TWI405754B - 芳基取代之磺醯胺化合物及其作為抗癌劑之用途 - Google Patents
芳基取代之磺醯胺化合物及其作為抗癌劑之用途 Download PDFInfo
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- TWI405754B TWI405754B TW099126681A TW99126681A TWI405754B TW I405754 B TWI405754 B TW I405754B TW 099126681 A TW099126681 A TW 099126681A TW 99126681 A TW99126681 A TW 99126681A TW I405754 B TWI405754 B TW I405754B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Description
本發明係關於一種芳基取代之磺醯胺化合物,特別是該化合物可用於抑制微管蛋白聚合且具有抗癌活性。特別言之,本發明係關於芳基取代之磺醯胺化合物及其在癌症治療中之用途。
本申請案依據35 U.S.C.§119(e)之規定主張2009年8月10日申請之美國臨時申請案第61/232,601號之優先權,該案之內容以引用的方式併入本文中。
微管為α微管蛋白及β微管蛋白構成之細胞內管。作為細胞骨架之重要組分,他們在癌症發展中必需的細胞分裂方面扮演重要角色。因此,微管/微管蛋白作為癌症療法之標靶已引起極大關注。
本發明係基於意外發現某些芳基取代之磺醯胺化合物抑制微管蛋白聚合且具有有效的抗癌活性。因此,本發明係關於芳基取代之磺醯胺化合物及其在癌症治療中之用途。
在一態樣中,本發明提供一種式(I)之芳基取代之磺醯胺化合物:
在此式中,----
鍵為單鍵或雙鍵;X為N或CRa
,其中Ra
為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;Y不存在或為NRb
,其中Rb
為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;若Y不存在,或若Y為NRb
且----
鍵為單鍵,則R1
為芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;或若Y為NRb
且----
鍵為雙鍵,則R1
為烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;R2
為烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、鹵基、氰基、硝基、ORc
、SO2
NRc
Rd
、OC(O)Rc
、C(O)Rc
、C(O)ORc
、C(O)NRc
Rd
、NRc
Rd
、NHC(O)Rc
、NHC(O)NRc
Rd
或NHC(S)Rc
,其中Rc
及Rd
各獨立地為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;R3
為烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、鹵基、氰基、硝基、ORc
、SO2
NRc
Rd
、OC(O)Rc
、C(O)Rc
、C(O)ORc
、C(O)NRc
Rd
、NRc
Rd
、NHC(O)Rc
、NHC(O)NRc
Rd
或NHC(S)Rc
;m為0、1、2、3、4或5;且n為0、1、2、3、4、5或6。
上述芳基取代之磺醯胺化合物之一個子組包括式(II)化合物:
在此等化合物中,Y可不存在或為NH;X可為CH或N;R1
可為芳基(例如苯基)或雜芳基(例如呋喃基、吡啶基或噻吩基),各視情況經鹵基、鹵烷基、胺基、胺基烷基、羥基、烷氧基、氰基、硝基、CHO、羧基或醯基取代;或R2
可為ORc
(例如,其中Rc
為烷基)或SO2
NRc
Rd
。
上述芳基取代之磺醯胺化合物之另一子組包括R2
為ORc
或SO2
NRc
Rd
之化合物。在此等化合物中,R1
可為芳基(例如苯基)或雜芳基(例如呋喃基,吡啶基或噻吩基),各視情況經鹵基、鹵烷基、胺基、胺基烷基、羥基、烷氧基、氰基、硝基、CHO、羧基或醯基取代;Y可不存在或為NH;或X可為CH或N。
除非另外說明,否則術語「烷基」係指含有1至20個碳原子(例如C1
-C10
)之直鏈或分支鏈單價烴。烷基之實例包括(但不限於)甲基、乙基、正丙基、異丙基、正丁基、異丁基及第三丁基。術語「烯基」係指含有2至20個碳原子(例如C2
-C10
)及一或多個雙鍵之直鏈或分支鏈單價烴。烯基之實例包括(但不限於)乙烯基、丙烯基、烯丙基及1,4-丁二烯基。術語「炔基」係指含有2至20個碳原子(例如C2
-C10
)及一或多個參鍵之直鏈或分支鏈單價烴。炔基之實例包括(但不限於)乙炔基、1-丙炔基、1-丁炔基及2-丁炔基,及1-甲基-2-丁炔基。術語「烷氧基」係指-O-烷基。烷氧基之實例包括(但不限於)甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基及第三丁氧基。術語「胺基」係指NH2
、烷基胺基或芳基胺基。術語「烷基胺基」係指-N(R)-烷基,其中R可為H、烷基、烯基、炔基、環烷基、環烯基、雜環烷基、雜環烯基、芳基或雜芳基。
術語「環烷基」係指具有3至30個碳原子(例如C3
-C12
)之單價飽和烴環系統。環烷基之實例包括(但不限於)環丙基、環丁基、環戊基、環己基、1,4-伸環己基、環庚基、環辛基及金剛烷基。術語「環烯基」係指具有3至30個碳(例如C3
-C12
)及一或多個雙鍵之單價非芳族烴環系統。實例包括環戊烯基、環己烯基及環庚烯基。術語「雜環烷基」係指具有一或多個雜原子(諸如O、N、S或Se)之單價非芳族5至8員單環、8至12員雙環或11至14員三環環系統。雜環烷基之實例包括(但不限於)哌嗪基、吡咯啶基、二氧雜環己烷基、嗎啉基及四氫呋喃基。術語「雜環烯基」係指具有一或多個雜原子(諸如O、N、S或Se)及一或多個雙鍵之單價非芳族5至8員單環、8至12員雙環或11至14員三環環系統。
術語「芳基」係指單價6碳單環、10碳雙環、14碳三環芳族環系統。芳基之實例包括(但不限於)苯基、萘基及蒽基。術語「雜芳基」係指具有一或多個雜原子(諸如O、N、S或Se)之單價芳族5至8員單環、8至12員雙環或11至14員三環環系統。雜芳基之實例包括吡啶基、呋喃基、咪唑基、苯并咪唑基、嘧啶基、噻吩基、喹啉基、吲哚基、四唑基及噻唑基。
上文所提及之烷基、烯基、炔基、環烷基、雜環烷基、環烯基、雜環烯基、胺基、芳基及雜芳基包括經取代與未經取代之官能基。胺基、環烷基、雜環烷基、環烯基、雜環烯基、芳基及雜芳基上之可能取代基包括(但不限於)C1
-C10
烷基、C2
-C10
烯基、C2
-C10
炔基、C3
-C20
環烷基、C3
-C20
環烯基、C1
-C20
雜環烷基、C1
-C20
雜環烯基、C1
-C10
烷氧基、芳基、芳氧基、雜芳基、雜芳氧基、胺基、C1
-C10
烷基胺基、芳基胺基、羥基、鹵基、側氧基(O=)、硫酮基(S=)、硫基、矽烷基、C1
-C10
烷硫基、芳硫基、C1
-C10
烷基磺醯基、芳基磺醯基、醯基胺基、胺基醯基、胺基硫醯基、甲脒基、巰基、醯胺基、硫脲基、硫氰基、磺醯胺基、胍基、脲基、氰基、硝基、醯基、硫醯基、醯氧基、胺甲醯胺基、胺甲醯基(-C(O)NH2
)、羧基(-COOH)及羧酸酯基。另一方面,烷基、烯基、炔基或伸烷基上之可能取代基包括C1
-C10
烷基除外之上文所列舉之所有取代基。環烷基、環烯基、雜環烷基、雜環烯基、芳基及雜芳基亦可彼此稠合。
適當時,本文所述之芳基取代之磺醯胺化合物包括該等化合物本身,以及其鹽、其溶劑合物及其前藥。舉例而言,陰離子與芳基取代之磺醯胺化合物上帶正電之基團(例如胺基)之間可形成鹽。適合之陰離子包括氯離子、溴離子、碘離子、硫酸根、硫酸氫根、胺基磺酸根、硝酸根、磷酸根、檸檬酸根、甲烷磺酸根、三氟乙酸根、麩胺酸根、葡萄糖醛酸根、戊二酸根、蘋果酸根、順丁烯二酸根、丁二酸根、反丁烯二酸根、酒石酸根、甲苯磺酸根、水楊酸根、乳酸根、萘磺酸根及乙酸根。同樣地,陽離子與芳基取代之磺醯胺化合物上帶負電之基團(例如羧酸根)之間亦可形成鹽。適合之陽離子包括鈉離子、鉀離子、鎂離子、鈣離子及銨陽離子,諸如四甲銨離子。芳基取代之磺醯胺化合物亦包括含有四級氮原子之彼等鹽。前藥之實例包括酯及其他醫藥學上可接受之衍生物,其在投與個體後即能夠提供具活性的芳基取代之磺醯胺化合物。
在另一態樣中,本發明係關於一種藉由使細胞與有效量之上述芳基取代之磺醯胺化合物接觸來抑制微管蛋白聚合的方法。
在另一態樣中,本發明係關於一種藉由投與有需要之個體有效量之上述芳基取代之磺醯胺化合物來治療癌症的方法。
一種含有一或多種上述芳基取代之磺醯胺化合物用於治療癌症之醫藥組合物,以及此治療性用途,及該等化合物用於製造供治療癌症用之藥物的用途亦在本發明之範疇內。
在以下描述中陳述本發明之一或多個實施例之細節。本發明之其他特徵、目的及優勢自發明說明及申請專利範圍將顯而易知。
以下展示本文所述之例示性化合物:
本文所述之芳基取代之磺醯胺化合物可由習知化學轉化法(包括保護基方法)製備,例如以下文獻中所述之方法:R. Larock,Comprehensive Organic Transformations
,VCH Publishers(1989);T.W. Greene及P.G.M. Wuts,Protective Groups in Organic Synthesis
,第3版,John Wiley and Sons (1999);L. Fieser及M. Fieser,Fieser and Fieser's Reagents for Organic Synthesis
,John Wiley and Sons(1994);及L. Paquette編,Encyclopedia of Reagents for Organic Synthesis
,John Wiley and Sons(1995)及其後續版本。
