TWI473793B - 芳基磺醯胺ccr3拮抗劑 - Google Patents
芳基磺醯胺ccr3拮抗劑 Download PDFInfo
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- TWI473793B TWI473793B TW99112528A TW99112528A TWI473793B TW I473793 B TWI473793 B TW I473793B TW 99112528 A TW99112528 A TW 99112528A TW 99112528 A TW99112528 A TW 99112528A TW I473793 B TWI473793 B TW I473793B
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- alkyl
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- optionally substituted
- aryl
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Description
本文提供一種適用於調節CCR3活性之芳基磺醯胺及其醫藥組合物。本文亦提供使用其治療、預防或改善CCR3介導之病症、疾病或病狀之一或多種症狀的方法。
本申請案主張2009年4月22日申請之美國臨時申請案第61/171,780號之優先權,該案之揭示內容以全文引用的方式併入本文中。
CC趨化因子受體3(CCR3)為一種7次跨膜G蛋白偶合受體,其結合於多種C-C趨化因子,包括嗜酸性粒細胞趨化因子(eotaxin)(CCL11)、嗜酸性粒細胞趨化因子-3(CCL26)、MCP-3(CCL7)、MCP-4(CCL13)及RANTES(CCL5)。已知CCR3為表現於過敏性發炎細胞(包括嗜酸性粒細胞、嗜鹼性粒細胞、肥大細胞及T輔助2型CD4+
細胞)上之主要趨化因子受體(Combadiere等人,J. Biol. Chem. 1995
,270
,16491-16494;Post等人,J. Immunol. 1995
,155
,5299-5305)。嗜酸性粒細胞與許多過敏性疾病之發病機制有關,諸如支氣管哮喘(Durham及Kay,Clin. Allergy 1985
,15
,411-418;Kroegel等人,J. Allergy Clin. Immunol. 1994
,93
,725-734)、過敏性鼻炎(Durham,Clin. Exp. Allergy 1998
,28增刊2
,11-16.)、異位性皮膚炎(Leung,J. Allergy Clin. Immunol
.1999
,104
,S99-108)及嗜酸性粒細胞性胃腸炎(Bischoff等人,Am. J. Gastro. 1999
,94
,3521-3529)。已證明活化之嗜酸性粒細胞釋放主要鹼性蛋白(MBP),其阻斷神經上之抑制性M2蕈毒鹼受體(M2R),增加乙醯膽鹼釋放,及增強迷走神經介導性支氣管收縮(Evans等人,J. Clin. Invest. 1997
,100
,2254-2262)。
許多報導指示CCR3在過敏性病狀中起重要作用。舉例而言,已報導,在特應性與非特應性哮喘患者中,CCR3及其配位體、嗜酸性粒細胞趨化因子、嗜酸性粒細胞趨化因子-2、RANTES及MCP-4之mRNA與蛋白質含量有所增加(Ying等人,J. Immunol. 1999
,99
,6321-6329)。亦已證明在實驗性哮喘之急性模型中CCR3基因缺失減少嗜酸性粒細胞募集(Humbles等人,Proc. Natl. Acad. Sci. USA 2002
,99
,1479-1484;Ma等人,J. Clin. Invest. 2002
,109
,621-628;Pope等人,J. Immunol. 2005
,175
,5341-5350;Fulkerson等人,Proc. Natl. Acad. Sci. USA 2006
,103
,16418-16423)。此外,研究已顯示CCR3拮抗劑(諸如抗CCR3單株抗體)阻斷CCR3-配位體與CCR3轉染物或嗜酸性粒細胞之結合,由此阻斷由C-C趨化因子(諸如嗜酸性粒細胞趨化因子、RANTES或MCP-3)誘導之嗜酸性粒細胞的趨化性(Heath等人,J. Clin. Invest. 1997
,99
,178-184;Grimaldi等人,J. Leukocyte Biol. 1999
,65
,846-853;Justice等人,Am. J. Physiol. 2003
,284
,L168-L178)。因此,CCR3拮抗劑可能適用於治療發炎性疾病,諸如過敏性鼻炎及過敏性哮喘。另外,CCR3拮抗劑亦可能適用於阻斷某些微生物(諸如HIV)對表現CCR3之細胞的感染,因為已知CCR3為某些微生物之進入共受體。
本文提供一種式I之芳基磺醯胺:
或其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥;其中:R1
、R2
、R3
、R4
、R5
及R6
各獨立地為(a)氫、鹵基、氰基、硝基或胍;(b)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基;或(c)-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(NR1a
)NR1b
R1c
、-OR1a
、-OC(O)R1a
、-OC(O)OR1a
、-OC(O)NR1b
R1c
、-OC(=NR1a
)NR1b
R1c
、-OS(O)R1a
、-OS(O)2
R1a
、-OS(O)NR1b
R1c
、-OS(O)2
NR1b
R1c
、-NR1b
R1c
、-NR1a
C(O)R1d
、-NR1a
C(O)OR1d
、-NR1a
C(O)NR1b
R1c
、-NR1a
C(=NR1d
)NR1b
R1c
、-NR1a
S(O)R1d
、-NR1a
S(O)2
R1d
、-NR1a
S(O)NR1b
R1c
、-NR1a
S(O)2
NR1b
R1c
、-SR1a
、-S(O)R1a
、-S(O)2
R1a
、-S(O)NR1b
R1c
或-S(O)2
NR1b
R1c
;R7
為(a)鹵基、氰基、硝基、側氧基(oxo)或胍;(b)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基;或(c)-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(NR1a
)NR1b
R1c
、-OR1a
、-OC(O)R1a
、-OC(O)OR1a
、-OC(O)NR1b
R1c
、-OC(=NR1a
)NR1b
R1c
、-OS(O)R1a
、-OS(O)2
R1a
、-OS(O)NR1b
R1c
、-OS(O)2
NR1b
R1c
、-NR1b
R1c
、-NR1a
C(O)R1d
、-NR1a
C(O)OR1d
、-NR1a
C(O)NR1b
R1c
、-NR1a
C(=NR1d
)NR1b
R1c
、-NR1a
S(O)R1d
、-NR1a
S(O)2
R1d
、-NR1a
S(O)NR1b
R1c
、-NR1a
S(O)2
NR1b
R1c
、-SR1a
、-S(O)R1a
、-S(O)2
R1a
、-S(O)NR1b
R1c
或-S(O)2
NR1b
R1c
;X為O或S;RYa
為-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(S)NR1b
R1c
、-C(S)NR1a
C(O)NR1b
R1c
、-C(NR1a
)NR1b
R1c
、-C(NNO2
)NR1b
R1c
、-S(O)R1a
、-S(O)2
R1a
、-S(O)NR1b
R1c
或-S(O)2
NR1b
R1c
;限制條件為RYa
既不為-C(O)O-第三丁基,亦不為-C(O)H;m為0至3之整數;n為1至3之整數;p為0至4之整數;且各R1a
、R1b
、R1c
及R1d
獨立地為氫、C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、雜芳基或雜環基;或每一對R1b
及R1c
連同其所連接之N原子一起獨立地形成雜芳基或雜環基;其中各烷基、烯基、炔基、環烷基、芳基、芳烷基、雜環基及雜芳基視情況經一或多個各獨立地選自以下之基團取代:(a)氰基、鹵基及硝基;(b)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基及雜環基,各視情況經一或多個(在一實施例中為一個、兩個、三個或四個)取代基Q取代;及(c)-C(O)Ra
、-C(O)ORa
、-C(O)NRb
Rc
、-C(NRa
)NRb
Rc
、-ORa
、-OC(O)Ra
、-OC(O)ORa
、-OC(O)NRb
Rc
、-OC(=NRa
)NRb
Rc
、-OS(O)Ra
、-OS(O)2
Ra
、-OS(O)NRb
Rc
、-OS(O)2
NRb
Rc
、-NRb
Rc
、-NRa
C(O)Rd
、-NRa
C(O)ORd
、-NRa
C(O)NRb
Rc
、-NRa
C(=NRd
)NRb
Rc
、-NRa
S(O)Rd
、-NRa
S(O)2
Rd
、-NRa
S(O)NRb
Rc
、-NRa
S(O)2
NRb
Rc
、-SRa
、-S(O)Ra
、-S(O)2
Ra
、-S(O)NRb
Rc
及-S(O)2
NRb
Rc
,其中各Ra
、Rb
、Rc
及Rd
獨立地為(i)氫;(ii)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基,各視情況經一或多個(在一實施例中為一個、兩個、三個或四個)取代基Q取代;或(iii)Rb
及Rc
連同其所連接之N原子一起形成視情況經一或多個(在一實施例中為一個、兩個、三個或四個)取代基Q取代之雜環基;其中各Q獨立地選自由以下組成之群:(a)氰基、鹵基及硝基;(b)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基及雜環基;及(c)-C(O)Re
、-C(O)ORe
、-C(O)NRf
Rg
、-C(NRe
)NRf
Rg
、-ORe
、-OC(O)Re
、-OC(O)ORe
、-OC(O)NRf
Rg
、-OC(=NRe
)NRf
Rg
、-OS(O)Re
、-OS(O)2
Re
、-OS(O)NRf
Rg
、-OS(O)2
NRf
Rg
、-NRf
Rg
、-NRe
C(O)Rh
、-NRe
C(O)ORh
、-NRe
C(O)NRf
Rg
、-NRe
C(=NRh
)NRf
Rg
、-NRe
S(O)Rh
、-NRe
S(O)2
Rh
、-NRe
S(O) NRf
Rg
、-NRe
S(O)2
NRf
Rg
、-SRe
、-S(O)Re
、-S(O)2
Re
、-S(O)NRf
Rg
及-S(O)2
NRf
Rg
;其中各Re
、Rf
、Rg
及Rh
獨立地為(i)氫;(ii)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基;或(iii)Rf
及Rg
連同其所連接之N原子一起形成雜環基。
在一實施例中,RYa
既不為-C(O)O-C1-6
烷基,亦不為-C(O)H。
本文亦提供醫藥組合物,其包含本文所揭示之化合物,例如式I化合物,包括其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥;以及一或多種醫藥學上可接受之載劑。
本文進一步提供一種調節CCR3活性之方法,其包含使CCR3與治療有效量之本文所揭示之化合物接觸,例如式I化合物,包括其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。
本文另外提供一種治療、預防或改善個體之CCR3介導之病症、疾病或病狀的一或多種症狀之方法,其包含向該個體投與治療有效量之本文所揭示之化合物,例如式I化合物,包括其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。
為促進瞭解本文中所述之本發明,下文定義許多術語。
通常,本文中所使用之命名法及本文所述之有機化學、藥物化學及藥理學中之實驗程序為此項技術中所熟知且常用者。除非另有定義,否則本文中所使用之所有技術及科學術語通常均具有與本發明所屬技術之一般技術者通常瞭解相同之含義。在本文中所使用之術語存在複數個定義的情況下,除非另有說明,否則以本節中之定義為準。
術語「個體」係指動物,包括(但不限於)靈長類動物(例如人類)、母牛、豬、綿羊、山羊、馬、狗、貓、兔、大鼠或小鼠。術語「個體」及「患者」在本文中在例如提及哺乳動物個體(諸如人類個體,在一實施例中為人類)時可互換使用。
術語「治療」意謂包括減輕或消除病症、疾病或病狀,或與該病症、疾病或病狀相關之一或多種症狀;或減輕或根除病症、疾病或病狀自身之病因。
術語「預防」意謂包括延遲及/或阻止病症、疾病或病狀及/或其伴隨症狀之發作的方法;阻止個體獲得病症、疾病或病狀;或降低個體獲得病症、疾病或病狀之風險。
術語「治療有效量」意謂包括化合物在投與時足以預防所治療病症、疾病或病狀之一或多種症狀的發展或在某種程度上減輕所治療病症、疾病或病狀之一或多種症狀的量。術語「治療有效量」亦指化合物足以引發生物分子(例如蛋白質、酶、RNA或DNA)、細胞、組織、系統、動物或人類之生物或醫學反應的量,其正為研究者、獸醫、醫生或臨床醫師所尋求。
術語「醫藥學上可接受之載劑」、「醫藥學上可接受之賦形劑」、「生理學上可接受之載劑」或「生理學上可接受之賦形劑」係指醫藥學上可接受之物質、組合物或媒劑,諸如液體或固體填充劑、稀釋劑、溶劑或囊封物質。在一實施例中,各組分在與醫藥調配物之其他成分相容的意義上為「醫藥學上可接受」,且適用於與人類及動物之組織或器官接觸而無過量毒性、刺激、過敏反應、免疫原性或其他問題或併發症,且與合理的益處/風險比相稱。參見Remington: The Science and Practice of Pharmacy
,第21版,Lippincott Williams & Wilkins: Philadelphia,PA,2005;Handbook of Pharmaceutical Excipients
,第5版,Rowe等人編,The Pharmaceutical Press and the American Pharmaceutical Association: 2005;及Handbook of Pharmaceutical Additives
,第3版,Ash及Ash編,Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation
,第2版,Gibson編,CRC Press LLC: Boca Raton,FL,2009。
術語「約」意謂如一般技術者所測定之特定值的可接受誤差,其部分取決於如何量測或測定該值。在某些實施例中,術語「約」意謂在1、2、3或4個標準偏差內。在某些實施例中,術語「約」意謂在指定值或範圍之50%、20%、15%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%或0.05%以內。
術語「活性成分」及「活性物質」係指向個體單獨或與一或多種醫藥學上可接受之賦形劑組合投與以治療、預防或改善病狀、病症或疾病之一或多種症狀的化合物。如本文中所用,「活性成分」及「活性物質」可為本文所述之化合物的光學活性異構體。
術語「藥物」、「治療劑」及「化學治療劑」係指向個體投與以治療、預防或改善病狀、病症或疾病之一或多種症狀的化合物或其醫藥組合物。
術語「烷基」係指直鏈或分支鏈飽和單價烴基,其中該烷基可視情況如本文所述經取代。在某些實施例中,烷基為具有1至20(C1-20
)、1至15(C1-15
)、1至10(C1-10
)或1至6(C1-6
)個碳原子之直鏈飽和單價烴基,或為具有3至20(C3-20
)、3至15(C3-15
)、3至10(C3-10
)或3至6(C3-6
)個碳原子之分支鏈飽和單價烴基。如本文中所用,直鏈C1-6
及分支鏈C3-6
烷基亦稱為「低碳數烷基」。烷基之實例包括(但不限於)甲基、乙基、丙基(包括所有異構形式)、正丙基、異丙基、丁基(包括所有異構形式)、正丁基、異丁基、第二丁基、第三丁基、戊基(包括所有異構形式)及己基(包括所有異構形式)。舉例而言,C1-6
烷基係指具有1至6個碳原子之直鏈飽和單價烴基或具有3至6個碳原子之分支鏈飽和單價烴基。
術語「烯基」係指直鏈或分支鏈單價烴基,其含有一或多個,在一實施例中含有一至五個,在另一實施例中含有一個碳-碳雙鍵。該烯基可如本文所述視情況經取代。術語「烯基」亦涵蓋如一般技術者所瞭解具有「順式」及「反式」組態或替代地稱為「Z」及「E」組態之基團。除非另外規定,否則如本文中所使用,術語「烯基」涵蓋直鏈與分支鏈烯基。舉例而言,C2-6
烯基係指具有2至6個碳原子之直鏈不飽和單價烴基或具有3至6個碳原子之分支鏈不飽和單價烴基。在某些實施例中,烯基為具有2至20(C2-20
)、2至15(C2-15
)、2至10(C2-10
)或2至6(C2-6
)個碳原子之直鏈單價烴基,或具有3至20(C3-20
)、3至15(C3-15
)、3至10(C3-10
)或3至6(C3-6
)個碳原子之分支鏈單價烴基。烯基之實例包括(但不限於)乙烯基、丙烯-1-基、丙烯-2-基、烯丙基、丁烯基及4-甲基丁烯基。
術語「炔基」係指直鏈或分支鏈單價烴基,其含有一或多個,在一實施例中含有一至五個,在另一實施例中含有一個碳-碳參鍵。該炔基可如本文所述視情況經取代。除非另外規定,否則術語「炔基」亦涵蓋直鏈與分支鏈炔基。在某些實施例中,炔基為具有2至20(C2-20
)、2至15(C2-15
)、2至10(C2-10
)或2至6(C2-6
)個碳原子之直鏈單價烴基,或具有3至20(C3-20
)、3至15(C3-15
)、3至10(C3-10
)或3至6(C3-6
)個碳原子之分支鏈單價烴基。炔基之實例包括(但不限於)乙炔基(-C≡CH)及炔丙基(-CH2
C≡CH)。舉例而言,C2-6
炔基係指具有2至6個碳原子之直鏈不飽和單價烴基或具有3至6個碳原子之分支鏈不飽和單價烴基。
術語「環烷基」係指環狀單價烴基,其可如本文所述視情況經取代。在一實施例中,環烷基可為飽和、及/或橋式、及/或非橋式、及/或稠合雙環基團。在某些實施例中,環烷基具有3至20(C3-20
)、3至15(C3-15
)、3至10(C3-10
)或3至7(C3-7
)個碳原子。環烷基之實例包括(但不限於)環丙基、環丁基、環戊基、環己基、環庚基、雙環[2.1.1]己基、雙環[2.2.1]庚基、十氫萘基及金剛烷基。
術語「芳基」係指含有至少一個芳族碳環之單價單環芳族基團及/或單價多環芳族基團。在某些實施例中,芳基具有6至20(C6-20
)、6至15(C6-15
)或6至10(C6-10
)個環原子。芳基之實例包括(但不限於)苯基、萘基、茀基、薁基、蒽基、菲基、芘基、聯苯及三聯苯。芳基亦指雙環或三環碳環,其中一個環為芳族環且其中其他環可為飽和、部分不飽和或芳族環,例如二氫萘基、茚基、二氫茚基或四氫萘基(萘滿基)。在某些實施例中,芳基可如本文所述視情況經取代。
術語「芳烷基」或「芳基-烷基」係指經芳基取代之單價烷基。在某些實施例中,烷基及芳基部分如本文所述視情況經取代。
術語「雜芳基」係指含有至少一個芳族環之單價單環芳族基團及/或多環芳族基團,其中至少一個芳族環在環中含有一或多個獨立地選自O、S及N之雜原子。雜芳基經由芳族環鍵結至分子之其餘部分。雜芳基之各環可含有一或兩個O原子、一或兩個S原子及/或一至四個N原子,限制條件為各環中之雜原子總數為四個或四個以下且各環含有至少一個碳原子。在某些實施例中,雜芳基具有5至20、5至15或5至10個環原子。單環雜芳基之實例包括(但不限於)呋喃基、咪唑基、異噻唑基、異噁唑基、噁二唑基、噁二唑基、噁唑基、吡嗪基、吡唑基、噠嗪基、吡啶基、嘧啶基、吡咯基、噻二唑基、噻唑基、噻吩基、四唑基、三嗪基及三唑基。雙環雜芳基之實例包括(但不限於)苯并呋喃基、苯并咪唑基、苯并異噁唑基、苯并哌喃基、苯并噻二唑基、苯并噻唑基、苯并噻吩基、苯并三唑基、苯并噁唑基、呋喃并吡啶基、咪唑并吡啶基、咪唑并噻唑基、吲嗪基、吲哚基、吲唑基、異苯并呋喃基、異苯并噻吩基、異吲哚基、異喹啉基、異噻唑基、啶基、噁唑并吡啶基、呔嗪基、喋啶基、嘌呤基、吡啶并吡啶基、吡咯并吡啶基、喹啉基、喹喏啉基、喹唑啉基、噻二唑并嘧啶基及噻吩并吡啶基。三環雜芳基之實例包括(但不限於)吖啶基、苯并吲哚基、咔唑基、二苯并呋喃基、呸啶基、啡啉基、啡啶基、啡呻嗪基、啡嗪基、啡噻嗪基、啡噁嗪基及基。在某些實施例中,雜芳基亦可如本文所述視情況經取代。
