合結晶形式B,該水合結晶形式B藉由包含五個或更多個2θ值(CuKα λ=1.5418 Å)之x射線粉末繞射圖案表徵,該等值選自由以下各者組成之群:14.294±0.2°、18.666±0.2°、22.353±0.2°、24.878±0.2°、26.163±0.2°、27.106±0.2°、27.744±0.2°及28.228±0.2°,其在約22℃之溫度下且x射線波長λ為1.5418 Å下測量。 在實施例17中,本發明為實例1之水合結晶形式B,其具有與圖1中所示之X射線粉末繞射光譜實質上相同的X射線繞射光譜。 提及X射線繞射峰位置之術語「實質上相同」意謂考慮到典型的峰位置及強度變化。舉例而言,熟習此項技術者將瞭解峰位置(2Ө)將顯示某一裝置間變化,通常多達0.2°。偶爾,視裝置校準差異而定,變化可高於0.2°。此外,熟習此項技術者將瞭解相對峰強度將顯示裝置間變化以及歸因於結晶度、較佳定向、所製備之樣品表面及熟習此項技術者已知之其他因素之變化,且應僅視為定性量測。 在實施例18中,本發明為實例1之水合結晶形式B,其具有與圖2(使用針孔樣品盤)及圖3(使用密閉式樣品盤)中所示實質上相同的差示掃描熱量測定(DSC)熱分析圖。 在實施例19中,本發明為實例1之水合結晶形式B,其具與圖4中所示實質上相同的熱解重量分析(TGA)圖。 視起始材料及程序之選擇而定,化合物可視不對稱碳原子之數目而定,以可能的立體異構體中之一種的形式或作為其混合物存在,例如作為純光學異構體,或作為立體異構體混合物,諸如外消旋體與非對映異構體之混合物。本發明意謂包括所有該等可能的立體異構體,包括外消旋混合物、非對映異構混合物及光學純形式。光學活性(R
)-及(S
)-立體異構體可使用對掌性合成組元或對掌性試劑製備,或使用習知技術解析。若化合物含有雙鍵,則取代基可為E或Z組態。若化合物含有經雙取代之環烷基,則環烷基取代基可具有順式或反式組態。亦意欲包括所有互變異構形式。 如本文所使用,術語「鹽(salt/salts)」係指本發明化合物之酸加成鹽或鹼加成鹽。「鹽」尤其包括「醫藥學上可接受之鹽」。術語「醫藥學上可接受之鹽」係指保留本發明化合物的生物效用及特性且通常在生物學上或其他方面所需要的鹽。在許多情況下,本發明化合物能夠藉助於胺基及/或羧基或其類似基團之存在而形成酸鹽及/或鹼鹽。 醫藥學上可接受之酸加成鹽可用無機酸及有機酸形成。 可衍生出鹽之無機酸包括例如氫氯酸、氫溴酸、硫酸、硝酸、磷酸及其類似物。 可衍生出鹽之有機酸包括例如乙酸、丙酸、乙醇酸、草酸、順丁烯二酸、丙二酸、丁二酸、反丁烯二酸、酒石酸、檸檬酸、苯甲酸、杏仁酸、甲磺酸、乙磺酸、甲苯磺酸、磺基水楊酸及其類似物。 在另一個態樣中,本發明提供呈以下形式之式I化合物:乙酸鹽、抗壞血酸鹽、己二酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、溴化物/氫溴酸鹽、碳酸氫鹽/碳酸鹽、硫酸氫鹽/硫酸鹽、樟腦磺酸鹽、癸酸鹽、氯化物/鹽酸鹽、氯茶鹼鹽、檸檬酸鹽、乙二磺酸鹽、反丁烯二酸鹽、葡庚糖酸鹽、葡糖酸鹽、葡萄糖醛酸鹽、麩胺酸鹽、戊二酸鹽、羥乙酸鹽、馬尿酸鹽、氫碘酸鹽/碘化物、羥乙磺酸鹽、乳酸鹽、乳糖酸鹽、月桂基硫酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、杏仁酸鹽、甲磺酸鹽、甲基硫酸鹽、半乳糖二酸鹽、萘甲酸鹽、萘磺酸鹽、菸鹼酸鹽、硝酸鹽、十八酸鹽、油酸鹽、乙二酸鹽、棕櫚酸鹽、雙羥萘酸鹽、磷酸鹽/磷酸氫鹽/磷酸二氫鹽、聚半乳糖醛酸鹽、丙酸鹽、癸二酸鹽、硬脂酸鹽、丁二酸鹽、磺基水楊酸鹽、硫酸鹽、酒石酸鹽、甲苯磺酸鹽、三氟甲磺酸鹽、三氟乙酸鹽或羥萘甲酸鹽。 本文中給定之任何式亦意欲表示化合物之未經標記之形式以及經同位素標記之形式。經同位素標記之化合物具有由本文給出之式所描繪的結構,例外為一或多個原子由具有選定原子質量或質量數之原子置換。 可併入至本發明化合物中之同位素包括例如氫之同位素。 此外,用較重同位素,尤其氘(亦即2
H或D)取代可得到由較大代謝穩定性產生之某些治療優勢,例如活體內半衰期增加或劑量需求減少或治療指數或耐受性得到改善。應理解,在此情形下,將氘視為式(I)、(II)或(III)化合物之取代基。氘之濃度可由同位素增濃因數定義。如本文所使用之術語「同位素增濃因數」意謂指定同位素之同位素豐度與天然豐度之間的比率。若本發明化合物中之取代基標示為氘,則該化合物所具有的各指定氘原子之同位素增濃因數分別為至少3500 (在各指定氘原子處52.5%氘併入)、至少4000 (60%氘併入)、至少4500 (67.5%氘併入)、至少5000 (75%氘併入)、至少5500 (82.5%氘併入)、至少6000 (90%氘併入)、至少6333.3 (95%氘併入)、至少6466.7 (97%氘併入)、至少6600 (99%氘併入)或至少6633.3 (99.5%氘併入)。應理解,術語「同位素增濃因數」可以與對氘所描述相同之方式應用於任何同位素。 可併入本發明化合物中之同位素之其他實例包括氫、碳、氮、氧、磷、氟及氯之同位素,諸如分別為3
H、11
C、13
C、14
C、15
N、18
F、31
P、32
P、35
S、36
Cl、123
I、124
I、125
I。因此應理解,本發明包括併入任意前述同位素中之一或多者的化合物,該等同位素包括例如放射性同位素,諸如3
H及14
C;或存在非放射性同位素諸如2
H及13
C之化合物。此類經同位素標記之化合物適用於代謝研究(使用14
C);反應動力學研究(使用例如2
H或3
H);偵測或成像技術,諸如正電子發射斷層攝影法(PET)或單光子發射電腦斷層攝影法(SPECT),包括藥物或受質組織分佈分析;或適用於患者之放射性治療。特定言之,18
F或經標記之化合物可能對於PET或SPECT研究而言為尤其需要的。經同位素標記之式(I)化合物一般可藉由熟習此項技術者所已知之習知技術,或藉由與隨附實例及製備中所描述之彼等製程類似的製程,使用經適當同位素標記之試劑替代先前採用之未標記試劑來製備。 根據本發明之醫藥學上可接受之溶劑合物包括結晶之溶劑可經同位素取代之彼等溶劑合物,例如D2
O、d6
-丙酮、d6
-DMSO。 如本文所使用,術語「醫藥組合物」係指本發明化合物或其醫藥學上可接受之鹽以及至少一種醫藥學上可接受之載劑,其呈適合於口服或非經腸投藥之形式。 如本文所使用,術語「醫藥學上可接受之載劑」係指適用於製備或使用醫藥組合物之物質且包括例如如熟習此項技術者已知之適合之稀釋劑、溶劑、分散介質、界面活性劑、抗氧化劑、防腐劑、等滲劑、緩衝劑、乳化劑、吸收延遲劑、鹽、藥物穩定劑、黏合劑、賦形劑、崩解劑、潤滑劑、潤濕劑、甜味劑、調味劑、染料及其組合(參見例如Remington The Science and Practice of Pharmacy,第22版. Pharmaceutical Press, 2013, 第1049-1070頁)。 術語本發明化合物之「治療有效量」係指將誘發個體之生物學或醫學反應、例如酶或蛋白質活性降低或抑制,或改善症狀、緩解病狀、減緩或延緩疾病進展或預防疾病等的本發明化合物的量。在一個非限制性實施例中,術語「治療有效量」係指如下本發明化合物之量:在將該量向個體投與時可有效地(1)至少部分地緩解、抑制、預防及/或改善病狀或病症或疾病,該病狀或病症或疾病(i)由GIRK1/4通道介導、或(ii)與GIRK1/4通道活性有關、或(iii)其特徵在於GIRK1/4通道之(正常或異常)活性;或(2)降低或抑制GIRK1/4通道之活性;或(3)降低或抑制GIRK1/4通道之表現。在另一非限制性實施例中,術語「治療有效量」係指當向細胞、或組織、或非細胞生物材料、或培養基投與時可有效地至少部分地減少或抑制GIRK1/4通道之活性;或至少部分地降低或抑制GIRK1/4通道之表現的本發明化合物之量。 如本文所使用,術語「個體」係指男性或女性人類。在其他實施例中,個體為人類。 如本文所使用,術語「抑制(inhibit/inhibition/inhibiting)」係指減少或遏止既定病狀、症狀、或病症或疾病,或顯著降低生物活性或過程之基線活性。 如本文所使用,術語「治療(treat/treating/treatment)」任何疾病或病症係指緩解或改善該疾病或病症(亦即,減緩或阻止該疾病或其至少一種臨床症狀之進展);或緩解或改善與該疾病或病症有關之至少一種物理參數或生物標記,包括對患者可能不可辨別的彼等物理參數或生物標記。 如本文所使用,術語「預防(prevent/preventing/prevention)」任何疾病或病症係指對該疾病或病症進行預防性治療;或延緩該疾病或病症之發作或進展。 如本文所使用,除非本文中另外指示或與上下文明顯矛盾,否則本發明之上下文中(尤其在申請專利範圍之上下文中)所使用的術語「一(a/an)」、「該(the)」及類似術語應解釋為涵蓋單數及複數兩者。 除非本文另外指示或與上下文明顯矛盾,否則本文中描述之所有方法可以任何適合順序進行。使用本文所提供之任何及所有實例或示例性語言(例如「諸如」)僅意欲更好地闡明本發明,且並不對另外所主張的本發明之範疇造成限制。 本發明之一或多種化合物之任何不對稱原子(例如碳或其類似原子)可以外消旋或對映異構性增濃之組態存在,例如(R
)-組態、(S
)-組態或(R,S
)-組態。在某些實施例中,各不對稱原子在(R
)組態或(S
)組態中具有至少50%對映異構體過量、至少60%對映異構體過量、至少70%對映異構體過量、至少80對映異構體過量、至少90%對映異構體過量、至少95%對映異構體過量或至少99%對映異構體過量。在具有不飽和雙鍵之原子處的取代基(若可能)可以順式
-(Z
)-或反式
-(E
)-形式存在。 相應地,如本文所使用,本發明化合物可呈可能的立體異構體、旋轉異構體、滯轉異構體、互變異構體或其混合物之一的形式,例如呈實質上純幾何(順式
或反式
)立體異構體、非對映異構體、光學異構體(對映體)、外消旋體或其混合物之形式。 任何所得立體異構體之混合物可基於組分之物理化學差異例如藉由層析及/或分步結晶分離成純的或實質上純的幾何或光學異構體、非對映異構體、外消旋體。 任何所得終產物或中間產物之外消旋體可藉由已知方法而解析為光學對映體,例如藉由分離其非對映異構體鹽(該鹽用光學活性酸或鹼獲得)及釋放光學活性酸性或鹼性化合物。特定言之,鹼性部分可因此用於將本發明化合物解析成其光學對映體,例如藉由分步結晶用光學活性酸形成之鹽,該光學活性酸例如酒石酸、二苯甲醯基酒石酸、二乙醯基酒石酸、二-O,O'
-對甲苯甲醯基酒石酸、杏仁酸、蘋果酸或樟腦-10-磺酸。外消旋產物亦可藉由對掌性層析、例如高壓液相層析(HPLC)使用對掌性吸附劑來解析。 本發明亦提供本發明化合物之前藥,其在活體內轉化成本發明化合物。前藥為活性或非活性化合物,在向個體投與前藥後,其經由活體內生理作用諸如水解、代謝及其類似者經化學修飾成本發明化合物。在製備及使用前藥方面所涉及之適合性及技術為熟悉此項技術者所熟知。可在概念上將前藥分成兩種非互斥類別,生物前驅體前藥及載體前藥。參見The Practice of Medicinal Chemistry
, Ch. 31-32 (Wermuth, Academic Press, San Diego, Calif., 編,2001)。一般而言,生物前驅體前藥為含有一或多個保護基且藉由代謝或溶劑分解轉化成活性形式之非活性或與相應活性藥物化合物相比活性較低的化合物。活性藥物形式及任何釋放之代謝產物均應具有可接受之低毒性。 載體前藥為例如改良吸收及/或至作用部位之定位傳遞之含有輸送部分的藥物化合物。對於該載體前藥,合乎需要地,藥物部分與輸送部分之間的鍵為共價鍵,前藥為非活性的或與藥物化合物相比活性較低,且任何釋放之輸送部分為可接受地無毒的。就輸送部分意欲增強吸收之前藥而言,輸送部分之釋放通常應較快。在其他情況下,需要採用提供緩慢釋放之部分,例如,某些聚合物或其他部分,諸如環糊精。舉例而言,載體前藥可用於改良以下特性中之一或多者:增加之親脂性、增加之藥理效應持續時間、增加之部位特異性、減少之毒性及不良反應、及/或藥物調配物之改良(例如穩定性、水溶性、對不合需要之感官或生物化學特性之遏止)。舉例而言,可藉由(a)羥基與親脂性羧酸(例如具有至少一個親脂性部分之羧酸)或(b)羧酸基團與親脂性醇(例如具有至少一個親脂性部分之醇,例如脂族醇)之酯化反應來增加親脂性。舉例而言,可藉由羥基與磷酸之酯化增加溶解度。 示例性的前藥為例如醇或苯酚之O
-醯基或O-磷酸鹽衍生物,其中醯基具有如本文所定義之意義。用於形成O-醯基前藥之適合之酸為例如經取代或未經取代之烷基甲酸、環烷基甲酸或苯甲基甲酸。胺已經掩蔽為經芳基羰氧基甲基取代之衍生物,其由活體內酯酶分解而釋放自由藥物及甲醛(Bungaard,J . Med . Chem .
2503 (1989))。此外,含有酸性NH基團諸如咪唑、醯亞胺、吲哚及其類似基團之藥物已用N-醯氧基甲基掩蔽(Bundgaard,Design of Prodrugs
, Elsevier (1985))。羥基已經掩蔽為酯及醚,鄰二醇已經掩蔽為環狀縮醛或縮酮。此外,本發明化合物(包括其鹽)亦可以其水合物之形式獲得,或包括用於其結晶之其他溶劑。本發明化合物可固有地或經設計以與醫藥學上可接受之溶劑(包括水)形成溶劑合物;因此,本發明意欲涵蓋溶劑化及非溶劑化形式兩者。術語「溶劑合物」係指本發明化合物(包括其醫藥學上可接受之鹽)與一或多種溶劑分子的分子複合物。此類溶劑分子為通常用於醫藥技術之已知對接受者無害的彼等溶劑分子,例如水、乙醇及其類似物。術語「水合物」係指其中溶劑分子為水之複合物。 在一個實施例中,式(I)、(II)或(III)化合物呈水合物形式。 通常,式(I)、(II)或(III)化合物可根據下文所提供之流程B、C、D製備。如下文流程A中所述製備所需中間產物J
。在流程A中芳族起始材料A
藉由強鹼(例如LDA或n-BuLi)去質子化且與例如烷基甲酸鹽或DMF反應以得到芳族醛。可使醛B
與去質子化炔(例如格林納(Grignard)試劑或鋰化物種)反應以得到苯甲醇C ,
其在適當氧化條件(諸如戴斯-馬丁(Dess-Martin)高碘烷試劑)下氧化成酮。或者,可由芳族酸E
來製備酮D
,芳族酸E
與胺偶合以形成醯胺F
,醯胺F
係用於與適當的格林納試劑反應之受質。苯胺在路易斯(Lewis)催化(例如AlCl3
、BF3
*Et2
O、Sc(OTf)3
)下之反應提供中間產物H ,
其可在鹼性條件(例如碳酸鉀)下環化成增環之4-吡啶酮。 X2
、X3
如發明內容中所定義且R1*
、R4*
、R5*
及R6*
包括如發明內容中對於R1
、R4
、R5
及R6
所定義之定義,但亦可為可轉化成R1
、R4
、R5
及R6
之取代基。 流程B描述式I化合物之合成,尤其其中R1
為CH2
OH、CHF2
、CHO、CN、CH3
,R3
為-ORa
或-NHRb
及/或R2
為C1-4
烷氧基、鹵基C1-4
烷氧基及-NH-C1-4
烷基之式(I)化合物之合成。可如流程B中所述製備通式Ia
及Ib
之實例。中間產物J
可藉由使用胺及醇之親核芳族取代及-必要時-隨後之保護基操縱直接轉化成化合物Ia
。對於中間產物K
,取代基R4
可例如藉由與鋅試劑反應或與硼酸進行鈴木(Suzuki)偶合來引入。對於中間產物L
,可使用二氧化硒將甲基氧化成醛,該醛可藉由例如NaBH4
還原轉化成一級醇。亦可藉由用適合之氟化劑氟化使醛官能基轉化成二氟甲基。此外,可藉由包括氧化成酸、形成醯胺及脫水之一連串反應使醛基轉化成腈。對於X2
= CCl之中間產物N ,
藉由醇、胺、格林納或鋅試劑之第二親核芳族取代可產生通式Ib
化合物。 流程C描述與流程B中所述者不同之各種R3
基團之引入。根據流程C,中間產物J
可經由Pd催化之鈴木偶合與硼酸偶合成通式Ic
之實例,其中R經由C-C鍵連接到環系統。或者,中間產物J
亦可與格林納試劑反應成化合物P ,
其可藉由在該流程中所指定之條件轉化成式Id
及Ie
之實例。中間產物J
與錫烷之反應提供例如中間產物O
及Q
,其可經由一組條件轉化成通式If
及Ig
之其他實例。 流程D描述R5
為C2-6
炔基之式I化合物之合成。中間產物J
可藉由親核芳族取代轉化成化合物R
。經由Pd/Cu催化(Sonogashira偶合)及-必要時-隨後之保護基操縱與末端炔反應產生通式Ih
之實例。 本發明進一步包括本發明方法之任何變型,其中可在其任何階段獲得之中間產物用作起始材料且進行其餘步驟,或其中在反應條件下原位形成起始材料,或其中反應組分以其鹽或光學純材料之形式使用。 本發明化合物及中間產物亦可根據熟習此項技術者一般已知之方法彼此轉化。 在另一態樣中,本發明提供一種醫藥組合物,其包含本發明化合物或其醫藥學上可接受之鹽及醫藥學上可接受之載劑。在另一實施例中,組合物包含至少兩種醫藥學上可接受之載劑,諸如本文所描述之彼等載劑。出於本發明之目的,除非另外指定,否則溶劑合物及水合物一般視為組合物。較佳地,醫藥學上可接受之載劑為無菌的。醫藥組合物可針對諸如口服投藥、非經腸投藥及經直腸投藥等之特定投藥途徑加以調配。另外,本發明之醫藥組合物可製成固體形式(包括但不限於膠囊、錠劑、丸劑、顆粒劑、散劑或栓劑)或液體形式(包括但不限於溶液、懸浮液或乳液)。可對醫藥組合物進行習知醫藥操作,諸如滅菌,及/或該等醫藥組合物可含有習知惰性稀釋劑、潤滑劑或緩衝劑以及佐劑,諸如防腐劑、穩定劑、潤濕劑、乳化劑及緩衝劑等。 通常,醫藥組合物為錠劑或明膠膠囊,其包含活性成分以及以下中之一或多者: a)稀釋劑,例如乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纖維素及/或甘胺酸; b)潤滑劑,例如二氧化矽、滑石、硬脂酸、硬脂酸之鎂鹽或鈣鹽及/或聚乙二醇;對於錠劑亦為如此 c)黏合劑,例如矽酸鎂鋁、澱粉糊、明膠、黃蓍、甲基纖維素、羧甲基纖維素鈉及/或聚乙烯吡咯啶酮;若需要 d)崩解劑,例如澱粉、瓊脂、褐藻酸或其鈉鹽或發泡混合物;及 e)吸收劑、著色劑、調味劑及甜味劑。 根據此項技術中已知之方法,錠劑可經薄膜包衣或腸溶包衣。 用於口服投藥之適合之組合物包括有效量之本發明化合物,其呈錠劑、口含錠、水性或油性懸浮液、分散性散劑或顆粒、乳液、硬或軟膠囊或糖漿或酏劑之形式。欲用於口服使用之組合物根據此項技術中已知用於醫藥組合物之製造的任何方法來製備,且此類組合物可含有一或多種選自由以下各者組成之群的試劑:甜味劑、調味劑、著色劑及防腐劑,以提供醫藥學上精緻且可口之製劑。錠劑可含有活性成分,該活性成分與適合於製造錠劑的醫藥學上可接受之無毒賦形劑摻和。舉例而言,此等賦形劑為惰性稀釋劑,諸如碳酸鈣、碳酸鈉、乳糖、磷酸鈣或磷酸鈉;粒化劑及崩解劑,例如玉米澱粉或褐藻酸;黏合劑,例如澱粉、明膠或阿拉伯膠;及潤滑劑,例如硬脂酸鎂、硬脂酸或滑石。錠劑未經包覆或藉由已知技術包覆以延緩胃腸道中之崩解及吸收,且藉此提供歷經更長時間段之持續作用。舉例而言,可採用時間延緩材料,諸如單硬脂酸甘油酯或二硬脂酸甘油酯。用於口服使用之調配物可以硬明膠膠囊形式或軟明膠膠囊形式呈現,在該等硬明膠膠囊中,活性成分與惰性固體稀釋劑例如碳酸鈣、磷酸鈣或高嶺土混合,在該等軟明膠膠囊中,活性成分與水或油介質例如花生油、液體石蠟或橄欖油混合。 某些可注射組合物為等滲水溶液或懸浮液,且栓劑宜自脂肪乳液或懸浮液製備。該等組合物可經滅菌,及/或含有佐劑,諸如防腐劑、穩定劑、潤濕劑或乳化劑、溶解促進劑、用於調控滲透壓之鹽及/或緩衝劑。另外,其亦可含有其他治療上有價值之物質。該等組合物根據習知混合、粒化或塗覆方法分別製備,且含有約0.1-75%之活性成分,或含有約1-50%之活性成分。 由於水可能促進某些化合物降解,本發明進一步提供包含本發明化合物作為活性成分之無水醫藥組合物及劑型。 本發明之無水醫藥組合物及劑型可使用無水或含有較低水份之成分及較低水分或較低濕度之條件製備。可製備且儲存無水醫藥組合物,從而維持其無水性質。因此,使用已知防止暴露於水之材料封裝無水組合物以使得其可包括於適合處方集套組中。適合的封裝之實例包括但不限於氣密密封式箔、塑膠、單位劑量容器(例如,小瓶)、泡殼包裝及條帶包裝。 本發明進一步提供醫藥組合物及劑型,其包含一或多種降低作為活性成分之本發明化合物之分解速率的藥劑。在本文中稱為「穩定劑」之此類試劑包括但不限於諸如抗壞血酸之抗氧化劑、pH緩衝劑或鹽緩衝劑等。本發明方法:
呈游離形式或呈醫藥上可接受鹽形式的式I至III中之任一者之化合物展現有價值的藥理學特性,例如GIRK1/4通道調節特性,例如如隨後章節中提供的活體外及活體內測試中所指示,且因此經指示用於療法或用作研究化學物質,例如用作工具化合物。 如先前所述,已將GIRK1/4識別為針對心房震顫之所需抗心律不整靶標。 另外,已將GIRK1/4阻斷劑描述為潛在地適用於竇房/房室結功能異常:GIRK1/4通道介導竇房結(SAN)及房室(AVN)結之自發去極化細胞的再極化。自迷走神經的神經傳出部分所釋放之乙醯膽鹼與此等組織中存在的M2蕈毒鹼受體結合,其繼而作用於GIRK1/4通道以將其打開且允許鉀離子自細胞流出。此再極化(或視流出程度而定,超極化)確定自發去極化之間的時序,且從而確定心跳速率及AV結的傳導速率。預期GIRK1/4通道之阻斷對抗乙醯膽鹼之負面變速性作用,且已對於選擇性肽GIRK1/4阻斷劑托肽平(tertiapin)觀測到此現象(Drici等人, 2000. The bee venom peptide tertiapin underlines the role of I(KACh) in acetylcholine-induced atrioventricular blocks. British journal of pharmacology131
, 569-577)。在人類起搏疾病(例如心房腔失調症候群)中竇房結或房室結為功能異常的,其可誘導多種心律不整,包括心搏徐緩及心搏停止。預期GIRK1/4阻斷可改善此類心律不整。舉例而言,在最近的研究中,顯示GIRK4之基因缺失拯救藉由所謂「起搏電流(funny current)」之心臟特異性沉默誘導的心臟脈衝產生及傳導之失效,該起搏電流介導竇房及房室組織中之自發去極化(Mesirca等人, 2014. Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation. Nature communications 5, 4664)。 此外,已將GIRK1/4阻斷劑描述為潛在地適用於原發性高醛固酮症:最近已在原發性醛固酮症-誘發高血壓之病狀-中涉及到KCNJ5
(編碼GIRK4)中之體細胞及生殖系功能獲得突變。此等突變改變GIRK4通道之選擇性過濾且允許鈉離子流入某些腎上腺細胞中。所得之細胞去極化允許鈣流入,其繼而增強醛固酮產生及分泌,且亦可誘導細胞增殖以產生分泌醛固酮之腺瘤(Scholl及Lifton, 2013. New insights into aldosterone-producing adenomas and hereditary aldosteronism: mutations in the K+ channel KCNJ5. Current opinion in nephrology and hypertension22