以下流程1中所示之途徑例示本發明之某些7-芳基(雜芳基)-6-氮雜吲哚-1-磺醯胺化合物及7-苯胺基-6-氮雜吲哚-1-磺醯胺化合物之合成。2-溴-3-硝基吡啶(1
)在-40℃至50℃下於THF中與溴化乙烯基鎂反應,得到7-溴-6-氮雜吲哚(2
),其與4-甲氧基苯基磺醯氯反應,得到7-溴-1-(4-甲氧基苯基磺醯基)-1H
-吡咯并[2,3-c]吡啶(3
)。接著,磺醯胺(3
)在甲苯/EtOH中用經取代或未經取代之苯基硼酸、Pd(PPh3
)4
及K2
CO3
加以處理,得到最終化合物(4
);或在吡啶中用經取代或未經取代之苯胺加以處理,得到最終化合物(5
)。
試劑與條件:(i)溴化乙烯基鎂、THF,-40℃至50℃;(ii)4-甲氧基苯基磺醯氯、Bu4
NHSO4
、KOH、CH2
Cl2
,室溫;(iii)經取代或未經取代之苯基硼酸、Pd(PPh3
)4
、K2
CO3
、甲苯/EtOH,回流;(iv)經取代或未經取代之苯胺、吡啶,110℃至120℃。
同樣地,以下流程2中所示之途徑例示本發明之某些7-芳基(雜芳基)-吲哚啉(吲哚)-1-磺醯胺化合物之合成。為合成吲哚-1-磺醯胺化合物(9
),還原1-溴-2-硝基苯(6
),得到7-溴-1H
-吲哚(7
),其與4-甲氧基苯基磺醯氯反應,得到7-溴-1-(4-甲氧基苯基磺醯基)-1H
-吲哚(8
)。接著,在甲苯/EtOH中用芳基或雜芳基硼酸、Pd(PPh3
)4
及K2
CO3
處理磺醯胺(8
),得到最終化合物(9
)。為合成吲哚啉-1-磺醯胺化合物(12
),進一步還原7-溴-1H
-吲哚(7
)(用NaCNBH3
及CH3
COOH,在室溫下),得到7-溴吲哚啉(10
),其與經取代之苯基磺醯氯反應,得到溴-吲哚啉-磺醯胺(11
)。接著,在甲苯/EtOH中用芳基或雜芳基硼酸、Pd(PPh3
)4
及K2
CO3
處理溴-吲哚啉-磺醯胺(11
),得到最終化合物(12
),可對其進行進一步修飾,獲得化合物(13
)。
試劑與條件:(a)溴化乙烯基鎂、THF,-40℃至50℃;(b) 4-甲氧基苯基磺醯氯、Bu4
NHSO4
、KOH、CH2
Cl2
,室溫;(c)多種芳基或雜芳基硼酸、Pd(PPh3
)4
、K2
CO3
、甲苯/EtOH,回流;(d) NaCNBH3
、CH3
COOH,室溫;(e) 4-甲氧基苯基磺醯氯、吡啶,回流;(f) Fe、NH4
Cl、異丙醇;(g)二甲胺鹽酸鹽、NaBH3
CN、Et3
N、EtOH;(h)首先,CH3
OC(O)CH=PPh3
、THF;接著,LiOH、MeOH、H2
O;繼而,O-(四氫-2H-哌喃-2-基)羥胺、PyBOP、Et3
N、DMF;最後,5% TFA、MeOH/CH2
Cl2
。
本發明化合物之合成亦可遵循例如以下文獻中所述之方法來達成:Tetrahedron lett. 2008
,49,5309;J. Org. Chem. 2001
,66,638;Tetrahedron 1995
,51,1167;及J. Org. Chem. 2002
,67,2345,如熟習此項技術者所瞭解可進行必要修改。
可藉由快速管柱層析、高效液相層析、結晶或任何其他適合方法進一步純化由此合成之芳基取代之磺醯胺化合物。
本文所提及之芳基取代之磺醯胺化合物可含有非芳族雙鍵及一或多個不對稱中心。因此,其可以外消旋體及外消旋混合物、單一對映異構體、個別非對映異構體、非對映異構混合物、及順式或反式異構形式存在。涵蓋所有該等異構形式。
本發明之範疇亦包含(1)含有有效量之至少一種本發明之芳基取代之磺醯胺化合物及醫藥學上可接受之載劑的醫藥組合物;及(2)藉由投與有治療需要之個體有效量之此類芳基取代之磺醯胺化合物來治療癌症的方法。
本文中所用之術語「治療」係指將芳基取代之磺醯胺化合物投與患有癌症或具有癌症症狀或患癌傾向之個體,旨在治癒、醫治、緩和、減輕、改變、救治、改善、改良、影響或降低病症風險、癌症症狀或患癌傾向。術語「有效量」係指活性劑賦予個體預期治療效果所需之量。如熟習此項技術者所瞭解,有效量可視投藥途徑、賦形劑使用及與其他藥劑共同使用之可能性而變化。
可由本發明方法治療之癌症包括多種器官之實體腫瘤與血液腫瘤。實體腫瘤之實例包括胰臟癌;膀胱癌;結腸直腸癌;乳癌,包括轉移性乳癌;前列腺癌,包括雄激素依賴性前列腺癌及非雄激素依賴性前列腺癌;腎癌,包括例如轉移性腎細胞癌;肝細胞癌;肺癌,包括例如非小細胞肺癌(NSCLC)、細支氣管肺泡癌(BAC)及肺腺癌;卵巢癌,包括例如進行性上皮癌或原發性腹膜癌;子宮頸癌;胃癌;食道癌;頭頸部癌,包括例如頭頸部鱗狀細胞癌;黑素瘤;神經內分泌癌,包括轉移性神經內分泌腫瘤;腦腫瘤,包括例如神經膠質瘤、退行性少突神經膠質瘤、成人多形性膠質母細胞瘤及成人退行性星形細胞瘤;骨癌;及軟組織肉瘤。血液惡性病之實例包括急性骨髓性白血病(AML);慢性骨髓性白血病(CML),包括加速期CML及急性轉化期CML(CML-BP);急性淋巴母細胞白血病(ALL);慢性淋巴球性白血病(CLL);霍奇金氏病(Hodgkin's disease,HD);非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma,NHL),包括濾泡性淋巴瘤及被套細胞淋巴瘤;B細胞淋巴瘤;T細胞淋巴瘤;多發性骨髓瘤(MM);瓦爾登斯特倫氏巨球蛋白血症(Waldenstrom's macroglobulinemia);骨髓發育不良症候群(MDS),包括難治性貧血(RA)、難治性貧血伴有環形鐵母細胞(refractory anemia with ringed siderblasts,RARS)、難治性貧血伴有過量母細胞(RAEB)及轉化中RAEB(RAEB-T);及脊髓增生症候群。
為實施本發明之方法,上述醫藥組合物可經口、非經腸、藉由吸入型噴霧、局部、經直腸、經鼻、經頰、經陰道或經由植入式儲集囊投與。本文中所用之術語「非經腸」包括皮下、皮內、靜脈內、肌肉內、關節內、動脈內、滑膜內、胸骨內、鞘內、病灶內及顱內注射或輸注技術。
可根據此項技術中已知之技術,使用適合之分散劑或濕潤劑(諸如Tween 80)及懸浮劑來調配無菌可注射組合物,例如無菌可注射水性或油性懸浮液。無菌可注射製劑亦可為於非經腸可接受之無毒稀釋劑或溶劑中之無菌可注射溶液或懸浮液,例如於1,3-丁二醇中之溶液。可採用之可接受媒劑及溶劑有甘露糖醇、水、林格氏溶液(Ringer's solution)及等張氯化鈉溶液。另外,無菌非揮發性油通常用作溶劑或懸浮介質(例如合成甘油單酯或甘油二酯)。諸如油酸之脂肪酸及其甘油酯衍生物適用於製備可注射劑,如同醫藥學上可接受之天然油,諸如橄欖油或蓖麻油,尤其呈其聚氧乙基化形式。此等油溶液或懸浮液亦可含有長鏈醇稀釋劑或分散劑,或羧甲基纖維素或類似分散劑。其他常用界面活性劑(諸如Tween或Span)或通常用於製造醫藥學上可接受之固體、液體或其他劑型的其他類似乳化劑或生物可用性增強劑亦可用於達成調配之目的。
供經口投與之組合物可為任何口服可接受之劑型,包括(但不限於)膠囊、錠劑、乳劑及水性懸浮液、分散液及溶液。在口服用錠劑之情況下,常用載劑包括乳糖及玉米澱粉。通常亦添加潤滑劑,諸如硬脂酸鎂。對於以膠囊形式經口投藥,適用之稀釋劑包括乳糖及乾燥玉米澱粉。當經口投與水性懸浮液或乳劑時,可將活性成分懸浮或溶解於與乳化劑或懸浮劑組合之油相中。必要時,可添加某些甜味劑、調味劑或著色劑。可根據醫藥調配技術中熟知之技術製備鼻用氣霧劑或吸入型組合物。含芳基取代之磺醯胺化合物的組合物亦可以供直腸投與之栓劑形式進行投藥。
醫藥組合物中之載劑必須在與調配物之活性成分相容(且較佳能夠使其穩定)的意義上為「可接受」的,且對所治療之個體無害。一或多種與具活性的芳基取代之磺醯胺化合物形成較易溶解之複合物的增溶劑(例如環糊精)可用作醫藥載劑以供傳遞活性化合物。其他載劑之實例包括膠狀二氧化矽、硬脂酸鎂、月桂基硫酸鈉及D&C黃色10號。
適合之活體外檢定可用於初步評估芳基取代之磺醯胺化合物在諸如抑制腫瘤細胞生長之抗癌活性方面的功效。可進一步檢查該等化合物在治療癌症方面之功效。舉例而言,可將化合物投與患有癌症之動物(例如小鼠模型),接著評估其治療效果。可基於結果以確定適當劑量範圍及投藥途徑。
在未作進一步詳述之情況下,咸信,以上描述足以實現本發明。因此,以下實例僅視作說明性的,而決不以任何方式限制本發明之其餘部分。本文中所引用之所有公開案藉此以全文引用的方式併入。
實例1
:合成[1-(4-甲氧基-苯磺醯基)-1H
-吡咯并[2,3-c]吡啶-7-基]-苯基-胺(化合物1)
7-溴-6-氮雜吲哚
(流程1中之2
):將2-溴-3-硝基吡啶(流程1中之1
,2.0 g,98%,9.7 mmol)於無水THF(80 mL)中之溶液冷卻至-78℃。添加過量溴化乙烯基鎂(1.0 M,於THF中,40 mL,40 mmol)。在-40℃至50℃下攪拌反應混合物1小時,接著用飽和NaHCO3
溶液淬滅。分離各層,且用EtOAc萃取水層(3次)。經合併之有機層以MgSO4
乾燥,過濾經乾燥之溶液,且濃縮濾液。藉由快速層析(EtOAc:正己烷=1:2)純化殘餘物,得到2
(1.1 g,60%)。
1
H NMR(500 MHz,CDCl3
):δ6.66(dd,1H,J
=2.9,2.1 Hz),7.43(dd,1H,J
=2.9,2.1 Hz),7.51(d,1H,J
=5.2 Hz),8.03(d,1H,J
=5.3 Hz),8.79(br,1H)。
7-溴-1-(4-甲氧基-苯磺醯基)-1 H -吡咯并[2,3-c]吡啶
(流程1中之3
):於二氯甲烷(100 mL)中含2
(2.0 g,10.15 mmol)之溶液中添加氫氧化鉀(1.71 g,30.45 mmol)及硫酸氫四正丁基銨(0.345 g,1.015 mmol)。攪拌由此形成之反應混合物30分鐘。向反應混合物中緩慢添加4-甲氧基磺醯氯(4.2 g,20.3 mmol)。1小時後,用水淬滅混合物且用CH2
Cl2
萃取。經合併之有機層以MgSO4
乾燥,過濾經乾燥之溶液,且濃縮濾液。藉由矽膠管柱層析(EtOAc:正己烷=1:1)純化殘餘物,得到3
(3.6 g,97%)。
1
H NMR(500 MHz,CDCl3
):δ3.84(s,3H),6.72(d,1H,J