術語「雜環基」或「雜環」係指含有至少一個非芳族環之單價單環非芳族環系及/或多環環系,其中一或多個非芳族環原子為獨立地選自O、S或N之雜原子;且其餘環原子為碳原子。在某些實施例中,雜環基具有3至20、3至15、3至10、3至8、4至7或5至6個環原子。雜環基經由非芳族環鍵結至分子之其餘部分。在某些實施例中,雜環基為單環、雙環、三環或四環環系,其可包括稠合或橋式環系,且其中氮或硫原子可視情況經氧化,氮原子可視情況經四級銨化,且一些環可為部分或完全飽和或芳族環。雜環基可在使得產生穩定化合物之任何雜原子或碳原子處連接於主結構。該等雜環基之實例包括(但不限於)氮呯基、苯并二噁烷基、苯并間二氧雜環戊烯基、苯并呋喃酮基、苯并哌喃酮基、苯并哌喃基、苯并四氫呋喃基、苯并四氫噻吩基、苯并噻喃基、苯并噁嗪基、β-咔啉基、烷基、色酮基、啉基、香豆素基、十氫異喹啉基、二氫苯并異噻嗪基、二氫苯并異噁嗪基、二氫呋喃基、二氫異吲哚基、二氫哌喃基、二氫吡唑基、二氫吡嗪基、二氫吡啶基、二氫嘧啶基、二氫吡咯基、二氧戊環基、1,4-二噻烷基、呋喃酮基、咪唑啶基、咪唑啉基、吲哚啉基、異苯并四氫呋喃基、異苯并四氫噻吩基、異烷基、異香豆素基、異吲哚啉基、異噻唑啶基、異噁唑啶基、嗎啉基、八氫吲哚基、八氫異吲哚基、噁唑啶酮基、噁唑啶基、環氧乙烷基、哌嗪基、哌啶基、4-哌啶酮基、吡唑啶基、吡唑啉基、吡咯啶基、吡咯啉基、啶基、四氫呋喃基、四氫異喹啉基、四氫哌喃基、四氫噻吩基、噻嗎啉基、噻唑啶基、四氫喹啉基及1,3,5-三噻烷基。在某些實施例中,雜環亦可如本文所述視情況經取代。
術語「鹵素」、「鹵化物」或「鹵基」係指氟、氯、溴及/或碘。
術語「視情況經取代」欲意謂諸如烷基、烯基、炔基、環烷基、芳基、芳烷基、雜芳基或雜環基之基團可經一或多個獨立地選自以下之取代基取代:例如(a)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基及雜環基,各視情況經一或多個(在一實施例中為一個、兩個、三個或四個)取代基Q取代;及(b)鹵基、氰基(-CN)、硝基(-NO2
)、-C(O)Ra
、-C(O)ORa
、-C(O)NRb
Rc
、-C(NRa
)NRb
Rc
、-ORa
、-OC(O)Ra
、-OC(O)ORa
、-OC(O)NRb
Rc
、-OC(=NRa
)NRb
Rc
、-OS(O)Ra
、-OS(O)2
Ra
、-OS(O)NRb
Rc
、-OS(O)2
NRb
Rc
、-NRb
Rc
、-NRa
C(O)Rd
、-NRa
C(O)ORd
、-NRa
C(O)NRb
Rc
、-NRa
C(=NRd
)NRb
Rc
、-NRa
S(O)Rd
、-NRa
S(O)2
Rd
、-NRa
S(O)NRb
Rc
、-NRa
S(O)2
NRb
Rc
、-SRa
、-S(O)Ra
、-S(O)2
Ra
、-S(O)NRb
Rc
及-S(O)2
NRb
Rc
,其中各Ra
、Rb
、Rc
及Rd
獨立地為(i)氫;(ii)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基,各視情況經一或多個(在一實施例中為一個、兩個、三個或四個)取代基Q取代;或(iii)Rb
及Rc
連同其所連接之N原子一起形成視情況經一或多個(在一實施例中為一個、兩個、三個或四個)取代基Q取代之雜芳基或雜環基。除非另外規定,否則如本文中所用,所有可取代之基團均「視情況經取代」。
在一實施例中,各Q獨立地選自由以下組成之群:(a)氰基、鹵基及硝基;及(b)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基及雜環基;及(c)-C(O)Re
、-C(O)ORe
、-C(O)NRf
Rg
、-C(NRe
)NRf
Rg
、-ORe
、-OC(O)Re
、-OC(O)ORe
、-OC(O)NRf
Rg
、-OC(=NRe
)NRf
Rg
、-OS(O)Re
、-OS(O)2
Re
、-OS(O)NRf
Rg
、-OS(O)2
NRf
Rg
、-NRf
Rg
、-NRe
C(O)Rh
、-NRe
C(O)ORh
、-NRe
C(O)NRf
Rg
、-NRe
C(=NRh
)NRf
Rg
、-NRe
S(O)Rh
、-NRe
S(O)2
Rh
、-NRe
S(O)NRf
Rg
、-NRe
S(O)2
NRf
Rg
、-SRe
、-S(O)Re
、-S(O)2
Re
、-S(O)NRf
Rg
及-S(O)2
NRf
Rg
;其中各Re
、Rf
、Rg
及Rh
獨立地為(i)氫;(ii)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基;或(iii)Rf
及Rg
連同其所連接之N原子一起形成雜芳基或雜環基。
在某些實施例中,「光學活性」及「對映異構活性」係指一組分子,其對映異構過量不小於約50%、不小於約70%、不小於約80%、不小於約90%、不小於約91%、不小於約92%、不小於約93%、不小於約94%、不小於約95%、不小於約96%、不小於約97%、不小於約98%、不小於約99%、不小於約99.5%或不小於約99.8%。在某些實施例中,化合物基於所述外消旋體之總重量計,包含約95%或95%以上之一種對映異構體及約5%或5%以下之另一種對映異構體。
在描述光學活性化合物時,字首R及S用於表示分子關於其對掌性中心之絕對組態。(+)及(-)用於表示化合物之旋光性,亦即偏振光之平面由光學活性化合物旋轉的方向。(-)字首指示化合物左旋,亦即化合物使偏振光之平面向左或逆時針旋轉。(+)字首指示化合物右旋,亦即化合物使偏振光之平面向右或順時針旋轉。然而,旋光性之符號(+)及(-)與分子之絕對組態R及S無關。
術語「溶劑合物」係指本文所提供之化合物或其鹽,其進一步包括化學計量或非化學計量之量的藉由非共價分子間力結合之溶劑。當溶劑為水時,所形成之溶劑合物為水合物。
術語「天然存在」或「天然」在與生物物質(諸如核酸分子、多肽、宿主細胞及其類似物)結合使用時係指存在於自然界中且未由人類操縱之物質。類似地,「非天然存在」或「非天然」係指不存在於自然界中或已由人類進行結構修飾或合成之物質。
術語「CCR3」係指CC趨化因子受體3或其變異體,其能夠介導細胞對多種趨化因子之反應,該等趨化因子包括(但不限於)嗜酸性粒細胞趨化因子(eotaxin)(CCL11)、嗜酸性粒細胞趨化因子-3(CCL26)、MCP-3(CCL7)、MCP-4(CCL13)及RANTES(CCL5)。CCR3變異體包括實質上與天然CCR3同源之蛋白質,亦即與天然CCR3之胺基酸序列相比具有一或多個天然或非天然存在之胺基酸缺失、插入或取代(例如CCR3衍生物、同源物及片段)的蛋白質。CCR3變異體之胺基酸序列與天然CCR3至少約80%一致、至少約90%一致或至少約95%一致。
術語「CCR3拮抗劑」係指例如部分或完全阻斷、降低、阻止、抑制或下調CCR3活性之化合物。術語「CCR3拮抗劑」亦指結合於CCR3受體、延遲CCR3受體之活化、使CCR3受體失活或使CCR3受體去敏之化合物。CCR3拮抗劑可藉由干擾CCR3受體與其趨化因子配位體之相互作用來起作用,該趨化因子配位體包括(但不限於)嗜酸性粒細胞趨化因子(CCL11)、嗜酸性粒細胞趨化因子-3(CCL26)、MCP-3(CCL7)、MCP-4(CCL13)及/或RANTES(CCL5)。
術語「CCR3介導之病症或疾病」及「由CCR3介導之病狀、病症或疾病」係指特徵為不當(例如低於或超過正常)CCR3活性之病狀、病症或疾病。不當CCR3功能活性可能由以下情形引起:CCR3在通常不表現CCR3之細胞中表現;CCR3表現或細胞內活化程度增加,導致例如發炎性及免疫相關性病症或疾病;或CCR3表現減少。CCR3介導之病狀、病症或疾病可完全或部分由不當CCR3活性介導。特定言之,CCR3介導之病狀、病症或疾病係調節CCR3受體可對潛在病狀或病症產生一些作用者,例如CCR3拮抗劑或促效劑使得至少一些所治療之患者得到一些改善。
化合物
本文提供適用於調節CCR3活性之芳基磺醯胺。本文亦提供包含該等化合物之醫藥組合物及使用該等化合物及組合物治療CCR3介導之病症、疾病或病狀之方法。
在一實施例中,本文提供一種式I之芳基磺醯胺:
或其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥;其中:R1
、R2
、R3
、R4
、R5
及R6
各獨立地為(a)氫、鹵基、氰基、硝基或胍;(b)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基;或(c)-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(NR1a
)NR1b
R1c
、-OR1a
、-OC(O)R1a
、-OC(O)OR1a
、-OC(O)NR1b
R1c
、-OC(=NR1a
)NR1b
R1c
、-OS(O)R1a
、-OS(O)2
R1a
、-OS(O)NR1b
R1c
、-OS(O)2
NR1b
R1c
、-NR1b
R1c
、-NR1a
C(O)R1d
、-NR1a
C(O)OR1d
、-NR1a
C(O)NR1b
R1c
、-NR1a
C(=NR1d
)NR1b
R1c
、-NR1a
S(O)R1d
、-NR1a
S(O)2
R1d
、-NR1a
S(O)NR1b
R1c
、-NR1a
S(O)2
NR1b
R1c
、-SR1a
、-S(O)R1a
、-S(O)2
R1a
、-S(O)NR1b
R1c
或-S(O)2
NR1b
R1c
;R7
為(a)鹵基、氰基、硝基、側氧基或胍;(b)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基;或(c)-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(NR1a
)NR1b
R1c
、-OR1a
、-OC(O)R1a
、-OC(O)OR1a
、-OC(O)NR1b
R1c
、-OC(=NR1a
)NR1b
R1c
、-OS(O)R1a
、-OS(O)2
R1a
、-OS(O)NR1b
R1c
、-OS(O)2
NR1b
R1c
、-NR1b
R1c
、-NR1a
C(O)R1d
、-NR1a
C(O)OR1d
、-NR1a
C(O)NR1b
R1c
、-NR1a
C(=NR1d
)NR1b
R1c
、-NR1a
S(O)R1d
、-NR1a
S(O)2
R1d
、-NR1a
S(O)NR1b
R1c
、-NR1a
S(O)2
NR1b
R1c
、-SR1a
、-S(O)R1a
、-S(O)2
R1a
、-S(O)NR1
bR1c
或-S(O)2
NR1b
R1c
;X為O或S;RYa
為-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(S)NR1b
R1c
、-C(S)NR1a
C(O)NR1b
R1c
、-C(NR1a
)NR1b
R1c
、-C(NNO2
)NR1b
R1c
、-S(O)R1a
、-S(O)2
R1a
、-S(O)NR1
bR1c
或-S(O)2
NR1b
R1c
;m為0至3之整數;n為1至3之整數;p為0至4之整數;且各R1a
、R1b
、R1c
及R1d
獨立地為氫、C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、雜芳基或雜環基;或每一對R1b
及R1c
連同其所連接之N原子一起獨立地形成雜芳基或雜環基;其中各烷基、烯基、炔基、環烷基、芳基、芳烷基、雜環基及雜芳基視情況經一或多個各獨立地選自以下之基團取代:(a)氰基、鹵基及硝基;(b)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基及雜環基,各視情況經一或多個(在一實施例中為一個、兩個、三個或四個)取代基Q取代;及(c)-C(O)Ra
、-C(O)ORa
、-C(O)NRb
Rc
、-C(NRa
)NRb
Rc
、-ORa
、-OC(O)Ra
、-OC(O)ORa
、-OC(O)NRb
Rc
、-OC(=NRa
)NRb
Rc
、-OS(O)Ra
、-OS(O)2
Ra
、-OS(O)NRb
Rc
、-OS(O)2
NRb
Rc
、-NRb
Rc
、-NRa
C(O)Rd
、-NRa
C(O)ORd
、-NRa
C(O)NRb
Rc
、-NRa
C(=NRd
)NRb
Rc
、-NRa
S(O)Rd
、-NRa
S(O)2
Rd
、-NRa
S(O)NRb
Rc
、-NRa
S(O)2
NRb
Rc
、-SRa
、-S(O)Ra
、-S(O)2
Ra
、-S(O)NRb
Rc
及-S(O)2
NRb
Rc
,其中各Ra
、Rb
、Rc
及Rd
獨立地為(i)氫;(ii)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基,各視情況經一或多個(在一實施例中為一個、兩個、三個或四個)取代基Q取代;或(iii)Rb
及Rc
連同其所連接之N原子一起形成視情況經一或多個(在一實施例中為一個、兩個、三個或四個)取代基Q取代之雜環基;其中各Q獨立地選自由以下組成之群:(a)氰基、鹵基及硝基;(b)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基及雜環基;及(c)-C(O)Re
、-C(O)ORe
、-C(O)NRf
Rg
、-C(NRe
)NRf
Rg
、-ORe
、-OC(O)Re
、-OC(O)ORe
、-OC(O)NRf
Rg
、-OC(=NRe
)NRf
Rg
、-OS(O)Re
、-OS(O)2
Re
、-OS(O)NRf
Rg
、-OS(O)2
NRf
Rg
、-NRf
Rg
、-NRe
C(O)Rh
、-NRe
C(O)ORh
、-NRe
C(O)NRf
Rg
、-NRe
C(=NRh
)NRf
Rg
、-NRe
S(O)Rh
、-NRe
S(O)2
Rh
、-NRe
S(O)NRf
Rg
、-NRe
S(O)2
NRf
Rg
、-SRe
、-S(O)Re
、-S(O)2
Re
、-S(O)NRf
Rg
及-S(O)2
NRf
Rg
;其中各Re
、Rf
、Rg
及Rh
獨立地為(i)氫;(ii)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基;或(iii)Rf
及Rg
連同其所連接之N原子一起形成雜環基。
在某些實施例中,在式I中,RYa
既不為-C(O)O-第三丁基,亦不為-C(O)H。
在某些實施例中,在式I中,RYa
既不為-C(O)O-第三丁基,亦不為-C(O)H。在某些實施例中,在式I中,RYa
不為-C(O)O-第三丁基。在某些實施例中,在式I中,化合物為4-(2-(3,5-二甲基苯氧基)-5-硝基苯基磺醯基)哌嗪-1-甲醛。
在另一實施例中,本文提供一種式I之芳基磺醯胺:
或其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥;其中:R1
、R2
、R3
、R4
、R5
及R6
各獨立地為(a)氫、鹵基、氰基、硝基或胍;(b)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基;或(c)-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(NR1a
)NR1b
R1c
、-OR1a
、-OC(O)R1a
、-OC(O)OR1a
、-OC(O)NR1b
R1c
、-OC(=NR1a
)NR1b
R1c
、-OS(O)R1a
、-OS(O)2
R1a
、-OS(O)NR1b
R1c
、-OS(O)2
NR1b
R1c
、-NR1b
R1c
、-NR1a
C(O)R1d
、-NR1a
C(O)OR1d
、-NR1a
C(O)NR1b
R1c
、-NR1a
C(=NR1d
)NR1b
R1c
、-NR1a
S(O)R1d
、-NR1a
S(O)2
R1d
、-NR1a
S(O)NR1b
R1c
、-NR1a
S(O)2
NR1b
R1c
、-SR1a
、-S(O)R1a
、-S(O)2
R1a
、-S(O)NR1b
R1c
或-S(O)2
NR1b
R1c
;R7
為(a)鹵基、氰基、硝基、側氧基或胍;(b)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基;或(c)-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(NR1a
)NR1b
R1c
、-OR1a
、-OC(O)R1a
、-OC(O)OR1a
、-OC(O)NR1b
R1c
、-OC(=NR1a
)NR1b
R1c
、-OS(O)R1a
、-OS(O)2
R1a
、-OS(O)NR1b
R1c
、-OS(O)2
NR1b
R1c
、-NR1b
R1c
、-NR1a
C(O)R1d
、-NR1a
C(O)OR1d
、-NR1a
C(O)NR1b
R1c
、-NR1a
C(=NR1d
)NR1b
R1c
、-NR1a
S(O)R1d
、-NR1a
S(O)2
R1d
、-NR1a
S(O)NR1b
R1c
、-NR1a
S(O)2
NR1b
R1c
、-SR1a
、-S(O)R1a
、-S(O)2
R1a
、-S(O)NR1b
R1c
或-S(O)2
NR1b
R1c
;X為O或S;RYa
為-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(NR1a
)NR1b
R1c
、-S(O)R1a
、-S(O)2
R1a
、-S(O)NR1b
R1c
或-S(O)2
NR1b
R1c
;限制條件為RYa
既不為-C(O)O-第三丁基,亦不為-C(O)H;m為0至3之整數;n為1至3之整數;p為0至4之整數;且各R1a
、R1b
、R1c
及R1d
獨立地為氫、C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、雜芳基或雜環基;或每一對R1b
及R1c
連同其所連接之N原子一起獨立地形成雜芳基或雜環基;其中各烷基、烯基、炔基、環烷基、芳基、芳烷基、雜環基及雜芳基視情況經一或多個各獨立地選自以下之基團取代:(a)氰基、鹵基及硝基;(b)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基及雜環基,各視情況經一或多個(在一實施例中為一個、兩個、三個或四個)取代基Q取代;及(c)-C(O)Ra
、-C(O)ORa
、-C(O)NRb
Rc
、-C(NRa
)NRb
Rc
、-ORa
、-OC(O)Ra
、-OC(O)ORa
、-OC(O)NRb
Rc
、-OC(=NRa
)NRb
Rc
、-OS(O)Ra
、-OS(O)2
Ra
、-OS(O)NRb
Rc
、-OS(O)2
NRb
Rc
、-NRb
Rc
、-NRa
C(O)Rd
、-NRa
C(O)ORd
、-NRa
C(O)NRb
Rc
、-NRa
C(=NRd
)NRb
Rc
、-NRa
S(O)Rd
、-NRa
S(O)2
Rd
、-NRa
S(O)NRb
Rc
、-NRa
S(O)2
NRb
Rc
、-SRa
、-S(O)Ra
、-S(O)2
Ra
、-S(O)NRb
Rc
及-S(O)2
NRb
Rc
,其中各Ra
、Rb
、Rc
及Rd
獨立地為(i)氫;(ii)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基,各視情況經一或多個(在一實施例中為一個、兩個、三個或四個)取代基Q取代;或(iii)Rb
及Rc
連同其所連接之N原子一起形成視情況經一或多個(在一實施例中為一個、兩個、三個或四個)取代基Q取代之雜環基;其中各Q獨立地選自由以下組成之群:(a)氰基、鹵基及硝基;(b)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基及雜環基;及(c)-C(O)Re
、-C(O)ORe
、-C(O)NRf
Rg
、-C(NRe
)NRf
Rg
、-ORe
、-OC(O)Re
、-OC(O)ORe
、-OC(O)NRf
Rg
、-OC(=NRe
)NRf
Rg
、-OS(O)Re
、-OS(O)2
Re
、-OS(O)NRf
Rg
、-OS(O)2
NRf
Rg
、-NRf
Rg
、-NRe
C(O)Rh
、-NRe
C(O)ORh
、-NRe
C(O)NRf
Rg
、-NRe
C(=NRh
)NRf
Rg
、-NRe
S(O)Rh
、-NRe
S(O)2
Rh
、-NRe
S(O)NRf
Rg
、-NRe
S(O)2
NRf
Rg
、-SRe
、-S(O)Re
、-S(O)2
Re
、-S(O)NRf
Rg
及-S(O)2
NRf
Rg
;其中各Re
、Rf
、Rg
及Rh
獨立地為(i)氫;(ii)C1-6
烷基、C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基;或(iii)Rf
及Rg
連同其所連接之N原子一起形成雜環基。
在一實施例中,RYa
既不為-C(O)O-C1-6
烷基,亦不為-C(O)H。在另一實施例中,RYa
為-C(O)O-C1-6
烷基,但不為-C(O)O-第三丁基。
在一實施例中,在式I中,R1
、R2
、R3
、R4
及R5
各獨立地為氫、鹵基或C1-6
烷基;R6
為氰基或硝基;R7
為C1-6
烷基;X為O或S;m為0、1或2;n為1或2;p為0、1、2、3或4;且RYa
為-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(S)NR1b
R1c
、-C(S)NR1a
C(O)NR1b
R1c
、-C(NNO2
)NR1b
R1c
、-S(O)2