, 141-147)。因此可能的係選擇性GIRK4阻斷劑可防止鈉離子流入,及其伴隨的對此等患者中之醛固酮分泌之促進。 因此,本發明化合物可適用於治療選自以下各者之病症:心律不整、心房震顫、原發性高醛固酮症、高血壓及心房腔失調症候群。 由此,作為另一實施例,本發明提供式(I)至(III)中任一者之化合物在療法中之用途。在另一實施例中,療法係選自可藉由抑制GIRK1/4通道來治療之疾病。在另一實施例中,疾病係選自心律不整、心房震顫、原發性高醛固酮症、高血壓及心房腔失調症候群,適合地心房震顫。 由此,作為另一實施例,本發明提供式(I)至(III)中任一者之化合物以用於療法。在另一實施例中,療法係選自可藉由抑制GIRK1/4通道來治療之疾病。在另一實施例中,疾病係選自心律不整、心房震顫、原發性高醛固酮症、高血壓及心房腔失調症候群,適合地心房震顫。 在另一實施例中,本發明提供一種治療藉由抑制GIRK1/4通道來治療之疾病的方法,其包含投與治療可接受量之式(I)至(III)中之任一者之化合物。在另一實施例中,疾病係選自心律不整、心房震顫、原發性高醛固酮症、高血壓及心房腔失調症候群,適合地心房震顫。 由此,作為另一實施例,本發明提供式(I)至(III)中任一者之化合物在用於製造藥劑之用途。在另一實施例中,藥劑用於治療可藉由抑制GIRK1/4通道來治療之疾病。在另一實施例中,疾病係選自心律不整、心房震顫、原發性高醛固酮症、高血壓及心房腔失調症候群,適合地心房震顫。 在本發明之一個實施例中,提供(S)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮;或其醫藥學上可接受之鹽,用於治療心律不整、心房震顫、原發性高醛固酮症、高血壓及/或心房腔失調症候群,適合地心房震顫。 在本發明之又一實施例中,提供(R)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮,或其醫藥學上可接受之鹽,用於治療心律不整、心房震顫、原發性高醛固酮症、高血壓及/或心房腔失調症候群,適合地心房震顫。 在本發明之又一實施例中,提供8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮或其醫藥學上可接受之鹽,用於治療心律不整、心房震顫、原發性高醛固酮症、高血壓及/或心房腔失調症候群,適合地心房震顫。 在本發明之又一實施例中,提供(R)-8-氯-1-(2,6-二氯苯基)-5-(3,4-二羥丁基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮或其醫藥學上可接受之鹽,用於治療心律不整、心房震顫、原發性高醛固酮症、高血壓及/或心房腔失調症候群,適合地心房震顫。 在本發明之又一實施例中,提供(S)-8-氯-1-(2,6-二氯苯基)-5-(3,4-二羥丁基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮或其醫藥學上可接受之鹽,用於治療心律不整、心房震顫、原發性高醛固酮症、高血壓及/或心房腔失調症候群,適合地心房震顫。 在本發明之又一實施例中,提供8-氯-1-(2,6-二氯苯基)-5-(3,4-二羥丁基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮或其醫藥學上可接受之鹽,用於治療心律不整、心房震顫、原發性高醛固酮症、高血壓及/或心房腔失調症候群,適合地心房震顫。 在又一實施例中,本發明係關於如前述實施例1-13F中任一項之化合物或其醫藥學上可接受之鹽,用於治療心律不整、心房震顫、原發性高醛固酮症、高血壓及/或心房腔失調症候群。 對於約50-70 kg之個體,本發明之醫藥組合物或組合可呈約1-1000 mg活性成分,或約1-500 mg、或約1-250 mg、或約1-150 mg、或約0.5-100 mg、或約1-50 mg活性成分之單位劑量。化合物、醫藥組合物或其組合之治療有效劑量視個體之物種、體重、年齡及所治療之個別病狀、病症或疾病或其嚴重性而定。一般熟練之醫師、臨床醫生或獸醫可容易地確定預防、治療或抑制病症或疾病之進展所需要的各活性成分之有效量。 上文所引用之劑量特性可有利地使用哺乳動物例如小鼠、大鼠、犬、猴、小型豬,或其經分離之器官、組織及標本在活體外及活體內測試中論證。本發明化合物可在活體外以溶液例如水溶液之形式施用,且在活體內經腸、非經腸、經靜脈內施用,例如以懸浮液、乳液之形式或以水溶液形式施用。活體外劑量可在約10-2
莫耳濃度與10-9
莫耳濃度之間的範圍內。活體內之治療有效量可視投藥途徑而定在約0.1-500 mg/kg之間或1-100 mg/kg之間的範圍內。 根據本發明之化合物的活性可藉由以下活體外方法來評估。 1.緩衝液:
a.外部緩衝液 :
10mM NaCl、50mM 葡萄糖酸鈉、80mM葡萄糖酸鉀、1.8mM CaCl2
、1mM MgCl2
、10mM HEPES、10mM葡萄糖,pH 7.4;重量莫耳滲透濃度300-310 Osm/L。 b.內部緩衝液 :
30mM KCl、100mM葡萄糖酸鉀、1mM MgCl2 、
10mM HEPES、1mM EGTA、10mM NaCl,pH 7.2;重量莫耳滲透濃度284-292 Osm/L。 2.化合物:
a. 在384孔聚丙烯平板中製備於100% DMSO中之七倍化合物稀釋系列(10 mM至20 μM)。 b. 普羅帕酮(Sigma Aldrich,目錄號P4670)用作陽性對照且DMSO用於中性控制 c. 在384孔聚丙烯平板中使於DMSO中之1 ul化合物再懸浮於65.7 ul外部緩衝液中,且裝入Molecular Devices Quattro中之平板1(Plate 1)區 3.Quattro 設置:
a. 將384孔Population貼板(Molecular Devices#9000-0902)載入至Quattro中 b. 用20% DMSO及50% EtOH填充Quattro F-浸泡槽 c. 用外部緩衝液填充Quattro緩衝液槽 d. 將內部緩衝液燒瓶連接至Quattro內部緩衝液管 e. 將PBS (磷酸鹽緩衝鹽水,減去Ca++
及Mg++
,pH 7.4)瓶連接至Quattro上的F頭及E頭洗滌 4.抗生素:
a. 使5.6 mg雙性黴素B (Sigma Aldrich,目錄號A2411)再懸浮於175 ul DMSO中 b. 將所得溶液添加至50 ml內部緩衝液中,混合且連接至Quattro上的抗生素管端口 5.細胞:
a. 在以下細胞培養基中使用GIRK 1/4 HEK293穩定生長至約80%融合之細胞(獲自ChanTest, 14656 Neo Parkway, Cleveland, Ohio 44128):含有10%(v/v)胎牛血清、青黴素/鏈黴素(在來自100X儲備液之「1×」濃度下)、0.5 mg/ml G418及0.1 mg/ml吉歐黴素之DMEM。 b. 用PBS洗滌細胞(減去Ca++
及Mg++
),使用Detachin分離細胞(Genlantis, 11011 Torreyana, 聖地亞哥, 加利福尼亞州92121),且再懸浮於外部緩衝液(2.0-2.1×106
個細胞/ml之5 ml最終體積)中 c. 載入至Quattro之細胞槽中 6.分析方案:
使用IonWorks v2軟體控制Quattro以執行以下步驟: a. 將3.5 ul細胞加3.5 ul外部緩衝液添加至Quattro貼板之孔中 b. 使雙性黴素B及內部緩衝液循環於細胞上 c. 應用以下電壓方案:脈衝1:15mV持續300毫秒(ms),隨後為脈衝2:120mV持續400 ms,隨後脈衝3:-15mV持續400 ms,及最終脈衝4:-120mV至40mV歷時500 ms (此係電壓斜坡)。 d. 自脈衝1開始在1200-1220 ms之間的時間點處(亦即在斜坡電壓期期間)測量內向性鉀電流之量值。 e. 向孔添加3.5 ul經稀釋之化合物(或DMSO)且重複步驟c-d (最終化合物濃度為50 μM至0.1 μM,對於有效化合物0.5 μM至0.01 μM且各濃度以一式四份(例如在4個單獨的孔中)測試。 f. 添加化合物之前相對於添加化合物之後電流量值之間的差值得到GIRK1/4抑制之測量。 7.數據分析:
藉由繪製電流抑制之百分比(標準化為僅DMSO控制)作為化合物濃度的函數使用標準數據分析軟體來計算IC50
值。 使用第1號測試分析(如本申請案中所描述)本發明化合物展現如下文所提供之表1的抑制功效。表 1 化合物之抑制活性 本發明之組合:
本發明化合物可與一或多種其他治療劑同時、或在其之前、或在其之後投與。本發明化合物可藉由相同或不同投與途徑單獨投與,或與其他試劑在同一醫藥組合物中一起投與。治療劑為例如化合物、肽、抗體、抗體片段或核酸,當其併與本發明化合物組合投與病患時,其為治療上活性的或可增強治療活性。 在一個實施例中,本發明提供一種產品,其包含式(I)至(III)中任一者之化合物及至少一種作為在療法中同時、單獨或依序使用之組合製劑的其他治療劑。在一個實施例中,療法為治療會對GIRK1/4通道之抑制起反應的疾病或病狀。呈組合製劑所提供之產品包括一起在同一醫藥組合物中之組合物(包含式(I)至(III)中任一者之化合物)及其他治療劑,或呈單獨形式(例如呈套組形式)之式(I)至(III)中任一者之化合物及其他治療劑。 在一個實施例中,本發明提供包含式(I)至(III)中任一者之化合物及另一治療劑的醫藥組合物。如上文所述,醫藥組合物視情況可包含醫藥學上可接受之載劑。 在一個實施例中,本發明提供包含兩種或超過兩種各別醫藥組合物之套組,該等醫藥組合物中之至少一者含有式(I)至(III)中任一者之化合物。在一個實施例中,該套組包含用於分別保存該等組合物之構件,諸如容器、分隔的瓶或分隔的箔片包。該套組之一個實例為泡殼包裝,如通常用於錠劑、膠囊及其類似物之包裝。 本發明套組可用於投與不同劑型,例如以經口及非經腸方式於不同劑量區間投與各別組合物,或用於針對彼此滴定各別組合物。為輔助順從性,本發明之套組通常包含投與之說明。 在本發明之組合療法中,本發明化合物及另一治療劑可由相同或不同製造商製造及/或調配。此外,本發明化合物及另一治療劑可在以下情況中結合為組合療法:(i)在將組合產品交給醫師之前(例如在套組包含本發明化合物及另一治療劑的情況下);(ii)由醫師本人(或在醫師指導下)在投藥之前不久;(iii)由患者本人,例如在依序投與本發明化合物及另一治療劑期間。 因此,本發明提供式(I)至(III)中任一者之化合物在用於治療對抑制GIRK1/4通道起反應之疾病或病狀之用途,其中將該藥劑製備成與另一治療劑一起投與。本發明亦提供另一治療劑在用於治療對抑制GIRK1/4通道起反應之疾病或病狀之用途,其中該藥劑與式(I)至(III)中任一者之化合物一起投與。 本發明亦提供式(I)至(III)中任一者之化合物在用於治療對抑制GIRK1/4通道起反應之疾病或病狀之方法,其中式(I)、(II)或(III)化合物製備成與另一治療劑一起投與。本發明亦提供另一治療劑在用於治療對抑制GIRK1/4通道起反應之疾病或病狀之方法,其中其他治療劑製備成與式(I)至(III)中任一者之化合物一起投與。本發明亦提供式(I)至(III)中任一者之化合物在用於治療對抑制GIRK1/4通道起反應之疾病或病狀之方法,其中式(I)化合物與另一治療劑一起投與。本發明亦提供另一治療劑在用於治療對抑制GIRK1/4通道起反應之疾病或病狀之方法,其中其他治療劑與式(I)至(III)中任一者之化合物一起投與。 本發明亦提供式(I)至(III)中任一者之化合物在用於治療對抑制GIRK1/4通道起反應之疾病或病狀之用途,其中患者預先(例如在24小時內)用另一治療劑治療。本發明亦提供另一治療劑在用於治療對抑制GIRK1/4通道起反應之疾病或病狀之用途,其中患者預先(例如在24小時內)用式(I)、(II)或(III)化合物治療。 在一個實施例中,其他治療劑係選自:任何其他抗心律不整劑,諸如I類劑(例如奎尼丁(quinidine)、利多卡因(lidocaine)及普羅帕酮),II類劑(例如普萘洛爾(propranolol),III類劑(例如索他洛爾(sotalol)、多非利特(dofetilide)、胺碘酮(amiodarone)、決奈達隆(dronedarone)、布地達隆(budiodarone)、阿齊利特(azimilide)及伊布利特(ibutilide)),IV類劑(例如地爾硫卓(diltiazem)及維拉帕米(verapamil)),「V類劑」(例如腺苷)、強心苷(例如洋地黃及烏巴苷)及其他影響心房不應性之藥物(例如描述於WO2013112932中之I Na,Late
阻斷劑);止血調節劑,包括抗血栓藥,諸如纖維蛋白溶解之活化劑;凝血酶抑制劑;VIla因子抑制劑;抗凝劑,諸如維生素K拮抗劑(例如華法林(warfarin))、肝素及其低分子量類似物(例如達肝素(dalteparin))、Xa因子抑制劑(例如利伐沙班(rivaroxaban)及阿派沙班(apixaban),及直接凝血酶抑制劑(例如阿加曲班(argatroban));抗血小板劑,諸如環加氧酶抑制劑(例如阿司匹林及NSAID)、二磷酸腺苷(ADP)受體抑制劑(例如氯吡格雷(clopidogrel))、磷酸二酯酶抑制劑(例如西洛他唑(cilostazol)、醣蛋白IIB/IIA抑制劑(例如替羅非班(tirofiban))及腺苷再吸收抑制劑(例如雙嘧達莫(dipyridamole));抗血脂異常劑,諸如HMG-CoA還原酶抑制劑(他汀類)及其他膽固醇降低劑;PPARa促效劑(纖維酸酯,例如吉非羅齊(gemfibrozil)及非諾貝特(fenofibrate));膽酸螯合劑(例如消膽胺);膽固醇吸收抑制劑(例如植物固醇(亦即植物甾醇),合成抑制劑);膽甾醇酯轉移蛋白(CETP)抑制劑;迴腸膽酸傳送系統抑制劑(IBAT抑制劑);膽酸結合樹脂;菸鹼酸(菸酸)及其類似物;抗氧化劑;及ω-3脂肪酸;抗高血壓劑,包括腎上腺素激導性受體拮抗劑,諸如β阻斷劑(例如阿替洛爾(atenolol))、α阻斷劑(例如多沙唑嗪(doxazosin))及混合α/β阻斷劑(例如拉貝洛爾(labetalol));腎上腺素激導性受體促效劑,包括α-2促效劑(例如可樂定(clonidine));血管收縮素轉化酶(ACE)抑制劑(例如賴諾普利(lisinopril)),鈣離子通道阻斷劑,諸如二氫吡啶(例如硝苯地平(nifedipine))、苯基烷基胺(例如維拉帕米)及苯并硫氮雜卓(benzothiazepine)(例如地爾硫卓);血管緊張素II受體拮抗劑(例如洛沙坦(losartan));醛固酮受體拮抗劑(例如依普利酮(eplerenone));中樞作用腎上腺素藥物,諸如中樞α促效劑(例如可樂定);及利尿劑(例如呋喃苯胺酸(furosemide));抗肥胖劑,諸如食慾抑制劑(例如麻黃素),包括去甲腎上腺素劑(例如苯丁胺(phentermine))及血清素活性劑(例如諾美婷(sibutramine)),胰臟脂肪酶抑制劑(例如羅氏鮮(orlistat)),微粒體轉移蛋白(MTP)調節劑,二醯基甘油醯基轉移酶(DGAT)抑制劑,及大麻素(CBI)受體拮抗劑(例如利莫那班(rimonabant));胰島素及胰島素類似物;胰島素促分泌物,包括磺醯脲(例如格列吡嗪(glipizide))及膳食性葡萄糖調節因子(有時稱為「短效促分泌物」),諸如美格列奈(meglitinides)(例如瑞格列奈(repaglinide)及那格列奈(nateglinide));改進腸促胰島素作用之藥劑,例如二肽基肽酶IV (DPP-4)抑制劑(例如維格列汀(vildagliptin)、西他列汀(sitagliptin)、LAF237、MK-431),及類升糖素肽-I (GLP-1)促效劑(例如艾塞那肽(exenatide));胰島素增敏劑,包括過氧化體增殖物活化受體γ (PPARy)促效劑,諸如噻唑啶二酮(例如吡格列酮(pioglitazone)及羅格列酮(rosiglitazone),及具有PPARα、γ及δ活性之任何組合之藥劑;調節肝葡萄糖平衡之藥劑,例如雙胍(例如二甲雙胍)、果糖1,6-二磷酸酶抑制劑、肝糖磷酸化酶抑制劑、肝糖合成酶激酶抑制劑及葡糖激酶活化因子;經設計以減少/減緩腸之葡萄糖吸收之藥劑,諸如α-葡糖苷酶抑制劑(例如米格列醇(miglitol )及阿卡波糖(acarbose));拮抗升糖素作用或降低升糖素分泌之藥劑,諸如澱粉素類似物(例如普蘭林肽(pramlintide));防止由腎臟再吸收葡萄糖之藥劑,諸如鈉依賴性葡萄糖轉運子2 (SGLT-2)抑制劑。 術語「HMG-Co-A還原酶抑制劑」(亦稱為β-羥基-β-甲基戊二醯基輔酶A還原酶抑制劑)包括可用於降低血液中包括膽固醇在內的脂質含量的活性劑。實例包括阿托伐他汀(atorvastatin)、西立伐他汀(cerivastatin)、康百汀(compactin)、達伐他汀(dalvastatin)、二氫康百汀(dihydrocompactin)、氟多他汀(fluindostatin)、氟伐他汀(fluvastatin)、洛伐他汀(lovastatin)、匹伐他汀(pitavastatin)、美伐他汀(mevastatin)、普伐他汀(pravastatin)、羅素他汀(rosuvastatin)、利伐他汀(rivastatin)、辛伐他汀(simvastatin)及維洛他汀(velostatin)或其醫藥學上可接受之鹽。 術語「ACE抑制劑」(亦稱為血管收縮素轉化酶抑制劑)包括中斷血管收縮素I酶促降解成血管收縮素II之分子。此類化合物可用於調控血壓及用於治療充血性心臟衰竭。實例包括阿拉普利(alacepril)、貝那普利(benazepril)、貝那普拉(benazeprilat)、卡托普利(captopril)、西羅普利(ceronapril)、西拉普利(cilazapril)、地拉普利(delapril)、依那普利(enalapril)、依那普拉(enaprilat)、福辛普利(fosinopril)、咪達普利(imidapril)、賴諾普利(lisinopril)、莫西普利(moexipril)、莫福普利(moveltopril)、培哚普利(perindopril)、喹那普利(quinapril)、雷米普利(ramipril)、螺普利(spirapril)、替莫普利(temocapril)及群多普利(trandolapril)或其藥學上可接受之鹽。 血管收縮素II受體拮抗劑或其醫藥學上可接受之鹽應理解為結合至血管收縮素II受體之AT1受體亞型但未導致該受體活化之活性成分。由於AT1受體之抑制,此等拮抗劑可例如用作抗高血壓藥或用於治療充血性心臟衰竭。 術語「利尿劑」包括噻嗪衍生物(例如氯噻嗪、氫氯噻嗪、甲氯噻嗪及氯噻酮)。 DPP-IV負責使GLP-1不活化。更特定言之,DPP-IV產生GLP-1受體拮抗劑且由此縮短對GLP-1之生理響應。GLP-1為胰臟胰島素分泌之主要刺激劑,且對葡萄糖處置具有直接有益效應。DPP-IV抑制劑可為肽,或較佳為非肽。DPP-IV抑制劑在各種情況下一般地且特定地揭示於例如WO 98/19998、DE 196 16 486 A1、WO 00/34241及WO 95/15309中,在各種情況下詳言之在化合物申請專利範圍及實施例之最終產物中,最終產物、醫藥製劑及申請專利範圍之標的物以對此等公開案引用之方式併入本申請案中。較佳為分別特定揭示於WO 98/19998之實例3及WO 00/34241之實例1中之彼等化合物。 GLP-1為促胰島素蛋白,其例如由W.E. Schmidt等人描述於Diabetologia, 28, 1985, 704-707中及US 5,705,483中。術語「GLP-1促效劑」包括GLP-1(7-36)NH2
之變體及類似物,其特別揭示於US 5,120,712、US 5,118666、US 5,512,549、WO 91/11457及C. Orskov等人, J. Biol. Chem. 264 (1989) 12826中。其他實例包括GLP-1(7-37),在該化合物中,Arg36
之羧基端醯胺官能基由GLP-1(7-36)NH2
分子及其變體及類似物之第37位之Gly置換,包括GLN9
-GLP-1(7-37)、D-GLN9
-GLP-1(7-37)、乙醯基LYS9
-GLP-1(7-37)、LYS18
-GLP-1(7-37)且特定言之GLP-1(7-37)OH、VAL8
-GLP-1(7-37)、GLY8
-GLP-1(7-37)、THR8
-GLP-1(7-37)、MET8
-GLP-1(7-37)及4-咪唑丙醯基-GLP-1。亦特別較佳為由Greig等人在Diabetologia 1999, 42, 45-50中所述之GLP促效劑類似物腸促胰島素類似物-4。 醛固酮合成酶抑制劑或其醫藥學上可接受之鹽理解為具有抑制醛固酮產生之特性的活性成分。醛固酮合成酶(CYP11B2)為催化腎上腺皮質中醛固酮產生之最後步驟(亦即11-去氧皮質酮轉化成醛固酮)之粒線體細胞色素P450酶。用所謂醛固酮合成酶抑制劑抑制醛固酮產生已知為治療血鉀過低、高血壓、充血性心臟衰竭、心房震顫或腎衰竭之成功變化形式。此類醛固酮合成酶抑制活性易於由熟習此項技術者根據標準分析(例如US 2007/0049616)來測定。 醛固酮合成酶抑制劑之類別包含類固醇及非類固醇醛固酮合成酶抑制劑,後者為最佳的。 較佳為市售之醛固酮合成酶抑制劑或已由衛生當局批准之彼等醛固酮合成酶抑制劑。 醛固酮合成酶抑制劑之類別包含具有不同結構特徵之化合物。舉例而言,可提及選自由以下各者組成之群的化合物:非類固醇芳香酶抑制劑阿那曲唑(anastrozole)、法屈唑(fadrozole) (包括其(+)-對映異構體),以及類固醇芳香酶抑制劑依西美坦(exemestane),或在適用之各情況下其醫藥學上可接受之鹽。 最佳非類固醇醛固酮合成酶抑制劑之實例為下式之法屈唑之鹽酸鹽的(+)-對映異構體(美國專利4617307及4889861)。 或若適當,則為其醫藥學上可接受之鹽。 較佳之類固醇醛固酮拮抗劑為下式之依普利酮(cf. EP 122232A)或螺內酯;或在各情況下若適當,為其醫藥學上可接受之鹽。 適用於該組合之醛固酮合成酶抑制劑為一般地且特定地揭示於例如US2007/0049616中,詳言之化合物申請專利範圍及實施例之最終產物中之化合物及類似物,最終產物、醫藥製劑及申請專利範圍之標的物以引用此公開案之方式併入本申請案中。 術語醛固酮合成酶抑制劑亦包括WO2008/076860、WO2008/076336、WO2008/076862、WO2008/027284、WO2004/046145、WO2004/014914、WO2001/076574中所揭示之化合物及類似物。 此外,醛固酮合成酶抑制劑亦包括美國專利申請案US2007/0225232、US2007/0208035、US2008/0318978、US2008/0076794、US2009/0012068、US20090048241及PCT申請案WO2006/005726、WO2006/128853、WO2006128851、WO2006/128852、WO2007065942、WO2007/116099、WO2007/116908、WO2008/119744及歐洲專利申請案EP 1886695中所揭示之化合物及類似物。 術語「CETP抑制劑」係指抑制膽甾醇酯轉移蛋白(CETP)介導之自HDL傳送各種膽甾醇酯及甘油三酯至LDL及VLDL之化合物。此類CETP抑制活性易於由熟習此項技術者根據標準分析(例如美國專利第6,140,343號)來測定。實例包括揭示於美國專利第6,140,343號及美國專利第6,197,786號中之化合物(例如,[2R,4S]4-[(3,5-雙-三氟甲基-苯甲基)-甲氧羰基-胺基]-2-乙基-6-三氟甲基-3,4-二氫-2H-喹啉-1-甲酸乙酯(托徹普(torcetrapib));揭示於美國專利第6,723,752號中之化合物(例如(2R)-3-{[3-(4-氯-3-乙基-苯氧基)-苯基]-[[3-(1,1,2,2-四氟-乙氧基)-苯基]-甲基]-胺基}-1,1,1-三氟-2-丙醇);揭示於美國專利申請案第10/807,838號中之化合物;揭示於美國專利第5,512,548號中之多肽衍生物;分別揭示於J. Antibiot.
, 49(8): 815- 816 (1996)及Bioorg. Med. Chem. Lett.