=3.7 Hz),6.94(d,2H,J
=8.9 Hz),7.46(d,1H,J
=5.1 Hz),7.77(d,2H,J
=8.9 Hz),8.07(d,1H,J
=3.7 Hz),8.12(d,1H,J
=5.2 Hz)。
1-(4-甲氧基-苯磺醯基)-1 H -吡咯并[2,3-c]吡啶-7-基]-苯基-胺
(化合物1):將溶於吡啶(1 mL)中之3
(0.2 g,0.54 mmol)及苯胺(0.2 mL,2.17 mmol)之溶液在密封圓瓶中於120℃至130℃下加熱24小時。移除溶劑,且藉由快速層析(EtOAc:正己烷=1:3)純化殘餘物,得到化合物1(78 mg,38%)。
熔點(「mp」):138.5-139.7℃;1
H NMR(500 MHz,CDCl3
):δ
3.75(s,3H),6.62(d,1H,J
=3.5 Hz),6.80(d,2H,J
=8.9 Hz),6.90(d,1H,J
=5.5 Hz),7.05(t,1H,J
=7.4,7.5 Hz),7.36(t,2H,J
=7.7,8.0 Hz),7.66(d,2H,J
=8.9 Hz),7.71(d,1H,J
=3.7 Hz),7.74(d,2H,J
=7.7 Hz),7.99(d,1H,J
=5.3 Hz),9.19(s,1H);13
C NMR(100 MHz,CDCl3
):δ
55.5,108.0,109.6,114.5,119.0,119.2,121.8,128.4,128.8,129.0,131.2,139.6,140.5,141.1,143.9,163.7;MS(EI)m/z
: 379.1(M+
,30%),208.1(100%);C20
H17
N3
O3
S(M+
)之HRMS(EI):計算值379.0990;實驗值379.0990。
實例2
:合成4-[1-(4-甲氧基-苯磺醯基)-1H
-吡咯并[2,3-c]吡啶-7-基胺基]-苯酚(化合物2)
以類似於實例1中所述之方式製備化合物2。
1
H NMR(500 MHz,CDCl3
):δ
3.78(s,3H),6.62(d,1H,J
=3.7 Hz),6.72(d,2H,J
=8.7 Hz),6.84(d,2H,J
=9.1 Hz),6.85(d,1H,J
=5.4 Hz),7.30(d,2H,J
=8.7 Hz),7.68(d,2H,J
=9.0 Hz),7.72(d,1H,J
=3.7 Hz),7.89(d,1H,J
=5.4 Hz),8.85(s,1H);MS(EI)m/z
: 395.2(M+
,37%),224.1(100%);C20
H17
N3
O4
S(M+
)之HRMS(EI):計算值395.0934;實驗值395.0934。
實例3
:合成[1-(4-甲氧基-苯磺醯基)-1H
-吡咯并[2,3-c]吡啶-7-基]-二甲基-胺(化合物3)
以類似於實例1中所述之方式製備化合物3。
熔點:154.8-157.5℃;1
H NMR(500 MHz,CDCl3
):δ
2.79(s,6H),3.73(s,3H),6.57(d,1H,J
=3.7 Hz),6.75(d,2H,J
=8.9 Hz),6.94(d,1H,J
=5.2 Hz),7.56(d,2H,J
=8.9 Hz),7.75(d,1H,J
=3.7 Hz),7.97(d,1H,J
=5.2 Hz);MS(EI)m/z
: 331.1(M+
,39%),160.0(100%);C16
H17
N3
O3
S(M+
)之HRMS(EI):計算值331.0996;實驗值331.0996。
實例4
:合成[1-(4-甲氧基-苯磺醯基)-1H
-吡咯并[2,3-c]吡啶-7-基]-(4-甲氧基-苯基)-胺(化合物4)
以類似於實例1中所述之方式製備化合物4。
熔點:155.5-158.3℃;1
H NMR(500 MHz,CDCl3
):δ
3.78(s,3H),3.83(s,3H),6.62(d,1H,J
=3.7 Hz),6.83(d,2H,J
=9.0 Hz),6.85(d,1H,J
=5.4 Hz),6.94(d,2H,J
=8.9 Hz),7.58(d,2H,J
=8.9 Hz),7.68(d,2H,J
=9.0 Hz),7.70(d,1H,J
=3.6 Hz),7.94(d,1H,J
=5.4 Hz),9.03(s,1H);13
C NMR(125 MHz,CDCl3
):δ
55.5,55.6,107.4,109.7,114.2,114.6,118.8,121.9,128.6,129.2,131.2,133.6,139.6,141.3,144.6,155.2,163.8;MS(EI)m/z
: 409.2(M+
,100%),238.1(81%);C21
H19
N3
O4
S(M+
)之HRMS(EI):計算值409.1097;實驗值409.1098。
實例5
:合成(4-氟-苯基)-[1-(4-甲氧基-苯磺醯基)-1H
-吡咯并[2,3-c]吡啶-7-基]-胺(化合物5)
以類似於實例1中所述之方式製備化合物5。
熔點:125.1-127.1℃;1
H NMR(500 MHz,CDCl3
):δ
3.74(s,3H),6.62(d,1H,J
=3.6 Hz),6.80(d,2H,J
=9.0 Hz),6.89(d,1H,J
=5.3 Hz),7.05(dd,2H,J
=8.7,8.7 Hz),7.65(d,2H,J
=9.0 Hz),7.69(dd,2H,J
=9.0,4.4 Hz),7.69(d,1H,J
=4.0 Hz),7.95(d,1H,J
=5.2 Hz),9.14(s,1H);13
C NMR(100 MHz,CDCl3
):δ
55.6,108.0,109.7,114.6,115.3,115.5,118.9,121.2,128.5,129.1,131.3,136.5,139.7,141.1,144.0,157.0,159.4,163.9;MS(EI)m/z
: 397.1(M+
,58%),226.1(100%);C20
H16
N3
O3
SF(M+
)之HRMS(EI):計算值397.0895;實驗值397.0895。
實例6
:合成1-(4-甲氧基-苯磺醯基)-7-苯基-1H
-吡咯并[2,3-c]吡啶(化合物6)
用肆(三苯基膦)鈀(0.016 g,0.014 mmol)處理溶於甲苯(8 mL)中之3
(0.1 g,0.273 mmol)之溶液。接著依序添加K2
CO3
水溶液(2 M,1 mL)、溶於EtOH(5 mL)中之苯基酸(0.037 g,0.3 mmol)溶液。接著使所得混合物回流24小時。移除溶劑,且藉由快速層析(EtOAc:正己烷=2:3)純化殘餘物,得到化合物6(26.6 mg,27%)。
熔點:148.9-151.0℃;1
H NMR(500 MHz,CDCl3
):δ
3.79(s,3H),6.73(d,2H,J
=8.9 Hz),6.76(d,1H,J
=3.7 Hz),7.18(d,2H,J
=8.9 Hz),7.37(t,3H,J
=7.1,7.5 Hz),7.42(d,1H,J
=5.1 Hz),7.46(d,2H,J
=6.9 Hz),7.88(d,1H,J
=3.7 Hz),8.44(d,1H,J
=5.3 Hz);MS(EI)m/z
: 364.1(M+
,36%),193.1(100%);C20
H16
N2
O3
S(M+
)之HRMS(EI):計算值364.0872;實驗值364.0873。
實例7:
合成4-[1-(4-甲氧基-苯磺醯基)-1H
-吡咯并[2,3-c]吡啶-7-基]-苯甲酸甲酯(化合物7)
以類似於實例6中所述之方式製備化合物7。
熔點:143.5-146.5℃;1
H NMR(500 MHz,CDCl3
):δ
3.81(s,3H),3.96(s,3H),6.74(d,2H,J
=8.9 Hz),6.77(d,1H,J
=3.7 Hz),7.18(d,2H,J
=8.9 Hz),7.44(d,1H,J
=5.2 Hz),7.52(d,2H,J
=8.3 Hz),7.86(d,1H,J
=3.7 Hz),8.03(d,2H,J
=8.2 Hz),8.46(d,1H,J
=5.1 Hz);MS(EI)m/z
: 422.1(M+
,27%),171.0(100%);C22
H18
N2
O5
S(M+
)之HRMS(EI):計算值422.0941;實驗值422.0941。
實例8
:合成7-(4-氟-苯基)-1-(4-甲氧基-苯磺醯基)-1H
-吡咯并[2,3-c]吡啶(化合物8)
以類似於實例6中所述之方式製備化合物8。
熔點:136.0-137.0℃;1
H NMR(500 MHz,CDCl3
):δ
3.80(s,3H),6.75(d,2H,J
=8.8 Hz),6.75(d,1H,J
=4.2 Hz),7.03(t,2H,J
=8.6,8.7 Hz),7.20(d,2H,J
=8.9 Hz),7.40(d,1H,J
=5.1 Hz),7.43(ddd,2H,J
=8.3,8.3,2.7 Hz),7.85(d,1H,J
=3.7 Hz),8.42(d,1H,J
=5.1 Hz);13
C NMR(100 MHz,CDCl3
):δ
55.6,108.9,114.0,114.4,114.6,128.8,131.0,134.1,136.2,139.8,142.6,147.2,161.6,163.6,164.0;MS(EI)m/z
: 382.1(M+
,63%),211.1(93%);C20
H15
N2
O3
SF(M+
)之HRMS(EI):計算值382.0783;實驗值382.0783。
實例9
:合成7-(4-氯-苯基)-1-(4-甲氧基-苯磺醯基)-1H
-吡咯并[2,3-c]吡啶(化合物9)
以類似於實例6中所述之方式製備化合物9。
熔點:125.5-128.5℃;1
H NMR(500 MHz,CDCl3
):δ
3.81(s,3H),6.76(d,1H,J
=3.8 Hz),6.76(d,2H,J
=8.8 Hz),7.20(d,2H,J
=9.0 Hz),7.28(d,2H,J