R1a
或-S(O)2
NR1b
R1c
;其中各R1a
及R1c
獨立地為(a)氫;(b)視情況經一個、兩個或三個取代基取代之C1-6
烷基,該或該等取代基各獨立地選自氰基、鹵基、C3-7
環烷基、C6-14
芳基、雜芳基、雜環基、-C(O)Ra
、-C(O)ORa
及-SRa
,其中該環烷基、芳基、雜芳基及雜環基各進一步視情況經一個、兩個或三個取代基取代,該或該等取代基各獨立地為鹵基或C1-6
烷基;(c)視情況經C6-14
芳基取代之C2-6
烯基;(d)視情況經一或兩個C1-6
烷基取代之C3-7
環烷基;(e)視情況經一個、兩個或三個取代基取代之C6-14
芳基,該或該等取代基各獨立地選自鹵基、硝基、氰基、-ORa
、-C(O)Ra
及C1-6
烷基,其中該烷基進一步視情況經一個、兩個或三個鹵基取代;(f)視情況經一個、兩個或三個取代基取代之雜芳基,該或該等取代基各獨立地為鹵基或C1-6
烷基;或(g)雜環基;且R1b
為氫或C1-6
烷基。
在另一實施例中,在式I中,R1
、R2
、R3
、R4
及R5
各獨立地為氫、鹵基或C1-6
烷基;R6
為氰基或硝基;R7
為C1-6
烷基;X為O或S;m為0、1或2;n為1或2;p為0、1、2、3或4;且RYa
為-C(O)R1a
、-C(O)O R1a
、-C(O)NR1b
R1c
、-C(S)NR1b
R1c
、-C(S)NR1a
C(O)NR1b
R1c
、-C(NNO2
)NR1b
R1c
、-S(O)2
R1a
或-S(O)2
NR1b
R1
c;其中各R1a
及R1c
獨立地為(a)氫;或(b)C1-6
烷基、C2-6
烯基、C3-7
環烷基、C6-14
芳基、雜芳基或雜環基,各視情況經一或兩個取代基取代,該或該等取代基各獨立地選自鹵基、氰基、硝基、C1-6
烷基、C3-7
環烷基、C6-14
芳基、雜芳基、雜環基、-ORa
、-SRa
及-C(O)Ra
,其中Ra
如本文所定義且該烷基、環烷基、芳基、雜芳基及雜環基各視情況進一步經一或兩個取代基取代,該或該等取代基各獨立地為鹵基或C1-6
烷基;且R1b
為氫或C1-6
烷基。
在另一實施例中,在式I中,R1
、R2
、R3
、R4
及R5
各獨立地為氫、鹵基或C1-6
烷基;R6
為氰基或硝基;R7
為C1-6
烷基;X為O或S;m為0、1或2;n為1或2;p為0、1、2、3或4;且RYa
為-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(S)NR1b
R1c
、-C(S)NR1a
C(O)NR1b
R1c
、-C(NNO2
)NR1b
R1c
、-S(O)2
R1a
或-S(O)2
NR1b
R1c
;其中各R1a
及R1c
獨立地為(a)氫;或(b)C1-6
烷基、C2-6
烯基、C3-7
環烷基、C6-14
芳基、雜芳基或雜環基,各視情況經一或兩個取代基取代,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、乙醯基、丙醯基及乙氧羰基;且R1b
為氫或C1-6
烷基。
在另一實施例中,在式I中,R1
、R2
、R3
、R4
及R5
各獨立地為氫、鹵基或C1-6
烷基;R6
為氰基或硝基;R7
為C1-6
烷基;X為O或S;m為0、1或2;n為1或2;p為0、1、2、3或4;且RYa
為-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(S)NR1b
R1c
、-C(S)NR1a
C(O)NR1b
R1c
、-C(NNO2
)NR1b
R1c
、-S(O)2
R1a
或-S(O)2
NR1b
R1c
;其中R1a
及R1c
各獨立地為(a)氫;(b)C1-6
烷基,視情況經選自氯、氰基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、丙醯基及乙氧羰基之取代基取代;(c)視情況經苯基取代之C2-6
烯基;(d)C3-7
環烷基;(e)視情況經一或兩個取代基取代之C6-14
芳基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基及乙醯基;(f)視情況經一或兩個甲基取代之雜芳基;或(g)雜環基;且R1b
為氫或C1-6
烷基。
在另一實施例中,在式I中,R1
、R2
、R3
、R4
及R5
各獨立地為氫、氯或甲基;R6
為氰基或硝基;X為O或S;m為0、1或2;n為1或2;p為0;且RYa
為-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(S)NR1b
R1c
、-C(S)NR1a
C(O)NR1b
R1c
、-C(NNO2
)NR1b
R1c
、-S(O)2
R1a
或-S(O)2
NR1b
R1c
;其中R1a
及R1c
各獨立地為(a)氫;(b)甲基、乙基、丙基(例如正丙基或異丙基)、丁基(例如正丁基、2-丁基、異丁基或第三丁基)或戊基(例如正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基),各視情況經選自氯、氰基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、丙醯基及乙氧羰基之取代基取代;(c)乙烯基或烯丙基,各視情況經苯基取代;(d)環丁基、環戊基或環己基;(e)視情況經一或兩個取代基取代之苯基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基及乙醯基;(f)呋喃基、噻吩基、異噁唑基、吡唑基、1,2,3-噻二唑基、吡啶基、吡唑基、苯并呋喃基、苯并[c
][1,2,5]噁二唑基、苯并噻吩基或苯并噻唑基,各視情況經一或兩個甲基取代;或(g)嗎啉基;且R1b
為氫、甲基或乙基。
在另一實施例中,在式I中,R1
、R2
、R3
、R4
及R5
各獨立地為氫、氯或甲基;R6
為氰基或硝基;X為O或S;m為0、1或2;n為1或2;p為0;且RYa
為-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(S)NR1b
R1c
、-C(S)NR1a
C(O)NR1b
R1c
、-C(NNO2
)NR1b
R1c
、-S(O)2
R1a
或-S(O)2
NR1b
R1c
;其中各R1a
及R1c
獨立地為氫、甲基、乙基、丙基(例如正丙基或異丙基)、丁基(例如正丁基、2-丁基、異丁基或第三丁基)或戊基(例如正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)、氯乙基、氯丙基、氯丁基、乙氧羰基乙基、甲硫基丙基、氰基甲基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基甲基、苯甲基、氯苯甲基、呋喃基甲基、嗎啉基乙基、丙醯基乙基、乙烯基、烯丙基、苯基乙烯基、環丁基、環戊基、環己基、苯基、氯苯基(例如2-氯苯基、3-氯苯基或4-氯苯基)、氟苯基(例如2-氟苯基、3-氟苯基或4-氟苯基)、氰基苯基(例如2-氰基苯基、3-氰基苯基或4-氰基苯基)、硝基苯基(例如2-硝基苯基、3-硝基苯基或4-硝基苯基)、甲基苯基(例如2-甲基苯基、3-甲基苯基或4-甲基苯基)、三氟甲基苯基(例如2-三氟甲基苯基、3-三氟甲基苯基或4-三氟甲基苯基)、乙基苯基(例如2-乙基苯基、3-乙基苯基或4-乙基苯基)、甲氧基苯基(例如2-甲氧基苯基、3-甲氧基苯基或4-甲氧基苯基)、乙醯基苯基(例如2-乙醯基苯基、3-乙醯基苯基或4-乙醯基苯基)、二氯苯基(例如2,3-二氯苯基、2,4-二氯苯基、2,5-二氯苯基、2,6-二氯苯基、3,4-二氯苯基或3,5-二氯苯基)、呋喃基(例如呋喃-2-基或呋喃-3-基)、噻吩基(例如噻吩-2-基或噻吩-3-基)、甲基-噻吩基、異噁唑基、二甲基吡唑基、甲基-1,2,3-噻二唑基、吡啶基(例如吡啶-2-基、吡啶-3-基或吡啶-4-基)、吡唑基(例如2-吡唑基或3-吡唑基)、苯并呋喃基、苯并[c
][1,2,5]噁二唑基、苯并噻吩基、苯并噻唑基或嗎啉基;且各R1b
獨立地為氫、甲基或乙基。
在又一實施例中,在式I中,R1
為氫;R2
為氯或甲基;R3
為氫;R4
為氯或甲基;R5
為氫;R6
為氰基;X為O或S;m為1;n為1;p為0;且RYa
為-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(S)NR1b
R1c
、-C(S)NR1a
C(O)NR1b
R1c
、-C(NNO2
)NR1b
R1c
、-S(O)2
R1a
或-S(O)2
NR1b
R1c
;其中各R1a
及R1c
獨立地為氫、甲基、乙基、異丙基、異丁基、第三丁基、1,1-二甲基丙基、2,2-二甲基丙基、2-氯乙基、3-氯丙基、4-氯丁基、2-乙氧羰基乙基、3-甲硫基丙基、1-氰基甲基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基甲基、苯甲基、3-氯苯甲基、呋喃-2-基甲基、2-嗎啉-4-基乙基、2-丙醯基乙基、乙烯基、烯丙基、2-苯基乙烯基、環丁基、環戊基、環己基、苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-氟苯基、3-氟苯基、4-氟苯基、4-氰基苯基、4-硝基苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、4-三氟甲基苯基、4-乙基苯基、4-甲氧基苯基、3-乙醯基苯基、3,4-二氯苯基、呋喃-2-基、噻吩-2-基、3-甲基-噻吩-2-基、異噁唑-5-基、2,5-二甲基吡唑-3-基、4-甲基-1,2,3-噻二唑-5-基、吡啶-2-基、2-吡唑基、苯并呋喃-2-基、苯并[c
][1,2,5]噁二唑-5-基、苯并噻吩-2-基、苯并噻唑-2-基或嗎啉-4-基;且各R1b
獨立地為氫、甲基或乙基。
在一實施例中,在式I中,R1
、R2
、R3
、R4
及R5
各獨立地為氫、鹵基或C1-6
烷基;R6
為氰基或硝基;R7
為C1-6
烷基;X為O或S;m為0、1或2;n為1或2;p為0、1、2、3或4;且RYa
為-C(O)R1a
、-C(O)NR1b
R1c
或-S(O)2
R1a
;其中R1a
及R1c
各獨立地為C1-6
烷基;視情況經一或兩個C1-6
烷基取代之C3-7
環烷基;或視情況經一或多個鹵基或C1-6
烷基取代之C6-14
芳基,其中該烷基進一步視情況經一個、兩個或三個鹵基取代;且R1b
為氫。
在另一實施例中,在式I中,R1
、R2
、R3
、R4
及R5
各獨立地為氫、鹵基或C1-6
烷基;R6
為氰基或硝基;R7
為C1-6
烷基;X為O或S;m為0、1或2;n為1或2;p為0、1、2、3或4;且RYa
為-
C(O)R1a
、-C(O)NR1b
R1c
或-S(O)2
R1a
;其中R1a
及R1c
各獨立地為C1-6
烷基;視情況經兩個甲基取代之C3-7
環烷基;或視情況經氟、氯、甲基、三氟甲基或乙基取代之C6-14
芳基;且R1b
為氫。
在另一實施例中,在式I中,R1
、R2
、R3
、R4
及R5
各獨立地為氫、氯或甲基;R6
為氰基或硝基;X為O或S;m為0、1或2;n為1或2;p為0;且RYa
為-C(O)R1a
、-C(O)NR1b
R1c
或-S(O)2
R1a
;其中R1a
及R1c
各獨立地為甲基、乙基、丙基(例如正丙基或異丙基)、丁基(例如正丁基、2-丁基、異丁基或第三丁基)、戊基(例如正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)、環丁基、環戊基、環己基、二甲基雙環[2.2.1]庚基(例如7,7-二甲基雙環[2.2.1]-庚基)、苯基、氟苯基(例如2-氟苯基、3-氟苯基或4-氟苯基)、氯苯基(例如2-氯苯基、3-氯苯基或4-氯苯基)、甲基苯基(例如2-甲基苯基、3-甲基苯基或4-甲基苯基)、三氟甲基苯基(例如2-三氟甲基苯基、3-三氟甲基苯基或4-三氟甲基苯基)或乙基苯基(例如2-乙基苯基、3-乙基苯基或4-乙基苯基);且R1b
為氫。
在又一實施例中,在式I中,R1
為氫;R2
為氯或甲基;R3
為氫;R4
為氯或甲基;R5
為氫;R6
為氰基;X為O或S;m為1;n為1;p為0;且RYa
為-C(O)R1a
、-C(O)NR1b
R1c
或-S(O)2
R1a
;其中R1a
及R1c
各獨立地為甲基、乙基、異丙基、異丁基、第三丁基、1,1-二甲基丙基、2,2-二甲基丙基、環丁基、環戊基、環己基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、2-氯苯基、4-氯苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、4-三氟甲基苯基或4-乙基苯基;且R1b
為氫。
式I中之基團R1
、R2
、R3
、R4
、R5
、R6
、R7
、R1a
、R1b
、R1c
、R1d
、RYa
、X、m、n及p進一步在本文所述之實施例中進行定義。本文關於該等基團所提供之實施例的所有組合均在本發明之範疇內。
在某些實施例中,R1
為氫、鹵基、氰基、硝基或胍。在某些實施例中,R1
為氫。在某些實施例中,R1
為鹵基。在某些實施例中,R1
為氟或氯。在某些實施例中,R1
為如本文所述視情況經取代之C1-6
烷基。在某些實施例中,R1
為視情況經一個、兩個或三個鹵基取代之C1-6
烷基。在某些實施例中,R1
為甲基、乙基、丙基(例如正丙基及異丙基)、丁基(例如正丁基、2-丁基、異丁基或第三丁基)或戊基(例如正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些實施例中,R1
為甲基。在某些實施例中,R1
為如本文所述視情況經取代之C1-6
烷氧基。在某些實施例中,R1
為視情況經一個、兩個或三個鹵基取代之C1-6
烷氧基。在某些實施例中,R1
為如本文所述視情況經取代之C2-6
烷硫基。在某些實施例中,R1
為視情況經一個、兩個或三個鹵基取代之C1-6
烷硫基。在某些實施例中,R1
為C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基,各如本文所述視情況經取代。在某些實施例中,R1
為-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(NR1a
)NR1b
R1c
、-OR1a
、-OC(O)R1a
、-OC(O)OR1a
、-OC(O)NR1b
R1c
、-OC(=NR1a
)NR1b
R1c
、-OS(O)R1a
、-OS(O)2
R1a
、-OS(O)NR1b
R1c
、-OS(O)2
NR1b
R1c
、-NR1b
R1c
、-NR1a
C(O)R1d
、-NR1a
C(O)OR1d
、-NR1a
C(O)NR1b
R1c
、-NR1a
C(=NR1d
)NR1b
R1c
、-NR1a
S(O)R1d
、-NR1a
S(O)2
R1d
、-NR1a
S(O)NR1b
R1c
、-NR1a
S(O)2
NR1
bR1c
、-SR1a
、-S(O)R1a
、-S(O)2
R1a
、-S(O)NR1b
R1c
或-S(O)2
NR1b
R1c
;其中R1a
、R1b
、R1c
及R1d
各如本文所定義。
在某些實施例中,R2
為氫、鹵基、氰基、硝基或胍。在某些實施例中,R2
為氫。在某些實施例中,R2
為鹵基。在某些實施例中,R2
為氟或氯。在某些實施例中,R2
為如本文所述視情況經取代之C1-6
烷基。在某些實施例中,R2
為視情況經一個、兩個或三個鹵基取代之C1-6
烷基。在某些實施例中,R2
為甲基、乙基、丙基(例如正丙基及異丙基)、丁基(例如正丁基、2-丁基、異丁基或第三丁基)或戊基(例如正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些實施例中,R2
為甲基。在某些實施例中,R2
為如本文所述視情況經取代之C1-6
烷氧基。在某些實施例中,R2
為視情況經一個、兩個或三個鹵基取代之C1-6
烷氧基。在某些實施例中,R2
為如本文所述視情況經取代之C2-6
烷硫基。在某些實施例中,R2
為視情況經一個、兩個或三個鹵基取代之C1-6
烷硫基。在某些實施例中,R2
為C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基,各如本文所述視情況經取代。在某些實施例中,R2
為-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(NR1a
)NR1b
R1c
、-OR1a
、-OC(O)R1a
、-OC(O)OR1a
、-OC(O)NR1b
R1c
、-OC(=NR1a
)NR1b
R1c
、-OS(O)R1a
、-OS(O)2
R1a
、-OS(O)NR1b
R1c
、-OS(O)2
NR1b
R1c
、-NR1b
R1c
、-NR1a
C(O)R1d
、-NR1a
C(O)OR1d
、-NR1a
C(O)NR1b
R1c
、-NR1a
C(=NR1d
)NR1b
R1c
、-NR1a
S(O)R1d
、-NR1a
S(O)2
R1d
、-NR1a
S(O)NR1b
R1c
、-NR1a
S(O)2
NR1b
R1c
、-SR1a
、-S(O)R1a
、-S(O)2
R1a
、-S(O)NR1b
R1c
或-S(O)2
NR1b
R1c
;其中R1a
、R1b
、R1c
及R1d
各如本文所定義。
在某些實施例中,R3
為氫、鹵基、氰基、硝基或胍。在某些實施例中,R3
為氫。在某些實施例中,R3
為鹵基。在某些實施例中,R3
為氟或氯。在某些實施例中,R3
為如本文所述視情況經取代之C1-6
烷基。在某些實施例中,R3
為視情況經一個、兩個或三個鹵基取代之C1-6
烷基。在某些實施例中,R3
為甲基、乙基、丙基(例如正丙基及異丙基)、丁基(例如正丁基、2。丁基、異丁基或第三丁基)或戊基(例如正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些實施例中,R3
為甲基。在某些實施例中,R3
為如本文所述視情況經取代之C1-6
烷氧基。在某些實施例中,R3
為視情況經一個、兩個或三個鹵基取代之C1-6
烷氧基。在某些實施例中,R3
為如本文所述視情況經取代之C2-6
烷硫基。在某些實施例中,R3
為視情況經一個、兩個或三個鹵基取代之C1-6
烷硫基。在某些實施例中,R3
為C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基,各如本文所述視情況經取代。在某些實施例中,R3
為-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(NR1a
)NR1b
R1c
、-OR1a
、-OC(O)R1a
、-OC(O)OR1a
、-OC(O)NR1b
R1c
、-OC(=NR1a
)NR1b
R1c
、-OS(O)R1a
、-OS(O)2
R1a
、-OS(O)NR1b
R1c
、-OS(O)2
NR1b
R1c
、-NR1b
R1c
、-NR1a
C(O)R1d
、-NR1a
C(O)OR1d
、-NR1a
C(O)NR1b
R1c
、-NR1a
C(=NR1d
)NR1b
R1c
、-NR1a
S(O)R1d
、-NR1a
S(O)2
R1d
、-NR1a
S(O)NR1b
R1c
、-NR1a
S(O)2
NR1b
R1c
、-SR1a
、-S(O)R1a
、-S(O)2
R1a
、-S(O)NR1b
R1c
或-S(O)2
NR1b
R1c
;其中R1a
、R1b
、R1c
及R1d
各如本文所定義。
在某些實施例中,R4
為氫、鹵基、氰基、硝基或胍。在某些實施例中,R4
為氫。在某些實施例中,R4
為鹵基。在某些實施例中,R4
為氟或氯。在某些實施例中,R4
為如本文所述視情況經取代之C1-6
烷基。在某些實施例中,R4
為視情況經一個、兩個或三個鹵基取代之C1-6
烷基。在某些實施例中,R4
為甲基、乙基、丙基(例如正丙基及異丙基)、丁基(例如正丁基、2-丁基、異丁基或第三丁基)或戊基(例如正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些實施例中,R4
為甲基。在某些實施例中,R4
為如本文所述視情況經取代之C1-6
烷氧基。在某些實施例中,R4
為視情況經一個、兩個或三個鹵基取代之C1-6
烷氧基。在某些實施例中,R4
為如本文所述視情況經取代之C2-6
烷硫基。在某些實施例中,R4
為視情況經一個、兩個或三個鹵基取代之C1-6
烷硫基。在某些實施例中,R4
為C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基,各如本文所述視情況經取代。在某些實施例中,R4
為-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(NR1a
)NR1b
R1c
、-OR1a
、-OC(O)R1a
、-OC(O)OR1a
、-OC(O)NR1b
R1c
、-OC(=NR1a
)NR1b
R1c
、-OS(O)R1a
、-OS(O)2
R1a
、-OS(O)NR1b
R1c
、-OS(O)2