; 6:1951-1954 (1996)中之膽甾醇酯之玫瑰菌素衍生物及含磷酸酯的類似物。此外,CETP抑制劑亦包括揭示於WO2000/017165、WO2005/095409及WO2005/097806中之彼等抑制劑。 在另一實施例中,其他治療劑係選自: 任何其他抗心律不整劑,諸如I類劑(例如奎尼丁、利多卡因及普羅帕酮)、II類劑(例如普萘洛爾)、III類劑(例如索他洛爾、多非利特、胺碘酮、決奈達隆、布地達隆、阿齊利特及伊布利特)、IV類劑(例如地爾硫卓及維拉帕米)、「V類劑」(例如腺苷)、強心苷(例如洋地黃及烏巴苷)及影響心房不應期之其他藥物(例如描述於WO2013112932中之I Na,Late
阻斷劑)。本發明之範例:
以下實例意欲說明本發明,且不應解釋為對其進行限制。溫度以攝氏度為單位給出。若未另外提及,則所有蒸發均在減壓下,通常在約15 mm Hg與100 mm Hg之間(= 20-133毫巴)進行。最終產物、中間物及起始物質之結構藉由標準分析方法(例如微量分析)及光譜特徵(例如MS、IR、NMR)來確定。所使用之縮寫為此項技術中習知之彼等者。 用於合成本發明化合物之所有起始物質、建構嵌段、試劑、酸、鹼、脫水劑、溶劑及催化劑均為市售可得的或可藉由一般熟習此項技術者已知的有機合成方法(Houben-Weyl第4版 1952, Methods of Organic Synthesis, Thieme, 第21卷)製得。此外,本發明化合物可藉由如以下實例中所示的一般熟習此項技術者已知之有機合成方法來產生。 已發現下文實例中之化合物對於GIRK1/4之IC50
值在約0.01 nM至約50,000 nM,更佳1nM至10,000 nM之範圍內。縮寫之列表 液相層析 (LC) 法 LC 方法 法 1 :
在Agilent 1100系統上利用XBridge C18管柱(3.5 µm,3.0×30 mm管柱)得到以分鐘為單位之滯留時間(Rt)。歷時1.7分鐘應用98/2至2/98之H2
O (+0.05%氫氧化銨)/CH3
CN (+0.05%氫氧化銨)之梯度,隨後在40℃之烘箱溫度下保持0.3分鐘(溶劑流速為2.0 mL/min)。LC 方 法 2
:在Agilent 1100系統上利用Sunfire C18管柱(3.5 µm,3.0×30 mm管柱)得到以分鐘為單位之滯留時間(Rt)。歷時1.7分鐘應用95/5至5/95之H2
O (+0.05%三氟乙酸)/CH3
CN (+0.05%三氟乙酸)之梯度,隨後在40℃之烘箱溫度下保持0.3分鐘(溶劑流速為2.0 mL/min)。LC 方 法 3
:在Agilent 1100系統上利用XBridge C18管柱(3.5 µm,3.0×30 mm管柱)得到以分鐘為單位之滯留時間(Rt)。歷時1.7分鐘應用98/2至2/98之H2
O (+0.05%氫氧化銨)/CH3
CN (+0.05%氫氧化銨)之梯度,隨後在40℃之烘箱溫度下保持0.3分鐘(溶劑流速為2.0 mL/min)。LC 方 法 4 :
在Waters AcQuity UPLC系統上利用AcQuity UPLC BEH C18 1.7µm 2.1×30mm管柱得到以分鐘為單位滯留時間(Rt)。歷時1.7分鐘應用98/2至2/98之H2
O (+0.05%氫氧化銨)/CH3
CN (+0.05%氫氧化銨)之梯度,隨後在50℃之烘箱溫度下保持0.3分鐘(溶劑流速為1.0 mL/min)。合成中間產物 1 至 13 5,8- 二氯 -1-(2,6- 二氯苯基 )-2- 甲基 -1,6- 萘啶 -4(1H)- 酮 ( 中間產物 1) 步驟 1 :
2,4,5-三氯菸鹼醛在-78℃下向2,4,5-三氯吡啶(5 g,27.4 mmol)於THF (150 ml)中之溶液中添加LDA (2 M於庚烷中,20.56 ml,41.1 mmol)。在-78℃下攪拌混合物1小時。隨後將於THF (20 mL)中之甲酸甲酯(8.23 g, 137 mmol)迅速添加至反應混合物,接著在-78℃下攪拌1小時。用飽和NH4
Cl水溶液淬滅反應混合物三次且用EtOAc萃取。合併之有機層經無水Na2
SO4
乾燥且在減壓下移除揮發物。用矽膠層析(於庚烷中之10-100% EtOAc)純化殘留物以獲得呈固體狀之標題化合物(4.2 g,73%產率)。ESI-MS m/z:211.8 [M+H]+
(Rt= 0.86 min,LC-方法1)1
H NMR (400 MHz, DCM-d 2
) δ ppm = 10.43 (s, 1H), 8.61 (s, 1H)。步驟 2 :
1-(2,4,5-三氯吡啶-3-基)丁-2-炔-1-醇在0℃下向於THF (30 ml)中之2,4,5-三氯菸鹼醛(2.11 g,10.03 mmol)溶液中添加溴化丙-1-炔-1-基鎂(0.5 M於THF中,26.1 ml,13.03 mmol)。在0℃下攪拌反應混合物1小時。向混合物中添加飽和NH4
Cl水溶液隨後用EtOAc萃取。合併之有機層用水及鹽水洗滌,經無水Na2
SO4
乾燥且在減壓下濃縮。用矽膠層析(於庚烷中之10-100% EtOAc)純化粗產物,得到標題化合物(1.95 g,78%產率)。ESI-MS m/z: 250.0 [M+H]+
(Rt = 0.94 min, LC-方法1)1
H NMR (400 MHz, DCM-d 2
) δ ppm = 8.42 (s, 1H), 6.13 (s, 1H), 3.11 (bs, 1H), 1.90 (s, 3H)。步驟 3 :
1-(2,4,5-三氯吡啶-3-基)丁-2-炔-1-酮使於DCM (60 ml)中之1-(2,4,5-三氯吡啶-3-基)丁-2-炔-1-醇(3.4 g,13.57 mmol)冷卻至0℃。隨後添加戴斯-馬丁試劑(6.91 g,16.29 mmol)。所得溶液在室溫下攪拌1小時。隨後謹慎地將其用飽和NaHCO3
溶液淬滅,接著用DCM稀釋。有機層用鹽水洗滌,用無水MgSO4
乾燥,經過濾且在減壓下濃縮。用矽膠層析(於庚烷中之10-100% EtOAc)純化粗產物,得到標題化合物(2.6 g,77%產率)。ESI-MSm
/z
: 248.0 [M+H]+
(Rt = 1.15 min, LC-方法1)1
H NMR (400 MHz, DCM-d 2
) δ ppm = 8.51 (s, 1H), 2.16 (s, 3H)。步驟 4 :
(E)-3-((2,6-二氯苯基)胺基)-1-(2,4,5-三氯吡啶-3-基)丁-2-烯-1-酮在0℃下向1-(2,4,5-三氯吡啶-3-基)丁-2-炔-1-酮(2.36 g,9.50 mmol)及2,6-二氯苯胺(1.69 g,10.45 mmol)於50 ml DCM中之溶液中添加AlCl3
(1.52 g,11.40 mmol)。在室溫下將反應混合物攪拌隔夜。向反應混合物中添加2 N NaOH溶液且其用DCM萃取三次。合併之有機層經無水Na2
SO4
乾燥且在減壓下濃縮。用矽膠層析(於庚烷中之10-100% EtOAc)純化粗產物,得到標題化合物(2.99 g,77%)。 ESI-MSm
/z
: 410.9 [M+H]+
(Rt = 1.39 min, LC法1)步驟 5 :
5,8-二氯-1-(2,6-二氯苯基)-2-甲基-1,6-萘啶-4(1H)-酮在室溫下向3-((2,6-二氯苯基)胺基)-1-(2,4,5-三氯吡啶-3-基)丁-2-烯-1-酮(2.99 g,7.28 mmol)於45 ml DMF中之溶液中添加K2
CO3
(3.02 g,21.85 mmol)。攪拌所得溶液隔夜。用水稀釋反應物且用EtOAc萃取三次。合併之有機層用鹽水洗滌,經無水Na2
SO4
乾燥且在減壓下濃縮。用矽膠層析(於庚烷中之10-100% EtOAc)純化粗產物,得到標題化合物(1.8 g,66%產率)。ESI-MSm
/z
: 375.0 [M+H]+
(Rt = 1.06 min, LC-方法1)1
H NMR (400 MHz, DMSO-d 6
) δ ppm = 8.51 (s, 1H), 7.83 - 7.72 (m, 3H), 6.63 (d,J
= 0.7 Hz, 1H), 1.94 (s, 3H)。5 , 8- 二氯 -1-(2,6- 二氯 -4- 氟苯基 )-2- 甲基 -1,6- 萘啶 -4(1H)- 酮 ( 中間產物 2) 在合成程序之步驟4中以與中間產物1
類似的方式但使用2,6-二氯-4-氟苯胺製備中間產物2
以獲得作為標題化合物之白色粉末。2
:1
H NMR (400 MHz, DMSO-d6
) δ ppm = 8.32 - 8.76 (m, 1 H), 7.92 (d, J=8.31 Hz, 2 H), 6.63 (d, J=0.73 Hz, 1 H), 1.96 (s, 3 H)。3,5- 二氯 -4-(5,8- 二氯 -2- 甲基 - 4- 側氧基 -1,6- 萘啶 -1(4H)- 基 ) 苯甲腈 ( 中間產物 3) 在合成程序之步驟4中以與中間產物1
類似的方式但使用2,6-二氯-4-氰基苯胺及BF3
*OEt2
製備中間產物3
以獲得黃色粉末。3 : 1
H NMR (400 MHz, 氯仿-d3
) δ ppm = 8.33 (s, 1H), 7.80 (s, 2H), 6.49 (d,J
= 0.7 Hz, 1H), 1.95 (d,J
= 0.6 Hz, 3H)。1-(4- 溴 -2,6- 二氯苯基 )-5,8- 二氯 -2- 甲基 - 1,6- 萘啶 -4(1H)- 酮 ( 中間產物 4) 在合成程序之步驟4中以與中間產物1
類似的方式但使用2,6-二氯-4-氟苯胺製備中間產物4
以獲得作為標題化合物之白色粉末。4
:1
H NMR (400 MHz, DMSO-d
6) δ ppm = 8.53 (s, 1H), 8.16 (s, 2H), 6.62 (d, J = 0.7 Hz, 1H), 1.96 (s, 3H)3- 氯 -2-(5,8- 二氯 -2- 甲基 -4- 側氧基 -1,6- 萘啶 -1(4H)- 基 ) 苯甲腈 ( 中間產物 5) 在如下文所述之合成程序的步驟4中以與中間產物1
類似的方式但使用2-氰基-6-氯苯胺及三氟甲磺酸鈧製備中間產物5。步驟 4 :
3-氯-2-((4-側氧基-4-(2,4,5-三氯吡啶-3-基)丁-2-烯-2-基)胺基)苯甲腈在室溫下向1-(2,4,5-三氯吡啶-3-基)丁-2-炔-1-酮(600 mg,2.415 mmol)及2-胺基-3-氯苯并腈(0.368 g,2.415 mmol)於DCM (15 ml)中之混合溶液中謹慎地添加三氟甲烷磺酸鈧(1.12 g,2.415 mmol)。在室溫下攪拌隔夜之後,用1 N NaOH水溶液淬滅混合物,產物用DCM萃取。有機層用鹽水洗滌,經無水硫酸鈉乾燥,過濾且在真空中濃縮。藉由矽膠管柱層析用0-50%於庚烷中之EtOAc洗脫來純化粗殘留物以提供產物:3-氯-2-((4-側氧基-4-(2,4,5-三氯吡啶-3-基)丁-2-烯-2-基)胺基)苯甲腈(0.166 g,17.2%), ESI-MS m/z:400.2 [M+H]+
及3-氯-2-(5,8-二氯-2-甲基-4-側氧基-1,6-萘啶-1(4H)-基)苯甲腈(0.143 g,16.2%產率)ESI-MS m/z:364.2 [M+H]+ 1
H NMR (400 MHz, MeCN-d
3) δ ppm = 8.36 (s, 1 H) 7.87 - 8.06 (m, 2 H) 7.62 - 7.85 (m, 1 H) 6.47 (d,J
=0.63 Hz, 1 H) 1.98 (s, 3 H)步驟 5 :
3-氯-2-(5,8-二氯-2-甲基-4-側氧基-1,6-萘啶-1(4H)-基)苯甲腈在95℃攪拌下3-氯-2-((4-側氧基-4-(2,4,5-三氯吡啶-3-基)丁-2-烯-2-基)胺基)苯甲腈(0.49 g,1.22 mmol)及碳酸鉀(0.422 g,3.05 mmol)於DMF (10 mL)中之混合物1小時。冷卻至室溫後,混合物用水稀釋,且產物用EtOAc萃取。有機層用水、鹽水洗滌,經無水硫酸酯乾燥,過濾且在減壓下濃縮。經由矽膠急驟層析使用0-100%EtOAc/於庚烷中作為洗脫劑來純化殘留物,得到標題化合物(0.31 g,70%)。5 :
ESI-MSm
/z
:364.2 [M+H]+
。1
H NMR (400 MHz, MeCN-d 3
) δ ppm = 8.36 (s, 1 H) 7.87 - 8.06 (m, 2 H) 7.62 - 7.85 (m, 1 H) 6.47 (d,J
=0.63 Hz, 1 H) 1.98 (s, 3 H)3- 氯 -2-(5 , 8- 二氯 -2- 甲基 -4- 側氧基 -1,6- 萘啶 -1(4H)- 基 )-5- 氟苯甲腈 ( 中間產物 6) 以與中間產物5類似的方式但使用2-胺基-3-氯-5-氟苯甲腈製備中間產物6
,其藉由以下程序合成以獲得白色粉末。6 :
ESI-MSm
/z
:382.2 [M+H]+
製備2-胺基-3-氯-5-氟苯甲腈將NCS (4.75 g,35.6 mmol)添加至2-胺基-5-氟苯甲腈(4.4 g,32.3 mmol)於MeCN (92 ml)中之溶液中。在80℃下攪拌所得混合物隔夜。在體積於真空中減少至一半之後,將殘留物倒入水中,沈澱物藉由過濾來採集,用水洗滌,經乾燥以提供所期望的苯胺(4 g,73%)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm = 7.64 (dd,J
=8.40, 2.97 Hz, 1 H) 7.50 (dd,J
=8.40, 2.97 Hz, 1 H) 6.08 (br s, 2 H)2-((( 第三丁基二甲基矽烷基 ) 氧基 ) 甲基 )-5,8- 二氯 -1-(2,6- 二氯苯基 )-1,6- 萘啶 -4(1H)- 酮 ( 中間產物 7 ) 步驟 1 :
2,4,5-三氯菸鹼醛在-78℃下向2,4,5-三氯吡啶(5 g,27.4 mmol)於150 ml THF中之溶液中添加LDA (2 M於庚烷中,20.56 ml,41.1 mmol)。在-78℃下攪拌混合物1小時。隨後將於THF (20 mL)中之甲酸甲酯(8.23 g, 137 mmol)迅速添加至反應混合物,接著在-78℃下攪拌1小時。用飽和NH4
Cl水溶液淬滅反應混合物三次且用EtOAc萃取。合併之有機層經無水Na2
SO4
乾燥,且在減壓下移除揮發物。用矽膠層析(於庚烷中之10-100%EtOAc)純化殘留物以獲得呈固體狀的所需化合物(4.2 g,73%)。ESI-MSm
/z
: 211.8 [M+H]+
(Rt= 0.86 min,LC-方法1),1
H NMR (400 MHz, DCM-d 2
) δ ppm = 10.43 (s, 1H), 8.61 (s, 1H)。步驟 2 :
4-((第三丁基二甲基矽烷基)氧基)-1-(2,4,5-三氯吡啶-3-基)丁-2-炔-1-醇使於20 ml THF中之第三丁基二甲基(丙-2-炔-1-基氧基)矽烷(11.14 g,65.4 mmol)冷卻至-78℃且逐滴添加n-BuLi (1.6 M,24.52 ml,39.2 mmol)。在-78℃下攪拌混合物45分鐘,且隨後用2,4,5-三氯菸鹼醛(6.88 g,32.7 mmol)於40 ml THF中之溶液處理。使混合物在-78℃下攪拌2小時。由LC-MS監測反應進程,其顯示醛起始材料之徹底消耗。混合物用飽和NH4
Cl淬滅,且用EtOAc萃取。有機層用水和鹽水洗滌,在Na2
SO4
下乾燥,過濾且減壓濃縮以得到呈黃色液體狀之粗化合物,其在無其他任何純化之情況下使用。ESI-MSm
/z
:382 [M+H]+
(Rt = 1.47 min,LC-方法1)1
H NMR (400 MHz, DCM-d 2
) δ ppm = 8.32 (s, 1H), 6.27 - 5.96 (m, 1H), 4.40 - 4.15 (m, 2H), 0.93 (s, 9H), 0.02 (s, 6H)。步驟 3 :
4-((第三丁基二甲基矽烷基)氧基)-1-(2,4,5-三氯吡啶-3-基)丁-2-炔-1-酮在0℃下向4-((第三丁基二甲基矽烷基)氧基)-1-(2,4,5-三氯吡啶-3-基)丁-2-炔-1-醇(12.45 g,32.7 mmol)於DCM (131 ml)中之攪拌溶液中添加戴斯-馬丁高碘烷(16.64 g,39.2 mmol)。所得溶液在室溫下攪拌30分鐘。由LC-MS監測反應進程,其顯示起始材料之徹底消耗。反應混合物用NaHCO3
飽和溶液謹慎地淬滅,接著用DCM稀釋。過濾出沈澱物。有機層用飽和NaHCO3
洗滌且用鹽水洗滌,經無水Na2
SO4
乾燥。在減壓下濃縮有機層。藉由矽膠管柱層析(於庚烷中之10-100% EtOAc)來純化粗化合物以獲得所需化合物(7.5 g,61%)。ESI-MSm
/z
:380 [M+H]+
(Rt = 1.66 min,LC-方法1)1
H NMR (400 MHz, DCM-d 2
) δ ppm = 8.38 (s, 1H), 4.44 (s, 2H), 0.82 (s, 9H), 0.01 (s, 6H)。步驟 4 :
(E)-4-((第三丁基二甲基矽烷基)氧基)-3-((2,6-二氯苯基)胺基)-1-(2,4,5-三氯吡啶-3-基)丁-2-烯-1-酮在0℃下向4-((第三丁基二甲基矽烷基)氧基)-1-(2,4,5-三氯吡啶-3-基)丁-2-炔-1-酮(7.41 g,19.56 mmol)於DCM (185 ml)中之攪拌溶液中添加2,6-二氯苯胺(3.49 g,21.52 mmol)接著一次性添加AlCl3
(2.87 g,21.52 mmol),且反應混合物在室溫下攪拌2小時。由LC-MS監測反應進程,其顯示起始材料之徹底消耗。向反應混合物添加2 N NaOH(20 mL)且混合物在室溫下攪拌30分鐘。反應混合物用DCM萃取且合併之有機層用鹽水洗滌經無水Na2
SO4
乾燥。在減壓下濃縮有機層。藉由矽膠管柱層析(於庚烷中之10-100% EtOAc)來純化粗化合物以獲得標題化合物(6.4 g,61%產率)。ESI-MSm
/z
:540.9 [M+H]+
(Rt = 2.01min,LC-方法1)步驟 5 :
2-(((第三丁基二甲基矽烷基)氧基)甲基)-5,8-二氯-1-(2,6-二氯苯基)-1,6-萘啶-4(1H)-酮向(E)-4-((第三丁基二甲基矽烷基)氧基)-3-((2,6-二氯苯基)胺基)-1-(2,4,5-三氯吡啶-3-基)丁-2-烯-1-酮(6.37 g,11.78 mmol)於DMF (47 ml)中之攪拌溶液中添加碳酸鉀(8.14 g,58.9 mmol)且反應混合物在80℃下攪拌3小時。將反應混合物倒入冰水中稀釋且用EtOAc萃取。合併之有機層用鹽水洗滌,經無水Na2
SO4
乾燥且在減壓下蒸發。藉由矽膠管柱層析(於庚烷中之10-100% EtOAc)來純化粗化合物以獲得所需化合物(4.6 g,77%產率)。7 :
ESI-MSm
/z
:504.9 [M+H]+
(Rt = 1.62, LC-方法1)1
H NMR (400 MHz, DCM-d 2
) δ ppm = 8.26 (s, 1H), 7.48 (d,J
= 2.0 Hz, 3 H), 6.73 (s, 1H), 4.05 - 3.90 (m, 2H), 0.85 (s, 9H). 0.01 (s, 6H)。5,8- 二氯 -1-(2,6- 二氯苯基 )-2-( 甲氧基甲基 )-1,6- 萘啶 -4(1H)- 酮 ( 中間產物 8) 在合成程序之步驟2中以與中間產物7
類似的方式但使用3-甲氧基丙-1-炔製備中間產物8
以獲得白色粉末。8 :
ESI-MSm
/z
:405.2 [M+H]+
(Rt = 1.08 min,LC-方法1);1
H NMR (400 MHz, DCM-d 2
) δ ppm = 8.33 (s, 1H), 7.63 - 7.49 (m, 3H), 6.71 (s, 1H), 3.88 (s, 2H), 3.32 (s, 3H)。3- 氯 -2-(5,8- 二氯 -2- 環丙基 -4- 側氧基 -1,6- 萘啶 -1(4H)- 基 ) 苯甲腈 ( 中間產物 9 ) 在合成程序之步驟2中以與中間產物7
類似的方式但使用乙炔基環丙烷並且在步驟4中使用2-胺基-3-氯苯并腈製備中間產物9
以獲得白色粉末。9
:ESI-MSm
/z
:392.0 [M+H]+
(Rt = 1.01 min,LC-方法1)8- 溴 -5- 氯 -1-(2,6- 二氯苯基 )-2- 甲基 -1,6- 萘啶 -4(1H)- 酮 ( 中間產物 10) 以與中間產物1
類似的方式使用5-溴-2,4-二氯吡啶作為起始物質製備中間產物10
以獲得白色粉末。10
:1
H NMR (400 MHz, 氯仿-d3
) δ ppm = 8.50 (s, 1H), 7.50 (s, 3H), 6.51 (d,J
= 0.7 Hz, 1H), 1.96 (dd,J
= 2.5, 0.7 Hz, 3H)。5,7- 二氯 -1-(2,6- 二氯苯基 )-2- 甲基 -1,6- 萘啶 -4(1H)- 酮 ( 中間產物 11) 步驟 1 :
2,4,6-三氯菸鹼醛使於無水THF (100 ml)中之2,4,6-三氯吡啶(5 g,27.4 mmol)冷卻至-78℃。在-78℃下緩慢添加正丁基鋰溶液(22.27 ml,28.8 mmol)(1.6 M於己烷中)。溶液在-78℃下攪拌30分鐘,隨後用甲酸乙酯溶液(10.15 g,137 mmol)處理,使內部溫度維持在低於-74℃。在-78℃下攪拌所得溶液直至所有起始材料耗盡(由TLC監測,9:1庚烷/EtOAc),隨後在-78℃下用飽和氯化銨溶液及50 ml 0.5N HCl水溶液在劇烈攪拌下淬滅。隨後使其升溫至室溫。經淬滅混合物用EtOAc萃取,有機相用鹽水洗滌,經MgSO4
乾燥且濃縮。藉由矽膠急驟層析用0-20% EtOAc/庚烷純化粗殘留物(淡黃色固體)以提供5.1 g (88%產率)呈白色固體之所需2,4,6-三氯菸鹼醛。1
H NMR (400 MHz, 氯仿-d
3) δ ppm = 10.42 (s, 1H), 7.45 (s, 1H)。 其餘步驟以如對中間產物1
所述之類似的方式來製備,製得呈白色粉末狀之中間產物11
。11: 1
H NMR (400 MHz, 氯仿-d3
) δ ppm = 7.75 - 7.53 (m, 3H), 6.42 (d,J
= 0.8 Hz, 1H), 6.29 (s, 1H), 1.97 (d,J
= 0.8 Hz, 3H)。3,5- 二氯 -4-( 5- 氟 -2- 甲基 -4- 側氧基 -1,7- 萘啶 -1(4H)- 基 ) 苯甲腈 ( 中間產物 12) 步驟 1 :
3,5-二氟-N-甲氧基-N-甲基異菸鹼醯胺使3,5-二氟異菸酸(18.78 g,118 mmol)、N,O-鹽酸二甲基羥胺(12.09 g,124 mmol)、HATU (47.1 g,124 mmol)及DIPEA (61.9 ml,354 mmol)懸浮於DCM (236 ml)中。使混合物在室溫下攪拌24小時。混合物在減壓下濃縮。殘留物用EtOAc萃取,用飽和NH4
Cl水溶液(2×)、水、飽和NaHCO3
及鹽水洗滌。有機層經硫酸鈉乾燥且濃縮。藉由矽膠層析使用於庚烷中之0-75% EtOAc作為洗脫劑純化粗產物,得到標題化合物(18.9 g,79%產率)。ESI-MSm
/z
:203.1 [M+H]+
(Rt = 0.81 min,LC-方法2)1