=8.5 Hz),7.35(d,2H,J
=8.5 Hz),7.42(d,1H,J
=5.3 Hz),7.86(d,1H,J
=3.8 Hz),8.42(d,1H,J
=5.1 Hz);13
C NMR(100 MHz,CDCl3
):δ
55.6,108.8,114.0,114.9,127.7,128.7,128.9,130.6,130.7,134.1,134.3,138.4,139.8,142.5,146.9,163.6;MS(EI)m/z
: 398.1(M+
,56%),227.0(42%),171.0(100%);C20
H15
N2
O3
SCl(M+
)之HRMS(EI):計算值398.0499;實驗值398.0499。
實例10
:合成4-[1-(4-甲氧基-苯磺醯基)-1H
-吡咯并[2,3-c]吡啶-7-基]-苯酚(化合物10)
以類似於實例6中所述之方式製備化合物10。
熔點:179-182℃;1
H NMR(500 MHz,CDCl3
):δ3.68(s,3H),6.62-6.65(m,5H),7.04-7.07(m,4H),7.29(d,1H,J
=5.23 Hz),7.78(d,1H,J
=3.68 Hz),8.14(d,1H,J
=5.37 Hz);MS(EI)m/z
: 380.0(M+
,32.5%),209.0(100.0%);C20
H16
N2
O4
S(M+
)之HRMS(EI):計算值380.0830;實驗值380.0824。
實例11
:合成1-(4-甲氧基-苯磺醯基)-7-(4-甲氧基-苯基)-1H
-吡咯并[2,3-c]吡啶(化合物11)
熔點:162.8-164.8℃;1
H NMR(500 MHz,CDCl3
):δ
3.79(s,3H),3.88(s,3H),6.73(d,1H,J
=3.8 Hz),6.73(d,2H,J
=8.9 Hz),6.89(d,2H,J
=8.7 Hz),7.21(d,2H,J
=9.0 Hz),7.34(d,1H,J
=5.2 Hz),7.43(d,2H,J
=8.7 Hz),7.84(d,1H,J
=3.7 Hz),8.41(d,1H,J
=5.1 Hz);13
C NMR(100 MHz,CDCl3
):δ
55.1,55.5,109.0,112.9,113.8,114.0,128.7,128.8,130.5,130.9,132.6,134.0,139.7,142.6,148.1,159.6,163.4;MS(EI)m/z
: 394.1(M+
,25%),223.1(100%);C21
H18
N2
O4
S(M+
)之HRMS(EI):計算值394.0990;實驗值394.0991。
實例12
:合成{4-[1-(4-甲氧基-苯磺醯基)-1H
-吡咯并[2,3-c]吡啶-7-基]-苯基}-二甲基-胺(化合物12)
以類似於實例6中所述之方式製備化合物12。
熔點:111.5-114.5℃;1
H NMR(500 MHz,CDCl3
):δ
3.02(s,6H),3.77(s,3H),6.70(d,2H,J
=9.2 Hz),6.71(d,2H,J
=8.7 Hz),6.72(d,1H,J
=3.8 Hz),7.24(d,2H,J
=8.8 Hz),7.25(d,1H,J
=5.1 Hz),7.45(d,2H,J
=8.7 Hz),7.80(d,1H,J
=3.6 Hz),8.38(d,1H,J
=5.1 Hz);MS(EI)m/z
: 407.2(M+
,20%),236.1(100%);C22
H21
N3
O3
S(M+
)之HRMS(EI):計算值407.1305;實驗值407.1305。
實例13
:合成1-(4-甲氧基-苯磺醯基)-7-吡啶-4-基-1H
-吡咯并[2,3-c]吡啶(化合物13)
以類似於實例6中所述之方式製備化合物13。
熔點:193.1-194.3℃;1
H NMR(500 MHz,CDCl3
):δ3.81(s,3H),6.72-6.79(m,3H),7.19(d,2H,J
=8.93 Hz),7.32-7.33(m,2H),7.48(dd,1H,J
=4.49 Hz),7.87(d,1H,J
=3.62 Hz),8.46(d,1H,J
=5.12 Hz),8.60(d,2H,J
=5.93 Hz)。MS(EI)m/z
: 365.0(M+
,100.0%);C19
H15
N3
O3
S(M+
)之HRMS(EI):計算值365.0834;實驗值365.0836。
實例14
:合成1-(4-甲氧基-苯磺醯基)-7-(4-硝基-苯基)-1H
-吡咯并[2,3-c]吡啶(化合物14)
以類似於實例6中所述之方式製備化合物14。
熔點:177.5-178.8℃;1
H NMR(500 MHz,CDCl3
):δ3.82(s,3H),6.76(d,2H,J
=8.91 Hz),7.79(d,1H,J
=3.685 Hz),7.20(d,2H,J
=8.69 Hz),7.47(d,1H,J
=5.11 Hz),7.64(d,2H,J
=8.67 Hz),7.83(d,1H,J
=3.71 Hz),8.21(d,2H,J
=8.62 Hz),8.48(d,1H,J
=5.08 Hz);MS(EI)m/z
: 409.0(M+
,32.0%),171.0(100.0%);C20
H15
N3
O5
S(M+
)之HRMS(EI):計算值409.0732;實驗值409.0730。
實例15
:合成1-(4-甲氧基-苯磺醯基)-7-(4-三氟甲基-苯基)-1H
-吡咯并[2,3-c]吡啶(化合物15)
以類似於實例6中所述之方式製備化合物15。
熔點:143.1-144.9℃;1
H NMR(500 MHz,CDCl3
):δ3.81(s,3H),6.74(d,J
=8.8 Hz,2H),6.78(d,J
=3.6 Hz,1H),7.16(d,J
=8.8 Hz,2H),7.47(d,J
=5.2 Hz,1H),7.49(d,J
=8.0 Hz,2H),7.56(d,J
=8.0 Hz,2H),7.88(d,J
=3.6 Hz,1H),8.45(d,J
=5.1 Hz,1H)。
實例16
:合成7-呋喃-2-基-1-(4-甲氧基-苯磺醯基)-1H
-吡咯并[2,3-c]吡啶(化合物16)
以類似於實例6中所述之方式製備化合物16。
熔點:127.1-130.3℃;1
H NMR(500 MHz,CDCl3
):δ3.79(s,3H),6.56(q,1H,J
=2.36 Hz),6.70(d,1H,J
=3.70 Hz),6.80(d,2H,J
=8.94 Hz),6.83(d,1H,J
=3.315 Hz),7.36(d,1H,J
=5.14 Hz),7.42(d,2H,J
=9.02 Hz),7.47(s,1H),7.74(d,1H,J
=3.71 Hz),8.43(d,1H,J
=5.08 Hz);MS(EI)m/z
: 354.1(M+
,17.0%),184.1(100.0%);C18
H14
N2
O4
S(M+
)之HRMS(EI):計算值354.0674;實驗值354.0676。
實例17
:合成4-[1-(4-甲氧基-苯磺醯基)-2,3-二氫-1H
-吲哚-7-基]-苯甲腈(化合物17)
7-溴-1-(4-甲氧基-苯磺醯基)-2,3-二氫-1 H -吲哚(流程2中之11
,其中R2
=OCH3
):在0℃、於N2
下,用氰基硼氫化鈉(0.14 g,2.29 mmol)處理溶於冰醋酸(1.5 mL)中之7-溴-1H
-吲哚(0.30 g,1.53 mmol)溶液。添加氫氧化鈉水溶液淬滅過量酸之後,接著用CH2
Cl2
(20 mL×3)萃取所得混合物。經合併之有機層以MgSO4
乾燥,過濾經乾燥之溶液,且濃縮濾液。將殘餘物溶解於吡啶中,且添加4-甲氧基苯基磺醯氯。使反應混合物回流隔夜。移除溶劑,且藉由急驟層析(EtOAc:正己烷=1:2)純化殘餘物,得到11
(370.6 mg,87%)。
1
H NMR(500 MHz,CDCl3
):δ2.40(t,2H,J
=7.22 Hz),3.85(s,3H),3.97(t,2H,J
=7.25 Hz),6.88(d,2H,J
=8.9 Hz),6.99(t,1H,J
=7.59 Hz),7.04(d,1H,J
=7.02 Hz),7.46(d,1H,J
=7.72 Hz),7.60(d,2H,J
=8.89 Hz)。
4-[1-(4-甲氧基-苯磺醯基)-2,3-二氫-1H-吲哚-7-基]-苯甲腈
:在N2
下,用肆(三苯基膦)鈀(0.02 g,0.02 mmol)處理溶於甲苯(10 mL)中之11
(0.15 g,0.40 mmol)溶液。接著依序添加K2
CO3
水溶液(2 M,1.4 mL)、溶於EtOH(8 mL)中之4-氰基苯基酸(0.24 g,1.63 mmol)溶液。使所得混合物回流24小時。移除溶劑,且藉由快速層析(EtOAc:正己烷=1:3)純化殘餘物,得到化合物17(50.0 mg,31%)。
熔點:157.2-158.9℃;1
H NMR(500 MHz,CDCl3
):δ2.34(t,J
=7.4 Hz,2H),3.83(s,3H),4.03(t,J
=7.3 Hz,2H),6.79(d,J
=8.8 Hz,2H),7.11(d,J
=6.9 Hz,1H),7.24-7.31(m,4H),7.70(d,J
=8.3 Hz,2H),7.78(d,J
=8.3 Hz,2H);MS(EI)m/z
: 390(M+
,100%);C22
H18
O3
N2
S1
(M+
)之HRMS(EI):計算值390.1038;實驗值390.1040。
實例18
:合成4-[1-(4-甲氧基-苯磺醯基)-1H
-吲哚-7-基]-苯甲腈(化合物18)
以類似於實例17中所述之方式製備化合物18。
熔點:164.3-165.7℃;1
H NMR(500 MHz,CDCl3
):δ3.79(s,3H),6.74-6.76(m,3H),7.03(d,1H,J
=7.45 Hz),7.19(d,2H,J
=8.86 Hz),7.28(d,1H,J