NR1b
R1c
、-NR1b
R1c
、-NR1a
C(O)R1d
、-NR1a
C(O)OR1d
、-NR1a
C(O)NR1b
R1c
、-NR1a
C(=NR1d
)NR1b
R1c
、-NR1a
S(O)R1d
、-NR1a
S(O)2
R1d
、-NR1a
S(O)NR1b
R1c
、-NR1a
S(O)2
NR1b
R1c
、-SR1a
、-S(O)R1a
、-S(O)2
R1a
、-S(O)NR1b
R1c
或-S(O)2
NR1b
R1c
;其中R1a
、R1b
、R1c
及R1d
各如本文所定義。
在某些實施例中,R5
為氫、鹵基、氰基、硝基或胍。在某些實施例中,R5
為氫。在某些實施例中,R5
為鹵基。在某些實施例中,R5
為氟或氯。在某些實施例中,R5
為如本文所述視情況經取代之C1-6
烷基。在某些實施例中,R5
為視情況經一個、兩個或三個鹵基取代之C1-6
烷基。在某些實施例中,R5
為甲基、乙基、丙基(例如正丙基及異丙基)、丁基(例如正丁基、2-丁基、異丁基或第三丁基)或戊基(例如正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些實施例中,R5
為甲基。在某些實施例中,R5
為如本文所述視情況經取代之C1-6
烷氧基。在某些實施例中,R5
為視情況經一個、兩個或三個鹵基取代之C1-6
烷氧基。在某些實施例中,R5
為如本文所述視情況經取代之C2-6
烷硫基。在某些實施例中,R5
為視情況經一個、兩個或三個鹵基取代之C1-6
烷硫基。在某些實施例中,R5
為C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基,各如本文所述視情況經取代。在某些實施例中,R5
為-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(NR1a
)NR1b
R1c
、-OR1a
、-OC(O)R1a
、-OC(O)OR1a
、-OC(O)NR1b
R1c
、-OC(=NR1a
)NR1b
R1c
、-OS(O)R1a
、-OS(O)2
R1a
、-OS(O)NR1b
R1c
、-OS(O)2
NR1b
R1c
、-NR1b
R1c
、-NR1a
C(O)R1d
、-NR1a
C(O)OR1d
、-NR1a
C(O)NR1b
R1c
、-NR1a
C(=NR1d
)NR1b
R1c
、-NR1a
S(O)R1d
、-NR1a
S(O)2
R1d
、-NR1a
S(O)NR1b
R1c
、-NR1a
S(O)2
NR1b
R1c
、-SR1a
、-S(O)R1a
、-S(O)2
R1a
、-S(O)NR1b
R1c
或-S(O)2
NR1b
R1c
;其中R1a
、R1b
、R1c
及R1d
各如本文所定義。
在某些實施例中,R1
、R2
、R3
、R4
及R5
中之兩者為鹵基或如本文所述視情況經取代之C1-6
烷基。在某些實施例中,R1
、R2
、R3
、R4
及R5
中之兩者為鹵基或如本文所述視情況經取代之C1-6
烷基,且其餘三者為氫。在某些實施例中,R1
、R2
、R3
、R4
及R5
中之兩者為氯或甲基。在某些實施例中,R1
、R2
、R3
、R4
及R5
中之兩者為氯或甲基,且其餘三者為氫。在某些實施例中,R1
、R3
及R5
為氫,且R2
及R4
為鹵基或如本文所述視情況經取代之C1-6
烷基。在某些實施例中,R1
、R3
及R5
為氫,且R2
及R4
為氯或甲基。在某些實施例中,R1
、R3
及R5
為氫,且R2
及R4
為氯。在某些實施例中,R1
、R3
及R5
為氫,且R2
及R4
為甲基。在某些實施例中,R2
、R3
及R5
為氫,且R1
及R4
為鹵基或如本文所述視情況經取代之C1-6
烷基。在某些實施例中,R2
、R3
及R5
為氫,且R1
及R4
為氯或甲基。在某些實施例中,R2
、R3
及R5
為氫,且R1
及R4
為氯。在某些實施例中,R2
、R3
及R5
為氫,且R1
及R4
為甲基。
在某些實施例中,R6
為氫、鹵基、氰基、硝基或胍。在某些實施例中,R6
為氫。在某些實施例中,R6
為鹵基。在某些實施例中,R6
為氟或氯。在某些實施例中,R6
為氰基。在某些實施例中,R6
為硝基。在某些實施例中,R6
為如本文所述視情況經取代之C1-6
烷基。在某些實施例中,R6
為視情況經一個、兩個或三個鹵基取代之C1-6
烷基。在某些實施例中,R6
為甲基、乙基、丙基(例如正丙基及異丙基)、丁基(例如正丁基、2-丁基、異丁基或第三丁基)或戊基(例如正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些實施例中,R6
為甲基。在某些實施例中,R6
為如本文所述視情況經取代之C1-6
烷氧基。在某些實施例中,R6
為視情況經一個、兩個或三個鹵基取代之C1-6
烷氧基。在某些實施例中,R6
為如本文所述視情況經取代之C2-6
烷硫基。在某些實施例中,R6
為視情況經一個、兩個或三個鹵基取代之C1-6
烷硫基。在某些實施例中,R6
為C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基,各如本文所述視情況經取代。在某些實施例中,R6
為-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(NR1a
)NR1b
R1c
、-OR1a
、-OC(O)R1a
、-OC(O)OR1a
、-OC(O)NR1b
R1c
、-OC(=NR1a
)NR1b
R1c
、-OS(O)R1a
、-OS(O)2
R1a
、-OS(O)NR1b
R1c
、-OS(O)2
NR1b
R1c
、-NR1b
R1c
、-NR1a
C(O)R1d
、-NR1a
C(O)OR1d
、-NR1a
C(O)NR1b
R1c
、-NR1a
C(=NR1d
)NR1b
R1c
、-NR1a
S(O)R1d
、-NR1a
S(O)2
R1d
、-NR1a
S(O)NR1b
R1c
、-NR1a
S(O)2
NR1b
R1c
、-SR1a
、-S(O)R1a
、-S(O)2
R1a
、-S(O)NR1b
R1c
或-S(O)2
NR1b
R1c
;其中R1a
、R1b
、R1c
及R1d
各如本文所定義。
在某些實施例中,R7
為鹵基、氰基、硝基、側氧基或胍。在某些實施例中,R7
為鹵基。在某些實施例中,R7
為氟或氯。在某些實施例中,R7
為氰基。在某些實施例中,R7
為硝基。在某些實施例中,R7
為側氧基。在某些實施例中,R7
為如本文所述視情況經取代之C1-6
烷基。在某些實施例中,R7
為視情況經一個、兩個或三個鹵基取代之C1-6
烷基。在某些實施例中,R7
為甲基、乙基、丙基(例如正丙基及異丙基)、丁基(例如正丁基、2-丁基、異丁基或第三丁基)或戊基(例如正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些實施例中,R7
為甲基。在某些實施例中,R7
為如本文所述視情況經取代之C1-6
烷氧基。在某些實施例中,R7
為視情況經一個、兩個或三個鹵基取代之C1-6
烷氧基。在某些實施例中,R7
為如本文所述視情況經取代之C2-6
烷硫基。在某些實施例中,R7
為視情況經一個、兩個或三個鹵基取代之C1-6
烷硫基。在某些實施例中,R7
為C2-6
烯基、C2-6
炔基、C3-7
環烷基、C6-14
芳基、C7-15
芳烷基、雜芳基或雜環基,各如本文所述視情況經取代。在某些實施例中,R7
為-C(O)R1a
、-C(O)OR1a
、-C(O)NR1b
R1c
、-C(NR1a
)NR1b
R1c
、-OR1a
、-OC(O)R1a
、-OC(O)OR1a
、-OC(O)NR1b
R1c
、-OC(=NR1a
)NR1b
R1c
、-OS(O)R1a
、-OS(O)2
R1a
、-OS(O)NR1b
R1c
、-OS(O)2
NR1b
R1c
、-NR1b
R1c
、-NR1a
C(O)R1d
、-NR1a
C(O)OR1d
、-NR1a
C(O)NR1b
R1c
、-NR1a
C(=NR1d
)NR1b
R1c
、-NR1a
S(O)R1d
、-NR1a
S(O)2
R1d
、-NR1a
S(O)NR1b
R1c
、-NR1a
S(O)2
NR1b
R1c
、-SR1a
、-S(O)R1a
、-S(O)2
R1a
、-S(O)NR1b
R1c
或-S(O)2
NR1b
R1c
;其中R1a
、R1b
、R1c
及R1d
各如本文所定義。
在某些實施例中,X為O。在某些實施例中,X為S。
在某些實施例中,RYa
為-C(O)R1a
,其中R1a
如本文所定義。在某些實施例中,RYa
不為-C(O)H。在某些實施例中,RYa
為-C(O)OR1a
,其中R1a
如本文所定義。在某些實施例中,RYa
為-C(O)OR1a
,其中R1a
如本文所定義,限制條件為R1a
不為-第三丁基、9-茀基甲基或苯甲基。在某些實施例中,RYa
為-C(O)O-乙基。在某些實施例中,RYa
為-C(O)NR1b
R1c
,其中R1b
及R1c
各如本文所定義。在某些實施例中,RYa
為-C(S)NR1b
R1c
,其中R1b
及R1c
各如本文所定義。在某些實施例中,RYa
為-C(S)NR1a
C(O)NR1b
R1c
,其中R1a
、R1b
及R1c
各如本文所定義。在某些實施例中,RYa
為-C(NR1a
)NR1b
R1c
,其中R1a
、R1b
及R1c
各如本文所定義。在某些實施例中,RYa
為-C(NNO2
)NR1b
R1c
,其中R1b
及R1c
各如本文所定義。在某些實施例中,RYa
為-S(O)R1a
,其中R1a
如本文所定義。在某些實施例中,RYa
為-S(O)2
R1a
,其中R1a
如本文所定義。在某些實施例中,RYa
為-S(O)NR1b
R1c
,其中R1b
及R1c
各如本文所定義。在某些實施例中,RYa
為-S(O)2
NR1b
R1c
,其中R1a
及R1d
各如本文所定義。
在某些實施例中,m為0。在某些實施例中,m為1。在某些實施例中,m為2。在某些實施例中,m為3。
在某些實施例中,n為1。在某些實施例中,n為2。在某些實施例中,n為3。
在某些實施例中,m為1且n為1。在某些實施例中,m為1且n為2。
在某些實施例中,p為0。在某些實施例中,p為1。在某些實施例中,p為2。在某些實施例中,p為3。在某些實施例中,p為4。
在某些實施例中,R1a
為氫。在某些實施例中,R1a
為如本文所述視情況經取代之C1-6
烷基。在某些實施例中,R1a
為視情況經一個、兩個或三個取代基取代之C1-6
烷基,該或該等取代基各獨立地選自氰基、鹵基、C3-7
環烷基、C6-14
芳基、雜芳基、雜環基、-C(O)Ra
、-C(O)ORa
及-SRa
,其中該環烷基、芳基、雜芳基及雜環基各進一步視情況經一個、兩個或三個取代基取代,該或該等取代基各獨立地為鹵基或C1-6
烷基。在某些實施例中,R1a
為視情況經一或兩個取代基取代之C1-6
烷基,該或該等取代基各獨立地選自鹵基、氰基、硝基、C1-6
烷基、C3-7
環烷基、C6-14
芳基、雜芳基、雜環基、-ORa
、-SRa
及-C(O)Ra
,其中Ra
如本文所定義且該烷基、環烷基、芳基、雜芳基及雜環基各視情況進一步經一或兩個取代基取代,該或該等取代基各獨立地為鹵基或C1-6
烷基。在某些實施例中,R1a
為視情況經一或兩個取代基取代之C1-6
烷基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、乙醯基、丙醯基及乙氧羰基。在某些實施例中,R1a
為C1-6
烷基,視情況經一個選自氯、氰基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、丙醯基及乙氧羰基之取代基取代。在某些實施例中,R1a
為甲基、乙基、丙基(例如正丙基及異丙基)、丁基(例如正丁基、2-丁基、異丁基或第三丁基)或戊基(例如正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些實施例中,R1a
為甲基、乙基、異丙基、異丁基、第三丁基、1,1-二甲基丙基或2,2-二甲基丙基。在某些實施例中,R1a
為C1-6
烷基、甲基、乙基、丙基(例如正丙基或異丙基)、丁基(例如正丁基、2-丁基、異丁基或第三丁基)或戊基(例如正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基),各視情況經選自氯、氰基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、丙醯基及乙氧羰基之取代基取代。在某些實施例中,R1a
為甲基、乙基、丙基(例如正丙基或異丙基)、丁基(例如正丁基、2-丁基、異丁基或第三丁基)或戊基(例如正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)、氯乙基、氯丙基、氯丁基、乙氧羰基乙基、甲硫基丙基、氰基甲基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基甲基、苯甲基、氯苯甲基、呋喃基甲基、嗎啉基乙基或丙醯基乙基。在某些實施例中,R1a
為甲基、乙基、異丙基、異丁基、第三丁基、1,1-二甲基丙基、2,2-二甲基丙基、2-氯乙基、3-氯丙基、4-氯丁基、2-乙氧羰基乙基、3-甲硫基丙基、1-氰基甲基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基甲基、苯甲基、3-氯苯甲基、呋喃-2-基甲基、2-嗎啉-4-基乙基或2-丙醯基乙基。
在某些實施例中,R1a
為如本文所述視情況經取代之C2-6
烯基。在某些實施例中,R1a
為視情況經C6-14
芳基取代之C2-6
烯基。在某些實施例中,R1a
為視情況經一或兩個取代基取代之C2-6
烯基,該或該等取代基各獨立地選自鹵基、氰基、硝基、C1-6
烷基、C3-7
環烷基、C6-14
芳基、雜芳基、雜環基、-ORa
、-SRa
及-C(O)Ra
,其中Ra
如本文所定義且該烷基、環烷基、芳基、雜芳基及雜環基各視情況進一步經一或兩個取代基取代,該或該等取代基各獨立地為鹵基或C2-6
烯基。在某些實施例中,R1a
為視情況經一或兩個取代基取代之C2-6
烯基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、乙醯基、丙醯基及乙氧羰基。在某些實施例中,R1a
為視情況經C6-14
芳基取代之C2-6
烯基。在某些實施例中,R1a
為視情況經苯基取代之C2-6
烯基。在某些實施例中,R1a
為乙烯基或烯丙基,各視情況經苯基取代。在某些實施例中,R1a
為乙烯基、烯丙基或苯基乙烯基。在某些實施例中,R1a
為乙烯基、烯丙基或2-苯基乙烯基。
在某些實施例中,R1a
為如本文所述視情況經取代之C2-6
炔基。在某些實施例中,R1a
為如本文所述視情況經取代之C3-7
環烷基。在某些實施例中,R1a
為視情況經一或兩個C1-6
烷基取代之C3-7
環烷基。在某些實施例中,R1a
為視情況經一或兩個取代基取代之C3-7
環烷基,該或該等取代基各獨立地選自鹵基、氰基、硝基、C1-6
烷基、C3-7
環烷基、C6-14
芳基、雜芳基、雜環基、-ORa
、-SRa
及-C(O)Ra
,其中Ra
如本文所定義且該烷基、環烷基、芳基、雜芳基及雜環基各視情況進一步經一或兩個取代基取代,該或該等取代基各獨立地為鹵基或C1-6
烷基。在某些實施例中,R1a
為視情況經一或兩個取代基取代之C3-7
環烷基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、乙醯基、丙醯基及乙氧羰基。在某些實施例中,R1a
為視情況經一或兩個C1-6
烷基取代之C3-7
環烷基。在某些實施例中,R1a
為視情況經兩個甲基取代之C3-7
環烷基。在某些實施例中,R1a
為環丁基、環戊基、環己基或二甲基雙環-[2.2.1]庚基(例如7,7-二甲基雙環[2.2.1]-庚基)。在某些實施例中,R1a
為環丁基、環戊基或環己基。在某些實施例中,R1a
為環丁基、環戊基、環己基或(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基。
在某些實施例中,R1a
為如本文所述視情況經取代之C6-14
芳基。在某些實施例中,R1a
為視情況經一個、兩個或三個取代基取代之C6-14
芳基,該或該等取代基各獨立地選自鹵基、硝基、氰基、-ORa
、-C(O)Ra
及C1-6
烷基,其中該烷基進一步視情況經一個、兩個或三個鹵基取代。在某些實施例中,R1a
為視情況經一或兩個取代基取代之C6-14
芳基,該或該等取代基各獨立地選自鹵基、氰基、硝基、C1-6
烷基、C3-7
環烷基、C6-14
芳基、雜芳基、雜環基、-ORa
、-SRa
及-C(O)Ra
,其中Ra
如本文所定義且該烷基、環烷基、芳基、雜芳基及雜環基各視情況進一步經一或兩個取代基取代,該或該等取代基各獨立地為鹵基或C1-6
烷基。在某些實施例中,R1a
為視情況經一或兩個取代基取代之C6-14
芳基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、乙醯基、丙醯基及乙氧羰基。在某些實施例中,R1a
為視情況經一或兩個取代基取代之C6-14
芳基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基及乙醯基。在某些實施例中,R1a
為視情況經一或兩個取代基取代之苯基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基及乙醯基。在某些實施例中,R1a
為視情況經一或多個鹵基或C1-6
烷基取代之C6-14
芳基,其中該烷基視情況經一個、兩個或三個鹵基取代。在某些實施例中,R1a
為視情況經氟、氯、甲基、三氟甲基或乙基取代之C6-14
芳基。在某些實施例中,R1a
為苯基、氟苯基(例如2-氟苯基、3-氟苯基或4-氟苯基)、氯苯基(例如2-氯苯基、3-氯苯基或4-氯苯基)、甲基苯基(例如2-甲基苯基、3-甲基苯基或4-甲基苯基)、三氟甲基苯基(例如2-三氟甲基苯基、3-三氟甲基苯基或4-三氟甲基苯基)或乙基苯基(例如2-乙基苯基、3-乙基苯基或4-乙基苯基)。在某些實施例中,R1a
為苯基、3-氟苯基、3-甲基苯基、4-氯苯基、4-甲基苯基、4-三氟甲基苯基或4-乙基苯基。在某些實施例中,R1a
為苯基、氯苯基(例如2-氯苯基、3-氯苯基或4-氯苯基)、氟苯基(例如2-氟苯基、3-氟苯基或4-氟苯基)、氰基苯基(例如2-氰基苯基、3-氰基苯基或4-氰基苯基)、硝基苯基(例如2-硝基苯基、3-硝基苯基或4-硝基苯基)、甲基苯基(例如2-甲基苯基、3-甲基苯基或4-甲基苯基)、三氟甲基苯基(例如2-三氟甲基苯基、3-三氟甲基苯基或4-三氟甲基苯基)、乙基苯基(例如2-乙基苯基、3-乙基苯基或4-乙基苯基)、甲氧基苯基(例如2-甲氧基苯基、3-甲氧基苯基或4-甲氧基苯基)、乙醯基苯基(例如2-乙醯基苯基、3-乙醯基苯基或4-乙醯基苯基)、二氯苯基(例如2,3-二氯苯基、2,4-二氯苯基、2,5-二氯苯基、2,6-二氯苯基、3,4-二氯苯基或3,5-二氯苯基)。在某些實施例中,R1a
為苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-氟苯基、3-氟苯基、4-氟苯基、4-氰基苯基、4-硝基苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、4-三氟甲基苯基、4-乙基苯基、4-甲氧基苯基、3-乙醯基苯基或3,4-二氯苯基。
在某些實施例中,R1a
為如本文所述視情況經取代之雜芳基。在某些實施例中,R1a
為視情況經一個、兩個或三個取代基取代之雜芳基,該或該等取代基各獨立地為鹵基或C1-6
烷基。在某些實施例中,R1a
為視情況經一或兩個取代基取代之雜芳基,該或該等取代基各獨立地選自鹵基、氰基、硝基、C1-6
烷基、C3-7
環烷基、C6-14
芳基、雜芳基、雜環基、-ORa
、-SRa
及-C(O)Ra
,其中Ra
如本文所定義且該烷基、環烷基、芳基、雜芳基及雜環基各視情況進一步經一或兩個取代基取代,該或該等取代基各獨立地為鹵基或C1-6
烷基。在某些實施例中,R1a
為視情況經一或兩個取代基取代之雜芳基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、乙醯基、丙醯基及乙氧羰基。在某些實施例中,R1a
為視情況經一或兩個甲基取代之雜芳基。在某些實施例中,R1a
為呋喃基、噻吩基、異噁唑基、吡唑基、1,2,3-噻二唑基、吡啶基、吡唑基、苯并呋喃基、苯并[c
][1,2,5]噁二唑基、苯并噻吩基或苯并噻唑基,各視情況經一或兩個甲基取代。在某些實施例中,R1a
為呋喃基(例如呋喃-2-基或呋喃-3-基)、噻吩基(例如噻吩-2-基或噻吩-3-基)、甲基-噻吩基、異噁唑基、二甲基吡唑基、甲基-1,2,3-噻二唑基、吡啶基(例如吡啶-2-基、吡啶-3-基或吡啶-4-基)、吡唑基(例如2-吡唑基或3-吡唑基)、苯并呋喃基、苯并[c][1,2,5]噁二唑基、苯并噻吩基或苯并噻唑基。在某些實施例中,R1a