H NMR (400 MHz, DMSO-d 6
) δ ppm = 9.16 (s, 2H), 4.03 (s, 3H), 3.82 (s, 3H)。步驟 2 :
3,5-二氟-N-甲氧基-N-甲基異菸鹼醯胺將3,5-二氟-N-甲氧基-N-甲基異菸鹼醯胺(10.25 g,50.7 mmol)溶解於THF(127 ml)中且使反應混合物冷卻至0℃。隨後使用添加漏斗緩慢添加(約30分鐘)溴化丙-1-炔-1-基鎂(0.5 M於THF中,304 ml,152 mmol)且使混合物隔夜升溫至室溫。第二天,藉由在0℃下將其添加至0.5 N HCl攪拌溶液中來淬滅且用DCM萃取(3×)。經硫酸鈉乾燥經合併之有機層且在減壓下濃縮。用矽膠層析(於庚烷中之0-50% EtOAc)純化殘留物以獲得呈固體狀之標題化合物(7.22 g,79%產率)。ESI-MSm
/z
:182.0 [M+H]+
(Rt = 1.11 min, LC-方法2);1
H NMR (400 MHz, DMSO-d 6
) δ ppm = 8.74 (s, 2H), 2.22 (s, 3H)。步驟 3 :
3-(2,6-二氯-4-氰基苯基)-6-(3,5-二氟吡啶-4-基)-2,2-二氟-4-甲基-2,3-二氫-1,3,2-氧雜硼雜苯-1-鎓-2-鹽將1-(3,5-二氟吡啶-4-基)丁-2-炔-1-酮(7.86 g,43.4 mmol)及4-胺基-3,5-二氯苯甲腈(9.74 g,52.1 mmol)溶解於DCM (174 ml)中,且混合物用BF3
*OEt2
處理(16.50 ml,130 mmol)。在50℃下攪拌反應混合物隔夜。第二天經由緩慢添加至飽和NaHCO3
溶液將其淬滅。一些MeOH用於徹底溶解及轉移反應混合物。用DCM (3×)萃取混合物。經硫酸鈉乾燥經合併之有機層且在減壓下濃縮。藉由矽膠管柱層析(於庚烷中之10-100% EtOAc)純化殘留物,得到標題化合物(10.05 g,55.7%產率)。 ESI-MSm
/z
: 368.0 [M+H]+
(Rt = 1.43 min,LC-方法2)步驟 4 :
3,5-二氯-4-(5-氟-2-甲基-4-側氧基-1,7-萘啶-1(4H)-基)苯甲腈將3-(2,6-二氯-4-氰基苯基)-6-(3,5-二氟吡啶-4-基)-2,2-二氟-4-甲基-2,3-二氫-1,3,2-氧雜氮雜硼雜苯-1-鎓-2-鹽(17.16 g,41.3 mmol)及K2
CO3
(28.5 g,206 mmol)於THF (110mL)及MeOH (55mL)中之混合物在50℃下加熱1.5小時。向反應混合物添加EtAOc。溶液用水和鹽水洗滌、經Na2
SO4
乾燥、過濾且在真空中濃縮。藉由矽膠急驟管柱層析(於庚烷中之0-100% EtOAc)純化殘留物以提供標題化合物(8.26 g,57%)。12 :
HRMS計算值 348.0095 [M+H]+
; 測定值348.0102;1
H NMR (400 MHz, DMSO-d
6) δ ppm = 9.06 (s, 2H), 8.99 (d,J
= 2.3 Hz, 1H), 8.61 (s, 1H), 6.92 (s, 1H)。3,5- 二氯 -4-(5- 溴 -2- 甲基 -4- 側氧基 -1,7- 萘啶 -1(4H)- 基 ) 苯甲腈 ( 中間產物 13) 步驟 1 :
3-溴-5-氟異菸鹼醛在-78℃下向LDA溶液(1 M於己烷/THF中,12.55 mL,12.55 mmol)中逐滴添加3-溴-5-氟吡啶(1.84 g,10.46 mmol)於THF (20 ml)中之溶液。在-78℃下攪拌混合物1小時。隨後向反應混合物中添加DMF (1.62 mL,1.53 g,20.91 mmol)。在於-78℃下攪拌30分鐘之後,反應混合物用飽和NaHCO3
水溶液淬滅接著用EtOAC萃取三次且用DCM萃取兩次。合併所有有機層且經無水Na2
SO4
乾燥。濾出固體。在減壓下移除揮發物且用矽膠層析(DCM)純化殘留物以獲得標題化合物(0.478 g,22%)。1
H NMR (400 MHz, 氯仿-d3
) δ ppm = 10.36 (s, 1H), 8.75 (s, 1H), 8.63 - 8.57 (m, 1H)。步驟 2 :
1-(3-溴-5-氟吡啶-4-基)丁-2-炔-1-醇在0 ℃下向3-溴-5-氟異菸鹼醛(0.656 g,3.22 mmol)於THF (5 mL)中之溶液中添加溴化丙-1-炔-1-基鎂溶液(0.5 M於THF中,8.36 mL,4.18 mmol)。在於0 ℃下攪拌2小時之後,添加過量飽和NaHCO3
溶液以淬火反應混合物接著用EtOAc萃取兩次且用DCM萃取兩次。合併所有有機層且經無水Na2
SO4
乾燥。濾出固體。在減壓下移除揮發物以獲得標題化合物(0.78 g,99%)。其未經進一步純化即直接用於下一步驟中。ESI-MSm
/z
: 245.9 [M+H]+
(Rt = 0.92 min., LC-方法3)步驟 3 :
1-(3-溴-5-氟吡啶-4-基)丁-2-炔-1-酮在0℃下向1-(3-溴-5-氟吡啶-4-基)丁-2-炔-1-醇(0.78 g,3.2 mmol)於DCM (30 mL)中之溶液中添加戴斯-馬丁試劑(1.63 g,3.84 mmol)。在室溫下攪拌反應混合物30分鐘接著用過量飽和NaHCO3
水溶液淬滅。用DCM萃取混合物三次。合併所有DCM層,經濃縮且隨後用矽膠層析(10%EtOAc/庚烷)純化以獲得標題化合物。ESI-MSm
/z
: 244.2 [M+H]+
(Rt = 1.17 min, LC-方法3)。步驟 4 :
4-((4-(3-溴-5-氟吡啶-4-基)-4-側氧基丁-2-烯-2-基)胺基)-3,5-二氯苯甲腈及6-(3-溴-5-氟吡啶-4-基)-3-(2,6-二氯-4-氰基苯基)-2,2-二氟-4-甲基-2H-1,3,2-氧雜氮雜硼雜苯-3-鎓-2-鹽1-(3-溴-5-氟吡啶-4-基)丁-2-炔-1-酮(2.50 g,10.33 mmol)、4-胺基-3,5-二氯苯甲腈(2.22 g,11.88 mmol)及BF3
*OEt2
(8.80 g,62.0 mmol)於DCE (120 mL)中之混合物在80℃下攪拌隔夜。反應混合物用1 NNaOH水溶液淬滅,接著用DCM萃取三次。合併DCM層且經無水Na2
SO4
乾燥。濾出固體。在減壓下移除揮發物且用矽膠層析(10-50% EtOAc/庚烷)純化殘留物以獲得以下之混合物:4-((4-(3-溴-5-氟吡啶-4-基)-4-側氧基丁-2-烯-2-基)胺基)-3,5-二氯苯甲腈(ESI-MS m/z: 429.7 [M+H]+
(Rt= 1.22 min, LC-方法3)) 與其BF2
錯合物6-(3-溴-5-氟吡啶-4-基)-3-(2,6-二氯-4-氰基苯基)-2,2-二氟-4-甲基-2H-1,3,2-氧雜氮雜硼雜苯-3-鎓-2-鹽(ES-
-MS m/z: 475.9 [M-H]-
(Rt= 1.37 min, LC-方法3)) (總計3.84 g)。混合物直接用於下一步驟中。步驟 5 :
4-(5-溴-2-甲基-4-側氧基-1,7-萘啶-1(4H)-基)-3,5-二氯苯甲腈向獲自步驟4之混合物(2.50 g)於DMF (15 mL)中之溶液中添加K2
CO3
(3.22 g,23.31 mmol)。將反應混合物在100℃下攪拌25分鐘。濾出固體。在減壓下移除揮發物且用矽膠層析(20-50% EtOAc/庚烷)純化殘留物以獲得呈棕色固體狀之標題化合物(1.2 g)。13:
ESI-MSm
/z
: 410.0 [M+H]+ 1
H NMR (400 MHz, DMSO-d
6) δ ppm = 8.69 (s, 1 H), 8.58 (s, 2 H), 8.24 (s, 1 H), 6.50 (s, 1 H), 2.00 (s, 3 H)。實例之合成 實例 1 至 57 之合成
式Ia
、Ib
之以下實例已自中間產物1 至 13
藉由用醇及胺之親核芳族取代製備。若需要,作為最終步驟對分子中之額外醇官能基上的保護基進行去除保護基。通用方法:
在反應瓶中,使中間產物1 至 13
(通常0.1-0.25 mmol,1當量)、醇(5-10當量)或胺(1.2當量)、K2
CO3
(5-10當量)與DMAP (0.1-0.5當量)於MeCN (1-3 mL)中混合。在較差溶解度之情況下所使用的其他溶劑為THF或NMP或DMF。將所得反應混合物在80℃下加熱1-16小時。反應混合物用EtOAc稀釋且用水洗滌。有機層經Na2
SO4
乾燥,經過濾且在真空中濃縮。藉由矽膠層析或在非常極性產物之情況下藉由逆相HPLC(於MeCN/水中之0.1%氨)純化殘留物以獲得呈白色或灰白色固體狀之所需產物Ia 、 Ib
(40-80%產率)。在其中醇或胺具有數種反應性親核中心之情況下,試劑在用TBDMS、Boc基團保護額外的官能基或作為縮酮之情況下使用。在此情況下藉由在室溫下利用於DCM中之TFA處理、在0℃下利用於THF中之TBAF處理或在室溫下利用AcOH/水(約2/1)處理來去除保護基。在如上文所述之水溶液處理之後,藉由矽膠層析或在非常極性產物之情況下藉由逆相HPLC (於MeCN/水中之0.1%氨)純化粗產物以獲得呈白色或灰白色固體狀之所需產物Ia 、 Ib
。實例 1 : (S)-8- 氯 -1-(2,6- 二氯苯基 )-5-(2,3- 二羥基丙氧基 )-2-( 羥甲基 )-1,6- 萘啶 -4(1H)- 酮 步驟 1 :
將(R)-2-(((第三丁基二甲基矽烷基)氧基)甲基)-8-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-1,6-萘啶-4(1H)-酮 2-(((第三丁基二甲基矽烷基)氧基)甲基)-5,8-二氯-1-(2,6-二氯苯基)-1,6-萘啶-4(1H)-酮(中間產物7,1.3 g,2.58 mmol)溶解於MeCN(15 mL)中。此溶液用碳酸鉀(1.069 g,7.73 mmol)、DMAP (0.157 g,1.289 mmol)及(R)-(2,2-二甲基-1,3-二氧戊環-4-基)甲醇(1.022 g,7.73 mmol)處理。所得混合物在80℃下加熱隔夜。第二天將反應混合物濾出且用ACN沖洗。在真空中濃縮有機層。藉由矽膠管柱層析(於庚烷中之10-50% EtOAc)純化殘留物以提供標題化合物(0.8 g,52%產率)。ESI-MSm
/z
: 601.0 [M+H]+
(Rt = 3.53 min, LC-方法1);1
H NMR (400 MHz, DCM-d
2) δ ppm = 8.03 (s, 1H), 7.47 (s, 3H), 6.67 (s, 1H), 4.60 - 4.39 (m, 3H), 4.24 - 4.10 (m, 1H), 4.10 - 3.93 (m, 3H), 1.40 (s, 3H), 1.36 (s, 3H), 0.85 (s, 9H), 0.0 (s, 6H)。步驟 2 :
(S)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮 將水(2 ml)及乙酸(3 ml)預混合並且添加至含有(R)-2-(((第三丁基二甲基矽烷基)氧基)甲基)-8-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-1,6-萘啶-4(1H)-酮(0.280 g,0.467 mmol)之燒瓶中。為促進起始材料溶解,燒瓶經超聲處理5-10分鐘。反應混合物在室溫下攪拌隔夜並且接著進行LC/MS。其以26℃之光束電流溫度及20毫巴之真空在真空中濃縮。將大部分乙酸去除且其餘水溶液在冰浴中冷卻並且用EtOAc稀釋。緩慢添加10%碳酸鈉水溶液直至pH 7。分離各層,並且有機相用鹽水洗滌,經硫酸鈉乾燥,過濾,且濃縮。藉由矽膠管柱層析(於DCM中之0-10% MeOH)純化殘留物以得到具有97% ee之標題化合物(0.15 g,72%產率) (觀測到實例9
之約3%區位異構物形成) 。 1
: ESI-MSm
/z
: 446.9 [M+H]+
(Rt = 0.74 min, LC-方法4)1
H NMR (400 MHz, DCM-d
2) δ ppm = 8.13 (s, 1H), 7.58 - 7.43 (m, 3H), 6.94 (s, 1H), 4.70 (dd,J
= 11.2, 1.7 Hz, 1H), 4.39 (dd,J
= 11.2, 3.8 Hz, 1H), 4.07 (s, 2H), 4.04 - 3.97 (m, 1H), 3.91 (dd,J
= 11.7, 2.1 Hz, 1H), 3.78 (dd,J
= 11.6, 5.2 Hz, 1H)。 或者,可藉由以下步驟製備實例1:HPLC 法 :
管柱:Waters Acquity BEH C18長度100 mm,內徑2.1 mm,粒徑:1.7 µm。 移動相:A:0.05% TFA水溶液,B:0.05% TFA甲醇溶液 梯度:
流動速率 0.4 mL/min 偵測 UV 220 nm 管柱溫度:30攝氏度。 用於樣品製劑之溶劑:乙腈 手性方法: 管柱:Daicel Chiralpak IE-3。長度150 mm,內徑4.6 mm,粒徑:3.0 µm。 移動相:A:於庚烷中之0.1% TFA,B:乙醇。(等度程式:A/B=70/30;運行時間:25 min) 流動速率 1.0 mL/min 偵測 UV 265 nm 管柱溫度:40攝氏度步驟 1 :
2-{[(第三丁基二甲基矽烷基)氧基]甲基}-8-氯-1-(2,6-二氯苯基)-5-{[(4R)-2,2-二甲基-1,3-二氧環戊-4-基]甲氧基}-1,4-二氫-1,6-萘啶-4-酮 在-10℃至-5℃下向((R)-2,2-二甲基-[1,3]二氧戊環-4-基)-甲醇(6.3 g, 47.59 mmol)於THF (140 mL)中之溶液中逐滴添加(2M於THF中,24 mL,47.59 mmol)。使反應在-5℃至0℃下攪拌1小時。隨後在-10℃至-5℃下逐滴添加2-{[(第三丁基二甲基矽烷基)氧基]甲基}-5,8-二氯-1-(2,6-二氯苯基)-1,4-二氫-1,6-萘啶-4-酮(中間產物7:20 g,39.658 mmol)於THF (60 mL)中之溶液。反應混合物在30分鐘內緩慢升溫至室溫且攪拌2小時。藉由HPLC監測反應進程。若起始材料<0.5%,則開始處理,否則反應藉由HPLC監測再攪拌4至16小時。將內部溫度為20至25℃之THF/H2
O=20mL/2mL添加至反應混合物中,隨後添加內部溫度為20至25℃之20% NH4
Cl溶液(100 mL)。分離各層,且含水層用乙酸乙酯萃取(2 × 100 mL)。合併之有機層用水(100 mL)洗滌,接著用20%鹽水(100 mL)洗滌。 結晶:有機層在減壓下濃縮以得到約40 g殘留物,隨後使用正庚烷(2×400ml)進行共沸液蒸餾直至獲得50 g殘留物。將正庚烷(400 mL)添加至殘留物中並且在30分鐘內將混合物加熱至內部溫度60℃,保持1至2小時,且隨後過濾熱混合物。在10小時內使濾液冷卻至0℃且攪拌6小時。經由過濾分離所形成之沈澱。將此濕濾餅懸浮於乙酸乙酯(20 mL)及正庚烷(200 mL)中並且在30分鐘內加熱至55℃。在55℃下攪拌所得溶液30分鐘。使溶液在6小時內緩慢冷卻至0℃且保持至少3小時。所得沈澱經過濾及乾燥,獲得呈灰白色固體狀之標題化合物(13.8 g,57%產率)。 ESI-MSm
/z
: 601.0 [M+H]+
; HPLC純度: 98.9%, 對映體過量: 99.1%;1
H NMR (400 MHz, DMSO-d6) δ ppm = 8.26 (s, 1 H), 7.82 - 7.68 (m , 3H), 6.53 (s, 1H), 4.53 - 4.38 (m, 3H), 4.17-4.08 (m, 1H), 4.06 - 3.98 (m, 3H), 1.37 (s, 3H), 1.33 (s, 3H), 0.85 (s, 9H), 0.02 - -0.05 (m, 6H);13
C NMR (101 MHz, DMSO-d6) δ ppm = -5.22, 18.37, 26.05, 26.20, 27.02, 60.72, 66.30, 67.09, 73.85, 109.20,110.04, 111.18, 114.93, 129.48, 133.07, 133.90, 136.12, 145.07, 150.45, 151.56, 162.57, 175.16步驟 2 :
(R)-8-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮 向2-{[第三丁基二甲基矽烷基)氧基]甲基}-8-氯-1-(2,6-二氯苯基)-5-{[(4R)-2,2-二甲基-1,3-二氧環戊-4-基]甲氧基}-1,4-二氫-1,6-萘啶-4-酮(15 g,25 mmol)於THF (50 mL)中之溶液中逐滴添加 三水合氟化四丁基銨(9.5 g,30 mmol)於THF (25 mL)中之溶液,其中內部溫度為20至25℃。使反應混合物攪拌2小時。藉由HPLC監測反應進程。HPLC顯示在起始材料徹底消耗之情況下96.8%產物。使反應混合物冷卻至內部溫度0至5℃,且隨後在內部溫度為0至5℃之情況下逐滴添加冰水(75 ml),隨後為乙酸異丙酯(75 ml)。 分離各層,且含水層用乙酸異丙酯萃取(75 mL)。 合併之有機層用水(1×75 mL)洗滌,接著用20%鹽水(1×75 mL)洗滌。 結晶:有機層在真空下濃縮以得到40 g殘留物,且隨後添加乙酸異丙酯(5 x150 mL)以進行共沸液蒸餾直至獲得50 g殘留物。使混合物冷卻至20至25℃並且添加產物晶種(6 mg)。保持混合物內部溫度為20至25℃持續2小時,隨後在30分鐘內使混合物升溫至內部溫度35±3℃,保持30分鐘並且在6小時內添加正庚烷(150 mL)。使混合物在小時內冷卻至內部溫度0±3℃且老化至少3小時。經由過濾獲得所需產物,且濕濾餅用正庚烷(15 mL)洗滌,且隨後在40℃下經真空乾燥以得到呈淡黃色固體狀之標題化合物(10.5 g,86.5%產率)。 ESI-MSm
/z
: 486.9 [M+H]+
; HPLC純度: 98.3%, 對映體過量: 99.6%;1
H NMR (400 MHz, DMSO-d6) δ ppm = 8.23 (s, 1 H), 7.78 - 7.68 (m , 3H), 6.54 (s, 1H), 5.85 (t, J = 6.0 Hz, 1H), 4.49 - 4.37 (m, 3H), 4.14 - 4.08 (m, 1H), 4.04 - 3.97 (m, 1H), 3.78 (d, J = 5.26 Hz, 2H), 1.36 (s, 3H), 1.31 (s, 3H).13
C NMR (101 MHz, DMSO-d6) δ ppm = 26.20, 27.00, 58.86, 66.33, 67.11, 73.86, 109.21, 110.00, 111.16, 114.06, 129.48, 133.15, 133.80, 135.98, 136.01, 145.00, 150.25, 153.49, 162.58, 175.10步驟 3 :
(S)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮 向400 ml Flexy立方體中饋入乙腈(67.9 g)及(R)-8-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮(13.1g,1.0當量)。向另一100 mL燒瓶中添加乙腈(29.1 g)、水(1.96 g)及Bi(OTf)3
(4.42 g,0.25當量)。在20±3℃下歷時15分鐘將對應的Bi(OTf)3
溶液添加至flexy立方體。歷時40分鐘使反應混合物冷卻至10±3℃且在10±3℃下保持45分鐘。此後,歷時30分鐘使反應混合物冷卻至0±3℃且當反應藉由UPLC分析完成時在0±3℃下保持30分鐘。向反應混合物中緩慢添加5重量% NaHCO3
水溶液(67 g)以保持溫度低於10℃。添加乙酸乙酯(120 g)且使混合物升溫至室溫。分離各相且用乙酸乙酯(59 g)及異丙醇(5.1 g)萃取水溶液。合併之有機相用20重量%鹽水(75 g)洗滌。有機溶劑更換為異丙醇且在50-100毫巴下於50℃下濃縮成32.6克剩餘殘留物。在50±3℃下歷時30分鐘向殘留物中添加甲基-第三丁基醚(20 g)。混合物再攪拌30分鐘直至沈澱出更多固體。歷時1小時添加甲基-第三丁基醚(80 g)。歷時2小時使溫度冷卻至23±3℃,歷時1小時添加甲基-第三丁基醚(60 g)且保持2小時。固體經過濾;濕濾餅用異丙醇(3.9 g)與甲基-第三丁基醚(37 g)之混合溶劑洗滌兩次。隨後將粗材料在25 ±3℃下溶解於乙腈(27.2 g)及水(103 g)中以變為澄清溶液。添加晶種(48 mg)且攪拌30分鐘,接著歷時2小時添加水(137.5 g)。混合物保持在25 ±3℃下1小時,且隨後歷時7小時冷卻至0 ±3℃。其經過濾且用水洗滌濕濾餅。濕濾餅在真空中於60℃下乾燥16小時以提供呈淡黃色固體狀之(S)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮(7.95 g,66%產率)。 ESI-MSm
/z
: 445.011 [M+H]+
; HPLC純度: 99.34%, 對映體過量: 99.3%;1
H NMR (400 MHz, DMSO-d6) δ ppm = 8.28 (s, 1 H), 7.91 - 7.70 (m , 3H), 6.62 (s, 1H), 5.91 (s, 1H), 5.24 (t, J = 5.38 Hz, 1H), 4.85 (t, J = 5.75 Hz, 2H), 3.85 (br d, J = 5.38 Hz, 2H), 3.75 (t, J = 5.56 Hz, 4H);13
C NMR (101 MHz, DMSO-d6) δ ppm = 58.27, 63.36,68.90, 69.03, 109.24 , 110.52, 113.35, 128.93, 132.48, 133.29, 135.35, 144.26, 149.95, 153.26, 162.20, 174.94 實例1A (水合物形式B):再結晶 :
在50℃下於攪拌下向實例1之200 mg非晶材料中添加1 ml乙腈/水(9:1,v/v)以得到澄清溶液。在此溫度下攪拌1小時之後,使溶液緩慢冷卻至5℃且出現白色沈澱。沈澱藉由離心分離且在40℃下乾燥12小時。獲得化合物之白色結晶粉末(改性水合物形式B)。 或者,水合物B可藉由在25℃下使(S)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮(來自實例1之任何形式)暴露於92% RH超過72小時或藉由在25℃下使(S)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮(來自實例1之任何形式)在純水中漿化至少72小時來產生。 a) X射線粉末繞射(XRPD)方法描述 在具有CuKα陽極(CuKα輻射(λ = 1.5418Å))之Bruker™D8 Advance繞射儀上記錄x射線粉末繞射圖案。將約75-100 mg之樣品置放於零背景矽晶圓試樣夾上且以x射線束為中心。由此確定之X射線繞射圖案顯示於圖1中且藉由最重要線條之反射線條表示於下文表2中。 表2.