=7.59 Hz),7.40(d,2H,J
=8.07 Hz),7.53(d,1H,J
=7.87 Hz),7.58(d,2H,J
=8.16 Hz),7.65(d,1H,J
=3.73 Hz)。
實例19
:合成7-(4-氟-苯基)-1-(4-甲氧基-苯磺醯基)-1H
-吲哚(化合物19)
以類似於實例17中所述之方式製備化合物19。
熔點:181.2-182.4℃;1
H NMR(500 MHz,CDCl3
):δ3.79(s,3H),6.73-6.74(m,3H),6.95(t,2H,J
=8.63 Hz),7.01(d,1H,J
=7.32 Hz),7.18-7.24(m,5H),7.49(d,1H,J
=7.72 Hz),7.70(d,1H,J
=3.63 Hz);13
C NMR(100 MHz,CDCl3
):δ55.6,110.0,113.8,114.1,120.6,123.7,128.6,129.7,129.8,130.8,131.0,133.4,133.5,136.6,136.7,160.8,163.2,163.3;MS(EI)m/z
: 381.0(M+
,93.1%),210.0(100.0%)。
實例20
:合成4-[1-(4-甲氧基-苯磺醯基)-2,3-二氫-1H
-吲哚-7-基]-苯基胺(化合物20)
以類似於實例17中所述之方式製備化合物20。
熔點:183.9-185.6℃;1
H NMR(500 MHz,CDCl3
):δ2.30(t,J
=7.3 Hz,2H),3.81(s,3H),4.01(t,J
=7.4 Hz,2H),6.73-6.78(m,4H),6.96(d,J
=6.9 Hz,1H),7.17(t,J
=7.5 Hz,1H),7.26-7.28(m,1H),7.34-7.35(m,2H),7.50-7.51(m,2H)。
實例21
:合成7-(3,4-二氟-苯基)-1-(4-甲氧基-苯磺醯基)-2,3-二氫-1H
-吲哚(化合物21)
以類似於實例17中所述之方式製備化合物21。
熔點:180.2-181.4℃;1
H NMR(500 MHz,CDCl3
):δ2.33(t,2H,J
=7.37 Hz),3.82(s,3H),4.02(t,2H,J
=7.38 Hz),6.79(d,2H,J
=8.85 Hz),7.06(bd,1H,J
=7.03 Hz),7.15-7.24(m,3H),7.32(d,2H,J
=8.81 Hz),7.37-7.40(m,1H),7.44-7.48(m,1H);13
C NMR(125 MHz,CDCl3
):δ52.0,55.5,113.8,116.9,117.1,117.3,124.1,124.2,124.3,127.3,128.9,129.2,129.5,133.6,137.4,138.5,140.0,148.2,148.3,148.8,149.0,150.6,150.8,151.3,151.4,163.2;MS(EI)m/z
: 400.9(M+
,2.0%),230.2(100%);C21
H17
F2
NO3
S(M+
)之HRMS(EI):計算值401.089;實驗值401.0905。
實例22
:合成1-(4-甲氧基-苯磺醯基)-7-五氟苯基-2,3-二氫-1H
-吲哚(化合物22)
以類似於實例17中所述之方式製備化合物22。
熔點:108.1-109.2℃;1
H NMR(500 MHz,CDCl3
):δ2.87(t,J
=8.4 Hz,2H),3.80(s,3H),3.89(t,J
=8.4 Hz,2H),6.88(d,J
=8.8 Hz,2H),6.96(t,J
=7.4 Hz,1H),7.06(d,J
=7.3 Hz,1H),7.18(t,J
=7.7 Hz,1H),7.63(d,J
=8.1 Hz,1H),7.71(d,J
=8.9 Hz,2H)。
實例23
:合成1-(4-甲氧基-苯磺醯基)-7-(4-甲氧基-苯基)-2,3-二氫-1H
-吲哚(化合物23)
以類似於實例17中所述之方式製備化合物23。
熔點:176.3-177.4℃;1
H NMR(500 MHz,CDCl3
):δ2.32(t,2H,J
=7.31 Hz),3.81(s,3H),3.84(s,3H),4.02(t,2H,J
=7.34 Hz),6.77(d,2H,J
=8.92 Hz),6.95(d,2H,J
=8.72 Hz),6.99(d,1H,J
=7.50 Hz),7.18(t,1H,J
=7.52 Hz),7.27(d,1H,J
=7.59 Hz),7.32(d,2H,J
=8.9 Hz),7.61(d,2H,J
=8.69 Hz);13
C NMR(100 MHz,CDCl3
):δ51.0,55.1,55.5,113.6,123.0,127.1,129.2,129.3,129.5,132.9,135.4,138.2,139.9,158.5,163.1;MS(EI)m/z
: 395.0(M+
,15.0%),224.2(100.0%);C22
H21
NO4
S(M+
)之HRMS(EI):計算值395.1191;實驗值395.1185。
實例24
:合成1-(4-甲氧基-苯磺醯基)-7-吡啶-4-基-2,3-二氫-1H
-吲哚(化合物24)
以類似於實例17中所述之方式製備化合物24。
熔點:195.9-196.8℃;1
H NMR(500 MHz,CDCl3
):δ2.19(t,2H,J
=7.39 Hz),3.80(s,3H),3.92(t,2H,J
=7.45 Hz),6.70(d,2H,J
=8.91 Hz),7.03(d,1H,J
=7.06 Hz),7.15-7.22(m,4H),7.55(dd,2H,J
=4.58 Hz),8.44(dd,2H,J
=4.83 Hz);MS(EI)m/z
: 366.1(M+
,34.1%),195.1(100.0%);C20
H18
N2
O3
S(M+
)之HRMS(EI):計算值366.1038;實驗值366.1041。
實例25
:合成7-(6-氟-吡啶-3-基)-1-(4-甲氧基-苯磺醯基)-2,3-二氫-1H
-吲哚(化合物25)
以類似於實例17中所述之方式製備化合物25。
熔點:139.8-141.7℃;1
H NMR(500 MHz,CDCl3
):δ2.36(t,J
=7.3 Hz,2H),3.82(s,3H),4.03(t,J
=7.4 Hz,2H),6.80(d,J
=8.7 Hz,2H),6.97(dd,J
=8.4,2.7 Hz,1H),7.11(d,J
=6.7 Hz,1H),7.23-7.28(m,3H),7.32(d,J
=8.8 Hz,2H),8.08-8.12(m,1H),8.45(m,1H)。
實例26
:合成4-[1-(4-甲氧基-苯磺醯基)-2,3-二氫-1H
-吲哚-7-基]-苯酚(化合物26)
以類似於實例17中所述之方式製備化合物26。
熔點:179.4-180.5℃;1
H NMR(500 MHz,CDCl3
):δ2.29(t,2H,J
=7.27 Hz),3.80(s,3H),4.02(t,2H,J
=7.31 Hz),6.79(d,2H,J
=8.83 Hz),6.82(d,2H,J
=8.53 Hz),6.98(d,1H,J
=7.44 Hz),7.18(t,1H,J
=7.54 Hz),7.28(d,1H,J
=7.61 Hz),7.34(d,2H,J
=8.82 Hz),7.55(d,2H,J
=8.59 Hz);13
C NMR(100 MHz,CDCl3
):δ51.9,55.5,77.2,113.8,115.3,123.0,127.2,129.0,129,4,129.6,135.5,138.2,139.8,154.8,163.1;MS(EI)m/z
: 381.1(M+
,7.0%),210.2(100.0%);C21
H19
NO4
S(M+
)之HRMS(EI):計算值381.1034;實驗值381.1033。
實例27
:合成1-(4-甲氧基-苯磺醯基)-7-苯基-2,3-二氫-1H
-吲哚(化合物27)
以類似於實例17中所述之方式製備化合物27。
熔點:165.9-167.8℃;1
H NMR(500 MHz,CDCl3
):δ2.00(t,2H,J
=7.32 Hz),3.52(s,3H),3.68(t,2H,J
=7.42 Hz),6.50(d,2H,J
=8.83 Hz),6.73(d,1H,J
=7.06 Hz),6.88-6.96(m,4H),7.30(d,2H,J
=7.55 Hz);MS(EI)m/z
: 433.0(M+
,5.7%),194.0(100.0%);C22
H18
F3
NO3
S(M+
)之HRMS(EI):計算值433.0959;實驗值433.0956。
實例28
:合成7-(4-氟-苯基)-1-(4-甲氧基-苯磺醯基)-2,3-二氫-1H
-吲哚(化合物28)
以類似於實例17中所述之方式製備化合物28。
熔點:178.1-179.4℃;1
H NMR(500 MHz,CDCl3
):δ2.33(t,2H,J
=7.33 Hz),3.82(s,3H),4.02(t,2H,J
=7.38 Hz),6.78(d,2H,J
=8.77 Hz),7.04(d,1H,J
=7.30 Hz),7.10(t,2H,J
=8.66 Hz),7.21(t,1H,J
=7.50 Hz,H-5),7.27(d,1H,J
=7.89 Hz,H-6),7.32(d,2H,J
=8.77 Hz,H-2",6"),7.63(d,2H,J
=7.95 Hz,H-2',6');MS(EI)m/z
: 383.0(M+
,16.6%),212.0(100.0%);C21
H18
FNO3
S(M+
)之HRMS(EI):計算值383.0991;實驗值383.0922。
實例29
:合成7-呋喃-2-基-1-(4-甲氧基-苯磺醯基)-2,3-二氫-1H
-吲哚(化合物29)
以類似於實例17中所述之方式製備化合物29。
熔點:176.7-177.7℃;1
H NMR(500 MHz,CDCl3
):δ2.16(t,2H,J