為呋喃-2-基、噻吩-2-基、3-甲基-噻吩-2-基、異噁唑-5-基、2,5-二甲基吡唑-3-基、4-甲基-1,2,3-噻二唑-5-基、吡啶-2-基、2-吡唑基、苯并呋喃-2-基、苯并[c
][1,2,5]噁二唑-5-基、苯并噻吩-2-基或苯并噻唑-2-基。
在某些實施例中,R1a
為雜環基。在某些實施例中,R1a
為視情況經一或兩個取代基取代之雜環基,該或該等取代基各獨立地選自鹵基、氰基、硝基、C1-6
烷基、C3-7
環烷基、C6-14
芳基、雜芳基、雜環基、-ORa
、-SRa
及-C(O)Ra
,其中Ra
如本文所定義且該烷基、環烷基、芳基、雜芳基及雜環基各視情況進一步經一或兩個取代基取代,該或該等取代基各獨立地為鹵基或C1-6
烷基。在某些實施例中,R1a
為視情況經一或兩個取代基取代之雜環基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、乙醯基、丙醯基及乙氧羰基。在某些實施例中,R1a
為嗎啉基。在某些實施例中,R1a
為嗎啉-4-基。
在某些實施例中,R1b
為氫。在某些實施例中,R1b
為如本文所述視情況經取代之C1-6
烷基。在某些實施例中,R1b
為甲基或乙基。在某些實施例中,R1b
為如本文所述視情況經取代之C2-6
烯基。在某些實施例中,R1b
為如本文所述視情況經取代之C2-6
炔基。在某些實施例中,R1b
為如本文所述視情況經取代之C3-7
環烷基。在某些實施例中,R1b
為如本文所述視情況經取代之C6-14
芳基。在某些實施例中,R1b
為如本文所述視情況經取代之雜芳基。在某些實施例中,R1b
為如本文所述視情況經取代之雜環基。
在某些實施例中,R1c
為氫。在某些實施例中,R1c
為如本文所述視情況經取代之C1-6
烷基。在某些實施例中,R1c
為視情況經一個、兩個或三個取代基取代之C1-6
烷基,該或該等取代基各獨立地選自氰基、鹵基、C3-7
環烷基、C6-14
芳基、雜芳基、雜環基、-C(O)Ra
、-C(O)ORa
及-SRa
,其中該環烷基、芳基、雜芳基及雜環基各進一步視情況經一個、兩個或三個取代基取代,該或該等取代基各獨立地為鹵基或C1-6
烷基。在某些實施例中,R1c
為視情況經一或兩個取代基取代之C1-6
烷基,該或該等取代基各獨立地選自鹵基、氰基、硝基、C1-6
烷基、C3-7
環烷基、C6-14
芳基、雜芳基、雜環基、-ORa
、-SRa
及-C(O)Ra
,其中Ra
如本文所定義且該烷基、環烷基、芳基、雜芳基及雜環基各視情況進一步經一或兩個取代基取代,該或該等取代基各獨立地為鹵基或C1-6
烷基。在某些實施例中,R1c
為視情況經一或兩個取代基取代之C1-6
烷基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、乙醯基、丙醯基及乙氧羰基。在某些實施例中,R1c
為C1-6
烷基,視情況經一個選自氯、氰基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、丙醯基及乙氧羰基之取代基取代。在某些實施例中,R1c
為甲基、乙基、丙基(例如正丙基及異丙基)、丁基(例如正丁基、2-丁基、異丁基或第三丁基)或戊基(例如正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)。在某些實施例中,R1c
為甲基、乙基、異丙基、異丁基、第三丁基、1,1-二甲基丙基或2,2-二甲基丙基。在某些實施例中,R1c
為C1-6
烷基、甲基、乙基、丙基(例如正丙基或異丙基)、丁基(例如正丁基、2-丁基、異丁基或第三丁基)或戊基(例如正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基),各視情況經選自氯、氰基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、丙醯基及乙氧羰基之取代基取代。在某些實施例中,R1c
為甲基、乙基、丙基(例如正丙基或異丙基)、丁基(例如正丁基、2-丁基、異丁基或第三丁基)或戊基(例如正戊基、2-戊基、3-戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基或2,2-二甲基丙基)、氯乙基、氯丙基、氯丁基、乙氧羰基乙基、甲硫基丙基、氰基甲基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基甲基、苯甲基、氯苯甲基、呋喃基甲基、嗎啉基乙基或丙醯基乙基。在某些實施例中,R1c
為甲基、乙基、異丙基、異丁基、第三丁基、1,1-二甲基丙基、2,2-二甲基丙基、2-氯乙基、3-氯丙基、4-氯丁基、2-乙氧羰基乙基、3-甲硫基丙基、1-氰基甲基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基甲基、苯甲基、3-氯苯甲基、呋喃-2-基甲基、2-嗎啉-4-基乙基或2-丙醯基乙基。
在某些實施例中,R1c
為如本文所述視情況經取代之C2-6
烯基。在某些實施例中,R1c
為視情況經C6-14
芳基取代之C2-6
烯基。在某些實施例中,R1c
為視情況經一或兩個取代基取代之C2-6
烯基,該或該等取代基各獨立地選自鹵基、氰基、硝基、C1-6
烷基、C3-7
環烷基、C6-14
芳基、雜芳基、雜環基、-ORa
、-SRa
及-C(O)Ra
,其中Ra
如本文所定義且該烷基、環烷基、芳基、雜芳基及雜環基各視情況進一步經一或兩個取代基取代,該或該等取代基各獨立地為鹵基或C1-6
烷基。在某些實施例中,R1c
為視情況經一或兩個取代基取代之C2-6
烯基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、乙醯基、丙醯基及乙氧羰基。在某些實施例中,R1c
為視情況經C6-14
芳基取代之C2-6
烯基。在某些實施例中,R1c
為視情況經苯基取代之C2-6
烯基。在某些實施例中,R1c
為乙烯基或烯丙基,各視情況經苯基取代。在某些實施例中,R1c
為乙烯基、烯丙基或苯基乙烯基。在某些實施例中,R1c
為乙烯基、烯丙基或2-苯基乙烯基。
在某些實施例中,R1c
為如本文所述視情況經取代之C2-6
炔基。在某些實施例中,R1c
為如本文所述視情況經取代之C3-7
環烷基。在某些實施例中,R1c
為視情況經一或兩個C1-6
烷基取代之C3-7
環烷基。在某些實施例中,R1c
為視情況經一或兩個取代基取代之C3-7
環烷基,該或該等取代基各獨立地選自鹵基、氰基、硝基、C1-6
烷基、C3-7
環烷基、C6-14
芳基、雜芳基、雜環基、-ORa
、-SRa
及-C(O)Ra
,其中Ra
如本文所定義且該烷基、環烷基、芳基、雜芳基及雜環基各視情況進一步經一或兩個取代基取代,該或該等取代基各獨立地為鹵基或C1-6
烷基。在某些實施例中,R1c
為視情況經一或兩個取代基取代之C3-7
環烷基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、乙醯基、丙醯基及乙氧羰基。在某些實施例中,R1c
為視情況經一或兩個C1-6
烷基取代之C3-7
環烷基。在某些實施例中,R1c
為視情況經兩個甲基取代之C3-7
環烷基。在某些實施例中,R1c
為環丁基、環戊基、環己基或二甲基雙環-[2.2.1]庚基(例如7,7-二甲基雙環[2.2.1]-庚基)。在某些實施例中,R1c
為環丁基、環戊基或環己基。在某些實施例中,R1c
為環丁基、環戊基、環己基或(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基。
在某些實施例中,R1c
為如本文所述視情況經取代之C6-14
芳基。在某些實施例中,R1c
為視情況經一個、兩個或三個取代基取代之C6-14
芳基,該或該等取代基各獨立地選自鹵基、硝基、氰基、-ORa
、-C(O)Ra
及C1-6
烷基,其中該烷基進一步視情況經一個、兩個或三個鹵基取代。在某些實施例中,R1c
為視情況經一或兩個取代基取代之C6-14
芳基,該或該等取代基各獨立地選自鹵基、氰基、硝基、C1-6
烷基、C3-7
環烷基、C6-14
芳基、雜芳基、雜環基、-ORa
、-SRa
及-C(O)Ra
,其中Ra
如本文所定義且該烷基、環烷基、芳基、雜芳基及雜環基各視情況進一步經一或兩個取代基取代,該或該等取代基各獨立地為鹵基或C1-6
烷基。在某些實施例中,R1c
為視情況經一或兩個取代基取代之C6-14
芳基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、乙醯基、丙醯基及乙氧羰基。在某些實施例中,R1c
為視情況經一或兩個取代基取代之C6-14
芳基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基及乙醯基。在某些實施例中,R1c
為視情況經一或兩個取代基取代之苯基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基及乙醯基。在某些實施例中,R1c
為視情況經一或多個鹵基或C1-6
烷基取代之C6-14
芳基,其中該烷基視情況經一個、兩個或三個鹵基取代。在某些實施例中,R1c
為視情況經氟、氯、甲基、三氟甲基或乙基取代之C6-14
芳基。在某些實施例中,R1c
為苯基、氟苯基(例如2-氟苯基、3-氟苯基或4-氟苯基)、氯苯基(例如2-氯苯基、3-氯苯基或4-氯苯基)、甲基苯基(例如2-甲基苯基、3-甲基苯基或4-甲基苯基)、三氟甲基苯基(例如2-三氟甲基苯基、3-三氟甲基苯基或4-三氟甲基苯基)或乙基苯基(例如2-乙基苯基、3-乙基苯基或4-乙基苯基)。在某些實施例中,R1c
為苯基、3-氟苯基、3-甲基苯基、4-氯苯基、4-甲基苯基、4-三氟甲基苯基或4-乙基苯基。在某些實施例中,R1c
為苯基、氯苯基(例如2-氯苯基、3-氯苯基或4-氯苯基)、氟苯基(例如2-氟苯基、3-氟苯基或4-氟苯基)、氰基苯基(例如2-氰基苯基、3-氰基苯基或4-氰基苯基)、硝基苯基(例如2-硝基苯基、3-硝基苯基或4-硝基苯基)、甲基苯基(例如2-甲基苯基、3-甲基苯基或4-甲基苯基)、三氟甲基苯基(例如2-三氟甲基苯基、3-三氟甲基苯基或4-三氟甲基苯基)、乙基苯基(例如2-乙基苯基、3-乙基苯基或4-乙基苯基)、甲氧基苯基(例如2-甲氧基苯基、3-甲氧基苯基或4-甲氧基苯基)、乙醯基苯基(例如2-乙醯基苯基、3-乙醯基苯基或4-乙醯基苯基)、二氯苯基(例如2,3-二氯苯基、2,4-二氯苯基、2,5-二氯苯基、2,6-二氯苯基、3,4-二氯苯基或3,5-二氯苯基)。在某些實施例中,R1c
為苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-氟苯基、3-氟苯基、4-氟苯基、4-氰基苯基、4-硝基苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、4-三氟甲基苯基、4-乙基苯基、4-甲氧基苯基、3-乙醯基苯基或3,4-二氯苯基。
在某些實施例中,R1c
為如本文所述視情況經取代之雜芳基。在某些實施例中,R1c
為視情況經一個、兩個或三個取代基取代之雜芳基,該或該等取代基各獨立地為鹵基或C1-6
烷基。在某些實施例中,R1c
為視情況經一或兩個取代基取代之雜芳基,該或該等取代基各獨立地選自鹵基、氰基、硝基、C1-6
烷基、C3-7
環烷基、C6-14
芳基、雜芳基、雜環基、-ORa
、-SRa
及-C(O)Ra
,其中Ra
如本文所定義且該烷基、環烷基、芳基、雜芳基及雜環基各視情況進一步經一或兩個取代基取代,該或該等取代基各獨立地為鹵基或C1-6
烷基。在某些實施例中,R1c
為視情況經一或兩個取代基取代之雜芳基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、乙醯基、丙醯基及乙氧羰基。在某些實施例中,R1c
為視情況經一或兩個甲基取代之雜芳基。在某些實施例中,R1c
為呋喃基、噻吩基、異噁唑基、吡唑基、1,2,3-噻二唑基、吡啶基、吡唑基、苯并呋喃基、苯并[c
][1,2,5]噁二唑基、苯并噻吩基或苯并噻唑基,各視情況經一或兩個甲基取代。在某些實施例中,R1c
為呋喃基(例如呋喃-2-基或呋喃-3-基)、噻吩基(例如噻吩-2-基或噻吩-3-基)、甲基-噻吩基、異噁唑基、二甲基吡唑基、甲基-1,2,3-噻二唑基、吡啶基(例如吡啶-2-基、吡啶-3-基或吡啶-4-基)、吡唑基(例如2-吡唑基或3-吡唑基)、苯并呋喃基、苯并[c
][1,2,5]噁二唑基、苯并噻吩基或苯并噻唑基。在某些實施例中,R1c
為呋喃-2-基、噻吩-2-基、3-甲基-噻吩-2-基、異噁唑-5-基、2,5-二甲基吡唑-3-基、4-甲基-1,2,3-噻二唑-5-基、吡啶-2-基、2-吡唑基、苯并呋喃-2-基、苯并[c
][1,2,5]噁二唑-5-基、苯并噻吩-2-基或苯并噻唑-2-基。
在某些實施例中,R1c
為雜環基。在某些實施例中,R1c
為視情況經一或兩個取代基取代之雜環基,該或該等取代基各獨立地選自鹵基、氰基、硝基、C1-6
烷基、C3-7
環烷基、C6-14
芳基、雜芳基、雜環基、-ORa
、-SRa
及-C(O)Ra
,其中Ra
如本文所定義且該烷基、環烷基、芳基、雜芳基及雜環基各視情況進一步經一或兩個取代基取代,該或該等取代基各獨立地為鹵基或C1-6
烷基。在某些實施例中,R1c
為視情況經一或兩個取代基取代之雜環基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S
,2S
,4R
)-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、乙醯基、丙醯基及乙氧羰基。在某些實施例中,R1c
為嗎啉基。在某些實施例中,R1c
為嗎啉-4-基。
在某些實施例中,R1b
及R1c
連同其所連接之N原子一起獨立地形成如本文所述視情況經取代之雜芳基。在某些實施例中,R1b
及R1c
連同其所連接之N原子一起獨立地形成如本文所述視情況經取代之雜環基。
在某些實施例中,R1d
為氫。在某些實施例中,R1d
為如本文所述視情況經取代之C1-6
烷基。在某些實施例中,R1d
為如本文所述視情況經取代之C2-6
烯基。在某些實施例中,R1d
為如本文所述視情況經取代之C2-6
炔基。在某些實施例中,R1d
為如本文所述視情況經取代之C3-7
環烷基。在某些實施例中,R1d
為如本文所述視情況經取代之C6-14
芳基。在某些實施例中,R1d
為如本文所述視情況經取代之雜芳基。在某些實施例中,R1d
為如本文所述視情況經取代之雜環基。
在一實施例中,本文提供一種選自由以下組成之群的化合物:
及
及其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體及兩種或兩種以上互變異構體之混合物;及其醫藥學上可接受之鹽、溶劑合物、水合物及前藥。
除非規定特定立體化學,否則本文所提供之化合物意欲涵蓋所有可能的立體異構體。雖然本文所提供之化合物含有烯基或伸烯基,但化合物可以幾何順式/反式(或Z/E)異構體中之一者或混合物形式存在。雖然結構異構體可互相轉化,但化合物可以單一互變異構體或互變異構體之混合物形式存在。在含有例如亞胺基,酮基或肟基之化合物中可採取質子互變異構之形式;或在含有芳族部分之化合物中可採取所謂價數互變異構之形式。從而單一化合物可展現一種以上類型之異構現象。
本文所提供之化合物可為對映異構純的,諸如單一對映異構體或單一非對映異構體;或為立體異構混合物,諸如對映異構體之混合物,例如兩種對映異構體之外消旋混合物,或兩種或兩種以上非對映異構體之混合物。因此,熟習此項技術者將認識到,對於在活體內經歷差向異構化之化合物,投與呈(R
)形式之化合物與投與呈(S
)形式之化合物等效。製備/分離個別對映異構體之習知技術包括由適合光學純前驅體合成、由非對掌性起始物質不對稱合成、或拆分對映異構混合物,例如對掌性層析、再結晶、拆分、非對映異構鹽形成或衍生為非對映異構加合物隨後分離。
當本文所提供之化合物含有酸性或鹼性部分時,其亦可以醫藥學上可接受之鹽形式提供(參見Berge等人,J. Pharm. Sci. 1977
,66
),1-19;及「Handbook of Pharmaceutical Salts,Properties,and Use,」Stahl及Wermuth編;Wiley-VCH and VHCA,Zurich,2002)。
適用於製備醫藥學上可接受之鹽的酸包括(但不限於)乙酸、2,2-二氯乙酸、醯化胺基酸、己二酸、海藻酸、抗壞血酸、L-天冬胺酸、苯磺酸、苯甲酸、4-乙醯胺基苯甲酸、硼酸、(+)-樟腦酸、樟腦磺酸、(+)-(1S
)-樟腦-10-磺酸、癸酸、己酸、辛酸、肉桂酸、檸檬酸、環己胺磺酸、環己烷胺磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羥基-乙烷磺酸、甲酸、反丁烯二酸、半乳糖二酸、龍膽酸、葡糖庚酸、D-葡萄糖酸、D-葡糖醛酸、L-麩胺酸、α-酮戊二酸、乙醇酸、馬尿酸、氫溴酸、鹽酸、氫碘酸、(+)-L-乳酸、(±)-DL-乳酸、乳糖酸、月桂酸、順丁烯二酸、(-)-L-蘋果酸、丙二酸、(±)-DL-杏仁酸、甲烷磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羥基-2-萘甲酸、菸鹼酸、硝酸、油酸、乳清酸、乙二酸、棕櫚酸、雙羥萘酸、過氯酸、磷酸、L-焦麩胺酸、葡萄糖二酸、水楊酸、4-胺基-水楊酸、癸二酸、硬脂酸、丁二酸、硫酸、鞣酸、(+)-L-酒石酸、硫氰酸、對甲苯磺酸、十一碳烯酸及戊酸。
在一實施例中,本文所提供之化合物為鹽酸鹽。
適用於製備醫藥學上可接受之鹽的鹼包括(但不限於)無機鹼,諸如氫氧化鎂、氫氧化鈣、氫氧化鉀、氫氧化鋅或氫氧化鈉;及有機鹼,諸如一級、二級、三級及四級脂族及芳族胺,包括L-精胺酸、苄苯乙胺(benethamine)、苄星青黴素(benzathine)、膽鹼、地阿諾(deanol)、二乙醇胺、二乙胺、二甲胺、二丙胺、二異丙胺、2-(二乙基胺基)-乙醇、乙醇胺、乙胺、乙二胺、異丙胺、N
-甲基-葡糖胺、海卓胺(hydrabamine)、1H
-咪唑、L-離胺酸、嗎啉、4-(2-羥基乙基)-嗎啉、甲胺、哌啶、哌嗪、丙胺、吡咯啶、1-(2-羥基乙基)-吡咯啶、吡啶、啶、喹啉、異喹啉、二級胺、三乙醇胺、三甲胺、三乙胺、N-甲基-D-葡糖胺、2-胺基-2-(羥基甲基)-1,3-丙二醇及緩血酸胺。
本文所提供之化合物亦可以前藥形式提供,該前藥為化合物(例如式I化合物)之功能衍生物且在活體內容易轉化為母體化合物。前藥通常適用,因為在一些情形下,其可比母體化合物更易投與。其可例如藉由經口投與而可供生物利用,而母體化合物卻並非如此。與母體化合物相比,前藥在醫藥組合物中亦可具有提高之溶解度。前藥可藉由包括酶促方法及代謝水解之各種機制轉化為母藥。參見Harper,Progressin Drug Research 1962
,4
,221-294;Morozowich等人,「Design of Biopharmaceutical Properties through Prodrugs and Analogs,」Roche編,APHA Acad. Pharm. Sci. 1977;「Bioreversible Carriers in Drug in Drug Design,Theory and Application,」Roche編,APHA Acad. Pharm. Sci. 1987;「Design of Prodrugs,」Bundgaard,Elsevier,1985;Wang等人,Curr. Pharm. Design 1999
,5
,265-287;Pauletti等人,Adv. Drug. Delivery Rev . 1997
,27
,235-256;Mizen等人,Pharm. Biotech. 1998
,11
,345-365;Gaignault等人,Pract. Med. Chem. 1996
,671-696;Asgharnejad、「Transport Processes in Pharmaceutical Systems,」Amidon等人編,Marcell Dekker,185-218,2000;Balant等人,Eur. J. Drug Metab. Pharmacokinet. 1990
,15
,143-53;Balimane及Sinko,Adv. Drug Delivery Rev. 1999
,39
,183-209;Browne,Clin. Neuropharmacol. 1997
,20,1-12;Bundgaard,Arch. Pharm. Chem. 1979
,86
,1-39;Bundgaard,Controlled Drug Delivery 1987
,17
,179-96;Bundgaard,Adv. Drug Delivery Rev. 1992
,8
,1-38;Fleisher等人,Adv. Drug Delivery Rev. 1996
,19
,115-130;Fleisher等人,Methods Enzymol. 1985
,112
,360-381;Farquhar等人,J. Pharm. Sci. 1983
,72
,324-325;Freeman等人,J. Chem. Soc.