b)差示掃描熱量測定(DSC)及熱解重量分析(TGA) 形式B之差示掃描熱量測定(DSC)及熱解重量分析(TGA)使用TA儀器公司Q2000 (DSC)及Q5000 (TGA)跡線利用圖式2至3中指定之加熱範圍獲得。DSC 方法描述
準確稱重0.5-1.5 mg各測試物質至具有針孔之樣品盤中及封閉(密閉式)樣品盤中。空樣品盤用作參考。DSC熱分析圖記錄如下:將設備之溫度調節至約-40℃,且以10℃/min之加熱速率在50 mL/min之氮氣流下加熱至300℃。用至少99.9999%純度之銦在50 mL/min之氮氣流下以10℃/min之加熱速率對於溫度及焓校準儀器至300℃。使用此方法所測量的樣品溫度之準確度在約±1℃內,且熔化熱可在約±5%之相對誤差內量測。 對於針孔樣品盤(圖2)l玻璃溫度起始:T起始
= 38.77℃,熔化吸熱起始:T起始
= 113.69℃ 對於密閉式樣品盤(圖3);熔化吸熱起始:T起始
= 82.30℃TGA 方法描述
準確稱重10-20 mg測試物質至Al-樣品盤中。TGA熱分析圖記錄如下:為避免重量損失,樣品盤具有氣密密封式蓋,該蓋僅在將樣品裝載至爐中之前的時刻自動刺穿。將溫度平衡至30℃且在25 mL/min之氮氣流下以10℃/min之加熱速率加熱至200℃。 用鎳及鋁對於溫度校準儀器,且用5及10 mg標準物對於重量校準。(圖4) 表1中之以下實例使用方法A製備:表 1 :實例 2-58 實例 40 之外消旋化合物之手性分離 實例 58 及 59 : 實例 58 及 59 中之一者為 (R)-8- 氯 -1-(2,6- 二氯苯基 )-5-(2,3- 二羥基 -3- 甲基丁氧基 )-2- 甲基 -1,6- 萘啶 -4(1H)- 酮 且另一者為 (S)- 8- 氯 -1-(2,6- 二氯苯基 )-5-(2,3- 二羥基 -3- 甲基丁氧基 )-2- 甲基 -1,6- 萘啶 -4(1H)- 酮
將8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基-3-甲基丁氧基)-2-甲基-1,6-萘啶-4(1H)-酮溶解於甲醇中且以各為1.6 ml之多個注射劑形式提供至手性製備型SFC (ChiralPak AD-H管柱,250×330 mm ID,5 μm,在38℃下流動速率80 ml/min),其使用於二氧化碳中之35% 2-丙醇作為移動相。在手性分離之後,洗脫份經由旋轉蒸發乾燥以得到作為第一洗脫峰(>99% ee)之實例58
及作為第二洗脫峰(>99% ee)之呈白色固體狀之實例59
。滯留時間在ChiralPak AD-H管柱上獲得,4.6×100 mm,5 µm管柱,在5.5分鐘內應用作為移動相的於二氧化碳中之2-丙醇5-55%梯度,隨後在38℃之烘箱溫度下保持0.1分鐘 (溶劑流速為5.0 ml/min) (實例 58 :
Rt = 4.23 min;實例 59 :
Rt = 4.68 min)如流程 B 中所描述製備以下實例 實例 60 : 8- 氯 -1-(2,6- 二氯 -4- 氟苯基 )-5-(2,3- 二羥基丙氧基 )-2-( 羥甲基 )-1,6- 萘啶 -4(1H)- 酮 步驟 1 :
8-氯-1-(2,6-二氯-4-氟苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-2-甲基-1,6-萘啶-4(1H)-酮5,8-二氯-1-(2,6-二氯-4-氟苯基)-2-甲基-1,6-萘啶-4(1H)-酮(中間產物2,0.4 g,1.02 mmol)、(2,2-二甲基-1,3-二氧戊環-4-基)甲醇(0.674 g,5.10 mmol)、K2
CO3
(0.423 g,3.06 mmol)及DMAP (0.037 g,0.306 mmol)於乙腈(10 mL)中之混合物在80℃下攪拌2天。濾出固體且隨後用矽膠層析(10-50% EtOAc/庚烷)純化反應混合物以獲得作為標題化合物(0.436 g,88%)之白色固體。ESI-MSm
/z
: 489.1 [M+H]+
(Rt = 1.42 min, LC-方法3)步驟 2 :
8-氯-1-(2,6-二氯-4-氟苯基)-5-(2,3-二羥基丙氧基)-4-側氧基-1,4-二氫-1,6-萘啶-2-甲醛8-氯-1-(2,6-二氯-4-氟苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-2-甲基-1,6-萘啶-4(1H)-酮(0.104 g,0.213 mmol)與SeO2
(0.036 g,0.32 mmol)於1,4-二噁烷(2 mL)中之混合物在90℃下攪拌隔夜。將另一批SeO2
(0.030 g,0.27 mmol)添加至反應混合物中,接著在100℃下攪拌隔夜。濾出固體。在減壓下移除揮發物以獲得粗產物。LC-MS指示標題化合物為粗產物之主要組分。ESI-MSm
/z
: 463.1 [M+H]+
(Rt = 1.02 min, LC-方法3)步驟 3 :
8-氯-1-(2,6-二氯-4-氟苯基)-5-(2,3-二羥基丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮向粗產物8-氯-1-(2,6-二氯-4-氟苯基)-5-(2,3-二羥基丙氧基)-4-側氧基-1,4-二氫-1,6-萘啶-2-甲醛(0.098 g,0.213 mmol)於EtOH (5 ml)中之溶液中添加NaBH4
(0.04 g,1.07 mmol)。在60℃下攪拌反應混合物5分鐘。濾出固體,接著用逆相HPLC (X橋30x50 mm 5um管柱,含有10 mM NH4
OH之ACN/H2
O,75 mL/min,1.5 mL注射劑,梯度:3.5分鐘內15-40%ACN)純化以獲得作為標題化合物(0.027g,26%)之白色固體。60:
HRMS: 計算值463.0031 [M+H]+
, 測定值463.0036;1
H NMR (400 MHz, DMSO-d
6) δ ppm = 8.26 (s, 1H), 7.88 (d, J = 8.3 Hz, 2H), 6.55 (s, 1H), 5.85 (bs, 1H), 4.88 (bs, 1H), 4.75 (bs, 1H), 4.38 (dd, J = 10.7, 5.5 Hz, 1H), 4.30 (dd, J = 10.7, 5.8 Hz, 1H), 3.78-3.91 (m, 3H), 3.58 (m, 2H) 藉由如對於上文實例所描述之類似的方法在步驟1中使用乙-1,2-二醇製備以下實例。實例 61 : 8- 氯 -1-(2,6- 二氯 -4- 氟苯基 )-5-(2- 羥基乙氧基 )-2-( 羥甲基 )-1,6- 萘啶 -4(1H)- 酮 61
: HRMS: 計算值 432.9925 [M+H]+
, 測定值 432.9919;1
H NMR (400 MHz, DMSO-d
6) δ ppm = 8.23 (s, 1H), 7.88 (d, J = 8.3 Hz, 2H), 6.52 (s, 1H), 5.82 (bs, 1H), 4.77 (bs, 1H), 4.42 (t, J = 5.5 Hz, 2H), 3.81 (s, 2H), 3.76 (q, J = 4.4 Hz, 2H)實例 62 : 8- 氯 -1-(2,6- 二氯苯基 )-2-( 二氟甲基 )-5-(2,3- 二羥基丙氧基 )1,6- 萘啶 -4(1H)- 酮 步驟 1 :
8-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-2-甲基-1,6-萘啶-4(1H)-酮 向5,8-二氯-1-(2,6-二氯苯基)-2-甲基-1,6-萘啶-4(1H)-酮(0.250g,0.668mmol)於NMP (1 mL)中之溶液中添加(2,2-二甲基-1,3-二氧戊環-4-基)甲醇(0.883 g,6.68 mmol)、K2
CO3
(0.277 g,2.005 mmol)及DMAP (0.008 g,0.067 mmol)。所得溶液在75℃下加熱1小時。將反應混合物加入EtOAc/水混合物。用EtOAc萃取水層。合併之有機層經無水Na2
SO4
乾燥,過濾且蒸發。用矽膠層析(於庚烷中之10-100% EtOAc)純化粗產物,得到標題化合物(0.277 g,79%)。ESI-MSm
/z
: 471.1 [M+H]+
(Rt = 1.17 min, LC-方法1),1
H NMR (400 MHz, DCM-d
2) δ ppm = 8.09 (s, 1H), 7.61 - 7.41 (m, 3H), 6.40 (d,J
= 0.7 Hz, 1H), 4.62 - 4.45 (m, 3H), 4.20 (dd,J
= 8.5, 6.1 Hz, 1H), 4.04 (dd,J
= 8.4, 6.2 Hz, 1H), 1.95 (s, 3H), 1.47 (s, 3H), 1.41 (s, 3H)。步驟 2 :
8-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-4-側氧基-1,4-二氫-1,6-萘啶-2-甲醛 使8-氯-1-(2,6-二氯苯基)-5-(3-羥基-2-(羥甲基)丙氧基)-2-甲基-1,6-萘啶-4(1H)-酮(0.123 g,0.262 mmol)與二氧化硒(0.035 g,0.314 mmol)於1,4-二噁烷(5 ml)中之混合物回流隔夜。濾出不溶物且用EtOAc洗滌。在減壓下濃縮有機層。向殘留物添加EtOAc及水。分離有機層且用EtOAc萃取水層。合併之有機層經無水Na2
SO4
乾燥,過濾且蒸發。用矽膠層析(於庚烷中之10-100% EtOAc)純化粗產物,得到標題化合物(0.057g,45%)。步驟 3 :
8-氯-1-(2,6-二氯苯基)-2-(二氟甲基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)1,6-萘啶-4(1H)-酮 向8-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-4-側氧基-1,4-二氫-1,6-萘啶-2-甲醛(0.056 g,0.116 mmol)於2ml DCM中之溶液中添加脫氧加氟物(0.320 mL,1.737 mmol)。所得混合物在室溫下攪拌過週末。其在0℃下用10% NaHCO3
溶液淬滅,隨後用CH2
Cl2
萃取。合併之有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾且在減壓下至乾燥。用矽膠層析(於庚烷中之10-100% EtOAc)純化殘留物,得到標題化合物(0.025 g,43%產率)。ESI-MSm
/z
: 505.1 [M+H]+
(Rt = 1.23 min, LC-方法1)。步驟 4 :
8-氯-1-(2,6-二氯苯基)-2-(二氟甲基)-5-(2,3-二羥基丙氧基)1,6-萘啶-4(1H)-酮 向8-氯-1-(2,6-二氯苯基)-2-(二氟甲基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-1,6-萘啶-4(1H)-酮(0.025 g,0.049 mmol)於0.5ml DCM中之溶液中添加0.5 ml TFA。攪拌反應混合物1.5小時。其隨後經濃縮。殘留物用ACN稀釋且經過LP-HCO3樹脂過濾以中和TFA鹽。濃縮濾過物以提供標題化合物(0.020 g,78%產率)。62:
ESI-MSm
/z
: 467.1 [M+H]+
(Rt = 1.91 min, LC-方法1);1
H NMR (400 MHz, DCM-d
2) δ ppm = 8.09 (s, 1H), 7.56 - 7.36 (m, 3H), 6.78 (s, 1H), 5.99 (t, J = 53.0 Hz, 1H), 4.64 (ddd, J = 11.2, 2.4, 1.2 Hz, 1H), 4.27 (dd, J = 11.2, 3.7 Hz, 1H), 3.98 - 3.79 (m, 2H), 3.77 - 3.61 (m, 1H)。實例 63 : 8- 氯 -1-(2,6- 二氯苯基 )-5-(2,3- 二羥基丙氧基 )-4- 側氧基 -1,4- 二氫 -1,6- 萘啶 -2- 甲腈 如實例63
中在步驟1及2中所描述製備8-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-4-側氧基-1,4-二氫-1,6-萘啶-2-甲醛。步驟 3 :
8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-4-側氧基-1,4-二氫-1,6-萘啶-2-羧酸向8-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-4-側氧基-1,4-二氫-1,6-萘啶-2-甲醛(0.358 g,0.740 mmol)於丙酮(1 mL)與水(1 mL)混合物中之溶液中添加亞氯酸鈉(0.134 g,1.48 mmol)及氨基磺酸(0.216 g,2.22 mmol)。在室溫下攪拌混合物隔夜。移除溶劑。殘留物用水洗滌,經過濾,且在真空下乾燥。其按原樣用於下一步驟。ESI-MSm
/z
: 460.9 [M+H]+
(Rt = 0.46 min, LC-方法4),1
H NMR (400 MHz, DMSO-d
6) δ ppm = 8.19 (s, 1H), 7.48 (d,J
= 4.2 Hz, 3H), 6.14 (s, 1H), 4.97 - 4.79 (m, 2H), 4.38 (dd,J
= 10.6, 5.5 Hz, 1H), 4.26 (dd,J
= 10.6, 6.0 Hz, 1H), 3.92 - 3.79 (m, 1H), 3.57 (dq,J
= 10.8, 5.5 Hz, 2H)。步驟 4 :
8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-4-側氧基-1,4-二氫-1,6-萘啶-2-甲醯胺向8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-4-側氧基-1,4-二氫-1,6-萘啶-2-羧酸(0.160 g,0.348 mmol)、HATU (0.397 g,1.044 mmol)及DIEA (0.304 mL,1.74 mmol)於DMF (4 mL)中之溶液中添加氯化銨(0.056 g,1.044 mmol)。在室溫下攪拌混合物隔夜。反應混合物用EtOAc稀釋且用水洗滌。用EtOAc萃取水層。合併之有機層經無水Na2
SO4
乾燥,過濾且在減壓下濃縮。用矽膠層析(於DCM中之0-10% MeOH)純化殘留物,得到標題化合物(0.132 g,83%)。ESI-MSm
/z
: 458.0 [M+H]+
(Rt = 0.68 min, LC-方法4),1
H NMR (400 MHz, DMSO-d
6) δ ppm = 8.38 (s, 1H), 8.29 (s, 1H), 7.79 (s, 1H), 7.66 - 7.50 (m, 3H), 6.42 (s, 1H), 4.88 (d,J
= 5.2 Hz, 1H), 4.71 (t,J
= 5.9 Hz, 1H), 4.44 - 4.21 (m, 2H), 3.87 (q,J
= 5.3 Hz, 1H), 3.66 - 3.48 (m, 2H)。步驟 5 :
8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-4-側氧基-1,4-二氫-1,6-萘啶-2-甲腈在0℃下(內部溫度不超過15℃-用內部溫度計監測)向8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-4-側氧基-1,4-二氫-1,6-萘啶-2-甲醯胺(0.130 g,0.283 mmol)於 THF (3 mL)及TEA (0.099 ml,0.709 mmol)中之溶液中逐滴添加TFAA (0.140 mL,0.992 mmol)。在0℃下攪拌反應物2小時。隨後將其倒入水中且產物用EtOAc萃取(3×)。合併之有機層用NaHCO3
飽和水溶液溶液、鹽水洗滌,且經無水Na2
SO4
乾燥,過濾並濃縮。用矽膠層析(於DCM中之0-10% MeOH)純化粗產物,得到標題化合物(0.09 g,72%)。63:
ESI-MSm
/z
: 442.0 [M+H]+
(Rt = 0.68 min, LC-方法4),1
H NMR (400 MHz, DCM-d
2) δ ppm = 8.25 (s, 1H), 7.61 (d,J
= 4.5 Hz, 3H), 6.99 (s, 1H), 4.70 - 4.59 (m, 4H), 4.52 (dd,J
= 10.9, 5.6 Hz, 1H), 4.39 (dt,J
= 11.1, 5.6 Hz, 2H)。實例 64 : 8- 氯 -1-(2,6- 二氯苯基 )-5- 羥基 -2-( 羥甲基 )-1,6- 萘啶 -4(1H)- 酮 向2-(((第三丁基二甲基矽烷基)氧基)甲基)-5,8-二氯-1-(2,6-二氯苯基)1,6-萘啶-4(1H)-酮(中間產物7,0.1 g,0.198 mmol)於水溶液(5 ml)中之溶液中添加1 N HCl (5 ml)。在80℃下攪拌所得混合物隔夜。其用NaHCO3
飽和水溶液中和且所需產物用EtOAc萃取。合併之有機層經無水Na2
SO4
乾燥,過濾,且濃縮。殘留物用MeCN與庚烷之混合物濕磨,得到標題化合物(0.043 g,55%產率)。64:
ESI-MSm
/z
: 372.8 [M+H]+
(Rt = 0.88 min, LC-方法1),1
H NMR (400 MHz, DCM-d
2) δ ppm = 8.19 (s, 1H), 7.57 (d, J = 2.8 Hz, 3H), 7.01 (s, 1H), 4.23 - 4.08 (m, 2H)。實例 65 : 1-(2,6- 二氯苯基 )-5-(2,3- 二羥基丙氧基 )-2- 甲基 -7-( 甲胺基 )-1,6- 萘啶 -4(1H)- 酮 步驟 1 :
7-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-2-甲基-1,6-萘啶-4(1H)-酮在室溫下向中間產物11 (1 g,2.67 mmol)於NMP (8 mL)中之溶液中添加DMAP (0.163 g,1.337 mmol)、K2
CO3
(1.108g,8.02mmol)及(2,2-二甲基-1,3-二氧戊環-4-基)甲醇(1.060 g,8.02 mmol)。在75℃下攪拌所得溶液1小時。使反應混合物冷卻至室溫,用鹽水淬滅,用EtOAc萃取。有機相用水、鹽水洗滌,經MgSO4
乾燥,且在真空中濃縮。藉由矽膠管柱層析用0-100% EtOAc/庚烷隨後5% MeOH/EtOAc洗脫以純化粗殘留物,以提供呈白色固體狀之標題化合物(0.51 g,40.6%產率)。LC/MS (m/z, [M+H]+
): 471.1步驟 2 :
1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-甲基-7-(甲胺基)1,6-萘啶-4(1H)-酮。 向7-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-2-甲基-1,6-萘啶-4(1H)-酮(20 mg,0.043 mmol)於惠尼格氏鹼(Hünig's base) (0.074 mL,0.426 mmol)及NMP (0.5 mL)中之溶液中添加甲胺鹽酸鹽且反應在90℃下加熱隔夜。反應經過濾且藉由鹼性製備型HPLC(Waters X橋 5um 30×100 mm,具有10 mM NH4OH之水/乙腈,75 mL/min,1.5 mL注射劑,在11.5分鐘時30-45% ACN)純化以獲得呈白色粉末狀之所需產物。將此白色粉末溶解於DCM (1 ml)中且添加TFA (1 ml)。所得溶液在室溫下攪拌隔夜。反應混合物經濃縮,用濃縮氨中和,且隨後藉由鹼性製備型HPLC(Waters X橋 5 um 30x100 mm,具有10 mM NH4OH之水/乙腈,75 mL/min,1.5 mL注射劑,在11.5分鐘時20-35% ACN)純化以獲得呈灰白色粉末狀之標題化合物(8.9 mg,0.021 mmol)。65:
HRMS: 計算值 424.0844 [M+H]+, 測定值 424.0830;1
H NMR (400 MHz, 氯仿-d
3) δ ppm = 7.56 - 7.46 (m, 2H), 7.40 (dd, J = 8.6, 7.5 Hz, 1H), 6.09 - 5.99 (m, 1H), 5.67 (s, 1H), 4.72 - 4.51 (m, 3H), 4.18 (d, J = 9.8 Hz, 1H), 4.02 - 3.70 (m, 4H), 2.64 (d, J = 5.1 Hz, 3H), 1.88 - 1.76 (m, 3H)。實例 66 : 1-(2,6- 二氯苯基 )-5-(2,3- 二羥基丙氧基 )7- 乙基 -2- 甲基 -1,6- 萘啶 -4(1H)- 酮及實例 67 : 1-(2- 氯 -6- 乙基苯基 )-5-(2,3- 二羥基丙氧基 )-7- 乙基 -2- 甲基 -1,6- 萘啶 -4(1H)- 酮 步驟 1 :
1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)7-乙基-2-甲基-1,6-萘啶-4(1H)-酮及1-(2-氯-6-乙基苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-7-乙基-2-甲基-1,6-萘啶-4(1H)-酮 在-78℃下於氮氣氛圍中將二乙基鋅(3.55 mL,3.55 mmol)溶液(1 M於庚烷中)逐滴添加至7-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-2-甲基-1,6-萘啶-4(1H)-酮(0.833 g,1.774 mmol)、DPPF (0.197 g,0.355 mmol)及Pd(OAc)2
(0.040 g,0.177 mmol)於甲苯(10 mL)中之混合物中。添加之後,反應在90℃下加熱1小時。使反應冷卻至室溫且用飽和NH4
Cl水溶液淬滅,用EtOAc稀釋且經過矽藻土過濾。有機相用鹽水洗滌,經無水MgSO4
乾燥且在真空中濃縮。藉由管柱層析用0-100% EtOAc/庚烷洗脫以純化粗殘留物,以獲得1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-7-乙基-2-甲基-1,6-萘啶-4(1H)-酮(0.7 g黃色固體,1.44 mmol)及1-(2-氯-6-乙基苯基)-5-(2,3-二羥基丙氧基)-7-乙基-2-甲基-1,6-萘啶-4(1H)-酮(0.012 g白色固體,0.025 mmol)。步驟 2 :
1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-7-乙基-2-甲基-1,6-萘啶-4(1H)-酮化合物及1-(2-氯-6-乙基苯基)-5-(2,3-二羥基丙氧基)7-乙基-2-甲基-1,6-萘啶-4(1H)-酮 將來自上文之兩個化合物分別溶解於DCM與TFA之1:1混合物中且在室溫下攪拌1小時。在移除揮發物且藉由鹼性製備型HPLC純化之後,獲得呈白色粉末狀之含有實例66
及67
的洗脫份。66:
HRMS: 計算值 423.0878 [M+H]+
, 測定值 423.0897;1
H NMR (400 MHz, 氯仿-d
3) δ ppm = 7.67 - 7.46 (m,3H), 6.34 (s, 1H), 5.74 (s, 1H), 4.84 (d, J = 11.5 Hz, 1H), 4.38 (dd, J = 11.4, 3.3 Hz, 1H), 4.07 - 3.94 (m, 2H), 3.87 (dd, J = 11.7, 5.4 Hz, 1H), 2.56 (q, J = 7.5 Hz, 2H), 1.95 (s, 3H), 1.16 (t, J = 7.5 Hz, 3H)。67:
HRMS: 計算值417.1581 [M+H]+
, 測定值 417.1626;1
H NMR (400 MHz, 氯仿-d
3) δ ppm = 7.59 - 7.32 (m, 3H), 6.37 (d, J = 15.1 Hz, 1H), 5.83 (d, J = 41.9 Hz, 1H), 4.97 - 4.74 (m, 1H), 4.37 (ddd, J = 10.9, 7.1, 3.1 Hz, 1H), 4.11 - 3.69 (m, 3H), 2.56 (dq, J = 15.1, 7.6 Hz, 2H), 2.29 (dddd, J = 30.2, 22.7, 15.0, 7.3 Hz, 2H), 1.93 (d, J = 9.4 Hz, 3H), 1.12 (dt, J = 11.1, 7.6 Hz, 6H)。實例 68 : 1-(2,6- 二氯苯基 )-5-(2,3- 二羥基丙氧基 )-7- 甲氧基 -2- 甲基 -1,6- 萘啶 -4(1H)- 酮 7-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-2-甲基-1,6-萘啶-4(1H)-酮(29 mg,0.062 mmol)、Na2
CO3
(19.63 mg,0.185 mmol),X-磷(5.75 mg,0.012 mmol)及Pd(OAc)2
(1.386 mg,6.17 µmol)於甲苯(0.5 mL)及MeOH (0.050 mL,1.235 mmol)中之混合物用氮氣吹掃且在80℃下加熱隔夜。冷卻後,混合物經濃縮,溶於乙酸乙酯中且經過矽膠塞過濾。移除溶劑且隨後將粗殘留物溶解於HOAc (1 ml)中。添加水(1 ml)。所得溶液在室溫下攪拌隔夜。反應混合物經濃縮,用濃縮氨中和,且隨後藉由鹼性製備型HPLC(Waters X橋 5 um 30x100 mm,具有10 mM NH4OH之水/乙腈,75 mL/min,1.5 mL注射劑,在11.5分鐘時15-30% ACN)純化以獲得呈灰白色粉末狀之標題化合物(11.8 mg,0.027 mmol)。68:
HRMS: 計算值 425.0671 [M+H]+
, 測定值 425.0685;1
H NMR (400 MHz, 氯仿-d
3) δ ppm = 7.64 - 7.43 (m, 3H), 6.27 - 6.18 (m, 1H), 5.28 (s, 1H), 4.84 (dd, J = 11.2, 1.5 Hz, 1H), 4.35 (dd, J = 11.2, 3.3 Hz, 1H), 4.10 - 3.96 (m, 3H), 3.96 - 3.82 (m, 5H), 1.93 (s, 3H)。實例 69 : 1-(2,6- 二氯苯基 )-5-(2,3- 二羥基丙氧基 )-8- 乙基 -2- 甲基 -1,6- 萘啶 -4(1H)- 酮 以與實例66
類似方式使用中間產物10
作為起始物質製備實例69 ,
以獲得白色粉末。69:
HRMS: 計算值 423.0878 [M+H]+
, 測定值 423.0888;1
H NMR (400 MHz, 氯仿-d
3) δ ppm = 7.96 (s, 1H), 7.59 - 7.44 (m, 3H), 6.42 (s, 1H), 5.23 (s, 1H), 4.77 (d, J = 10.8 Hz, 1H), 4.37 (dd, J = 11.1, 3.4 Hz, 1H), 3.93 (dd, J = 55.4, 11.9 Hz, 4H), 1.97 - 1.79 (m, 5H), 0.95 (t, J = 7.4 Hz, 3H)。實例 70 : N-(1-(2,6- 二氯 -4- 氰基苯基 )-2- 甲基 -4- 側氧基 -1,4- 二氫 -1,7- 萘啶 -5- 基 )-1H- 吡唑 -4- 磺胺 步驟 1 :
4-(5-胺基-2-甲基-4-側氧基-1,7-萘啶-1(4H)-基)-3,5-二氯苯甲腈將中間產物12
(0.028 g,0.080 mmol)、濃縮氨水(0.035 ml,0.402 mmol)於THF (0.5 ml)中之混合物在80℃下於密封管中加熱1小時。反應混合物在真空中濃縮且藉由鹼性製備型HPLC(Waters X橋 30×50 mm 5 um管柱,具有10 mM NH4
OH之ACN/H2
O,75 mL/min,1.5 mL注射劑,梯度:4.5分鐘內25-50% ACN)純化殘留物以獲得呈白色粉末狀之標題化合物(0.015 g,54%產率)。步驟 2 :
N-(1-(2,6-二氯-4-氰基苯基)-2-甲基-4-側氧基-1,4-二氫-1,7-萘啶-5-基)-1H-吡唑-4-磺胺 4-(5-胺基-2-甲基-4-側氧基-1,7-萘啶-1(4H)-基)-3,5-二氯苯甲腈(0.015 g,0.043 mmol)與1H-吡唑-4-磺醯氯(0.015 g,0.087 mmol)於吡啶(0.5 mL)中之混合物在80℃下攪拌隔夜。反應物在真空中濃縮。藉由鹼性製備型HPLC (Waters X橋 30×50 mm 5 um管柱,具有10 mM NH4
OH之ACN/H2O,75 mL/min,1.5 mL注射劑,梯度:4.5分鐘內25-50% ACN)純化殘留物以獲得呈灰白色粉末狀之標題化合物(4.8 mg)。70:
HRMS: 計算值 475.0147 [M+H]+
, 測定值 475.0142;1
H NMR (400 MHz, 氯仿-d
3) δ ppm = 13.01 (s, 1H), 8.78 (s, 1H), 8.05 (s, 2H), 7.94 (s, 2H), 7.58 (s, 1H), 6.40 (s, 1H), 2.05 (s, 3H)。實例 71 : 8- 氯 -1-(2,6- 二氯苯基 )-2- 甲基 -5-(1H-1,2,4- 三唑 -1- 基 )-1,6- 萘啶 -4(1H)- 酮 將中間產物1
(20 mg,0.053 mmol)與1,2,4-三唑-1-胺鈉(7.30 mg,0.080 mmol)於THF (1 mL)中之混合物在70℃下加熱2小時。濃縮反應混合物。藉由鹼性製備型HPLC (Waters X橋 30×50 mm 5 um管柱,具有10 mM NH4
OH之ACN/H2
O,75 mL/min,1.5 mL注射劑,梯度:4.5分鐘內25-50% ACN)以獲得呈灰白色粉末狀之標題化合物(17 mg)。71:
HRMS: 計算值 406.0029 [M+H]+
, 測定值 406.0036;1
H NMR (400 MHz, 氯仿-d
3) δ ppm = 8.54 (s, 1H), 8.49 (s, 1H), 8.16 (s, 1H), 7.53 (d, J = 2.4 Hz, 3H), 6.43 (s, 1H), 1.99 (s, 3H)。如流程 C 中所描述製備以下化合物 實例 72 : 3,5- 二氯 -4-(2- 甲基 -4- 側氧基 -5-(1H- 吡唑 -3- 基 )-1,7- 萘啶 -1(4H)- 基 ) 苯甲腈 將4-(5-溴-2-甲基-4-側氧基-1,7-萘啶-1(4H)-基)-3,5-二氯苯甲腈(中間產物13
,0.040 g,0.098 mmol)、(1H-吡唑-3-基)硼酸(0.044 g,0.391 mmol)、Pd(PPh3
)4
(0.011 g,9.78 μmol)及Cs2
CO3
(0.096 g,0.293 mmol)於二噁烷(2 mL)中之混合物於140℃下在微波中攪拌10小時。濾出固體。在減壓下移除揮發物且用矽膠層析(0-5% MeOH/DCM)純化殘留物以獲得粗產物,其進一步用逆相HPLC (X橋 30×50 mm 5 um管柱,具有5 mM NH4