=7.33 Hz),3.83(s,3H),4.00(t,2H,J
=7.40 Hz),6.51(q,1H,J
=1.71 Hz),6.81(d,2H,J
=8.86 Hz),6.95(d,1H,J
=7.57 Hz),6.98(d,1H,J
=3.28 Hz),7.19(t,1H,J
=7.61 Hz),7.39(d,2H,J
=8.90 Hz),7.51(d,1H,J
=1.12 Hz),7.60(d,1H,J
=8.12 Hz);MS(EI)m/z
: 355.0(M+
,15.7%),184.0(100.0%);C19
H17
NO4
S(M+
)之HRMS(EI):計算值355.0878;實驗值355.0881。
實例30
:合成1-(4-甲氧基-苯磺醯基)-7-噻吩-2-基-2,3-二氫-1H
-吲哚(化合物30)
以類似於實例17中所述之方式製備化合物30。
熔點:127.7-129.1℃;1
H NMR(500 MHz,CDCl3
):δ2.40(t,2H,J
=7.23 Hz),3.85(s,3H),3.98(t,2H,J
=7.21 Hz),6.80(d,1H,J
=8.85 Hz),6.87(d,2H,J
=8.85 Hz),6.89-7.05(m,3H),7.46-7.60(m,2H),7.60(d,2H,J
=8.85 Hz);MS(EI)m/z
: 371.0(M+
,15.7%),200.0(100.0%);C19
H17
NO3
S2
(M+
)之HRMS(EI):計算值371.0649;實驗值371.0657。
實例31
:合成{4-[1-(4-甲氧基-苯磺醯基)-2,3-二氫-1H
-吲哚-7-基]-苯基}-二甲基-胺(化合物31)
以類似於實例17中所述之方式製備化合物31。
熔點:178.4-179.7℃;1
H NMR(500 MHz,CDCl3
):δ2.30(t,2H,J
=7.30 Hz),2.99(s,6H),3.81(s,3H),4.02(t,2H,J
=7.34 Hz),6.75-6.78(m,4H),6.94(d,1H,J
=7.18 Hz),7.16(t,1H,J
=7.53 Hz),7.29(d,1H,J
=7.71 Hz),7.34(d,2H,J
=8.77 Hz),7.59(d,2H,J
=8.74 Hz);MS(EI)m/z
: 408.1(M+
,20.6%),237.1(100.0%);C23
H24
N2
O3
S(M+
)之HRMS(EI):計算值408.1507;實驗值408.1511。
實例32
:合成1-(4-甲氧基-苯磺醯基)-7-(3,4,5-三甲氧基-苯基)-2,3-二氫-1H
-吲哚(化合物32)
以類似於實例17中所述之方式製備化合物32。
熔點:202.5-204.8℃;1
H NMR(500 MHz,CDCl3
):δ2.21(t,2H,J
=7.28 Hz),3.65(s,3H),3.68(s,3H),3.70(s,6H),3.85(t,2H,J
=7.33 Hz),6.64(bd,2H,J
=8.85 Hz),6.71(s,2H),6.89(d,1H,J
=7.22 Hz),7.04(t,1H,J
=7.49 Hz,7.12-7.14(m,3H);MS(EI)m/z
: 455.0(M+
,36.3%),253.0(100.0%);C24
H25
NO6
S(M+
)之HRMS(EI):計算值455.1402;實驗值455.1410。
實例33
:合成7-(4-氯-苯基)-1-(4-甲氧基-苯磺醯基)-2,3-二氫-1H
-吲哚(化合物33)
以類似於實例17中所述之方式製備化合物33。
熔點:177.1-178.3℃;1
H NMR(500 MHz,CDCl3
):δ2.35(t,2H,J
=7.34 Hz),3.82(s,3H),4.03(t,2H,J
=7.41 Hz),6.78(d,2H,J
=8.86 Hz),7.06(bd,1H,J
=6.98 Hz),7.21(t,1H,J
=7.49 Hz),7.26(bd,1H,J
=6.95 Hz),7.31(d,2H,J
=8.83 Hz),7.37(d,2H,J
=8.37 Hz),7.59(d,2H,J
=8.45 Hz);MS(EI)m/z
: 399.0(M+
,26.5%),228.0(100.0%);C21
H18
ClNO3
S(M+
)之HRMS(EI):計算值399.0695;實驗值399.0703。
實例34
:合成1-(4-甲氧基-苯磺醯基)-7-(4-三氟甲基-苯基)-2,3-二氫-1H
-吲哚(化合物34)
以類似於實例17中所述之方式製備化合物34。
熔點:179.7-181.0℃;1
H NMR(500 MHz,CDCl3
):δ2.37(t,2H,J
=7.39 Hz),3.82(s,3H),4.05(t,2H,J
=7.36 Hz),6.78(d,2H,J
=8.83 Hz),7.10(d,1H,J
=7.02 Hz),7.23-7.31(m,4H),7.65(d,2H,J
=8.22 Hz),7.76(d,2H,J
=8.17 Hz);MS(EI)m/z
: 433.0(M+
,5.7%),194.0(100.0%);C22
H18
F3
NO3
S(M+
)之HRMS(EI):計算值433.0959;實驗值433.0956。
實例35
:合成7-(3-氟-苯基)-1-(4-甲氧基-苯磺醯基)-2,3-二氫-1H
-吲哚(化合物35)
以類似於實例17中所述之方式製備化合物35。
熔點:180.0-181.3℃;1
H NMR(500 MHz,CDCl3
):δ2.35(t,2H,J
=7.36 Hz),3.82(s,3H),4.02(t,2H,J
=7.36 Hz),6.79(d,2H,J
=8.82 Hz),6.06-6.07(m,2H),7.22(d,1H,J
=7.50 Hz),7.28-7.39(m,5H),7.46(d,1H,J
=7.69 Hz);MS(EI)m/z
: 383.0(M+
,20.6%),228.0(100.0%);C21
H18
ClNO3
S(M+
)之HRMS(EI):計算值399.0695;實驗值399.0703。
實例36
:合成1-(4-甲氧基-苯磺醯基)-7-吡啶-2-基-2,3-二氫-1H
-吲哚(化合物36)
以類似於實例17中所述之方式製備化合物36。
熔點:195.1-197℃;1
H NMR(500 MHz,CDCl3
):δ2.22(t,J
=7.3 Hz,2H),3.71(s,3H),3.92(t,J
=7.4 Hz,2H),6.71(d,J
=8.8 Hz,2H),7.01(d,J
=6.6 Hz,1H),7.15-7.20(m,4H),7.29-7.32(m,1H),7.93-7.96(m,1H),8.36(dd,J
=4.6,1.2 Hz,1H),8.70(d,J
=1.8 Hz,1H);MS(EI)m/z
366(M+
,40%),195(100%);C20
H18
O3
N2
S1
(M+
)之HRMS(EI):計算值366.1038;實驗值366.1036。
實例37
:合成1-(4-甲氧基-苯磺醯基)-7-(4-硝基-苯基)-2,3-二氫-1H
-吲哚(化合物37)
以類似於實例17中所述之方式製備化合物37。
熔點:177.1-178.4℃;1
H NMR(500 MHz,CDCl3
):δ2.34(t,2H,J
=7.40 Hz),3.82(s,3H),4.05(t,2H,J
=7.47 Hz),6.80(d,2H,J
=8.98 Hz),7.14(d,1H,J
=7.07 Hz),7.27-7.33(m,4H),7.82-7.84(m,2H),8.27-8.29(m,2H);MS(EI)m/z
: 410.0(M+
,5.2%),237.1(100.0%);C21
H18
N2
O5
S(M+
)之HRMS(EI):計算值410.0936;實驗值410.0944。
實例38
:合成4-[1-(4-甲氧基-苯磺醯基)-2,3-二氫-1H
-吲哚-7-基]-苯甲醛(化合物38)
以類似於實例17中所述之方式製備化合物38。
熔點:152-153℃;1
H NMR(500 MHz,CDCl3
):δ2.34(t,J
=7.3 Hz,2H),3.82(s,3H),4.04(t,J
=7.4 Hz,2H),7.10(d,J
=7.3 Hz,1H),7.24-7.27(m,2H),7.30-7.34(m,3H),7.85(d,J
=8.0 Hz,2H),7.94(d,J
=8.0 Hz,2H)。
實例39
:合成{4-[1-(4-甲氧基-苯磺醯基)-2,3-二氫-1H
-吲哚-7-基]-苯甲基}-二甲基-胺(化合物39)
以類似於實例17中所述之方式製備化合物39。
熔點:165-166℃;1
H NMR(500 MHz,CDCl3
):δ2.32(m,2H),2.23(s,6H),3.57(s,2H),3.81(s,3H),4.02(t,J
=7.3 Hz,2H),6.78(d,J
=8.7 Hz,2H),7.03(d,J
=7.2 Hz,1H),7.21(t,J
=7.4 Hz,1H),7.31-7.33(m,3H),7.38(d,J
=7.9 Hz,2H),7.65(d,J
=7.9 Hz,2H)。
實例40
:合成4-[1-(4-甲氧基-苯磺醯基)-2,3-二氫-1H
-吲哚-7-基]-苯甲酸(化合物40)
以類似於實例17中所述之方式製備化合物40。
熔點:130.3-132.1℃;1
H NMR(500 MHz,CD3
OD):δ2.21(t,J
=7.3 Hz,2H),3.70(s,3H),3.89-3.99(m,2H),6.68(d,J
=8.7 Hz,2H),6.97(d,J
=7.2 Hz,1H),7.11-7.20(m,3H),7.61(d,J
=8.2 Hz,2H),7.90(d,J
=7.3 Hz,1H),7.96(d,J
=8.2 Hz,2H)。
實例41
:合成N
-羥基-3-{4-[1-(4-甲氧基-苯磺醯基)-2,3-二氫-1H