,Chem. Commun. 1991
,875-877;Friis及Bundgaard,Eur. J. Pharm. Sci. 1996
,4
,49-59;Gangwar等人,Des. Biopharm. Prop. Prodrugs Analogs
,1977
,409-421;Nathwani及Wood,Drugs 1993
,45
,866-94;Sinhababu及Thakker,Adv. Drug Delivery Rev. 1996
,19
,241-273;Stella等人,Drugs 1985
,29
,455-73;Tan等人,Adv. Drug Delivery Rev. 1999
,39
,117-151;Taylor,Adv. Drug Delivery Rev. 1996
,19
,131-148;Valentino及Borchardt,Drug Discovery Today 1997
,2
,148-155;Wiebe及Knaus,Adv. Drug Delivery Rev. 1999
,39
,63-80;及Waller等人,Br. J. Clin. Pharmac. 1989
,28
,497-507。
合成方法
本文所提供之化合物可藉由熟習此項技術者已知之任何方法來製備、分離或獲得。舉例而言,可如流程1中所示製備式I化合物,其中P1
為氫或胺基保護基,例如Boc、Cbz或Fmoc;且X1
為離去基,例如氯、溴、碘、咪唑或甲酸酯。
化合物1
經由親核性芳族取代反應與化合物2
反應,形成化合物3
,同時釋放鹽酸鹽。用還原劑(例如亞硫酸氫鈉或氯化錫(II))使化合物3
之硝基還原為胺基,形成苯胺4
,該苯胺4
隨後經由山德邁爾反應(Sandmeyer reaction)轉化為磺醯氯5
。接著使化合物5
與胺6
偶合,其中在一些實施例中,胺基保護基P1
為視情況存在的。移除保護基P1
,產生化合物7
,使該化合物7
與RYa
X1
反應,形成式I化合物。
醫藥組合物
本文提供醫藥組合物,其包含本文所提供之化合物作為活性成分,例如式I化合物,包括其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥;以及醫藥學上可接受之媒劑、載劑、稀釋劑或賦形劑或其混合物。
本文所提供之化合物可單獨投與,或與一或多種本文所提供之其他化合物組合投與。包含本文所提供之化合物(例如式I化合物)的醫藥組合物可調配成用於經口、非經腸及表面投與之各種劑型。醫藥組合物亦可調配成改良釋放劑型,包括延遲、延長、長期、持續、脈動、控制、加速、快速、靶向、經規劃釋放;及胃滯留劑型。此等劑型可根據熟習此項技術者已知之習知方法及技術來製備(參見Remington: The Science and Practice of Pharmacy
、同上;Modified-Release Drug Delivery Technology
,第2版,Rathbone等人編,Marcel Dekker,Inc.: New York,NY,2008)。
在一實施例中,醫藥組合物係以用於經口投藥之劑型提供,其包含本文所提供之化合物,例如式I化合物,包括其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥;及一或多種醫藥學上可接受之賦形劑或載劑。
在另一實施例中,醫藥組合物係以用於非經腸投藥之劑型提供,其包含本文所提供之化合物,例如式I化合物,包括其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥;及一或多種醫藥學上可接受之賦形劑或載劑。
在另一實施例中,醫藥組合物係以用於表面投藥之劑型提供,其包含本文所提供之化合物,例如式I化合物,包括其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥;及一或多種醫藥學上可接受之賦形劑或載劑。
本文所提供之醫藥組合物可以單位劑型或多次劑型提供。如本文中所使用,單位劑型係指適於投與人類及動物個體且如此項技術中已知個別包裝之實體不連續單元。各單位劑量含有足以產生所需治療作用之預定量之活性成分,以及所需醫藥載劑或賦形劑。單位劑型之實例包括安瓿、注射器及個別包裝之錠劑及膠囊。單位劑型可呈單位劑型之部分或多個單位劑型投與。多次劑型為包裝於單個容器中欲以分開之單位劑型投與的複數個相同單位劑型。多次劑型之實例包括小瓶、錠劑或膠囊瓶,或品脫(pint)或加侖(gallon)瓶。
本文所提供之醫藥組合物可投與一次,或以一定時間間隔投與多次。應瞭解精確劑量及治療持續時間可隨所治療之患者的年齡、體重及狀況而變化,且可使用已知測試方案憑經驗確定或藉由自活體內或活體外測試或診斷資料推斷來確定。應進一步瞭解,對於任何特定個體,特定給藥方案應根據個體需要及投與調配物或指導投與調配物之人員的專業判斷隨時間調節。
A. 經口投藥
本文所提供之用於經口投藥之醫藥組合物可以用於經口投藥之固體、半固體或液體劑型提供。如本文中所使用,經口投藥亦包括經頰、經舌及舌下投藥。適合之口服劑型包括(但不限於)錠劑、速熔劑、咀嚼錠劑、膠囊、丸劑、片條(strip)、糖衣錠、口含錠、片劑、扁膠劑、丸粒、藥用口嚼錠、整裝散劑、發泡或非發泡散劑或顆粒、口腔噴霧(oral mist)、溶液、乳液、懸浮液、粉片、噴灑劑、酏劑及糖漿。除活性成分外,醫藥組合物亦可含有一或多種醫藥學上可接受之載劑或賦形劑,包括(但不限於)黏合劑、填充劑、稀釋劑、崩解劑、濕潤劑、潤滑劑、滑動劑、著色劑、染料遷移抑制劑、甜味劑、調味劑、乳化劑、懸浮劑及分散劑、防腐劑、溶劑、非水性液體、有機酸及二氧化碳源。
黏合劑或粒化劑賦予錠劑黏結性以確保在壓縮後錠劑保持完整。適合之黏合劑或粒化劑包括(但不限於)澱粉,諸如玉米澱粉、馬鈴薯澱粉及預膠凝化澱粉(例如STARCH 1500);明膠;糖,諸如蔗糖、葡萄糖、右旋糖、糖蜜及乳糖;天然及合成膠,諸如阿拉伯膠、海藻酸、海藻酸鹽、角叉菜(Irish moss)之萃取物、帕瓦爾膠(panwar gum)、印度膠(ghatti gum)、車前子殼(isabgol husk)之黏質、羧甲基纖維素、甲基纖維素、聚乙烯吡咯啶酮(PVP)、維格姆(Veegum)、落葉松阿拉伯半乳聚糖、粉末狀黃蓍膠及瓜爾膠(guar gum);纖維素,諸如乙基纖維素、乙酸纖維素、羧甲基纖維素鈣、羧甲基纖維素鈉、甲基纖維素、羥乙基纖維素(HEC)、羥丙基纖維素(HPC)、羥丙基甲基纖維素(HPMC);微晶纖維素,諸如AVICEL-PH-101、AVICEL-PH-103、AVICEL RC-581、AVICEL-PH-105(FMC Corp.,Marcus Hook,PA);及其混合物。適合之填充劑包括(但不限於)滑石、碳酸鈣、微晶纖維素、粉末狀纖維素、葡萄糖結合劑、高嶺土、甘露糖醇、矽酸、山梨糖醇、澱粉、預膠凝化澱粉及其混合物。本文所提供之醫藥組合物中黏合劑或填充劑之量隨調配物之類型而變化,且容易由一般技術者辨別。黏合劑或填充劑可以約50重量%至約99重量%存在於本文所提供之醫藥組合物中。
適合之稀釋劑包括(但不限於)磷酸二鈣、硫酸鈣、乳糖、山梨糖醇、蔗糖、肌醇、纖維素、高嶺土、甘露糖醇、氯化鈉、乾澱粉及糖粉。諸如甘露糖醇、乳糖、山梨糖醇、蔗糖及肌醇之某些稀釋劑當存在足夠量時可賦予一些壓縮錠劑允許在口中藉由咀嚼崩解之性質。該等壓縮錠劑可用作咀嚼錠劑。本文所提供之醫藥組合物中稀釋劑之量隨調配物之類型而變化,且容易由一般技術者辨別。
適合之崩解劑包括(但不限於)瓊脂;膨潤土;纖維素,諸如甲基纖維素及羧甲基纖維素;木製品;天然海綿;陽離子交換樹脂;海藻酸;膠,諸如瓜爾膠及維格姆HV;柑橘渣;交聯纖維素,諸如交聯羧甲纖維素;交聯聚合物,諸如交聯聚維酮;交聯澱粉;碳酸鈣;微晶纖維素,諸如羥基乙酸澱粉鈉;波拉克林鉀(polacrilin potassium);澱粉,諸如玉米澱粉、馬鈴薯澱粉、木薯澱粉及預膠凝化澱粉;黏土;海藻膠;及其混合物。本文所提供之醫藥組合物中崩解劑之量隨調配物之類型而變化,且容易由一般技術者辨別。本文所提供之醫藥組合物中崩解劑之量隨調配物之類型而變化,且容易由一般技術者辨別。本文所提供之醫藥組合物可含有約0.5重量%至約15重量%或約1重量%至約5重量%之崩解劑。
適合之潤滑劑包括(但不限於)硬脂酸鈣;硬脂酸鎂;礦物油;輕質礦物油;甘油;山梨糖醇;甘露糖醇;二醇,諸如甘油蘿酸酯及聚乙二醇(PEG);硬脂酸;月桂基硫酸鈉;滑石;氫化植物油,包括花生油、棉籽油、葵花籽油、芝麻油、橄欖油、玉米油及大豆油;硬脂酸鋅;油酸乙酯;月桂酸乙酯;瓊脂;澱粉;石鬆粉;二氧化矽或矽膠,諸如200(W.R. Grace Co.,Baltimore,MD)及(Cabot Co.,Boston,MA);及其混合物。本文所提供之醫藥組合物可含有約0.1重量%至約5重量%之潤滑劑。
適合之滑動劑包括(但不限於)膠態二氧化矽、CAB-O-(Cabot Co.,Boston,MA)及無石棉滑石。適合之著色劑包括(但不限於)以下任一者:經批准之合格水溶性FD&C染料及懸浮於氧化鋁水合物上之水不溶性FD&C染料,及色澱及其混合物。色澱為藉由使水溶性染料吸附於重金屬之水合氧化物上獲得之組合,產生不溶性形式之染料。適合之調味劑包括(但不限於)自植物(諸如果實)萃取之天然香料及產生宜人味感之化合物的合成摻和物,諸如胡椒薄荷及水楊酸甲酯。適合之甜味劑包括(但不限於)蔗糖、乳糖、甘露糖醇、糖漿、甘油及人造甜味劑(諸如糖精及阿斯巴甜糖)。適合之乳化劑包括(但不限於)明膠、阿拉伯膠、黃蓍膠、膨潤土及界面活性劑,諸如聚氧乙烯脫水山梨糖醇單油酸酯(20)、聚氧乙烯脫水山梨糖醇單油酸酯80(80)及三乙醇胺油酸酯。適合之懸浮劑及分散劑包括(但不限於)羧甲基纖維素鈉、果膠、黃蓍膠、維格姆、阿拉伯膠、羧甲基纖維素鈉、羥丙基甲基纖維素及聚乙烯吡咯啶酮。適合之防腐劑包括(但不限於)甘油、對羥基苯甲酸甲酯及對羥基苯甲酸丙酯、苯甲酸添加劑、苯甲酸鈉及乙醇。適合之濕潤劑包括(但不限於)丙二醇單硬脂酸酯、脫水山梨糖醇單油酸酯、二乙二醇單月桂酸酯及聚氧乙烯月桂基醚。適合之溶劑包括(但不限於)甘油、山梨糖醇、乙醇及糖漿。適用於乳液中之非水性液體包括(但不限於)礦物油及棉籽油。適合之有機酸包括(但不限於)檸檬酸及酒石酸。適合之二氧化碳源包括(但不限於)碳酸氫鈉及碳酸鈉。
應瞭解,許多載劑及賦形劑可發揮若干種功能,甚至在同一調配物中。
本文所提供之用於經口投藥的醫藥組合物可以壓縮錠劑、錠劑研粉、咀嚼口含錠、速溶錠劑、複壓錠劑或包覆腸溶包衣之錠劑、包覆糖衣之錠劑或包覆膜衣之錠劑形式提供。包覆腸溶包衣之錠劑為包覆有抵抗胃酸作用、但在腸中溶解或崩解、由此保護活性成分免受胃之酸性環境影響的物質之壓縮錠劑。腸溶包衣包括(但不限於)脂肪酸、脂肪、水楊酸苯酯、蠟、蟲膠、胺化蟲膠及乙酸纖維素鄰苯二甲酸酯。包覆糖衣之錠劑為由糖衣包圍之壓縮錠劑,該糖衣可有利於掩蓋令人不快的味道或氣味並保護錠劑以免氧化。包覆膜衣之錠劑為由水溶性物質之薄層或膜覆蓋的壓縮錠劑。膜衣包括(但不限於)羥乙基纖維素、羧甲基纖維素鈉、聚乙二醇4000及乙酸纖維素鄰苯二甲酸酯。膜衣賦予與糖衣相同之一般特徵。複壓錠劑為藉由一個以上壓縮循環製備之壓縮錠劑,包括層狀錠劑及壓製包覆包衣錠劑或乾式包覆包衣錠劑。
錠劑劑型可由單獨或與本文所述之一或多種載劑或賦形劑組合的呈粉末狀、結晶或顆粒形式之活性成分製備,該或該等載劑或賦形劑包括黏合劑、崩解劑、控制釋放聚合物、潤滑劑、稀釋劑及/或著色劑。調味劑及甜味劑尤其適用於形成咀嚼錠劑及口含錠。
本文所提供之用於經口投藥的醫藥組合物可以軟或硬膠囊形式提供,該等膠囊可由明膠、甲基纖維素、澱粉或海藻酸鈣製成。亦稱為乾式填充膠囊(DFC)之硬明膠膠囊由兩段組成,一段套於另一段上,由此完全封閉活性成分。軟彈性膠囊(SEC)為軟的球形殼,諸如明膠殼,其藉由添加甘油、山梨糖醇或類似多元醇來塑化。軟明膠殼可含有防腐劑以防止微生物生長。適合之防腐劑為如本文所述之防腐劑,包括對羥基苯甲酸甲酯及對羥基苯甲酸丙酯及山梨酸。本文所提供之液體、半固體及固體劑型可囊封於膠囊中。適合之液體及半固體劑型包括碳酸丙二酯、植物油或三酸甘油酯中之溶液及懸浮液。含有該等溶液之膠囊可如美國專利第4,328,245號、第4,409,239號及第4,410,545號中所述製備。膠囊亦可如熟習此項技術者所已知包覆包衣以改良或維持活性成分之溶解。
本文所提供之用於經口投藥的醫藥組合物可以液體及半固體劑型提供,包括乳液、溶液、懸浮液、酏劑及糖漿。乳液為兩相系統,其中一種液體以小球形式分散於另一種液體中,其可為水包油或油包水型。乳液可包括醫藥學上可接受之非水性液體或溶劑、乳化劑及防腐劑。懸浮液可包括醫藥學上可接受之懸浮劑及防腐劑。含水醇溶液可包括醫藥學上可接受之縮醛,諸如低碳數烷基醛之二(低碳數烷基)縮醛,例如二乙醇縮乙醛;及具有一或多個羥基之水可混溶性溶劑,諸如丙二醇及乙醇。酏劑為增甜之透明水醇溶液。糖漿為糖(例如蔗糖)之濃縮水溶液,且亦可含有防腐劑。對於液體劑型,例如,聚乙二醇溶液可用足量醫藥學上可接受之液體載劑(例如水)稀釋以易於量測以供投與。
其他適用液體及半固體劑型包括(但不限於)含有本文所提供之活性成分及二烷基化之單烷二醇或聚烷二醇的劑型,該二醇包括1,2-二甲氧基甲烷、二乙二醇二甲醚、三乙二醇二甲醚、四乙二醇二甲醚、聚乙二醇-350-二甲醚、聚乙二醇-550-二甲醚、聚乙二醇-750-二甲醚,其中350、550及750係指聚乙二醇之近似平均分子量。此等調配物可進一步包含一或多種抗氧化劑,諸如丁基化羥基甲苯(BHT)、丁基化羥基茴香醚(BHA)、沒食子酸丙酯、維生素E、氫醌、羥基香豆素、乙醇胺、卵磷脂、腦磷脂、抗壞血酸、蘋果酸、山梨糖醇、磷酸、亞硫酸氫鹽、偏亞硫酸氫鈉、硫代二丙酸及其酯、及二硫代胺基甲酸酯。
本文所提供之用於經口投藥的醫藥組合物亦可以脂質體、微胞、微球體或奈米系統之形式提供。微胞劑型可如美國專利第6,350,458號中所述製備。
本文所提供之用於經口投藥的醫藥組合物可以欲復原成液體劑型之非發泡或發泡顆粒及散劑形式提供。用於非發泡顆粒或散劑中之醫藥學上可接受之載劑及賦形劑可包括稀釋劑、甜味劑及濕潤劑。用於發泡顆粒或散劑中之醫藥學上可接受之載劑及賦形劑可包括有機酸及二氧化碳源。
著色劑及調味劑可用於所有上述劑型中。
本文所提供之用於經口投藥的醫藥組合物可調配成即刻或改良釋放劑型,包括延遲、持續、脈衝、控制、靶向及經規劃釋放形式。
B. 非經腸投藥
本文所提供之醫藥組合物可藉由注射、輸注或植入非經腸投與以供局部或全身投與。如本文中所使用,非經腸投藥包括靜脈內、動脈內、腹膜內、鞘內、心室內、尿道內、胸骨內、顱內、肌肉內、滑膜內、膀胱內及皮下投藥。
本文所提供之用於非經腸投藥的醫藥組合物可調配成任何適合於非經腸投藥之劑型,包括溶液、懸浮液、乳液、微胞、脂質體、微球體、奈米系統及適合於在注射之前溶解或懸浮於液體中的固體形式。該等劑型可根據熟習醫藥科學技術者已知之習知方法來製備(參見Remington: The Scienceand Practice of Pharmacy
,同上)。
欲用於非經腸投藥之醫藥組合物可包括一或多種醫藥學上可接受之載劑及賦形劑,包括(但不限於)水性媒劑、水可混溶性媒劑、非水性媒劑、防止微生物生長之抗微生物劑或防腐劑、穩定劑、溶解增強劑、等張劑、緩衝劑、抗氧化劑、局部麻醉劑、懸浮劑及分散劑、濕潤劑或乳化劑、錯合劑、鉗合劑或螯合劑、冷凍保護劑、凍乾保護劑、增稠劑、pH值調節劑及惰性氣體。
適合之水性媒劑包括(但不限於)水、食鹽水、生理食鹽水或磷酸鹽緩衝食鹽水(PBS)、氯化鈉注射液、林格氏注射液(Ringers injection)、等張右旋糖注射液、無菌水注射液、右旋糖及乳酸鹽林格氏注射液。適合之非水性媒劑包括(但不限於)植物來源之不揮發性油、蓖麻油、玉米油、棉籽油、橄欖油、花生油、薄荷油、紅花油、芝麻油、大豆油、氫化植物油、氫化大豆油及椰子油之中鏈三酸甘油酯及棕櫚籽油。適合之水可混溶性媒劑包括(但不限於)乙醇、1,3-丁二醇、液體聚乙二醇(例如聚乙二醇300及聚乙二醇400)、丙二醇、甘油、N
-甲基-2-吡咯啶酮、N
,N
-二甲基乙醯胺及二甲亞碸。
適合之抗微生物劑或防腐劑包括(但不限於)酚、甲酚、汞劑、苯甲醇、氯丁醇、對羥基苯甲酸甲酯及對羥基苯甲酸丙酯、硫柳汞、氯苄烷銨(例如苄索氯銨)、對羥基苯甲酸甲酯及對羥基苯甲酸丙酯、及山梨酸。適合之等張劑包括(但不限於)氯化鈉、甘油及右旋糖。適合之緩衝劑包括(但不限於)磷酸鹽及檸檬酸鹽。適合之抗氧化劑為如本文所述之抗氧化劑,包括亞硫酸氫鹽及偏亞硫酸氫鈉。適合之局部麻醉劑包括(但不限於)鹽酸普魯卡因(procaine hydrochloride)。適合之懸浮劑及分散劑為如本文所述之懸浮劑及分散劑,包括羧甲基纖維素鈉、羥丙基甲基纖維素及聚乙烯吡咯啶酮。適合之乳化劑為本文所述之乳化劑,包括聚氧乙烯脫水山梨糖醇單月桂酸酯、聚氧乙烯脫水山梨糖醇單油酸酯80及三乙醇胺油酸酯。適合之鉗合劑或螯合劑包括(但不限於)EDTA。適合之pH值調節劑包括(但不限於)氫氧化鈉、鹽酸、檸檬酸及乳酸。適合之錯合劑包括(但不限於)環糊精,包括α-環糊精、β-環糊精、羥基丙基-β-環糊精、磺酸基丁基醚-β-環糊精及磺酸基丁基醚7-β-環糊精(、CyDex、Lenexa,KS)。
當本文所提供之醫藥組合物經調配用於多次劑量投與時,多次劑量非經腸調配物必須含有抑細菌或抑真菌濃度之抗微生物劑。如此項技術中所已知及實踐,所有非經腸調配物必須無菌。
在一實施例中,用於非經腸投藥之醫藥組合物係以即用無菌溶液形式提供。在另一實施例中,醫藥組合物係以欲在使用之前用媒劑復原之無菌乾燥可溶性產物形式提供,包括凍乾散劑及皮下注射錠劑。在另一實施例中,醫藥組合物係以即用無菌懸浮液形式提供。在另一實施例中,醫藥組合物係以欲在使用之前用媒劑復原之無菌乾燥不溶性產物形式提供。在又一實施例中,醫藥組合物係以即用無菌乳液形式提供。
本文所提供之用於非經腸投藥的醫藥組合物可調配成即刻或改良釋放劑型,包括延遲、持續、脈衝、控制、靶向及經規劃釋放形式。
本文所提供之用於非經腸投藥的醫藥組合物可調配成懸浮液、固體、半固體或搖溶性液體以供以植入式藥物儲積器形式投與。在一實施例中,本文所提供之醫藥組合物分散於固體內部基質中,該固體內部基質由不溶於體液中、但允許醫藥組合物中之活性成分擴散穿過之外部聚合膜包圍。
適合之內部基質包括(但不限於)聚甲基丙烯酸甲酯、聚甲基丙烯酸丁酯、塑化或未塑化聚氯乙烯、塑化耐綸(nylon)、塑化聚對苯二甲酸乙二酯、天然橡膠、聚異戊二烯、聚異丁烯、聚丁二烯、聚乙烯、乙烯-乙酸乙烯酯共聚物、聚矽氧橡膠、聚二甲基矽氧烷、聚矽氧碳酸酯共聚物、親水性聚合物(諸如丙烯酸酯及甲基丙烯酸酯之水凝膠)、膠原蛋白、交聯聚乙烯醇及交聯之部分水解聚乙酸乙烯酯。
適合之外部聚合膜包括(但不限於)聚乙烯、聚丙烯、乙烯/丙烯共聚物、乙烯/丙烯酸乙酯共聚物、乙烯/乙酸乙烯酯共聚物、聚矽氧橡膠、聚二甲基矽氧烷、氯丁橡膠、氯化聚乙烯、聚氯乙烯、氯乙烯與乙酸乙烯酯、偏二氯乙烯、乙烯及丙烯之共聚物、離聚物聚對苯二甲酸乙二酯、丁基橡膠表氯醇橡膠、乙烯/乙烯醇共聚物、乙烯/乙酸乙烯酯/乙烯醇三元共聚物及乙烯/乙烯氧基乙醇共聚物。
C. 表面投藥
本文所提供之醫藥組合物可表面投與皮膚、孔口或黏膜。如本文中所使用,表面投藥包括皮膚(內)、經結膜、角膜內、眼內、經眼、經耳、經皮、經鼻、經陰道、經尿道、經呼吸道及經直腸投藥。