OH之ACN/H2
O,75 mL/min,1.5 mL注射劑,梯度:3.5分鐘內15-40% ACN)純化以獲得作為標題化合物(10 mg,25%產率)之白色粉末。72:
HRMS: 計算值 396.0419 [M+H]+
, 測定值 396.0422;1
H NMR (400 MHz, DMSO-d
6) δ ppm = 12.77 (bs, 1H), 8.60 (s, 2 H), 8.47 (s, 1 H), 8.25 (s, 1 H), 7.65 (bs., 1 H), 6.45 (d,J
=2.02 Hz, 1 H), 6.40 (s, 1 H), 2.01 (s, 3 H)。 使用與上文化合物類似方法製備以下化合物。實例 73 : 3,5- 二氯 -4-(2- 甲基 -5-(1- 甲基 -1H- 吡唑 -4- 基 )-4- 側氧基 -1,7- 萘啶 -1(4H)- 基 ) 苯甲腈 73
: HRMS: 計算值 410.0575 [M+H]+
, 測定值 410.0564.,1
H NMR (400 MHz, DMSO-d
6) δ ppm = 8.59 (s, 2H), 8.41 (s, 1H), 8.10 (s, 1H), 7.99 (s, 1H), 7.65 (s, 1H), 6.38 (s, 1H), 3.89 (s, 3H), 2.00 (s, 3H)。實例 74
:8- 氯 -1-(2,6- 二氯苯基 )-2-( 羥甲基 )-5-(3- 羥丙基 )-1,6- 萘啶 -4(1H)- 酮 步驟 1 :
5-(2-(1,3-二噁烷-2-基)乙基)-2-(((第三丁基二甲基矽烷基)氧基)甲基)-8-氯-1-(2,6-二氯苯基)-1,6-萘啶-4(1H)-酮向2-(((第三丁基二甲基矽烷基)氧基)甲基)-5,8-二氯-1-(2,6-二氯苯基)-1,6-萘啶-4(1H)-酮(中間產物7,0.2g,0.397mmol)於THF (4 mL)中之溶液中添加(2-(1,3-二噁烷-2-基)乙基)溴化鎂(0.5 M於THF中,1.03 mL,0.516 mmol)。混合物在室溫下攪拌1小時,接著添加另一批(2-(1,3-二噁烷-2-基)乙基)溴化鎂(0.5 M於THF中,1.0 mL,0.50 mmol)。反應混合物在室溫下再攪拌1小時。隨後添加水以淬滅反應混合物。在減壓下移除THF且用矽膠層析(10-40% EtOAc/庚烷)純化殘留物以獲得標題化合物(0.083 g,36%產率)。ESI-MSm
/z
: 585.2 [M+H]+
(Rt = 1.84 min, LC-方法3)步驟 2 :
3-(8-氯-1-(2,6-二氯苯基)-2-(羥甲基)-4-側氧基-1,4-二氫-1,6-萘啶-5-基)丙醛將5-(2-(1,3-二噁烷-2-基)乙基)-2-(((第三丁基二甲基矽烷基)氧基)甲基)-8-氯-1-(2,6-二氯苯基)-1,6-萘啶-4(1H)-酮(0.044 g,0.075 mmol)及HCl水溶液(1 N,0.678 mL,0.678 mmol)於THF (1 mL)中之混合物在60℃下攪拌3小時。反應混合物隨後用飽和NaHCO3
水溶液淬滅直至不再產生氣泡(CO2
)。此反應混合物直接用於下一步驟。LC-MS指示標題化合物為此步驟中之唯一產物。ESI-MSm
/z
: 412.8 [M+H]+
(Rt = 1.12 min, LC-方法3)步驟 3 :
8-氯-1-(2,6-二氯苯基)-2-(羥甲基)-5-(3-羥丙基)-1,6-萘啶-4(1H)-酮向來自步驟2之反應混合物添加EtOH (1 mL),且隨後添加NaBH4
(0.023 g,0.60 mmol)。所得混合物在室溫下攪拌20分鐘。濾出固體。在減壓下移除THF且用逆相HPLC (Waters X橋 30x50 mm 5um管柱,具有10 mM NH4
OH之ACN/H2
O,75 mL/min,1.5 mL注射劑,梯度:4.5分鐘內35-60% ACN)以獲得作為標題化合物之白色固體(0.025 g,步驟2及3之總產量77%)。74:
HRMS: 計算值 413.0227 [M+H]+
, 測定值 413.0213;1
H NMR (400 MHz, DMSO-d
6) δ ppm = 8.53 (s, 1H), 7.79 - 7.66 (m, 3H), 6.63 (s, 1H), 5.88 (s, 1H), 4.44 (t,J
= 4.9 Hz, 1H), 3.85 - 3.78 (m, 2H), 3.54-3.46 (m, 2H), 3.46 - 3.37 (m, 2H), 1.83 (dq,J
= 9.7, 6.7 Hz, 2H)實例 75 : 8- 氯 -1-(2,6- 二氯苯基 )-5-(3,4- 二羥丁基 )-2-( 羥甲基 )-1,6- 萘啶 -4(1H)- 酮 步驟 1 :
5-(丁-3-烯-1-基)-2-(((第三丁基二甲基矽烷基)氧基)甲基)-8-氯-1-(2,6-二氯苯基)-1,6-萘啶-4(1H)-酮向2-(((第三丁基二甲基矽烷基)氧基)甲基)-5,8-二氯-1-(2,6-二氯苯基)-1,6-萘啶-4(1H)-酮(0.3 g,0.595 mmol)於THF(6 mL)中之溶液中添加丁-3-烯-1-基溴化鎂(0.5 M於THF中,1.78 mL,0.892 mmol)。所得溶液在室溫下攪拌3小時。反應混合物用幾滴水淬滅且在減壓下濃縮。藉由矽膠層析(於庚烷中之0-50% EtOAc)純化殘留物,得到標題化合物(0.151 g,48%產率)。ESI-MSm
/z
: 525.1 [M+H]+
(Rt = 1.99 min, LC-方法1),1
H NMR (400 MHz, DCM-d
2) δ ppm = 8.38 (s, 1H), 7.47 (s, 3H), 6.68 (t,J
= 1.1 Hz, 1H), 6.04 - 5.87 (m, 1H), 5.14 - 4.87 (m, 2H), 4.00 (d,J
= 1.2 Hz, 2H), 3.54 (dd,J
= 8.5, 7.0 Hz, 2H), 2.54 - 2.40 (m, 2H), 0.86 (s, 9H), 0.0 (s, 6H)。步驟 2 :
2-(((第三丁基二甲基矽烷基)氧基)甲基)-8-氯-1-(2,6-二氯苯基)-5-(3,4-二羥丁基)-1,6-萘啶-4(1H)-酮將四氧化鋨(於第三丁醇中之2.5重量%溶液,0.133 ml,10.59 mmol)添加至5-(丁-3-烯-1-基)-2-(((第三丁基二甲基矽烷基)氧基)甲基)-8-氯-1-(2,6-二氯苯基)-1,6-萘啶-4(1H)-酮(0.111 g,0.212 mmol)與N-甲基嗎啉N-氧化物(0.027 g,0.233 mmol)於第三丁醇/水(2 ml/2 ml)混合物中之溶液。所得混合物在室溫下攪拌4小時。產物在EtOAc與鹽水之間分離且合併之有機萃取物經無水Na2
SO4
乾燥,過濾且在減壓下濃縮。藉由矽膠層析(於庚烷中之0-100% EtOAc)純化殘留物,得到標題化合物(0.077 g,65%產率)。ESI-MSm
/z
: 558.9 [M+H]+
(Rt = 1.55 min, LC-方法1),1
H NMR (400 MHz, DCM-d
2) δ ppm = 8.40 (s, 1H), 7.52 - 7.45 (m, 3H), 6.74 (t,J
= 1.1 Hz, 1H), 4.04 - 3.95 (m, 2H), 3.68 - 3.43 (m, 5H), 1.97 - 1.75 (m, 2H), 0.85 (s, 9H), 0.0 (s, 6H).步驟 3 :
8-氯-1-(2,6-二氯苯基)-5-(3,4-二羥丁基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮 在0℃下向於THF (2mL)中之2-(((第三丁基二甲基矽烷基)氧基)甲基)-8-氯-1-(2,6-二氯苯基)-5-(3,4-二羥丁基)-1,6-萘啶-4(1H)-酮(0.077 g,0.138 mmol)添加1 M TBAF於THF中之溶液 (0.207 mL,0.207 mmol)。反應物在0℃下攪拌1小時。將其用水淬滅且在EtOAc中稀釋。用EtOAc萃取水層。合併之有機層用鹽水洗滌,經無水Na2
SO4
乾燥,過濾且在減壓下濃縮。藉由矽膠層析(於DCM中之0-5% MeOH)純化殘留物,以得到標題化合物(0.031 g,46%產率)。75:
ESI-MSm
/z
: 443.2 [M+H]+
(Rt = 0.75, LC-方法1),1
H NMR (400 MHz, DCM-d
2) δ ppm = 8.47 (s, 1H), 7.55 (d, J = 1.9 Hz, 3H), 6.87 (t, J = 1.1 Hz, 1H), 4.11 (s, 2H), 3.78 - 3.45 (m, 5H), 2.08 - 1.84 (m, 2H)。以上外消旋體之手性分離 實例 76 及 77 :實例 76 及 77 中之一者為 (R)-8- 氯 -1-(2,6- 二氯苯基 )-5-(3,4- 二羥丁基 )-2-( 羥甲基 )-1,6- 萘啶 -4(1H)- 酮且另一者為 (S)-8- 氯 -1-(2,6- 二氯苯基 )-5-(3,4- 二羥丁基 )-2-( 羥甲基 )-1,6- 萘啶 -4(1H)- 酮
將218 mg 8-氯-1-(2,6-二氯苯基)-5-(3,4-二羥丁基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮(實例75
)溶解於20ml甲醇中且以各為多個1.6 ml之注射劑形式提供至手性製備型SFC (ChiralPak AD管柱,250×330 mm ID,5 mm,在38℃下流動速率50 ml/min),其使用含0.1%氨水的於二氧化碳中之40%乙醇作為移動相。在手性分離之後,洗脫份在40℃之光束電流溫度下經由旋轉蒸發乾燥以得到作為第一洗脫峰(82 mg,100% ee)之實例76
及作為第二洗脫峰(40 mg,98.8% ee)之呈白色固體狀之實例77
。滯留時間在ChiralPak IA管柱(4.6×100 mm,5 µm管柱)上獲得。在5.5分鐘內應用作為移動相的含10 mM NH4
OH之於二氧化碳中之1:1 MeOH/2-丙醇5-55%梯度,隨後在38℃之烘箱溫度下保持0.1分鐘 (溶劑流速為5.0 ml/min)。(實例 76 :
Rt = 3.63 min;實例 77 :
Rt = 4.24 min)實例 78 : 8- 氯 -1-(2,6- 二氯苯基 )-5-(2,3- 二羥丙基 )-2-( 羥甲基 )-1,6- 萘啶 -4(1H)- 酮 步驟 1 :
5-烯丙基-2-(((第三丁基二甲基矽烷基)氧基)甲基)-8-氯-1-(2,6-二氯苯基)-1,6-萘啶-4(1H)-酮在室溫下於氮氣氛圍中向中間產物7
(0.65 g,1.289 mmol)於甲苯(10 ml)中之溶液中添加烯丙基三-正丁基錫(0.799 mL,2.58 mmol)及PdCl2
(dppf)*CH2
Cl2
加合物(0.105 g,0.129 mmol)。所得溶液用氮氣吹掃且在80℃下加熱1小時。藉由管柱層析(固體裝載,於庚烷中之0-30%乙酸乙酯)之純化提供呈淡黃色油狀之5-烯丙基-2-(((第三丁基二甲基矽烷基)氧基)甲基)-8-氯-1-(2,6-二氯苯基)-1,6-萘啶-4(1H)-酮(0.6 g,1.18 mmol)。ESI-MS m/z: 511.0 [M+H]+步驟 2 :
2-(((第三丁基二甲基矽烷基)氧基)甲基)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥丙基)-1,6-萘啶-4(1H)-酮5-烯丙基-2-(((第三丁基二甲基矽烷基)氧基)甲基)-8-氯-1-(2,6-二氯苯基)-1,6-萘啶-4(1H)-酮(0.6 g,1.177 mmol)於1,4-二噁烷(8 mL)及水(1.6 mL)中之溶液用四氧化鋨(2.991 g,0.235 mmol)及NMO (0.414 g,3.53 mmol)處理。反應物在室溫下攪拌2小時。添加飽和偏亞硫酸氫鈉溶液且再攪拌混合物30分鐘。添加水且用乙酸乙酯萃取混合物。將合併之有機萃取物乾燥(Na2
SO4
),過濾且在真空中濃縮。藉由管柱層析(於庚烷中之0-100%乙酸乙酯)純化以提供呈白色泡沫固體狀之2-(((第三丁基二甲基矽烷基)氧基)甲基)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥丙基)-1,6-萘啶-4(1H)-酮(0.5 g,0.92 mmol)。ESI-MS m/z: 544.8 [M+H]+ 步驟 3 :
8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥丙基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮在室溫下向以上化合物(0.5 g,0.919 mmol)於乙酸(5 ml)中之溶液中添加水(5 ml)。所得溶液在室溫下攪拌隔夜。反應物經濃縮,用濃縮NH3
中和,且藉由鹼性製備型RP-HPLC (Waters X橋 30×50 mm 5 um管柱,含10 mM NH4
OH之ACN/H2
O,75 mL/min,1.5 mL注射劑,梯度:4.5分鐘內25-50% ACN)純化以獲得呈白色粉末狀之標題化合物(0.3 g,0.66 mmol)。78:
HRMS: 計算值 429.0176 [M+H]+
, 測定值 429.0169,1
H NMR (400 MHz, 氯仿-d
3) δ ppm = 8.45 (s, 1H), 7.49 (s, 3H), 6.94 (s, 1H), 4.92 (s, 1H), 4.26 (s, 1H), 4.05 (s, 2H), 3.66 (qd, J = 15.8, 14.3, 6.0 Hz, 5H), 2.91 (s, 1H)。以上外消旋體之手性分離 實例 79 及 80 :實例 79
及80 中之一者為 (R)-8- 氯 -1-(2,6- 二氯苯基 )-5-(2,3- 二羥丙基 )-2-( 羥甲基 )-1,6- 萘啶 -4(1H)- 酮且另一者為 (S)-8- 氯 -1-(2,6- 二氯苯基 )-5-(2,3- 二羥丙基 )-2-( 羥甲基 )-1,6- 萘啶 -4(1H)- 酮
外消旋體78
以各為1.6 ml之多個注射劑形式提供至手性製備型SFC (Cellulose-2管柱,250×330 mm內徑,5 μm,在38℃下流動速率為50 ml/min),其使用含0.1%氨水的於二氧化碳中之40%乙醇作為移動相。在手性分離之後,洗脫份在40℃之光束電流溫度下經由旋轉蒸發乾燥以得到作為第一洗脫峰(>98% ee)之實例79
及作為第二洗脫峰(>98% ee)之呈白色固體狀之實例80
。滯留時間在Cellulose-2管柱(4.6×150 mm,5 µm管柱)上獲得。在35℃之烘箱溫度下應用於二氧化碳中之40% MeOH(含0.05% DEA)之移動相(溶劑流速為2.4 ml/min) (實例 79
:Rt = 6.93 min;實例 80
:Rt = 7.68 min)79:
HRMS: 計算值 429.0176 [M+H]+
, 測定值 429.0171; 1H NMR (400 MHz, 氯仿-d
3) δ ppm = 8.46 (s, 1H), 7.49 (d, J = 4.8 Hz, 3H), 6.94 (s, 1H), 4.15 (m, 4H), 3.84 - 3.56 (m, 6H)。80:
HRMS: 計算值 429.0176 [M+H]+
, 測定值 429.0169;1
H NMR (400 MHz, 氯仿-d3
) δ ppm = 8.45 (s, 1H), 7.49 (d,J
= 4.6 Hz, 3H), 6.94 (s, 1H), 4.92 (s, 1H), 4.26 (s, 1H), 4.05 (s, 2H), 3.66 (qd,J
= 15.8, 14.3, 6.0 Hz, 5H), 2.91 (s, 1H)。 使用與來自中間產物1
之以上化合物類似的方法製備以下化合物。實例 81 : 8- 氯 -1-(2,6- 二氯苯基 )-5-(2,3- 二羥丙基 )-2- 甲基 -1,6- 萘啶 -4(1H)- 酮 81
: HRMS: 計算值 413.0227 [M+H]+
, 測定值 413.0230;1
H NMR (400 MHz, 氯仿-d
3) δ ppm = 8.45 (s, 1H), 7.49 (s, 3H), 4.98 - 4.81 (m, 1H), 4.27 (s, 1H), 3.82 - 3.53 (m, 4H), 2.96 (s, 1H), 1.98 (s, 3H)。實例 82 : 8- 氯 -1-(2,6- 二氯苯基 )-5-(1,2- 二羥乙基 )-2-( 羥甲基 )-1,6- 萘啶 -4(1H)- 酮 步驟 1 :
2-(((第三丁基二甲基矽烷基)氧基)甲基)-8-氯-1-(2,6-二氯苯基)-5-乙烯基-1,6-萘啶-4(1H)-酮在室溫下於氮氣氛圍中向中間產物7
(0.47g,0.932mmol)於乙腈(5 ml)及水(1 mL)中之溶液中添加乙烯基硼酸酐吡啶錯合物(0.317 g,1.864 mmol)、Na2
CO3
(0.198 g,1.864 mmol)及PdCl2
(dppf)*CH2
Cl2
加合物(0.076 g,0.093 mmol)。所得反應混合物用氮氣吹掃且在80℃下於密封管中加熱一小時。藉由管柱層析(固體裝載,於庚烷中之0-40%乙酸乙酯)之純化提供呈淡黃色油狀之2-(((第三丁基二甲基矽烷基)氧基)甲基)-8-氯-1-(2,6-二氯苯基)-5-乙烯基-1,6-萘啶-4(1H)-酮(0.4 g,0.81 mmol)。ESI-MS m/z: 497.0.0 [M+H]+
) 步驟2及3以如對於前述實例所描述之相同方式進行,以得到呈白色固體之8-氯-1-(2,6-二氯苯基)-5-(1,2-二羥乙基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮。82:
HRMS: 計算值415.0019 [M+H]+
, 測定值 415.0016;1
H NMR (400 MHz, 氯仿-d
3) δ ppm = 8.50 (s, 1H), 7.50 (s, 3H), 6.93 (s, 1H), 5.80 (d, J = 4.3 Hz, 1H), 5.30 (d, J = 6.0 Hz, 1H), 4.17 - 3.82 (m, 5H), 3.40 (s, 1H), 2.97 (s, 1H)。外消旋體之手性分離 實例 83 及 84 :實例 83 及 84 中之一者為 (R)-8- 氯 -1-(2,6- 二氯苯基 )-5-(1,2- 二羥乙基 )-2-( 羥甲基 )-1,6- 萘啶 -4(1H)- 酮且另一者為 (S)-8- 氯 -1-(2,6- 二氯苯基 )-5-(1,2- 二羥乙基 )-2-( 羥甲基 )-1,6- 萘啶 -4(1H)- 酮
將外消旋體82
溶解於甲醇中且以各為1.6 ml之多個注射劑形式提供至手性製備型SFC (Cellulose-2管柱,250×330 mm內徑,5 μm,在38℃下流動速率為50 ml/min),其使用含0.1%氨水的於二氧化碳中之40%乙醇作為移動相。在手性分離之後,洗脫份在40℃之光束電流溫度下經由旋轉蒸發乾燥以得到作為第一洗脫峰(>98% ee)之實例83
及作為第二洗脫峰(>98% ee)之呈白色固體狀之實例84
。滯留時間在ChiralPak AY管柱(4.6×150 mm,3 µm管柱)上獲得。在35℃之烘箱溫度下應用於二氧化碳中之50% 2-丙醇(含0.05% DEA)之移動相(溶劑流速為2 ml/min) (實例 83 :
Rt = 3.13 min;實例 84 :
Rt = 4.32 min)實例 85 : 8- 氯 -1-(2,6- 二氯苯基 )-5-(1,2- 二羥乙基 )-2- 甲基 -1,6- 萘啶 -4(1H)- 酮 步驟 1 :
8-氯-1-(2,6-二氯苯基)-2-甲基-5乙烯基-1,6-萘啶-4(1H)-酮向中間產物1
(1 g,2.67 mmol)於乙腈(10 ml)中之溶液中添加乙烯基硼酸乙酸酐吡啶錯合物(0.772 g,3.21 mmol)、2 .0 M K3
PO4
水溶液(2.67 ml,5.35 mmol)。在添加PdCl2
(dppf).CH2
Cl2
加合物(0.218 g,0.267 mmol)之前反應物經脫氣且置於氮氣下。混合物再次用氮氣吹掃,在80℃下於油浴中加熱回流1.5小時。使混合物冷卻至室溫,移除溶劑。使殘留物溶於EtOAC中。有機相用鹽水洗滌,經無水MgSO4
乾燥,過濾且在真空中濃縮。藉由管柱層析用0-50% EtOAC/庚烷洗脫以純化粗殘留物,以提供呈黃色固體狀之8-氯-1-(2,6-二氯苯基)-2-甲基-5乙烯基-1,6-萘啶-4(1H)-酮(0.85 g,8.32 mmol)。步驟 2 :
8-氯-1-(2,6-二氯苯基)-5-(1,2-二羥乙基)-2-甲基-1,6-萘啶-4(1H)-酮 步驟1之產物(0.8 g,2.188 mmol)於丙酮(10 mL)及水(2 mL)中之溶液在室溫下用NMO (0.769 g,6.56 mmol)及四氧化鋨(0.278 g,0.044 mmol)處理。反應物在室溫下於氮氣下攪拌16小時以得到兩種產物。此後,添加飽和Na2
S2
O3
溶液且持續30分鐘。添加水且用乙酸乙酯萃取混合物(2×)。合併之有機萃取物用鹽水洗滌,乾燥(Na2
SO4
),過濾,且在真空中濃縮。藉由管柱層析用0-100% EtOAC/庚烷洗脫以純化粗殘留物,以提供標題化合物(0.6 g,1.43 mmol)及8-氯-1-(2,6-二氯苯基)-5-(2-羥基乙醯基)-2-甲基-1,6-萘啶-4(1H)-酮(0.05 g,0.13 mmol)兩種產物。85:
HRMS: 計算值 399.0070 [M+H]+
, 測定值 399.0089;1
H NMR (400 MHz, 氯仿-d
3) δ ppm = 8.50 (s, 1H), 7.50 (m, 3H), 6.60 - 6.40 (s, 1H), 5.82 (t, J = 5.2 Hz, 1H), 4.14 - 3.92 (m, 2H), 2.01 - 1.91 (s, 3H)。實例 86 : 8- 氯 -1-(2,6- 二氯苯基 )-5-(2- 羥基乙醯基 )-2- 甲基 -1,6- 萘啶 -4(1H)- 酮 此化合物作在合成上文所描述之實例85
期間之副產物形成。86:
HRMS: 計算值 396.9915 [M+H]+
, 測定值 396.9914;1
H NMR (400 MHz, 氯仿-d
3) δ ppm = 8.58 (s, 1H), 7.53 (s, 3H), 6.49 (s, 1H), 4.68 (s, 2H), 2.04 (s, 3H)。實例 87 : 8- 氯 -1-(2,6- 二氯苯基 )-5-((2,3- 二羥基丙氧基 ) 甲基 )-2-( 羥甲基 )-1,6- 萘啶 -4(1H)- 酮 製備步驟1中所需要之錫烷:三丁基(((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)甲基)錫烷在0℃下於氮氣氛圍中向(2,2-二甲基-1,3-二氧戊環-4-基)甲醇(0.207 g,1.566 mmol)於THF (2 ml)及DMSO (2 mL)中之溶液中添加NaH (0.046 g,1.149 mmol)。所得溶液在室溫下攪拌30分鐘,且添加三丁基(碘甲基)錫烷(0.45 g,1.044 mmol)。所得溶液在室溫下攪拌隔夜。混合物經濃縮,溶於庚烷/EtOAc (7:1)中。有機相用鹽水洗滌,經無水MgSO4
乾燥,過濾且在真空中濃縮。粗殘留物(無色油)未經進一步純化即用於下一步驟。 在以上錫烷與中間產物7
之間進行Stille偶合且隨後以與實例78
類似的方式進行去除保護基步驟以得到標題化合物。87:
HRMS: 計算值 459.0281 [M+H]+
, 測定值 459.0277;1
H NMR (400 MHz, 氯仿-d
3) δ ppm = 8.48 (s, 1H), 7.60 - 7.40 (m, 3H), 6.93 (s, 1H), 5.37 - 5.18 (m, 2H), 4.80 (s, 1H), 4.42 (s, 1H), 4.04 (d, J = 5.5 Hz, 2H), 3.93 (s, 1H), 3.77 (ddd, J = 38.5, 9.8, 4.8 Hz, 4H), 3.54 (s, 1H)。實例 88 : 8- 氯 -1-(2,6- 二氯苯基 )-5-(((1,3- 二羥基丙 -2- 基 ) 氧基 ) 甲基 )-2-( 羥甲基 )-1,6- 萘啶 -4(1H)- 酮 此化合物類似於以上實例在製備所需要之錫烷中使用2,2-二甲基-1,3-二噁烷-5-醇來製備。88:
HRMS: 計算值 459.0281 M+H]+
, 測定值 459.0280;1
H NMR (400 MHz, 氯仿-d
3) δ ppm = 8.47 (s, 1H), 7.48 (d, J = 1.3 Hz, 3H), 6.92 (s, 1H), 5.42 (s, 2H), 4.04 (s, 2H), 3.81 - 3.57 (m, 5H)。實例 89 : 8- 氯 -1-(2,6- 二氯苯基 )-5-(2,4- 二羥基 -3- 側氧基丁 -2- 基 )-2- 甲基 -1,6- 萘啶 -4(1H)- 酮 步驟 1 :
5-乙醯基-8-氯-1-(2,6-二氯苯基)-2-甲基-1,6-萘啶-4(1H)-酮中間產物1
(0.5 g,1.337 mmol)、三丁基(1-乙氧基乙烯基)錫(0.628 g,1.738 mmol)與PdCl2
(dppf).CH2
Cl2
加合物(0.109 g,0.134 mmol)於甲苯(2 mL)中之混合物用氮氣吹掃且在80℃下加熱隔夜。冷卻至室溫後,在減壓下濃縮混合物。將殘留物加入EtOAc且經過矽膠塞過濾。移除溶劑且隨後將粗製乙氧基乙烯基中間產物(500 mg)溶解於四氫呋喃(50 mL)及1 N HCl酸(20 mL)之溶液中。在於室溫下攪拌混合物兩小時之後,在真空中移除四氫呋喃且藉由過濾收集白色固體(所需酮產物,0.3 g)。剩餘水相用乙酸乙酯萃取。合併有機層,乾燥(MgSO4
),且經濃縮。藉由管柱層析(於庚烷中之0-100%乙酸乙酯)之純化提供其他酮產物(黃色固體,0.08 g)。HRMS: 計算值 380.0064 [M+H]+
, 測定值 380.9960;1
H NMR (400 MHz, 氯仿-d
3) δ ppm = 8.53 (s, 1H), 7.52 (d, J = 2.7 Hz, 3H), 6.46 (d, J = 0.7 Hz, 1H), 2.64 (s, 3H)步驟 2 :
8-氯-1-(2,6-二氯苯基)-5-(2-羥基丁-3-烯-2-基)-2-甲基-1,6-萘啶-4(1H)-酮於氮氣氛圍中向來自步驟1之酮中間產物(0.2 g,0.524 mmol)於THF (1 mL)中之冰冷的溶液中逐滴添加於THF (3 mL)中之1 M乙烯基溴化鎂(0.681 mL,0.681 mmol)。反應物在0℃下攪拌5小時,隨後在0℃下用飽和NH4
Cl淬滅且用EtOAc萃取。有機相用鹽水洗滌,經MgSO4
乾燥,且經濃縮。藉由管柱層析用0-100% EtOAC/庚烷洗脫以純化粗產物,以獲得呈黃色固體之所需產物(0.048 g,0.11 mmol),ESI-MS m/z: 411.1 [M+H]+ 步驟 3 :
8-氯-1-(2,6-二氯苯基)-5-(2,4-二羥基-3-側氧基丁-2-基)-2-甲基-1,6-萘啶-4(1H)-酮在室溫下向步驟2之產物(50 mg,0.122 mmol)於二噁烷(3 ml)及水(0.2 ml)中之溶液中添加四氧化鋨(7.66 µl,0.024 mmol)及NMO (42.9 mg,0.366 mmol)。所得溶液在室溫下攪拌隔夜。反應物經濃縮且溶於EtOAC中。有機相用水、鹽水洗滌,乾燥(經MgSO4
),過濾且在真空中濃縮。藉由鹼性製備型HPLC (Waters X橋 30x50 mm 5 um管柱,含10 mM NH4
OH之ACN/H2
O,75 mL/min,1.5 mL注射劑,梯度:4.5內25-50% ACN)純化粗殘留物以得到8-氯-1-(2,6-二氯苯基)-5-(2,4-二羥基-3-側氧基丁-2-基)-2-甲基-1,6-萘啶-4(1H)-酮(4.6 mg,9.37 μmol)89:
HRMS: 計算值 441.0175 [M+H]+
, 測定值 441.0191;1
H NMR (400 MHz, 氯仿-d
3) δ ppm = 8.08 (s, 1H), 7.56 - 7.41 (m, 3H), 6.42 (s, 1H), 5.13 (s, 1H), 4.76 (dd, J = 10.7, 4.1 Hz, 1H), 4.63 (dd, J = 10.7, 4.6 Hz, 1H), 4.42 (s, 1H), 2.49 (s, 3H), 1.94 (s, 3H)。如流程 D 中所描述製備以下實例 實例 90 : 1-(4-(3- 胺基 -3- 甲基丁 -1- 炔 -1- 基 )-2,6- 二氯苯基 )-8- 氯 -5-(2,3- 二羥基丙氧基 )-2- 甲基 -1,6- 萘啶 -4(1H)- 酮 步驟 1 :
1-(4-溴-2,6-二氯苯基)-8-氯-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-2-甲基-1,6-萘啶-4(1H)-酮1-(4-溴-2,6-二氯苯基)-5,8-二氯-2-甲基-1,6-萘啶-4(1H)-酮(中間產物4
,0.2 g,0.442 mmol)、(2,2-二甲基-1,3-二氧戊環-4-基)甲醇(0.875 g,6.62 mmol)、K2
CO3
(0.366 g,2.65 mmol)及DMAP (11 mg,0.088 mmol)於乙腈(24 mL)中之混合物在75℃下攪拌隔夜。濾出固體。在減壓下移除揮發物且用矽膠層析(20-50% EtOAc/庚烷)純化殘留物以獲得標題化合物(0.212 g,88%)。ESI-MSm
/z
: 548.9 [M+H]+
(Rt = 1.50 min, LC-方法3)步驟 2 :
1-(4-(3-胺基-3-甲基丁-1-炔-1-基)-2,6-二氯苯基)-8-氯-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-2-甲基-1,6-萘啶-4(1H)-酮向1-(4-溴-2,6-二氯苯基)-8-氯-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-2-甲基-1,6-萘啶-4(1H)-酮(46 mg,0.084 mmol)、2-甲基丁-3-炔-2-胺(21 mg,0.252 mmol)、Pd(PPh3
)4
(19 mg,0.017 mmol)及CuI (6.4 mg,0.034 mmol)於DMF (用N2
預鼓泡30分鐘)中之混合物添加TEA (42 mg,0.419 mmol)。反應混合物在70℃下於N2
保護下攪拌1小時。在減壓下移除揮發物且用矽膠層析(1-5% MeOH/DCM)純化殘留物以獲得標題化合物。ESI-MSm
/z
: 552.0 [M+H]+
(Rt = 1.37 min, LC-方法3)步驟 3 :