-吲哚-7-基]-苯基}-丙烯醯胺(化合物41)
以類似於實例17中所述之方式製備化合物41。
熔點:200-201℃;1
H NMR(500 MHz,CDCl3
)δ2.20(t,J
=7.2 Hz,2H),3.70(s,3H),3.91(t,J
=7.3 Hz,2H),6.30(br,1H),6.68(d,J
=8.8 Hz,2H),6.95(d,J
=7.1 Hz,1H),7.12(1H,J
=7.5 Hz,1H),7.17-7.20(m,3H),7.43-7.57(m,5H)。
實例42
:合成4-[7-(4-氟-苯基)-2,3-二氫-吲哚-1-磺醯基]-苯磺醯胺(化合物42)
以類似於實例17中所述之方式製備化合物42。
熔點:188.7-190.2℃;1
H NMR(500 MHz,CDCl3
):δ2.28(t,2H,J
=7.3 Hz),3.97(t,2H,J
=7.3 Hz),6.93-6.97(m,3H),7.10-7.16(m,2H),7.37(d,2H,J
=8.3 Hz),7.44-7.46(m,2H),7.75(d,2H,J
=8.4 Hz);13
C NMR(100 MHz,CDCl3
):δ52.3,115.1,115.4,124.0,126.8,127.7,128.0,129.7,129.8,137.4,135.9,137.7,139.2,141.9,145.9,158.7,163.2;MS(EI)m/z
: 432.0(M+
,9.1%),212.0(100.0%)。
實例43
:合成4-(7-吡啶-4-基-2,3-二氫-吲哚-1-磺醯基)-苯磺醯胺(化合物43)
以類似於實例17中所述之方式製備化合物43。
熔點:241.7-242.9℃;1
H NMR(500 MHz,CDCl3
):δ2.33(t,2H,J
=7.3 Hz),4.02(t,2H,J
=7.3 Hz),7.08(bd,1H,J
=5.5 Hz),7.19-7.21(m,2H),7.37(d,2H,J
=8.2 Hz),7.47(d,2H,J
=5.5 Hz),7.77(d,2H,J
=8.3 Hz),8.40(d,2H,J
=5.5 Hz);MS(EI)m/z
: 415.0(M+
,9.1%),195.1(100.0%)。
實例44
:合成1-(4-甲氧基-苯磺醯基)-7-噻吩-2-基-1H
-吡咯并[2,3-c]吡啶(化合物44)
以類似於實例6中所述之方式製備化合物44。
熔點:112.2-113.7℃;1
H NMR(500 MHz,CDCl3
):δ3.78(s,3H),6.70(d,1H,J
=3.72 Hz),6.75(d,2H,J
=8.89 Hz),7.05(t,1H,J
=4.34 Hz),7.28(d,2H,J
=8.88 Hz),7.31(d,1H,J
=5.07 Hz),7.34(d,1H,J
=3.88 Hz),7.43(d,1H,J
=5.00 Hz),7.81(d,1H,J
=3.66 Hz),8.39(d,1H,J
=5.07 Hz);MS(EI)m/z
: 370.0(M+
,36.0%),199.1(100.0%);C18
H14
N2
O3
S2
(M+
)之HRMS(EI):計算值370.0445;實驗值370.0444。
實例45
:合成5-[1-(4-甲氧基-苯磺醯基)-1H
-吡咯并[2,3-c]吡啶-7-基]-呋喃-2-甲醛(化合物45)
以類似於實例6中所述之方式製備化合物45。
1
H NMR(500 MHz,CDCl3
):δ3.80(s,3H),6.74(d,J
=3.7 Hz,1H),6.86(d,J
=8.9 Hz,2H),6.98(d,J
=3.6 Hz,1H),7.40(d,J
=3.6 Hz,1H),7.50(d,J
=5.1 Hz,1H),7.54(d,J
=8.8 Hz,2H),7.70(d,J
=3.6 Hz,1H),8.48(d,J
=5.2 Hz,1H),9.62(s,1H)。
實例46
:合成1-(4-甲氧基-苯磺醯基)-7-吡啶-3-基-2,3-二氫-1H
-吲哚(化合物46)
以類似於實例17中所述之方式製備化合物46。
熔點:178.8-181.0℃;1
H NMR(500 MHz,CDCl3
):δ2.22(t,2H,J
=7.37 Hz),3.76(s,3H),3.92(t,2H,J
=7.44 Hz),6.71(d,2H,J
=8.83 Hz),7.01(d,1H,J
=6.69 Hz),7.15-7.20(m,4H),7.30(q,1H,J
=6.33 Hz),7.93-7.96(m,1H),8.36(q,1H,J
=4.78 Hz),8.70(d,1H,J
=1.83 Hz);MS(EI)m/z
: 366.0(M+
,40.7%),195.1(100.0%);C20
H18
N2
O3
S(M+
)之HRMS(EI):計算值366.1038;實驗值366.1036。
實例47
:合成7-(4-(1H
-四唑-5-基)苯基)-1-(4-甲氧基苯基磺醯基)吲哚啉(化合物47)
以類似於實例17中所述之方式製備化合物47。
1
H NMR(500 MHz,CD3
OD)δ
2.34(t,J
=7.3 Hz,2H),3.80(s,3H),4.07(t,J
=7.3 Hz,2H),6.88(d,J
=8.8 Hz,2H),7.14(d,J
=7.1 Hz,1H),7.27-7.37(m,4H),7.84(d,J
=8.3 Hz,2H),8.04(d,J
=8.2 Hz,2H)。
實例48
:合成4-(1-(4-甲氧基苯基磺醯基)吲哚啉-7-基)苯基磷酸鈉(化合物48)
以類似於實例17中所述之方式製備化合物48。
1
H NMR(500 MHz,D2
O+DMSO-d6)δ
2.38(t,J
=7.2 Hz,2H),3.90(s,3H),4.09(t,J
=7.3 Hz,2H),7.01(d,J
=8.8 Hz,2H),7.20(d,J
=7.2 Hz,1H),7.30-7.44(m,6H),7.71(d,J
=8.5 Hz,2H)。
實例49
:細胞生長抑制檢定
藉由測試上述實例中合成之芳基取代之磺醯胺化合物對哺乳動物癌細胞生長之抑制作用來評估該等化合物之抗癌活性。
將人類口腔表皮樣癌KB細胞、非小細胞肺癌H460細胞、結腸直腸癌HT29細胞及胃癌MKN45細胞培養於含有5%胎牛血清之RPMI-1640培養基中。用多種濃度之測試化合物處理細胞72小時。使用類似於Baguley等人,Anal Biochem,1984,139: 272-277中所述之亞甲基藍染料檢定來評估測試化合物對細胞生長之影響。接著獲得測試化合物之IC50
(亦即,與對照相比,產生50%生長抑制之測試化合物濃度)。使用亞甲基藍染料檢定針對此三種細胞株測試化合物16、17及24。ABT-751用作陽性對照(其係用Yoshino等人,J. Med. Chem. 1992,35,2496-2497中所述之方法合成;ABT-751之描述亦可見於以下文獻中:Koyanagi等人,Cancer Res. 1994,54,1702-1706;Yee等人,Cancer Res. 2005,11,6615-6624;及Mauer等人,J. Thorac. Oncol. 2008,3,613-636)。出乎意料的是,化合物16、17及24皆顯示比ABT-751甚低的IC50
值。參看下表1。
a
:標準差
此外,針對非小細胞肺癌A549及H1299細胞、結腸直腸癌HT29及正常人類臍靜脈內皮細胞(HUVEC)測試化合物24。出乎意料的是,此化合物對所有三種癌細胞株亦顯示較低IC50
值,而對正常HUVEC之IC50
值則高得多。參看下表2。
測試化合物1至40及化合物44對人類口腔表皮樣癌KB細胞增殖之抑制。出乎意料的是,除化合物39以外之所有測試化合物之IC50
值皆低於4 μM。其中,化合物1、2、4至6、9至11、13至15、18至20、23、25至27、30至31、33至34及40之IC50
值介於100 nM與700 nM之間;且化合物8、16、17、21、24、28至29、36至38及44之IC50
值介於1 nM與99 nM之間。
實例50
:針對多重抗藥性(MDR)KB細胞之細胞生長抑制檢定
KB-VIN10細胞係培養於含有10 nM長春新鹼(vincristine)之生長培養基中且藉由長春新鹼驅動之篩選而產生,且展現P-gp170/MDR過度表現。在24孔盤中以5000個細胞/毫升/孔之密度培養處於對數期之細胞。在使用前,於不含測試化合物之培養基中培養KB-VIN10細胞3天。用多種濃度之測試化合物處理細胞72小時。使用亞基藍染料檢定評估測試化合物對細胞生長之影響,即可獲得測試化合物之IC50
(亦即,與對照相比,產生50%生長抑制之測試化合物濃度)。在此檢定中測試化合物16及24。出乎意料的是,化合物16及24之IC50
值分別為30 nM及106 nM。相比之下,在相同檢定中,ABT-751之IC50
值為385 nM。
KB-VIN10及KB-TAX50細胞分別藉由長春新鹼及太平洋紫杉醇(paclitaxel)驅動之篩選而產生,且展現P-gp170/MDR過度表現。KB-7D細胞係藉由VP-16驅動之篩選而產生,其展現Top II向下調節及MRP過度表現。KB-CPT100及KB-CPT300細胞係藉由喜樹鹼(camptothecin)驅動之篩選而產生。KB-L30細胞係藉由BPR0L075驅動之篩選而產生,其展現β微管蛋白突變。(參看Liou,J. P.等人J. Med. Chem. 2004,47,4247-4257,及Kuo,C. C.等人Cancer Res. 2004,64,4621-4628。)
藉由測試上述實例中合成之芳基取代之磺醯胺化合物對此等抗藥性細胞株之抑制作用來評估該等化合物之抗癌活性。在此檢定中測試化合物24。出乎意料的是,化合物24顯示在90 nM至250 nM範圍內之IC50
值(下表3),顯示此化合物在治療多種多重抗藥性癌症方面為有效抗癌劑。
實例51
:微管蛋白聚合抑制檢定
使用如Bollag等人,Cancer Res.