本文所提供之醫藥組合物可調配成任何適合於表面投藥以用於局部或全身作用之劑型,包括乳液、溶液、懸浮液、乳膏、凝膠、水凝膠、軟膏、敷粉、敷料、酏劑、洗劑、懸浮液、酊劑、糊劑、泡沫、膜、氣溶膠、灌洗劑、噴霧、栓劑、繃帶及皮膚貼片。本文所提供之醫藥組合物的表面調配物亦可包含脂質體、微胞、微球體、奈米系統及其混合物。
適用於本文所提供之表面調配物中的醫藥學上可接受之載劑及賦形劑包括(但不限於)水性媒劑、水可混溶性媒劑、非水性媒劑、防止微生物生長之抗微生物劑或防腐劑、穩定劑、溶解增強劑、等張劑、緩衝劑、抗氧化劑、局部麻醉劑、懸浮劑及分散劑、濕潤劑或乳化劑、錯合劑、鉗合劑或螯合劑、滲透增強劑、冷凍保護劑、凍乾保護劑、增稠劑及惰性氣體。
醫藥組合物亦可藉由電穿孔、離子導入療法、超音波藥物透入療法、超音波電滲法或微針或無針注射,諸如POWDERJECTTM
(Chiron Corp.,Emeryville,CA)及BIOJECTTM
(Bioject Medical Technologies Inc.,Tualatin,OR)表面投與。
本文所提供之醫藥組合物可以軟膏、乳膏及凝膠之形式提供。適合之軟膏媒劑包括油性或烴媒劑,包括豬油、苯甲酸化豬油、橄欖油、棉籽油及其他油類、白石蠟脂;可乳化或吸附媒劑,諸如親水性石蠟脂、硫酸羥基硬脂及無水羊毛脂;水可移除性媒劑,諸如親水性軟膏;水溶性軟膏媒劑,包括不同分子量之聚乙二醇;油包水型(W/O)乳液或水包油型(O/W)乳液之乳液媒劑,包括十六醇、單硬脂酸甘油酯、羊毛脂及硬脂酸(參見Remington:The Science and Practice of Pharmacy
,同上)。此等媒劑為潤膚劑,但通常需要添加抗氧化劑及防腐劑。
適合之乳膏基劑可為水包油或油包水型。適合之乳膏媒劑可為水可洗型,且含有油相、乳化劑及水相。油相亦稱為「內部」相,其通常包含石蠟脂及脂肪醇(諸如十六醇或硬脂醇)。水相通常(不過未必)體積超過油相,且通常含有保濕劑。乳膏調配物中之乳化劑可為非離子型、陰離子型、陽離子型或兩性界面活性劑。
凝膠為半固體、懸浮液型系統。單相凝膠含有實質上均勻分佈於整個液體載劑中之有機大分子。適合之膠凝劑包括(但不限於)交聯丙烯酸聚合物,諸如卡波姆(carbomer)、羧基聚烯烴(carboxypolyalkylene)及;親水性聚合物,諸如聚環氧乙烷、聚氧乙烯-聚氧丙烯共聚物及聚乙烯醇;纖維素聚合物,諸如羥丙基纖維素、羥乙基纖維素、羥丙基甲基纖維素、羥丙基甲基纖維素鄰苯二甲酸酯及甲基纖維素;膠,諸如黃著膠及三仙膠;海藻酸鈉;及明膠。為了製備均勻凝膠,可添加諸如乙醇或甘油之分散劑,或可藉由濕磨、機械混合及/或攪拌來分散膠凝劑。
本文所提供之醫藥組合物可以栓劑、子宮托、桿劑、泥罨劑或粥狀敷劑、糊劑、散劑、敷料、乳膏、硬膏劑、避孕劑、軟膏、溶液、乳液、懸浮液、棉塞、凝膠、泡沫、噴霧或灌腸劑之形式經直腸、經尿道、經陰道或經陰道周圍技與。此等劑型可使用如Remington: The Science and Practice of Pharmacy
(同上)中所述之習知方法來製造。
直腸、尿道及陰道栓劑為用於插入身體孔口中之固體,其在常溫下為固體,但在體溫下熔融或軟化以將活性成分釋放於該孔口內。用於直腸及陰道栓劑中之醫藥學上可接受之載劑包括基劑或媒劑,諸如硬化劑,當與本文所提供之醫藥組合物一起調配時,其具有接近體溫之熔點;及如本文所述之抗氧化劑,包括亞硫酸氫鹽及偏亞硫酸氫鈉。適合之媒劑包括(但不限於)可可脂(可可豆油);甘油-明膠;碳蠟(聚氧乙二醇);鯨蠟;石蠟;白蠟及黃蠟;及脂肪酸之單酸甘油酯、二酸甘油酯及三酸甘油酯的適當混合物;及水凝膠,諸如聚乙烯醇、甲基丙烯酸羥基乙酯及聚丙烯酸。亦可使用各種媒劑之組合。直腸及陰道栓劑可藉由壓縮或模製來製備。直腸及陰道栓劑之典型重量為約2 g至約3 g。
本文所提供之醫藥組合物可以溶液、懸浮液、軟膏、乳液、成凝膠溶液、溶液用散劑、凝膠、眼睛插入物及植入物之形式經眼投與。
本文所提供之醫藥組合物可經鼻內或藉由吸入投與呼吸道。醫藥組合物可以單獨或與適合推進劑(諸如1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷)組合之使用加壓容器、泵、噴霧器、霧化器(諸如使用電流體動力學產生細霧之霧化器)或噴灑器傳遞之氣溶膠或溶液的形式提供。醫藥組合物亦可以單獨或與惰性載劑(諸如乳糖或磷脂)組合之用於吹入之乾粉及滴鼻劑形式提供。對於鼻內使用,散劑可包含生物黏合劑,包括聚葡萄胺糖或環糊精。
供在加壓容器、泵、噴霧器、霧化器或噴灑器中使用之溶液或懸浮液可經調配以含有乙醇、含水乙醇或適合於分散、溶解本文所提供之活性成分或延長其釋放之替代性藥劑;作為溶劑之推進劑;及/或界面活性劑,諸如脫水山梨糖醇三油酸酯、油酸或低聚乳酸。
本文所提供之醫藥組合物可經微米尺寸化為適合於藉由吸入傳遞之尺寸,諸如約50微米或更小,或約10微米或更小。該等尺寸之粒子可使用熟習此項技術者已知之粉碎方法來製備,諸如螺旋噴射研磨、流化床噴射研磨、形成奈米粒子之超臨界流體加工、高壓均質化、或噴霧乾燥。
供在吸入器或吹入器中使用之膠囊、發泡藥及藥筒可經調配以含有以下之粉末混合物:本文所提供之醫藥組合物;適合粉末基劑,諸如乳糖或澱粉;及效能調節劑,諸如l
-白胺酸、甘露糖醇或硬脂酸鎂。乳糖可為無水的或呈單水合物之形式。其他適合之賦形劑或載劑包括(但不限於)葡聚糖、葡萄糖、麥芽糖、山梨糖醇、木糖醇、果糖、蔗糖及海藻糖。本文所提供之用於吸入/鼻內投藥的醫藥組合物可進一步包含適合之香料,諸如薄荷腦及左薄荷腦;及/或甜味劑,諸如糖精及糖精鈉。
本文所提供之用於表面投藥的醫藥組合物可調配成即刻釋放或改良釋放,包括延遲、持續、脈衝、控制、靶向及經規劃釋放。
D. 改良釋放
本文所提供之醫藥組合物可調配成改良釋放劑型。如本文中所使用,術語「改良釋放」係指劑型釋放活性成分之速率或位置不同於即刻劑型藉由相同途徑投與時釋放活性成分之速率或位置。改良釋放劑型包括(但不限於)延遲、延長、長期、持續、脈動、控制、加速及快速、靶向、經規劃釋放及胃滯留劑型。改良釋放劑型中之醫藥組合物可使用熟習此項技術者已知之多種改良釋放裝置及方法來製備,包括(但不限於)基質控制釋放裝置、滲透控制釋放裝置、多微粒控制釋放裝置、離子交換樹脂、腸溶包衣、多層包衣、微球體、脂質體及其組合。活性成分之釋放速率亦可藉由改變活性成分之粒度及多形現象來改變。
改良釋放之實例包括(但不限於)以下專利中所述之改良釋放:美國專利第3,845,770號;第3,916,899號;第3,536,809號;第3,598,123號;第4,008,719號;第5,674,533號;第5,059,595號;第5,591,767號;第5,120,548號;第5,073,543號;第5,639,476號;第5,354,556號;第5,639,480號;第5,733,566號;第5,739,108號;第5,891,474號;第5,922,356號;第5,972,891號;第5,980,945號;第5,993,855號;第6,045,830號;第6,087,324號;第6,113,943號;第6,197,350號;第6,248,363號;第6,264,970號;第6,267,981號;第6,376,461號;第6,419,961號;第6,589,548號;第6,613,358號;及第6,699,500號。
1. 基質控制釋放裝置
本文所提供之呈改良釋放劑型的醫藥組合物可使用熟習此項技術者已知之基質控制釋放裝置來製造(參見Takada等人,「Encyclopedia of Controlled Drug Delivery,」第2卷,Mathiowitz編,Wiley,1999)。
在某些實施例中,本文所提供之呈改良釋放劑型的醫藥組合物係使用可侵蝕性基質裝置來調配,該裝置為遇水膨脹、可侵蝕性或可溶性聚合物,包括(但不限於)合成聚合物及天然存在之聚合物及衍生物,諸如多醣及蛋白質。
適用於形成可侵蝕性基質之物質包括(但不限於)甲殼素、聚葡萄胺糖、葡聚糖及支鏈澱粉;瓊脂膠、阿拉伯膠、刺梧桐膠、刺槐豆膠、黃著膠、角叉菜膠、印度膠、瓜爾膠、三仙膠及硬葡聚糖;澱粉,諸如糊精及麥芽糊精;親水性膠體,諸如果膠;磷脂,諸如卵磷脂;海藻酸鹽;丙二醇海藻酸酯;明膠;膠原蛋白;纖維素,諸如乙基纖維素(EC)、甲基乙基纖維素(MEC)、羧甲基纖維素(CMC)、CMEC、羥乙基纖維素(HEC)、羥丙基纖維素(HPC)、乙酸纖維素(CA)、丙酸纖維素(CP)、丁酸纖維素(CB)、乙酸丁酸纖維素(CAB)、CAP、CAT、羥丙基甲基纖維素(HPMC)、HPMCP、HPMCAS、乙酸羥丙基甲基纖維素偏苯三酸酯(HPMCAT)及乙基羥乙基纖維素(EHEC);聚乙烯吡咯啶酮;聚乙烯醇;聚乙酸乙烯酯;甘油脂肪酸酯;聚丙烯醯胺;聚丙烯酸;乙基丙烯酸或甲基丙烯酸之共聚物(,Rohm America,Inc.,Piscataway,NJ);聚(甲基丙烯酸2-羥基乙酯);聚丙交酯;L-麩胺酸與-L-麩胺酸乙酯之共聚物;可降解乳酸-乙醇酸共聚物;聚-D-(-)-3-羥基丁酸;及其他丙烯酸衍生物,諸如甲基丙烯酸丁酯、甲基丙烯酸甲酯、甲基丙烯酸乙酯、丙烯酸乙酯、甲基丙烯酸(2-二甲基胺基乙基)酯及甲基丙烯酸(三甲基胺基乙基)酯氯化物之均聚物及共聚物。
在某些實施例中,本文所提供之醫藥組合物係用非可侵蝕性基質裝置調配。活性成分溶解或分散於惰性基質中且主要藉由在投與後擴散穿過惰性基質來釋放。適合用作非可侵蝕性基質裝置之物質包括(但不限於)不溶性塑膠,諸如聚乙烯、聚丙烯、聚異戊二烯、聚異丁烯、聚丁二烯、聚甲基丙烯酸甲酯、聚甲基丙烯酸丁酯、氯化聚乙烯、聚氯乙烯、丙烯酸甲酯-甲基丙烯酸甲酯共聚物、乙烯-乙酸乙烯酯共聚物、乙烯/丙烯共聚物、乙烯/丙烯酸乙酯共聚物、氯乙烯與乙酸乙烯酯、偏二氯乙烯、乙烯及丙烯之共聚物、離聚物聚對苯二甲酸乙二酯、丁基橡膠、表氯醇橡膠、乙烯/乙烯醇共聚物、乙烯/乙酸乙烯酯/乙烯醇三元共聚物、乙烯/乙烯氧基乙醇共聚物、聚氯乙烯、塑化耐綸、塑化聚對苯二甲酸乙二酯、天然橡膠、聚矽氧橡膠、聚二甲基矽氧烷及聚矽氧碳酸酯共聚物;親水性聚合物,諸如乙基纖維素、乙酸纖維素、交聯聚維酮及交聯之部分水解聚乙酸乙烯酯;及脂肪化合物,諸如巴西棕櫚蠟、微晶蠟及三酸甘油酯。
在基質控制釋放系統中,所需釋放動力學可例如經由所使用之聚合物類型、聚合物黏度、聚合物及/或活性成分之粒度、活性成分與聚合物之比率、及組合物中之其他賦形劑或載劑來控制。
本文所提供之呈改良釋放劑型的醫藥組合物可藉由熟習此項技術者已知之方法來製備,包括直接壓縮、乾式或濕式粒化隨後壓縮、及熔融-粒化隨後壓縮。
2. 滲透控制釋放裝置
本文所提供之呈改良釋放劑型的醫藥組合物可使用滲透控制釋放裝置來製造,包括(但不限於)單腔室系統、雙腔室系統、不對稱膜技術(AMT)及擠壓核心系統(ECS)。一般而言,該等裝置具有至少兩個組分:(a)含有活性成分之核心;及(b)具有至少一個傳遞口之半透膜,其囊封該核心。該半透膜控制水自使用之水性環境流入核心以使得藥物因擠壓穿過傳遞口而釋放。
除活性成分外,滲透裝置之核心亦視情況包括滲透劑,其產生將水自使用環境輸送至裝置之核心中的驅動力。一類滲透劑為遇水膨脹之親水性聚合物,其亦稱為「滲透聚合物」及「水凝膠」。適合作為滲透劑之遇水膨脹的親水性聚合物包括(但不限於)親水性乙烯基及丙烯酸系聚合物、多醣(諸如海藻酸鈣)、聚環氧乙烷(PEO)、聚乙二醇(PEG)、聚丙二醇(PPG)、聚(甲基丙烯酸2-羥基乙酯)、聚(丙烯酸)、聚(甲基丙烯酸)、聚乙烯吡咯啶酮(PVP)、交聯PVP、聚乙烯醇(PVA)、PVA/PVP共聚物、PVA/PVP與疏水性單體(諸如甲基丙烯酸甲酯及乙酸乙烯酯)之共聚物、含有大PEO嵌段之親水性聚胺基甲酸酯、交聯羧甲纖維素鈉、角叉菜膠、羥乙基纖維素(HEC)、羥丙基纖維素(HPC)、羥丙基甲基纖維素(HPMC)、羧甲基纖維素(CMC)及羧乙基纖維素(CEC)、海藻酸鈉、聚卡波非(polycarbophil)、明膠、三仙膠及羥基乙酸澱粉鈉。
另一類滲透劑為滲透原,其能夠吸收水以影響周圍包衣之障壁兩側的滲透壓梯度。適合之滲透原包括(但不限於)無機鹽,諸如硫酸鎂、氯化鎂、氯化鈣、氯化鈉、氯化鋰、硫酸鉀、磷酸鉀、碳酸鈉、亞硫酸鈉、硫酸鋰、氯化鉀及硫酸鈉;糖,諸如右旋糖、果糖、葡萄糖、肌醇、乳糖、麥芽糖、甘露糖醇、棉子糖、山梨糖醇、蔗糖、海藻糖及木糖醇;有機酸,諸如抗壞血酸、苯甲酸、反丁烯二酸、檸檬酸、順丁烯二酸、癸二酸、山梨酸、己二酸、依地酸、麩胺酸、對甲苯磺酸、丁二酸及酒石酸;尿素;及其混合物。
可使用不同溶解速率之滲透劑來影響起初自劑型傳遞活性成分之快速程度。舉例而言,可使用諸如MANNOGEMTM
EZ(SPI Pharma,Lewes,DE)之非晶形糖來在最初幾小時期間提供較快傳遞以迅速產生所需治療作用,並逐漸且不斷地釋放剩餘量以長期維持治療性或預防性作用之所需量。在此情況下,以此速率釋放活性成分以置換代謝及排泄之活性成分的量。
核心亦可包括如本文所述之多種其他賦形劑及載劑以增強劑型之效能或提高穩定性或加工性。
適用於形成半透膜之物質包括各種等級之丙烯酸系物、乙烯基樹脂、醚、聚醯胺、聚酯及纖維素衍生物,其可透過水且在生理相關pH值下不溶於水,或易藉由化學改變(諸如交聯)變得不溶於水。適用於形成包衣之聚合物的實例包括塑化、未塑化及增強之乙酸纖維素(CA)、二乙酸纖維素、三乙酸纖維素、丙酸CA、硝酸纖維素、乙酸丁酸纖維素(CAB)、乙基胺基甲酸CA、CAP、甲基胺基甲酸CA、丁二酸CA、偏苯三酸乙酸纖維素(CAT)、二甲基胺基乙酸CA、乙基碳酸CA、氯乙酸CA、乙基草酸CA、甲基磺酸CA、丁基磺酸CA、對甲苯磺酸CA、乙酸瓊脂、三乙酸直鏈澱粉、乙酸β葡聚糖、三乙酸β葡聚糖、乙醛乙酸二甲酯、刺槐豆膠三乙酸酯、羥基化乙烯-乙酸乙烯酯、EC、PEG、PPG、PEG/PPG共聚物、PVP、HEC、HPC、CMC、CMEC、HPMC、HPMCP、HPMCAS、HPMCAT、聚(丙烯酸)及聚(丙烯酸酯)及聚(甲基丙烯酸)及聚(甲基丙烯酯)及其共聚物、澱粉、葡聚糖、糊精、聚葡萄胺糖、膠原蛋白、明膠、聚烯烴、聚醚、聚碸、聚醚碸、聚苯乙烯、聚鹵乙烯、聚乙烯酯及醚、天然蠟及合成蠟。
半透膜亦可為疏水性微孔膜,其中孔隙實質上由氣體填充且不會被水性介質潤濕,但水蒸氣可透過,如美國專利第5,798,119號中所揭示。該等疏水性但水蒸氣可透過之膜通常由疏水性聚合物構成,諸如聚烯烴、聚乙烯、聚丙烯、聚四氟乙烯、聚丙烯酸衍生物、聚醚、聚碸、聚醚碸、聚苯乙烯、聚鹵乙烯、聚偏二氟乙烯、聚乙烯酯及醚、天然蠟及合成蠟。
半透膜上之傳遞口可在包覆包衣後藉由機械或雷射鑽孔來形成。傳遞口亦可當場藉由腐蝕水溶性物質之栓塞或藉由使核心中凹痕上膜之較薄部分破裂來形成。另外,傳遞口可在包覆包衣過程期間形成,如在美國專利第5,612,059號及第5,698,220號中所揭示之類型的不對稱膜包衣之情況下。
所釋放之活性成分的總量及釋放速率可實質上經由半透膜之厚度及孔隙率、核心之組成及傳遞口之數目、尺寸及位置來調節。
滲透控制釋放劑型中之醫藥組合物可進一步包含如本文所述之其他習知賦形劑或載劑以提高調配物之效能或加工性。
滲透控制釋放劑型可根據熟習此項技術者已知之習知方法及技術來製備(參見Remington: The Science and Practice of Pharmacy
,同上;Santus及Baker,J. Controlled Release 1995
,35,1-21;Verma等人,Drug Development and Industrial Pharmacy 2000
,26
,695-708;Verma等人,J. Controlled Release 2002
,79
,7-27)。
在某些實施例中,本文所提供之醫藥組合物經調配成AMT控制釋放劑型,其包含包覆包含活性成分及其他醫藥學上可接受之賦形劑或載劑的核心之不對稱滲透膜。參見美國專利第5,612,059號及WO 2002/17918。AMT控制釋放劑型可根據熟習此項技術者已知之習知方法及技術來製備,包括直接壓縮、乾式粒化、濕式粒化及浸塗方法。
在某些實施例中,本文所提供之醫藥組合物經調配成ESC控制釋放劑型,其包含包覆包含活性成分、羥乙基纖維素及其他醫藥學上可接受之賦形劑或載劑的核心之滲透膜。
3. 多微粒控制釋放裝置
本文所提供之呈改良釋放劑型的醫藥組合物可製造成多微粒控制釋放裝置,其包含許多直徑在約10 μm至約3 mm、約50 μm至約2.5 mm或約100 μm至約1 mm範圍內之粒子、顆粒或丸粒。該等多微粒可藉由熟習此項技術者已知之方法來製備,包括濕式及乾式粒化、擠壓/滾圓法、滾筒-壓實、熔融-凝固及藉由噴塗種核來製備。參見例如,Multiparticulate Oral Drug Deliνery
;Marcel Dekker: 1994;及Pharmaceutical Pelletization Technology
;Marcel Dekker: 1989。
如本文所述之其他賦形劑或載劑可與醫藥組合物摻合以有助於加工及形成多微粒。所得粒子自身可構成多微粒裝置或可由各種成膜物質包覆,諸如腸溶聚合物、遇水膨脹及水溶性聚合物。多微粒可進一步加工成膠囊或錠劑。
4. 靶向傳遞
本文所提供之醫藥組合物亦可調配成靶向特定組織、受體或欲治療之個體身體的其他區域,包括基於脂質體、重密封紅血球及抗體之傳遞系統。實例包括(但不限於)以下專利中所揭示之實例:美國專利第6,316,652號;第6,274,552號;第6,271,359號;第6,253,872號;第6,139,865號;第6,131,570號;第6,120,751號;第6,071,495號;第6,060,082號;第6,048,736號;第6,039,975號;第6,004,534號;第5,985,307號;第5,972,366號;第5,900,252號;第5,840,674號;第5,759,542號;及第5,709,874號。
使用方法
在一實施例中,提供一種治療、預防或改善個體之與CCR3相關之病症、疾病或病狀的一或多種症狀之方法,其包含向該個體投與治療有效量之本文所提供之化合物,例如式I化合物,包括其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。在一實施例中,個體為哺乳動物。在另一實施例中,個體為人類。
在另一實施例中,提供一種治療、預防或改善個體之對調節CCR3活性起反應之病症、疾病或病狀的一或多種症狀之方法,其包含向該個體投與治療有效量之本文所提供之化合物,例如式I化合物,包括其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。在一實施例中,個體為哺乳動物。在另一實施例中,個體為人類。
在另一實施例中,提供一種治療、預防或改善個體之由CCR3受體介導之病症、疾病或病狀的一或多種症狀之方法,其包含向該個體投與治療有效量之本文所提供之化合物,例如式I化合物,包括其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。在一實施例中,個體為哺乳動物。在另一實施例中,個體為人類。
在另一實施例中,提供一種治療、預防或改善個體之嗜酸性粒細胞相關性病症、疾病或病狀的一或多種症狀之方法,其包含向該個體投與治療有效量之本文所提供之化合物,例如式I化合物,包括其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。在一實施例中,個體為哺乳動物。在另一實施例中,個體為人類。