1-(4-(3-胺基-3-甲基丁-1-炔-1-基)-2,6-二氯苯基)-8-氯-5-(2,3-二羥基丙氧基)-2-甲基-1,6-萘啶-4(1H)-酮1-(4-(3-胺基-3-甲基丁-1-炔-1-基)-2,6-二氯苯基)-8-氯-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-2-甲基-1,6-萘啶-4(1H)-酮(46 mg,0.084 mmol)及HCl水溶液(1 N,1.0 mL,1.0 mmol)於THF (2 mL)中之混合物在室溫下攪拌隔夜。反應混合物隨後用NaOH水溶液(1 N,1 mL,1.0 mmol)淬滅。隨後在減壓下移除THF且用逆相HPLC (Waters X橋 30x50 mm 5 um管柱,含10 mM NH4
OH之ACN/H2
O,75 mL/min,1.5 mL注射劑,梯度:4.5分鐘內25-50% ACN)純化殘留物以獲得作為標題化合物(26 mg,58%產率)之白色固體。90:
HRMS: 計算值 510.0749 [M+H]+
, 測定值 510.0752;1
H NMR (400 MHz, DMSO-d
6) δ ppm = 8.25 (s, 1H), 7.75 (s, 2H), 6.47 (d, J = 0.7 Hz, 1H), 4.87 (d, J = 5.2 Hz, 1H), 4.76 (t, J = 6.0 Hz, 1H), 4.37 (dd, J = 10.7, 5.5 Hz, 1H), 4.28 (dd, J = 10.7, 5.8 Hz, 1H), 3.86 (q, J = 5.3 Hz, 1H), 3.64 - 3.49 (m, 2H), 1.90 (s, 3H), 1.40 (s, 6H)實例 91 : 8- 氯 -1-(2,6- 二氯 -4-(3- 嗎啉基丙 -1- 炔 -1- 基 ) 苯基 )-5-(2- 羥基乙氧基 )-2- 甲基 -1,6- 萘啶 -4(1H)- 酮 此化合物類似於以上實例在步驟1中使用無保護乙烷-1,2-二醇且省略不必要的去除保護基步驟來製備91:
HRMS: 計算值 522.0754 [M+H]+
, 測定值 522.0751;1
H-NMR (400 MHz, DMSO-d
6) δ ppm = 8.23 (s, 1H), 7.88 (s, 2H), 6.45 (d, J = 0.8 Hz, 1H), 4.76 (t, J = 5.6 Hz, 1H), 4.41 (t, J = 5.5 Hz, 2H), 3.75 (q, J = 5.5 Hz, 2H), 3.65 - 3.60 (m, 4H), 3.59 (s, 2H), 2.58 - 2.53 (m, 4H), 1.95 - 1.82 (m, 3H)實例 92 : 8- 氯 -1-(2,6- 二氯 -4-(3-(1,1- 二氧離子基硫代嗎啉基 )) 丙 -1- 炔 -1- 基 ) 苯基 )-5-(2- 羥基乙氧基 )-2- 甲基 -1,6- 萘啶 -4(1H)- 酮 此化合物類似於以上實例在步驟1中使用無保護乙烷-1,2-二醇且省略不必要的去除保護基步驟來製備92:
HRMS: 計算值 570.0424 [M+H]+
, 測定值 570.0422;1
H NMR (400 MHz, DMSO-d
6) δ ppm = 8.23 (s, 1H), 7.87 (s, 2H), 6.45 (d, J = 0.7 Hz, 1H), 4.76 (t, J = 5.4 Hz, 1H), 4.41 (t, J = 5.5 Hz, 2H), 3.76 (d, J = 10.0 Hz, 4H), 3.23 - 3.13 (m, 4H), 3.05 (dd, J = 6.6, 3.5 Hz, 4H), 1.90 (s, 3H)實例 93 : 8- 氯 -1-(2,6- 二氯 -4-(3-( 二甲胺基 ) 丙 -1- 炔 -1- 基 ) 苯基 )-5-((2,2- 二甲基 -1,3- 二氧戊環 -4- 基 ) 甲氧基 )-2- 甲基 -1,6- 萘啶 -4(1H)- 酮 此化合物類似於以上實例在步驟2中使用N, N-二甲基丙-2-炔-1-胺且省略不必要之去除保護基步驟3來製備。93:
HRMS: 計算值 550.1067 [M+H]+
, 測定值 550.1076;1
H NMR (400 MHz, DMSO-d
6) δ ppm = 8.23 (s, 1H), 7.86 (s, 2H), 6.50 - 6.39 (m, 1H), 4.51 - 4.32 (m, 3H), 4.10 (td, J = 6.0, 3.2 Hz, 1H), 4.03 - 3.94 (m, 1H), 3.53 (s, 2H), 2.27 (s, 6H), 1.90 (s, 3H), 1.35 (s, 3H), 1.31 (s, 3H)製備磷酸鹽前藥 :
具有游離羥基之實例可如實例3所證實轉化成磷酸鹽前藥:實例 3 之前藥: (8- 氯 -1-(2,6- 二氯苯基 )-5-(2,3- 二羥基丙氧基 )-4- 側氧基 -1,4- 二氫 -1,6- 萘啶 -2- 基 ) 甲基二氫磷酸鹽 步驟1:2-(((第三丁基二甲基矽烷基)氧基)甲基)-8-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-1,6-萘啶-4(1H)-酮 2-(((第三丁基二甲基矽烷基)氧基)甲基)-5,8-二氯-1-(2,6-二氯苯基)-1,6-萘啶-4(1H)-酮(3.5 g,6.94 mmol)、(2,2-二甲基-1,3-二氧戊環-4-基)甲醇(4.59 g,34.7 mmol)、K2
CO3
(2.88 g,20.82 mmol)及DMAP (0.848 g,6.94 mmol)於ACN (40 mL)中之混合物在80℃下加熱隔夜。濾出反應混合物且用洗滌ACN。在真空中濃縮濾液。藉由矽膠層析(於庚烷中之10-50% EtOAc)純化殘留物,得到標題化合物(2.99 g,72%產率)。ESI-MSm
/z
: 601.1 [M+H]+
(Rt = 1.62 min, LC-方法1),1
H NMR (400 MHz, DCM-d
2) δ ppm = 8.03 (s, 1H), 7.47 (s, 3H), 6.67 (t,J
= 1.1 Hz, 1H), 4.60 - 4.40 (m, 3H), 4.22 - 3.92 (m, 4H), 1.40 (s, 3H), 1.36 (s, 3H), 0.85 (s, 9H), 0.0 (s, 6H)。步驟 2 :
8-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮 在0℃下向2-(((第三丁基二甲基矽烷基)氧基)甲基)-8-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-1,6-萘啶-4(1H)-酮(2.9 g,4.83 mmol)於THF (20 mL)中之溶液中添加1 M TBAF於THF (7.25 mL,7.25 mmol)中之溶液。反應物在0℃下攪拌1小時。將其用水淬滅且在EtOAc中稀釋。用EtOAc萃取水層。合併之有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾且在減壓下濃縮。藉由矽膠管柱層析(於庚烷中之10-100% EtOAc)純化殘留物,得到標題化合物(1.74 g,74%產率)。ESI-MSm
/z
: 487 [M+H]+
(Rt = 1.06 min, LC-方法1),1
H NMR (400 MHz, DCM-d
2) δ ppm = 8.14 (s, 1H), 7.54 (d, J = 1.9 Hz, 3H), 6.99 (s, 1H), 4.66 - 4.46 (m, 3H), 4.28 - 4.17 (m, 1H), 4.15 - 3.96 (m, 3H), 1.47 (s, 3H), 1.41 (s, 3H)。步驟 3 :
二苯甲基((8-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-4-側氧基-1,4-二氫-1,6-萘啶-2-基)甲基)磷酸鹽 在室溫下將惠尼格氏鹼(0.027 ml,0.154 mmol)及四苯甲基焦磷酸(0.078 g,0.144 mmol)添加至8-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮(0.05 g,0.103 mmol)於DCM (0.5 ml)中之溶液中,接著添加MgCl2
(9.80 mg,0.103 mmol)。所得混合物在室溫下攪拌隔夜。混合物經由20:1二氧化矽/MgSO4塞過濾且用EtOAc/醚洗滌。濾過物在減壓下濃縮且殘留物藉由矽膠層析(於庚烷中之0-100% EtOAc)純化,以得到標題化合物(0.061 g,79%產率)。ESI-MSm
/z
: 747.0 [M+H]+
(Rt = 1.43 min, LC-方法1),1
H NMR (400 MHz, DCM-d
2) δ ppm = 8.10 (s, 1H), 7.52 - 7.28 (m, 13H), 6.61 - 6.48 (m, 1H), 5.03 (d,J
= 8.6 Hz, 4H), 4.66 - 4.48 (m, 3H), 4.37 (dd,J
= 6.7, 0.8 Hz, 2H), 4.22 (dd,J
= 8.5, 6.1 Hz, 1H), 4.06 (dd,J
= 8.4, 6.2 Hz, 1H), 1.49 (s, 3H), 1.43 (s, 3H)。步驟 4 及 5 :
(8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-4-側氧基-1,4-二氫-1,6-萘啶-2-基)甲基二氫磷酸鹽 在氮氣下向二苯甲基((8-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-4-側氧基-1,4-二氫-1,6-萘啶-2-基)甲基)磷酸鹽(40 mg,0.054 mmol)與1,4-環己二烯(0.228 g,2.84 mmol)於MeOH (5 ml)中之溶液中添加10%活性炭上之鈀(含量),且混合物在室溫下於氮氣氛圍中攪拌4小時。隨後其經由濾紙(Nylon 0.45 µm)過濾且濃縮濾液以在減壓下乾燥。將二乙醚添加至固體中,攪拌混合物且傾析有機層。殘留物在真空下乾燥以提供兩種產物之混合物。將此混合物溶解於0.5 ml MeOH中且在室溫下添加TFA (0.044 ml,0.566 mmol)。所得溶液攪拌2小時且在減壓下濃縮。殘留物自ACN及水凍乾以提供呈白色固體之標題產物(0.026 g,87%產率)。如藉由LC-Mass在酸性條件下所觀測的,標題化合物亦含有一些2,2,2-三氟乙酸3-((8-氯-1-(2,6-二氯苯基)-4-側氧基-2-((膦醯氧基)甲基)-1,4-二氫-1,6-萘啶-5-基)氧基)-2-羥丙基酯。步驟 6 :
(8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-4-側氧基-1,4-二氫-1,6-萘啶-2-基)甲基二氫磷酸鹽單鈉鹽 將來自前一步驟之混合物(0.026 g)溶解於MeOH (1 ml)中。將NaHCO3
(0.015 g,0.183 mmol)於H2
O (1 ml)中之溶液添加至燒瓶中。所得溶液在室溫下攪拌5分鐘,且在減壓下濃縮。殘留物自ACN及水凍乾以提供標題化合物(0.026 g,99%產率)。ESI-MSm
/z
: 524.9 [M+H]+
(Rt = 0.66 min, LC-方法2)1
H NMR (400 MHz, 甲醇-d
4) δ ppm = 8.16 (s, 1H), 7.60 (s, 3H), 7.14 (t, J = 1.2 Hz, 1H), 4.61 - 4.47 (m, 2H), 4.35 (dd, J = 4.4, 1.2 Hz, 2H), 4.06 (p, J = 5.2 Hz, 1H), 3.81 - 3.66 (m, 2H)。
圖1說明實例1水合物形式B之x射線粉末繞射圖案。 圖2說明實例1水合物形式B使用針孔樣品盤之差示掃描熱量測定(DSC)。 圖3說明實例1水合物形式B使用密閉式樣品盤之差示掃描熱量測定(DSC)。 圖4說明實例1水合物形式B之熱解重量分析(TGA)。
Claims (22)
- 一種式I化合物,其中:X2 為CR2 或N;X3 為CH或N;R1 為C1-4 烷基、-CH2 CN、-CN、C1-4 烷氧基C1-4 烷基、鹵基-C1-4 烷基、-CH=N-OH、-CH=N-O-C1-4 烷基、-CH=N-O-(羥基C1-4 烷基)、羥基-C1-4 烷基、-CH2 OP(O)(OH)2 或C3-5 環烷基;R3 為-ORa ;-NHRb ;-C(O)NH2 ;-C(O)[羥基C1-4 烷基];視情況經一或多個獨立地選自OH及羥基C1-4 烷基之取代基取代之雜環基;視情況經一或多個C1-4 烷基取代之5員或6員環雜芳基;或R3 為經一或多個獨立地選自-C(O)[羥基C1-4 烷基]及-ORc 之取代基取代之C1-4 烷基;Ra 為經一或多個獨立地選自以下之取代基取代之-C1-6 烷基:-ORc 、-SO2 C1-4 烷基、-NHS(O)2 C1-4 烷基及進一步視情況經一或多個獨立地選自C1-4 烷基或羥基C1-4 烷基之取代基取代之雜環基;或Ra 為H、-[CH2 -CH2 -O]n -H、-[CH2 -CH2 -O]m -CH3 或視情況經一或多個C1-4 烷基取代之雜芳基;其中n為2-6且m為1-6;Rb 為經一或多個獨立地選自以下之取代基取代之-C1-6 烷基:-ORc 、-C(O)NH-C1-4 烷基、-C(O)NH-(羥基C1-4 烷基)、羥基C1-4 烷基、5員或6員雜芳基、雜環基、-SO2 C1-4 烷基及-NHS(O)2 C1-4 烷基;或Rb 為-S(O)2 雜芳基;或Rb 為視情況經一或多個羥基取代之4員至7員雜環基;或Rb 為H、-ORc 、-[CH2 -CH2 -O]n -H、-[CH2 -CH2 -O]m -CH3 或視情況經一或多個C1-4 烷基取代之雜芳基;其中n為2-6且m為1-6;Rc 為H或羥基C1-4 烷基;R2 為H、C1-4 烷氧基、鹵基-C1-4 烷氧基、鹵基、C1-4 烷基、-S-C1-4 烷基或-NH-C1-4 烷基;R4 為H、鹵基、鹵基-C1-4 烷基、C1-4 烷基、C3-5 環烷基;R5 為H、鹵基、CN、C1-4 烷氧基、羥基-C1-4 烷氧基、C1-4 烷氧基-C1-4 烷氧基、-CH=NH-O-C1-4 烷基、-CH=NH-O(羥基C1-4 烷基);或R5 為視情況經OH或NRg Rh 取代之C2-6 炔基,其中Rg 及Rh 獨立地為H或C1-4 烷基;或Rg 及Rh 與其所連接之氮一起形成視情況含有選自O、S或N之額外雜原子的4員至7員雜環基,其中該雜原子可呈其氧化形式;且其中該雜環基視情況經C1-4 烷基取代;R6 為鹵基、C1-4 烷基或CN;或其醫藥學上可接受之鹽。
- 如請求項1之化合物,其具有式II:; 或其醫藥學上可接受之鹽。
- 如請求項1之化合物,其具有式III:; 或其醫藥學上可接受之鹽。
- 如請求項1至3中任一項之化合物,其中:R1 為CH3 、環丙基、-CH2 OH或CH=NH-OH;或其醫藥學上可接受之鹽。
- 如請求項1或2之化合物,其中:R2 為H或-NH-CH3 ;或其醫藥學上可接受之鹽。
- 如請求項1至3中任一項之化合物,其中:R4 為H或鹵基;或其醫藥學上可接受之鹽。
- 如請求項1至3中任一項之化合物,其中:R5 為H、F、CN、經OH或硫代嗎啉取代之C2-4 炔基;或其醫藥學上可接受之鹽。
- 如請求項1至3中任一項之化合物,其中:R6 為Cl或CN;或其醫藥學上可接受之鹽。
- 如請求項1至3中任一項之化合物,其中R3 為羥基C1-6 烷基、羥基C1-6 烷氧基、-O-(CH2 CH2 -O)n H、-O-(CH2 CH2 -O)m CH3 、-NH-(CH2 CH2 O)n H、-NH-(CH2 CH2 -O)m CH3 、經羥基取代之氮雜環丁烷、經一或多個獨立地選自羥基及羥基C1-4 烷基之取代基取代之吡咯啶、或經羥基C1-4 烷基取代之哌嗪;或其醫藥學上可接受之鹽。
- 如請求項1至3中任一項之化合物,其中R3 選自以下基團: ;或其醫藥學上可接受之鹽。
- 如請求項10之化合物,其中R3 選自:;或其醫藥學上可接受之鹽。
- 如請求項3之化合物,其中R1 為CH3 或CH2 OH,R2 為H,R3 為-ORa 或-NHRb ,R4 為Cl,R5 為H或F,且R6 為Cl;或其醫藥學上可接受之鹽。
- 如請求項1之化合物,其選自由以下各者組成之群: (S)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; (R)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基-3-甲基丁氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-2-(羥甲基)-5-((3-(羥甲基)氧雜環丁-3-基)甲氧基)-1,6-萘啶-4(1H)-酮; N-(2-((8-氯-1-(2,6-二氯苯基)-2-(羥甲基)-4-側氧基-1,4-二氫-1,6-萘啶-5-基)氧基)乙基)甲磺醯胺; 8-氯-1-(2,6-二氯苯基)-5-(2-(2-(2-(2-羥基乙氧基)乙氧基)乙氧基)乙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(3-羥基-2-(羥甲基)丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-((1,3-二羥基丙-2-基)氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-2-(羥甲基)-5-(氧雜環丁-3-基甲氧基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-2-(羥甲基)-5-(2-(2-甲氧基乙氧基)乙氧基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(2-羥基乙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-((2-(2-(2-(2-羥基乙氧基)乙氧基)乙氧基)乙基)胺基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-((14-羥基-3,6,9,12-四氧雜十四烷基)氧基)-2-甲基-1,6-萘啶-4(1H)-酮; 5-(2,5,8,11,14,17-六氧雜十九烷-19-基氧基)-8-氯-1-(2,6-二氯苯基)-2-甲基-1,6-萘啶-4(1H)-酮; 3-氯-2-(8-氯-5-((2-(2-(2-(2-羥基乙氧基)乙氧基)乙氧基)乙基)胺基)-2-甲基-4-側氧基-1,6-萘啶-1(4H)-基)苯甲腈; 3-((8-氯-1-(2,6-二氯苯基)-2-甲基-4-側氧基-1,4-二氫-1,6-萘啶-5-基)胺基)-2-羥基-N-(2-羥乙基)丙醯胺; 3,5-二氯-4-(5-(2,3-二羥基丙氧基)-2-甲基-4-側氧基-1,7-萘啶-1(4H)-基)苯甲腈; 8-氯-1-(2,6-二氯苯基)-5-((17-羥基-3,6,9,12,15-五氧雜十七烷基)氧基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(3-(2,3-二羥基丙氧基)-2-羥基丙氧基)-2-甲基-1,6-萘啶-4(1H)-酮; 3-氯-2-(8-氯-5-(2-(2-(2-(2-羥基乙氧基)乙氧基)乙氧基)乙氧基)-2-甲基-4-側氧基-1,6-萘啶-1(4H)-基)苯甲腈; N-(2-((1-(2,6-二氯-4-氰基苯基)-2-甲基-4-側氧基-1,4-二氫-1,7-萘啶-5-基)胺基)乙基)甲磺醯胺; 3-氯-2-(8-氯-5-(2-(2-(2-(2-羥基乙氧基)乙氧基)乙氧基)乙氧基)-2-甲基-4-側氧基-1,6-萘啶-1(4H)-基)-5-氟苯甲腈; 8-氯-1-(2,6-二氯-4-氟苯基)-5-((17-羥基-3,6,9,12,15-五氧雜十七烷基)氧基)-2-甲基-1,6-萘啶-4(1H)-酮; 3,5-二氯-4-(8-氯-5-(4-(2-羥乙基)哌嗪-1-基)-2-甲基-4-側氧基-1,6-萘啶-1(4H)-基)苯甲腈; 8-氯-1-(2,6-二氯苯基)-2-甲基-5-(2,3,4-三羥基丁氧基)-1,6-萘啶-4(1H)-酮; 3,5-二氯-4-(5-((2-羥乙基)胺基)-2-甲基-4-側氧基-1,7-萘啶-1(4H)-基)苯甲腈; 8-氯-1-(2,6-二氯苯基)-5-(3-羥基-2,2-雙(羥甲基)丙氧基)-2-甲基-1,6-萘啶-4(1H)-酮; 3,5-二氯-4-(5-(3-羥基氮雜環丁-1-基)-2-甲基-4-側氧基-1,7-萘啶-1(4H)-基)苯甲腈; 8-氯-1-(2,6-二氯苯基)-5-(2-(2-(2-(2-羥基乙氧基)乙氧基)乙氧基)乙氧基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-((2R,4S)-4-羥基-2-(羥甲基)吡咯啶-1-基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯-4-氟苯基)-5-(2-(2-(2-(2-羥基乙氧基)乙氧基)乙氧基)乙氧基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-((3R,4S)-3,4-二羥基吡咯啶-1-基)-2-甲基-1,6-萘啶-4(1H)-酮; 3-氯-2-(8-氯-5-(2,3-二羥基丙氧基)-2-甲基-4-側氧基-1,6-萘啶-1(4H)-基)苯甲腈; 5-((2-(1H-咪唑-4-基)乙基)胺基)-8-氯-1-(2,6-二氯苯基)-2-甲基-1,6-萘啶-4(1H)-酮; N-(2-((8-氯-1-(2,6-二氯苯基)-2-甲基-4-側氧基-1,4-二氫-1,6-萘啶-5-基)氧基)乙基)甲磺醯胺; 8-氯-1-(2,6-二氯苯基)-5-((2-(2-(2-(2-羥基乙氧基)乙氧基)乙氧基)乙基)胺基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-甲基-1,6-萘啶-4(1H)-酮; (S)-8-氯-1-(2,6-二氯苯基)-5-((2,3-二羥丙基)胺基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基-3-甲基丁氧基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(3-羥基-2-(羥甲基)-2-甲基丙氧基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(2-羥基-2-甲基丙氧基)-2-甲基-1,6-萘啶-4(1H)-酮; 3,5-二氯-4-(8-氯-5-(((3R,4S)-4-羥基四氫呋喃-3-基)胺基)-2-甲基-4-側氧基-1,6-萘啶-1(4H)-基)苯甲腈; 3,5-二氯-4-(8-氯-5-((2-羥基乙氧基)胺基)-2-甲基-4-側氧基-1,6-萘啶-1(4H)-基)苯甲腈; 8-氯-1-(2,6-二氯苯基)-2-甲基-5-((1-甲基-1H-四唑-5-基)胺基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-2-甲基-5-((1-甲基-1H-四唑-5-基)氧基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-2-甲基-5-((2-甲基-2H-四唑-5-基)胺基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(2-羥基乙氧基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-((2-羥基乙氧基)胺基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-2-甲基-5-(氧雜環丁-3-基甲氧基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-2-(羥甲基)-5-((2-(甲基磺醯基)乙基)胺基)-1,6-萘啶-4(1H)-酮; 8-環丙基-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(3-羥基-2-(羥甲基)丙氧基)-2-(甲氧基甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-(甲氧基甲基)-1,6-萘啶-4(1H)-酮; 3-氯-2-(8-氯-2-環丙基-5-(2,3-二羥基丙氧基)-4-側氧基-1,6-萘啶-1(4H)-基)苯甲腈; 4-(5-((2-(1H-咪唑-4-基)乙基)胺基)-2-甲基-4-側氧基-1,7-萘啶-1(4H)-基)-3,5-二氯苯甲腈; 8-氯-1-(2,6-二氯苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; (R)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基-3-甲基丁氧基)-2-甲基-1,6-萘啶-4(1H)-酮; (S)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基-3-甲基丁氧基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯-4-氟苯基)-5-(2,3-二羥基丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯-4-氟苯基)-5-(2-羥基乙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-2-(二氟甲基)-5-(2,3-二羥基丙氧基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-4-側氧基-1,4-二氫-1,6-萘啶e-2-甲腈; 8-氯-1-(2,6-二氯苯基)-5-羥基-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-甲基-7-(甲胺基)-1,6-萘啶-4(1H)-酮; 1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-7-乙基-2-甲基-1,6-萘啶-4(1H)-酮; 1-(2-氯-6-乙基苯基)-5-(2,3-二羥基丙氧基)-7-乙基-2-甲基-1,6-萘啶-4(1H)-酮; 1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-7-甲氧基-2-甲基-1,6-萘啶-4(1H)-酮; 1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-8-乙基-2-甲基-1,6-萘啶-4(1H)-酮; N-(1-(2,6-二氯-4-氰基苯基 )-2-甲基-4-側氧基-1,4-二氫-1,7-萘啶-5-基)-1H-吡唑-4-磺醯胺; 8-氯-1-(2,6-二氯苯基)-2-甲基-5-(1H-1,2,4-三唑-1-基)-1,6-萘啶-4(1H)-酮; 3,5-二氯-4-(2-甲基-4-側氧基-5-(1H-吡唑-3-基)-1,7-萘啶-1(4H)-基)苯甲腈; 3,5-二氯-4-(2-甲基-5-(1-甲基-1H-吡唑-4-基)-4-側氧基-1,7-萘啶-1(4H)-基)苯甲腈; 8-氯-1-(2,6-二氯苯基)-2-(羥甲基)-5-(3-羥丙基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(3,4-二羥丁基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; (R)-8-氯-1-(2,6-二氯苯基)-5-(3,4-二羥丁基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; (S)-8-氯-1-(2,6-二氯苯基)-5-(3,4-二羥丁基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥丙基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; (R)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥丙基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; (S)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥丙基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥丙基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(1,2-二羥乙基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; (R)-8-氯-1-(2,6-二氯苯基)-5-(1,2-二羥乙基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; (S)-8-氯-1-(2,6-二氯苯基)-5-(1,2-二羥乙基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(1,2-二羥乙基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(2-羥基乙醯基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-((2,3-二羥基丙氧基)甲基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(((1,3-二羥基丙-2-基)氧基)甲基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯苯基)-5-(2,4-二羥基-3-氧丁-2-基)-2-甲基-1,6-萘啶-4(1H)-酮; 1-(4-(3-胺基-3-甲基丁-1-炔-1-基)-2,6-二氯苯基)-8-氯-5-(2,3-二羥基丙氧基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯-4-(3-嗎啉基丙-1-炔-1-基)苯基)-5-(2-羥基乙氧基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯-4-(3-(1,1-二氧離子基硫代嗎啉基)丙-1-炔-1-基)苯基)-5-(2-羥基乙氧基)-2-甲基-1,6-萘啶-4(1H)-酮; 8-氯-1-(2,6-二氯-4-(3-(二甲胺基)丙-1-炔-1-基)苯基)-5-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-2-甲基-1,6-萘啶-4(1H)-酮;及 (8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-4-側氧基-1,4-二氫-1,6-萘啶-2-基)甲基二氫磷酸酯;或其醫藥學上可接受之鹽。