2005,55
,2325-2333所述之濁度檢定來評估芳基取代之磺醯胺化合物對微管蛋白聚合之影響。
將富含微管相關蛋白(MAP)之微管蛋白(來自牛腦;Cytoskeleton,Denver,C.O.)溶解於反應緩衝液(100 mM PIPES,pH 6.9,2 mM MgCl2
,1 mM GTP)中,獲得4 mg/mL微管蛋白溶液。在測試化合物或2%(v/v)DMSO作為媒劑對照存在下,將微管蛋白溶液(每孔240 μg富含MAP之微管蛋白)置於96孔微量滴定板中。在37℃下,在PowerWave X微量板讀取器(BIO-TEK Instruments,Winooski,VT)中於以350 nm量測經測試化合物處理之溶液的吸光度,且每30秒記錄一次,持續30分鐘,以獲得吸光度曲線。接著計算曲線下面積(AUC)。由以下比率評估某一濃度之測試化合物對微管蛋白聚合之抑制功效:(AUC100
-AUC)/(AUC100
-AUC0
),其中AUC100
為未經處理之對照曲線的曲線下面積(亦即對應於100%聚合),且AUC0
為獲自10 μM秋水仙鹼(colchicine)之吸光度曲線的曲線下面積(亦即對應於0%聚合)。
在此檢定中測試化合物16、17及24。出乎意料的是,在2.5 μm濃度下,三種化合物對微管蛋白聚合皆顯示50%以上之抑制。
實例52
:評估抗血管新生活性
經由以下兩種檢定評估芳基取代之磺醯胺化合物之抗血管新生活性。
(i)細胞網絡形成抑制檢定
用含有膠原蛋白之細胞外基質塗佈96孔板之各孔,持續1小時以使凝膠凝固。在含有內皮細胞生長補充劑與20% FBS之M199培養基中製備濃度為1×105
個細胞/毫升之人類臍靜脈內皮細胞(HUVEC)懸浮液。接著,向該板之各個經凝膠塗佈之孔中添加100 μl細胞懸浮液。在存在或不存在測試化合物之情況下,於37℃下培育細胞18小時。在不存在測試化合物之情況下,培育12至18小時後,細胞網絡結構充分發展。使用200倍放大之光學顯微鏡對所形成之管數目進行計數。與對照相比,產生50%管形成抑制之測試化合物濃度即定為測試化合物之IC50
。
在此檢定中測試化合物24。出乎意料的是,化合物24顯示0.5 μM之IC50
,且在1.5 μM下完全抑制管的形成。
(ii) VEGF產生之抑制檢定
收集上述檢定(i)之培養基。由ELISA量測VEGF165含量。簡言之,將對VEGF具特異性之單株抗體預塗佈於微量板上。向孔中添加對照細胞培養基及檢定(i)之培養基,且所存在之任何VEGF皆由固定抗體結合於該等孔。洗去任何未結合之物質之後,向孔中添加對VEGF具特異性之酶聯結多株抗體。洗滌移除任何未結合之抗體-酶試劑之後,向孔中添加受質溶液,且顏色之顯示係與起始步驟中結合之VEGF之量成比例。停止顯色後量測顏色強度。
據觀測,化合物24在0.5 μM下抑制50%以上之VEGF產生。
實例53
:評估抗血管活性
藉由腫瘤組織中之免疫螢光染色來評估芳基取代之磺醯胺化合物之抗血管活性。
大鼠抗小鼠CD31抗體購自BD Biosciences。自對照組及測試化合物處理組中之小鼠收集腫瘤組織樣本。用丙酮及氯仿固定冷凍切片。為阻斷非特異性蛋白質,在4.5%魚膠(BB International Co.)中培育各樣本20分鐘。使用大鼠之抗小鼠CD31作為一次抗體且使用經德克薩斯紅(TexasRed)(Jackson)標記之山羊之抗大鼠IgG抗體作為二次抗體來偵測血管中CD31之表現。藉由首先進行計數,接著在5個隨機高倍顯微視野中對來自不同腫瘤樣本之CD31陽性細胞之數目求平均值來確定平均微血管密度(MVD)。
在此檢定中測試化合物24。出乎意料的是,與空白對照相比,化合物24在約96 nM下使血管面積降至1/5。
其他實施例
本說明書中所揭示之所有特徵可以任何組合形式進行組合。本說明書中所揭示之各個特徵可由用於達成相同、等效或類似目的之替代特徵進行替換。因此,除非另外明確說明,否則所揭示之各個特徵僅為一系列等效或類似之通用特徵的一個實例。
熟習此項技術者自以上描述可容易地確定本發明之基本特徵,且在不脫離本發明之精神及範疇的情況下可對本發明作出各種變化及修改以使其適於各種用法及條件。因此,其他實施例亦在以下申請專利範圍之範疇內。
Claims (10)
- 一種式(I)化合物,
- 如請求項1之化合物,其中X為CH。
- 如請求項2之化合物,其中R1 為芳基或雜芳基。
- 如請求項3之化合物,其中R2 為ORc 或SO2 NRc Rd 。
- 如請求項4之化合物,其中R2 為ORc ,其中Rc 為烷基。
- 如請求項5之化合物,其中R1 為苯基。
- 如請求項5之化合物,其中R1 為雜芳基。
- 一種如請求項1之化合物用於製造抑制微管蛋白聚合之藥劑之用途。
- 一種如請求項1之化合物用於製造治療癌症之藥劑之用途。
- 一種醫藥組合物,其包含如請求項1之化合物及醫藥上可接受之載劑。
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CA2871514C (en) | 2012-05-08 | 2020-08-25 | Merck Sharp & Dohme Corp. | Tetrahydronaphthyridine and related bicyclic compounds for inhibition of ror.gamma.activity and the treatment of disease |
US9394315B2 (en) | 2012-05-08 | 2016-07-19 | Lycera Corporation | Tetrahydro[1,8]naphthyridine sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease |
CN102875549B (zh) * | 2012-09-14 | 2015-11-04 | 浙江大学 | 7-芳(甲)胺基-5-胺基-6-氮杂吲哚衍生物及制备与用途 |
CN105579438B (zh) * | 2013-09-27 | 2019-12-06 | 阿勒根公司 | 用于皮肤修复的化合物和方法 |
WO2015095792A1 (en) | 2013-12-20 | 2015-06-25 | Merck Sharp & Dohme Corp. | Carbamate benzoxaxine propionic acids and acid derivatives for modulation of rorgamma activity and the treatment of disease |
WO2015090233A1 (en) | 2013-12-20 | 2015-06-25 | Sunshine Lake Pharma Co., Ltd. | Aromatic heterocyclic compounds and their application in pharmaceuticals |
WO2015095795A1 (en) | 2013-12-20 | 2015-06-25 | Merck Sharp & Dohme Corp. | TETRAHYDRONAPHTHYRIDINE, BENZOXAZINE, AZA-BENZOXAZINE, AND RELATED BICYCLIC COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE |
US9663502B2 (en) | 2013-12-20 | 2017-05-30 | Lycera Corporation | 2-Acylamidomethyl and sulfonylamidomethyl benzoxazine carbamates for inhibition of RORgamma activity and the treatment of disease |
CN106132422A (zh) | 2014-02-27 | 2016-11-16 | 莱斯拉公司 | 使用视黄酸受体相关孤儿受体γ的激动剂的过继细胞疗法&相关治疗方法 |
US10246455B2 (en) * | 2014-04-11 | 2019-04-02 | Taipei Medical University | Histone deacetylase inhibitors |
US9896441B2 (en) | 2014-05-05 | 2018-02-20 | Lycera Corporation | Tetrahydroquinoline sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease |
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JP2018510135A (ja) | 2015-02-11 | 2018-04-12 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | RORγT阻害剤としての置換ピラゾール化合物及びその使用 |
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CN107980042B (zh) | 2015-06-11 | 2021-10-08 | 莱斯拉公司 | 用作RORγ激动剂和用于治疗疾病的芳基二氢-2H-苯并[b][1,4]噁嗪磺酰胺和相关化合物 |
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