- 一種(S)-8-氯-1-(2,6-二氯苯基)-5-(2,3-二羥基丙氧基)-2-(羥甲基)-1,6-萘啶-4(1H)-酮之水合物之結晶形式,其中當使用波長為1.5418 Å之CuKα輻射且在約22℃之溫度下量測時,其具有包含選自以下各者之一或多個峰值的X射線粉末繞射(XRPD)圖案之表徵:7.0 ± 0.2 °2θ、14.1 ± 0.2 °2θ、18.5 ± 0.2 °2θ、24.7 ± 0.2 °2θ、26.0 ± 0.2 °2θ及26.9 ± 0.2 °2θ。
- 一種醫藥組合物,其包含治療有效量之如請求項1至13中任一項之化合物或其醫藥學上可接受之鹽及一或多種醫藥學上可接受之載劑。
- 一種組合,其包含治療有效量之如請求項1至13中任一項之化合物及一或多種治療活性助劑。
- 如請求項16之組合,其中該助劑選自I類抗心律不整劑、II類抗心律不整劑、III類抗心律不整劑、IV類抗心律不整劑、V類抗心律不整劑、強心苷及其他影響心房不應期之藥物;止血調節劑、抗血栓藥;凝血酶抑制劑;VIla因子抑制劑;抗凝劑、Xa因子抑制劑及直接凝血酶抑制劑;抗血小板劑、環加氧酶抑制劑、二磷酸腺苷(ADP)受體抑制劑、磷酸二酯酶抑制劑、醣蛋白IIB/IIA、腺苷再吸收抑制劑;抗血脂異常劑、HMG-CoA還原酶抑制劑、其他膽固醇降低劑;PPARa促效劑;膽酸螯合劑、膽固醇吸收抑制劑;膽甾醇酯轉移蛋白(CETP)抑制劑;迴腸膽酸傳送系統抑制劑(IBAT抑制劑);膽酸結合樹脂;菸鹼酸及其類似物;抗氧化劑;ω-3脂肪酸;抗高血壓劑,包括腎上腺素激導性受體拮抗劑、β阻斷劑、α阻斷劑、混合α/β阻斷劑;腎上腺素激導性受體促效劑、α-2促效劑;血管收縮素轉化酶(ACE)抑制劑、鈣離子通道阻斷劑;血管緊張素II受體拮抗劑;醛固酮受體拮抗劑;中樞作用腎上腺素藥物、中樞α促效劑;及利尿劑;抗肥胖劑、胰臟脂肪酶抑制劑、微粒體轉移蛋白(MTP)調節劑、二醯基甘油醯基轉移酶(DGAT)抑制劑、大麻素(CBI)受體拮抗劑;胰島素及胰島素類似物;胰島素促分泌物;改進腸促胰島素作用之藥劑、二肽基肽酶IV (DPP -4)抑制劑、類升糖素肽-I (GLP-1)促效劑;胰島素增敏劑、過氧化體增殖物活化受體γ (PPARy)促效劑、調節肝葡萄糖平衡之藥劑、果糖1,6-二磷酸酶抑制劑、肝糖磷酸化酶抑制劑、肝糖合成酶激酶抑制劑、葡糖激酶活化劑;經設計以減少/減緩腸之葡萄糖吸收之藥劑、α-葡糖苷酶抑制劑;拮抗升糖素作用或降低升糖素分泌之藥劑、澱粉素類似物;防止由腎臟再吸收葡萄糖之藥劑,及鈉依賴性葡萄糖轉運子2 (SGLT-2)抑制劑。
- 一種如請求項1至13中任一項之化合物或其醫藥學上可接受之鹽的用途,其用於製造供用以治療或預防有需要之個體中疾病或病症之藥劑,該疾病或病症對GIRK受體之抑制起反應。
- 如請求項18之用途,其中該疾病或病症選自心律不整、心房震顫、原發性高醛固酮症、高血壓及心房腔失調症候群(sick sinus syndrome)。
- 如請求項1至3中任一項之化合物或其醫藥學上可接受之鹽,其用作藥劑。
- 如請求項1至3中任一項之化合物或其醫藥學上可接受之鹽,其用於治療或預防對GIRK受體之抑制起反應之疾病或病症。
- 如請求項1至3中任一項之化合物或其醫藥學上可接受之鹽,其用於治療心律不整、心房震顫、原發性高醛固酮症、高血壓或心房腔失調症候群。
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Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JOP20190086A1 (ar) | 2016-10-21 | 2019-04-18 | Novartis Ag | مشتقات نافثيريدينون جديدة واستخدامها في معالجة عدم انتظام ضربات القلب |
SG11202012973RA (en) * | 2018-06-27 | 2021-01-28 | Bristol Myers Squibb Co | Naphthyridinone compounds useful as t cell activators |
WO2022074567A1 (en) | 2020-10-06 | 2022-04-14 | Novartis Ag | Pharmaceutical compositions comprising naphthyridinone derivatives and their use in the treatment of arrhythmia |
AR127698A1 (es) * | 2021-11-23 | 2024-02-21 | Novartis Ag | Derivados de naftiridinona para el tratamiento de una enfermedad o un trastorno |
Family Cites Families (83)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1022214A (en) | 1963-01-31 | 1966-03-09 | Sterling Drug Inc | Novel 1,3-disubstituted-1,4-dihydro-4-oxo-1,7-naphthyridines and their preparation |
IL51092A0 (en) | 1976-12-10 | 1977-02-28 | Abic Ltd | Naphthyridine derivatives and their preparation |
JPS57176957A (en) | 1981-04-24 | 1982-10-30 | Nissan Chem Ind Ltd | Preparation of 1-(2',6'-dichlorophenyl)-2-indolinone |
JPS57176959A (en) | 1981-04-24 | 1982-10-30 | Nissan Chem Ind Ltd | 1-(2',6'-dichlorophenyl)-2,3bis(methylthio) indole and its preparation |
JPS57176958A (en) | 1981-04-24 | 1982-10-30 | Nissan Chem Ind Ltd | 1-(2',6'-dichlorophenyl)-2-methylthioindole and its preparation |
JPS57176956A (en) | 1981-04-24 | 1982-10-30 | Nissan Chem Ind Ltd | Preparation of 1-(2',6'-dichlorophenyl)-2-indolinone |
US4617307A (en) | 1984-06-20 | 1986-10-14 | Ciba-Geigy Corporation | Substituted imidazo[1,5-A]pyridine derivatives as aromatase inhibitors |
US4889861A (en) | 1982-12-21 | 1989-12-26 | Ciba-Geigy Corp. | Substituted imidazo[1,5-a]pyridine derivatives and other substituted bicyclic derivatives and their use as aromatase inhibitors |
FI77669C (fi) | 1983-04-13 | 1989-04-10 | Ciba Geigy Ag | 20-spiroxaner och analoger, som innehaoller en oeppen ring e, foerfarande foer deras framstaellning samt dessa innehaollande farmaceutiska preparat. |
US4698341A (en) | 1983-07-30 | 1987-10-06 | Godecke Aktiengesellschaft | Use of 1,6-naphthyridinone derivatives in treating pulmonary thrombosis |
US4767762A (en) * | 1985-12-23 | 1988-08-30 | Abbott Laboratories | Tricyclic quinoline and naphthyride antibacterials |
US5120712A (en) | 1986-05-05 | 1992-06-09 | The General Hospital Corporation | Insulinotropic hormone |
US5118666A (en) | 1986-05-05 | 1992-06-02 | The General Hospital Corporation | Insulinotropic hormone |
ES2113879T3 (es) | 1990-01-24 | 1998-05-16 | Douglas I Buckley | Analogos de glp-1 utiles para el tratamiento de diabetes. |
AU1625192A (en) | 1991-05-31 | 1992-12-03 | Zeneca Limited | Heterocyclic derivatives |
EP0618803A4 (en) | 1991-12-19 | 1995-03-22 | Southwest Found Biomed Res | POLYPEPTIDE INHIBITING PROTEIN TRANSFER TO CHOLESTERYL ESTERS, ANTIBODIES AGAINST SYNTHETIC POLYPEPTIDE AND ANTI-ATHEROSCLEROSIS PROPHYLACTIC AND THERAPEUTIC TREATMENTS. |
IL111785A0 (en) | 1993-12-03 | 1995-01-24 | Ferring Bv | Dp-iv inhibitors and pharmaceutical compositions containing them |
US5705483A (en) | 1993-12-09 | 1998-01-06 | Eli Lilly And Company | Glucagon-like insulinotropic peptides, compositions and methods |
US5512549A (en) | 1994-10-18 | 1996-04-30 | Eli Lilly And Company | Glucagon-like insulinotropic peptide analogs, compositions, and methods of use |
WO1996012704A1 (fr) | 1994-10-20 | 1996-05-02 | Wakunaga Seiyaku Kabushiki Kaisha | Nouveau derive de pyridone-carboxylate, ou sel de celui-ci, et antibacterien le contenant comme principe actif |
DK0897919T3 (da) | 1996-04-19 | 2004-09-27 | Wakunaga Pharma Co Ltd | Nye pyridoncarboxylsyrederivater eller salte deraf samt antibakterielle midler indeholdende disse som den aktive bestanddel |
DE122010000020I1 (de) | 1996-04-25 | 2010-07-08 | Prosidion Ltd | Verfahren zur Senkung des Blutglukosespiegels in Säugern |
TW492957B (en) | 1996-11-07 | 2002-07-01 | Novartis Ag | N-substituted 2-cyanopyrrolidnes |
WO1998023592A1 (fr) | 1996-11-28 | 1998-06-04 | Wakunaga Pharmaceutical Co., Ltd. | Nouveaux derives d'acide pyridonecarboxylique ou leurs sels, et medicaments contenant ceux-ci en tant que principe actif |
JP2002517486A (ja) | 1998-06-12 | 2002-06-18 | バーテックス ファーマシューティカルズ インコーポレイテッド | p38のインヒビター |
AU5509099A (en) | 1998-08-03 | 2000-02-28 | Basf Corporation | Pyridinones for the treatment of sexual dysfunction |
US6197786B1 (en) | 1998-09-17 | 2001-03-06 | Pfizer Inc | 4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines |
GT199900147A (es) | 1998-09-17 | 1999-09-06 | 1, 2, 3, 4- tetrahidroquinolinas 2-sustituidas 4-amino sustituidas. | |
CO5150173A1 (es) | 1998-12-10 | 2002-04-29 | Novartis Ag | Compuestos n-(glicilo sustituido)-2-cianopirrolidinas inhibidores de peptidasa de dipeptidilo-iv (dpp-iv) los cuales son efectivos en el tratamiento de condiciones mediadas por la inhibicion de dpp-iv |
US6677341B2 (en) | 1999-09-23 | 2004-01-13 | Pharmacia Corporation | (R)-Chiral halogenated substituted heteroaryl benzyl aminoalcohol compounds useful for inhibiting cholesteryl ester transfer protein activity |
NZ521855A (en) | 2000-04-12 | 2004-10-29 | Novartis Ag | Use of an aldosterone synthase inhibitor in combination with an angiotensin I receptor antagonist or an angiotensin I receptor antagonist plus a dirruretic to treat various conditions |
JP2003040866A (ja) | 2001-07-31 | 2003-02-13 | Nippon Kayaku Co Ltd | N置換インドール誘導体、その製造法及びそれを有効成分とする害虫防除剤 |
IL160707A0 (en) * | 2001-09-26 | 2004-08-31 | Bayer Pharmaceuticals Corp | 1, 8-naphthyridine derivatives as antidiabetics |
US20040248956A1 (en) | 2002-01-29 | 2004-12-09 | Hagmann William K | Substituted imidazoles as cannabinoid receptor modulators |
ES2274268T3 (es) | 2002-05-31 | 2007-05-16 | Bayer Pharmaceuticals Corporation | Compuestos y composiciones para el tratamiento de la diabetes y trastornos relacionados con la diabetes. |
ATE335744T1 (de) | 2002-08-07 | 2006-09-15 | Novartis Pharma Gmbh | Organische verbindungen als mittel zur behandlung von aldosteronbedingten zuständen |
JP2006508970A (ja) | 2002-11-18 | 2006-03-16 | ノバルティス アクチエンゲゼルシャフト | イミダゾ[1,5a]ピリジン誘導体およびアルデステロンにより仲介される疾患の処置方法 |
EP1670795A1 (en) | 2003-09-18 | 2006-06-21 | ALTANA Pharma AG | Pharmacologically active imidazo 4,5-c pyridines |
EP1667685B1 (en) | 2003-09-23 | 2012-03-14 | Merck Sharp & Dohme Corp. | Quinazoline potassium channel inhibitors |
DE602005014955D1 (de) | 2004-03-26 | 2009-07-30 | Lilly Co Eli | Verbindungen und verfahren zur behandlung von dyslipidämie |
UA90269C2 (ru) | 2004-04-02 | 2010-04-26 | Мицубиси Танабе Фарма Корпорейшн | Тетрагидрохинолиновые производные и способ их получения |
DE102004018198A1 (de) | 2004-04-15 | 2005-11-03 | Merck Patent Gmbh | Sulfonamide |
BRPI0510410A (pt) | 2004-05-28 | 2007-10-23 | Speedel Experimenta Ag | compostos orgánicos |
AR050251A1 (es) | 2004-05-28 | 2006-10-11 | Speedel Experimenta Ag | Compuestos heterociclicos con nitrogeno heteroatomico y composicion farmaceutica en base al compuesto |
CA2568159A1 (en) | 2004-05-28 | 2005-12-15 | Speedel Experimenta Ag | Tetrahydro-imidazo [1,5-a] pyridin derivatives as aldosterone synthase inhibitors |
NZ587547A (en) | 2004-06-24 | 2012-09-28 | Vertex Pharma | Modulators of ATP-Binding Cassette Transporters |
WO2006005726A2 (en) | 2004-07-09 | 2006-01-19 | Speedel Experimenta Ag | Heterocyclic compounds |
DE102004054215A1 (de) | 2004-11-10 | 2006-05-11 | Merck Patent Gmbh | Pyridopyrimidinonderivate |
TW200716634A (en) | 2005-05-31 | 2007-05-01 | Speedel Experimenta Ag | Heterocyclic spiro-compounds |
TW200716636A (en) | 2005-05-31 | 2007-05-01 | Speedel Experimenta Ag | Heterocyclic spiro-compounds |
TW200716105A (en) | 2005-05-31 | 2007-05-01 | Speedel Experimenta Ag | Imidazole compounds |
CA2613522A1 (en) | 2005-06-27 | 2007-01-04 | Exelixis, Inc. | Imidazole based lxr modulators |
GT200600381A (es) | 2005-08-25 | 2007-03-28 | Compuestos organicos | |
EP1783114A1 (en) | 2005-11-03 | 2007-05-09 | Novartis AG | N-(hetero)aryl indole derivatives as pesticides |
RU2448703C2 (ru) | 2005-11-23 | 2012-04-27 | Дзе Борд Оф Риджентс Оф Дзе Юниверсити Оф Техас Систем | Онкогенное ras-специфичное цитотоксическое соединение и способы его применения |
TW200804378A (en) | 2005-12-09 | 2008-01-16 | Speedel Experimenta Ag | Organic compounds |
WO2007116908A1 (ja) | 2006-04-04 | 2007-10-18 | Taiyo Nippon Sanso Corporation | メタン分離方法、メタン分離装置及びメタン利用システム |
TW200808812A (en) | 2006-04-12 | 2008-02-16 | Speedel Experimenta Ag | Imidazo compounds |
TW200808813A (en) | 2006-04-12 | 2008-02-16 | Speedel Experimenta Ag | Imidazo compounds |
EP1886695A1 (en) | 2006-06-27 | 2008-02-13 | Speedel Experimenta AG | Pharmaceutical combination of an aldosterone synthase inhibitor and a glucocorticoid receptor antagonist or a cortisol synthesis inhibitor or a corticotropin releasing factor antagonist |
WO2008027284A1 (en) | 2006-08-25 | 2008-03-06 | Novartis Ag | Fused imidazole derivatives for the treatment of disorders mediated by aldosterone synthase and/or 11-beta-hydroxylase and/or aromatase |
WO2008076862A2 (en) | 2006-12-18 | 2008-06-26 | Novartis Ag | 1-substituted imidazole derivatives and their use as aldosterone synthase inhibitors |
EP2213668A3 (en) | 2006-12-18 | 2010-11-24 | Novartis AG | Imidazoles as aldosterone synthase inhibitors |
MX2009006630A (es) | 2006-12-18 | 2009-06-30 | Novartis Ag | Derivados de 4-imidazolil-1,2,3,4-tetrahidro-quinola y su uso como inhibidores de aldosterona / 11-beta-hidroxilasa. |
US8324235B2 (en) | 2007-03-29 | 2012-12-04 | Novartis Ag | Heterocyclic spiro-compounds |
AR070449A1 (es) | 2008-02-22 | 2010-04-07 | Otsuka Pharma Co Ltd | Compuesto de benzodiazepina y composicion farmaceutica |
WO2010012745A2 (en) | 2008-07-29 | 2010-02-04 | Boehringer Ingelheim International Gmbh | Benzimidazoles |
EP2464974A1 (en) | 2009-08-10 | 2012-06-20 | UCL Business PLC | Functionalisation of solid substrates |
GB0917571D0 (en) | 2009-10-07 | 2009-11-25 | Karobio Ab | Novel estrogen receptor ligands |
JP5894161B2 (ja) | 2010-08-25 | 2016-03-23 | ネオファーム カンパニー, リミテッド | 新規の複素環化合物及びこれを用いた炎症性疾患治療用組成物 |
EP2524915A1 (en) | 2011-05-20 | 2012-11-21 | Sanofi | 2-Amino-3-(imidazol-2-yl)-pyridin-4-one derivatives and their use as VEGF receptor kinase inhibitors |
MX2014000374A (es) | 2011-07-12 | 2014-03-21 | Hoffmann La Roche | Compuesto de aminometil quinolona. |
NZ627942A (en) | 2012-01-27 | 2016-03-31 | Gilead Sciences Inc | Combination therapies using late sodium ion channel blockers and potassium ion channel blockers |
CA2873861C (en) | 2012-04-05 | 2021-01-19 | Boehringer Ingelheim International Gmbh | Naphthyridinone derivatives as inhibitors of cytomegalovirus dna polymerase |
US9067894B1 (en) | 2013-03-07 | 2015-06-30 | Vanderbilt University | Compound, composition, and method of activating GIRK potassium channel and use of same for treating conditions of interest |
WO2014152317A2 (en) | 2013-03-15 | 2014-09-25 | Melinta Therapeutics, Inc. | Methods of treating gonorrhea infections using quinolone antibiotics |
US10266551B2 (en) | 2013-03-15 | 2019-04-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
AR096022A1 (es) | 2013-04-11 | 2015-12-02 | Basf Se | Compuestos de pirimidinio sustituido, útiles para combatir plagas de animales |
WO2015019347A1 (en) | 2013-08-08 | 2015-02-12 | Yeda Research And Development Company Ltd. | Girk as a therapeutic target of immune disorders and a marker of b cell subtypes |
JP2015143209A (ja) | 2013-12-26 | 2015-08-06 | 学校法人近畿大学 | ピリドンカルボン酸系抗菌薬のアルコキシカルボニルヘミアセタール型エステルプロドラッグ |
US20170266199A1 (en) | 2014-08-21 | 2017-09-21 | Glaxosmithkline Intellectual Property Development Limited | Heterocyclic amides as rip1 kinase inhibitors as medicaments |
EA035465B1 (ru) * | 2015-06-09 | 2020-06-22 | Байер Фарма Акциенгезельшафт | 7-замещенные 1-арил-нафтиридин-3-амиды карбоновой кислоты в качестве положительных аллостерических модуляторов мускаринового рецептора m2, способ их получения, их применение для лечения и/или профилактики заболеваний и лекарственное средство, содержащее эти соединения |
JOP20190086A1 (ar) | 2016-10-21 | 2019-04-18 | Novartis Ag | مشتقات نافثيريدينون جديدة واستخدامها في معالجة عدم انتظام ضربات القلب |
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