在另一實施例中,提供一種治療、預防或改善個體之嗜鹼性粒細胞相關性病症、疾病或病狀的一或多種症狀之方法,其包含向該個體投與治療有效量之本文所提供之化合物,例如式I化合物,包括其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。在一實施例中,個體為哺乳動物。在另一實施例中,個體為人類。
在另一實施例中,提供一種治療、預防或改善個體之肥大細胞相關性病症、疾病或病狀的一或多種症狀之方法,其包含向該個體投與治療有效量之本文所提供之化合物,例如式I化合物,包括其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。在一實施例中,個體為哺乳動物。在另一實施例中,個體為人類。
在另一實施例中,提供一種治療、預防或改善個體之發炎性疾病的一或多種症狀之方法,其包含向該個體投與治療有效量之本文所提供之化合物,例如式I化合物,包括其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。在一實施例中,個體為哺乳動物。在另一實施例中,個體為人類。
可用本文所提供之化合物(例如式I化合物,包括其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥)治療的病症、疾病或病狀包括(但不限於):(1)發炎性或過敏性疾病,包括全身過敏及過敏症、異位性皮膚炎、蕁麻疹、藥物過敏、昆蟲蜇咬過敏、食物過敏(包括乳糜瀉及其類似疾病)及肥大細胞增多症;(2)發炎性腸病,包括克羅恩氏病(Crohn's disease)、潰瘍性結腸炎、回腸炎及腸炎;(3)血管炎及貝塞特氏症候群(Behcet's syndrome);(4)牛皮癬及發炎性皮膚病,包括皮膚炎、濕疹、異位性皮膚炎、過敏性接觸性皮炎、蕁麻疹、病毒性皮膚病變(包括來源於人類乳頭狀瘤病毒、HIV或RLV感染之皮膚病變)、細菌性、真菌性及其他寄生蟲性皮膚病變,及皮膚紅斑狼瘡;(5)哮喘及呼吸道過敏性疾病,包括過敏性哮喘、運動誘發性哮喘、過敏性鼻炎、中耳炎、過敏性結膜炎、過敏性肺病及慢性阻塞性肺病;(6)自體免疫疾病,包括關節炎(包括類風濕性及牛皮癬性)、全身性紅斑狼瘡、I型糖尿病、重症肌無力、多發性硬化症、格雷氏病(Graves' disease)及絲球體腎炎;(7)移植排斥反應(包括同種異體移植排斥反應及移植物抗宿主疾病),例如皮膚移植排斥反應、實體器官移植排斥反應、骨髓移植排斥反應;(8)發熱;(9)心血管病症,包括急性心臟衰竭、低血壓、高血壓、心絞痛、心肌梗塞、心肌病、充血性心臟衰竭、動脈粥樣硬化、冠狀動脈病、再狹窄及血管狹窄;(10)腦血管病症,包括創傷性腦損傷、中風、缺血性再灌注損傷及動脈瘤;(11)乳房、皮膚、前列腺、子宮頸、子宮、卵巢、睪丸、膀胱、肺、肝、喉、口腔、結腸及胃腸道(例如食道、胃、胰臟)、腦、甲狀腺、血液及淋巴系統之癌症;(12)纖維化、結締組織疾病及肉狀瘤病;(13)生殖器及生殖病狀,包括勃起困難;(14)胃腸病症,包括胃炎、潰瘍、噁心、胰腺炎及嘔吐;(15)神經病症,包括阿茲海默氏病(Alzheimer's disease);(16)睡眠障礙,包括失眠、發作性睡病、睡眠呼吸暫停症候群及皮克威克症候群(Pickwick Syndrome);(17)疼痛;(18)腎病;(19)眼病,包括青光眼;及(20)傳染性疾病,包括HIV。
在某些實施例中,病症、疾病或病狀係選自由以下組成之群:哮喘、過敏性哮喘、運動誘發性哮喘、過敏性鼻炎、常年性過敏性鼻炎、季節性過敏性鼻炎、異位性皮膚炎、接觸性過敏反應、接觸性皮膚炎、結膜炎、過敏性結膜炎、嗜酸性粒細胞性支氣管炎、食物過敏、嗜酸性粒細胞性胃腸炎、發炎性腸病、潰瘍性結腸炎、克羅恩氏病、肥大細胞增多症、高IgE症候群、全身性紅斑狼瘡、牛皮癬、痤瘡、多發性硬化症、同種異體移植排斥反應、再灌注損傷、慢性阻塞性肺病、徹奇-斯全司症候群(Churg-Strauss syndrome)、竇炎、嗜鹼性白血病、慢性蕁麻疹、嗜鹼性白血球增多症、牛皮癬、濕疹、COPD(慢性阻塞性肺病)、關節炎、類風濕性關節炎、牛皮癬性關節炎及骨關節炎。
在某些實施例中,病症、疾病或病狀為哮喘、運動誘發性哮喘、過敏性鼻炎、異位性皮膚炎、慢性阻塞性肺病或過敏性結膜炎。
視欲治療之病症、疾病或病狀及個體狀況而定,本文所提供之化合物或醫藥組合物可藉由經口、非經腸(例如肌肉內、腹膜內、靜脈內、ICV、腦池內注射或輸注、皮下注射、或植入)、吸入、經鼻、經陰道、經直腸、舌下或表面(例如經皮或局部)投藥途徑來投與且可單獨調配或以適合劑量單位與適合於各投藥途徑之醫藥學上可接受之賦形劑、載劑、佐劑及媒劑一起調配。亦提供投與含本文所提供之呈儲積式調配物的化合物或醫藥組合物,其中活性成分釋放持續預定時期。
在治療、預防或改善哮喘、過敏性鼻炎、濕疹、牛皮癬、異位性皮膚炎、發熱、敗血症、全身性紅斑狼瘡、糖尿病、類風濕性關節炎、多發性硬化症、動脈粥樣硬化、移植排斥反應、發炎性腸病、癌症或其他與CCR3受體相關之病狀、病症或疾病的一或多種症狀時,適當劑量通常在每日每公斤個體體重約0.001 mg至100 mg(每日約0.001 mg至100 mg/kg)、每日約0.01 mg/kg至約75 mg/kg、每日約0.1 mg/kg至約50 mg/kg、每日約0.5 mg/kg至約25 mg/kg或每日約1 mg/kg至約20 mg/kg之範圍內,其可以單次或多次劑量投與。在此範圍內,劑量可在每日約0.005 mg/kg至約0.05 mg/kg、約0.05 mg/kg至約0.5 mg/kg、約0.5 mg/kg至約5.0 mg/kg、約1 mg/kg至約15 mg/kg、約1至約20 mg/kg或約1至約50 mg/kg範圍內。在某些實施例中,劑量在每日約0.001 mg/kg至約100 mg/kg範圍內。在某些實施例中,劑量在每日約0.01 mg/kg至約75 mg/kg範圍內。在某些實施例中,劑量在每日約0.1 mg/kg至約50 mg/kg範圍內。在某些實施例中,劑量在每日約0.5 mg/kg至約25 mg/kg範圍內。在某些實施例中,劑量在每日約1 mg/kg至約20 mg/kg範圍內。
對於經口投藥,本文所提供之醫藥組合物可調配成含有以下之錠劑的形式以根據症狀調節給與所治療之患者的劑量:約1.0 mg至約1,000 mg活性成分,在一實施例中約1 mg、約5 mg、約10 mg、約15 mg、約20 mg、約25 mg、約50 mg、約75 mg、約100 mg、約150 mg、約200 mg、約250 mg、約300 mg、約400 mg、約500 mg、約600 mg、約750 mg、約800 mg、約900 mg及約1,000 mg活性成分。醫藥組合物可按照每日1至4次之方案投與,包括每日一次、兩次、三次及四次。
然而,應瞭解,用於任何特定患者之特定劑量及給藥頻率可改變且將視多種因素而定,包括所用之特定化合物的活性、該化合物之代謝穩定性及作用時間長度、年齡、體重、一般健康狀況、性別、飲食、投藥模式及時間、排泄速率、藥物組合、特定病狀之嚴重程度及宿主經歷之療法。
本文亦提供調節CCR3活性之方法,其包含使CCR3受體與本文所提供之化合物接觸,例如式I化合物,包括其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥。在一實施例中,CCR3受體由細胞表現。
本文所提供之化合物(例如式I化合物,包括其對映異構體、對映異構體之混合物、兩種或兩種以上非對映異構體之混合物、互變異構體或兩種或兩種以上互變異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物、水合物或前藥)亦可與其他適用於治療、預防或改善本文所提供之化合物適用的病症、疾病或病狀之一或多種症狀的藥劑組合或組合使用,該等病症、疾病或病狀包括哮喘、過敏性鼻炎、濕疹、牛皮癬、異位性皮膚炎、發熱、敗血症、全身性紅斑狼瘡、糖尿病、類風濕性關節炎、多發性硬化症、動脈粥樣硬化、移植排斥反應、發炎性腸病、癌症、傳染性疾病及上述彼等病變。
在某些實施例中,本文所提供之化合物可與此項技術中已知之一或多種類固醇藥物組合,該等藥物包括(但不限於)包括醛固酮、倍氯米松(beclometasone)、倍他米松(betamethasone)、乙酸去氧皮質酮(deoxycorticosterone acetate)、氟氫可的松(fludrocortisone)、氫皮質酮(hydrocortisone)(皮質醇)、潑尼龍(prednisolone)、潑尼松(prednisone)、甲潑尼龍(methylprednisolone)、地塞米松(dexamethasone)及曲安西龍(triamcinolone)之群。
在某些實施例中,本文所提供之化合物可與此項技術中已知之一或多種抗細菌劑組合,該等抗細菌劑包括(但不限於)包括以下之群:阿米卡星(amikacin)、胺羥芐青黴素(amoxicillin)、安比西林(ampicillin)、胂凡納明(arsphenamine)、阿奇黴素(azithromycin)、胺曲南(aztreonam)、阿洛西林(azlocillin)、枯草菌素(bacitracin)、羧苄青黴素(carbenicillin)、頭孢克洛(cefaclor)、頭孢羥胺苄(cefadroxil)、頭孢孟多(cefamandole)、頭孢唑林(cefazolin)、頭孢力新(cephalexin)、頭孢地尼(cefdinir)、頭孢托侖酯(cefditorin)、頭孢吡肟(cefepime)、頭孢克肟(cefixime)、頭孢哌酮(cefoperazone)、頭孢噻肟(cefotaxime)、頭孢噻吩(cefoxitin)、頭孢泊肟(cefpodoxime)、頭孢丙烯(cefprozil)、頭孢他啶(ceftazidime)、頭孢布烯(ceftibuten)、頭孢唑肟(ceftizoxime)、頭孢曲松(ceftriaxone)、頭孢呋辛(cefuroxime)、氯黴素(chloramphenicol)、西司他丁(cilastin)、環丙沙星(ciprofloxacin)、克拉黴素(clarithromycin)、克林達黴素(clindamycin)、氯唑西林(cloxacillin)、黏菌素(colistin)、達福普丁(dalfopristin)、地美環素(demeclocycline)、雙氯西林(dicloxacillin)、地紅黴素(dirithromycin)、多西環素(doxycycline)、紅黴素(erythromycin)、恩氟沙星(enrofloxacin)、爾他培南(ertepenem)、乙胺丁醇(ethambutol)、氟氯西林(flucloxacillin)、磷黴素(fosfomycin)、呋喃唑酮(furazolidone)、加替沙星(gatifloxacin)、格爾德黴素(geldanamycin)、建它黴素(gentamicin)、除莠黴素(herbimycin)、亞胺培南(imipenem)、異煙肼(isoniazid)、卡那黴素(kanamycin)、左氧氟沙星(levofloxacin)、利奈唑胺(linezolid)、洛美沙星(lomefloxacin)、氯碳頭孢(loracarbef)、磺胺米隆(mafenide)、莫西沙星(moxifloxacin)、美羅培南(meropenem)、甲硝噠唑(metronidazole)、美洛西林(mezlocillin)、二甲胺四環素(minocycline)、莫匹羅星(mupirocin)、萘夫西林(nafcillin)、新黴素(neomycin)、奈替米星(netilmicin)、硝化呋喃妥因(nitrofurantoin)、諾氟沙星(norfloxacin)、氧氟沙星(ofloxacin)、土黴素(oxytetracycline)、青黴素(penicillin)、哌拉西林(piperacillin)、平板黴素(platensimycin)、多黏菌素B(polymyxin B)、百浪多息(prontocil)、吡嗪醯胺(pyrazinamide)、奎普斯汀(quinupristine)、利福平(rifampin)、羅紅黴素(roxithromycin)、壯觀黴素(spectinomycin)、鏈黴素(streptomycin)、磺胺醋醯胺(sulfacetamide)、磺胺甲二唑(sulfamethizole)、磺胺甲噁唑(sulfamethoxazole)、替考拉寧(teicoplanin)、泰利黴素(telithromycin)、四環素(tetracycline)、替卡西林(ticarcillin)、妥布拉黴素(tobramycin)、三甲氧苄二胺嘧啶(trimethoprim)、醋竹桃黴素(troleandomycin)、曲伐沙星(trovafloxacin)及萬古黴素(vancomycin)。
在某些實施例中,本文所提供之化合物可與此項技術中已知之一或多種抗真菌劑組合,該等抗真菌劑包括(但不限於)包括以下之群:阿莫羅芬(amorolfine)、兩性黴素B(amphotericin B)、阿尼芬淨(anidulafungin)、聯苯苄唑(bifonazole)、布替萘芬(butenafine)、布康唑(butoconazole)、卡泊芬淨(caspofungin)、環吡酮(ciclopirox)、克黴唑(clotrimazole)、益康唑(econazole)、芬替康唑(fenticonazole)、非律平(filipin)、氟康唑(fluconazole)、異康唑(isoconazole)、伊曲康唑(itraconazole)、酮康唑(ketoconazole)、米卡芬淨(micafungin)、咪康唑(miconazole)、萘替芬(naftifine)、遊黴素(natamycin)、制黴菌素(nystatin)、奧昔康唑(oxyconazole)、雷夫康唑(ravuconazole)、泊沙康唑(posaconazole)、龜裂殺菌素(rimocidin)、舍他康唑(sertaconazole)、硫康唑(sulconazole)、特比萘芬(terbinafine)、特康唑(terconazole)、噻康唑(tioconazole)及伏立康唑(voriconazole)。
在某些實施例中,本文所提供之化合物可與此項技術中已知之一或多種抗凝血劑組合,該等抗凝血劑包括(但不限於)包括醋硝香豆素(acenocoumarol)、阿加曲班(argatroban)、比伐盧定(bivalirudin)、來匹盧定(lepirudin)、方達珀魯(fondaparinux)、肝素(heparin)、苯茚二酮(phenindione)、華法令(warfarin)及希美加群(ximelagatran)之群。
在某些實施例中,本文所提供之化合物可與此項技術中已知之一或多種溶血栓藥組合,該等溶血栓藥包括(但不限於)包括阿尼普酶(anistreplase)、瑞替普酶(reteplase)、t-PA(阿替普酶(alteplase)活化酶(activase))、鏈激酶(streptokinase)、替奈普酶(tenecteplase)及尿激酶(urokinase)之群。
在某些實施例中,本文所提供之化合物可與此項技術中已知之一或多種非類固醇消炎劑組合,該等非類固醇消炎劑包括(但不限於)醋氯芬酸(aceclofenac)、阿西美辛(acemetacin)、阿莫匹靈(amoxiprin)、阿司匹靈(aspirin)、阿紮丙宗(azapropazone)、貝諾酯(benorilate)、溴芬酸(bromfenac)、卡洛芬(carprofen)、塞內昔布(celecoxib)、膽鹼水楊酸鎂(choline magnesium salicylate)、雙氯芬酸(diclofenac)、二氟尼柳(diflunisal)、依託度酸(etodolac)、依託昔布(etoricoxib)、法伊西明(faislamine)、芬布芬(fenbufen)、非諾洛芬(fenoprofen)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、吲哚美辛(indometacin)、酮基布洛芬(ketoprofen)、酮咯酸(ketorolac)、氯諾昔康(lornoxicam)、洛索洛芬(loxoprofen)、盧米羅可(lumiracoxib)、甲氯芬那酸(meclofenamic acid)、甲芬那酸(mefenamic acid)、美儂西康(meloxicam)、安乃近(metamizole)、水楊酸甲酯(methyl salicylate)、水楊酸鎂(magnesium salicylate)、萘丁美酮(nabumetone)、萘普生(naproxen)、 尼美舒利(nimesulide)、羥布宗(oxyphenbutazone)、帕瑞昔布(parecoxib)、苯基丁氮酮(phenylbutazone)、吡羅昔康(piroxicam)、雙水楊酯(salicyl salicylate)、舒林酸(sulindac)、苯磺唑酮(sulfinpyrazone)、舒洛芬(suprofen)、替諾昔康(tenoxicam)、噻洛芬酸(tiaprofenic acid)及托美丁(tolmetin)。
在某些實施例中,本文所提供之化合物可與此項技術中已知之一或多種抗血小板劑組合,該等抗血小板劑包括(但不限於)阿昔單抗(abciximab)、西洛他唑(cilostazol)、氯吡格雷(clopidogrel)、雙嘧達莫(dipyridamole)、噻氯匹定(ticlopidine)及替羅非班(tirofibin)。
本文所提供之化合物亦可與其他種類之化合物組合投與,該等化合物包括(但不限於):(1)α-腎上腺素激導性藥劑;(2)抗心律不整藥;(3)抗動脈粥樣硬化劑,諸如ACAT抑制劑;(4)抗生素,諸如蒽環黴素(anthracycline)、博來黴素(bleomycin)、絲裂黴素(mitomycin)、更生黴素(dactinomycin)及普卡黴素(plicamycin);(5)抗癌劑及細胞毒性劑,例如烷基化劑,諸如氮芥、烷基磺酸鹽、亞硝基脲、乙烯亞胺及三氮烯;(6)抗凝血劑,諸如醋硝香豆素(acenocoumarol)、阿加曲班(argatroban)、比伐盧定(bivalirudin)、來匹盧定(lepirudin)、方達珀魯(fondaparinux)、肝素(heparin)、苯茚二酮(phenindione)、華法令(warfarin)及希美加群(ximelagatran);(7)抗糖尿病劑,諸如雙胍(例如二甲雙胍(metformin))、葡糖苷酶抑制劑(例如阿卡波糖(acarbose))、胰島素、美格列奈(meglitinide)(例如瑞格列奈(repaglinide))、磺醯脲(例如格列美脲(glimepiride)、格列本脲(glyburide)及格列吡嗪(glipizide))、噻唑啶二酮(例如曲格列酮(troglitazone)、羅格列酮(rosiglitazone)及吡格列酮(pioglitazone))及PPAR-γ促效劑;(8)抗真菌劑,諸如阿莫羅芬(amorolfine)、兩性黴素B(amphotericin B)、阿尼芬淨(anidulafungin)、聯苯苄唑(bifonazole)、布替萘芬(butenafine)、布康唑(butoconazole)、卡泊芬淨(caspofungin)、環吡酮(ciclopirox)、克黴唑(clotrimazole)、益康唑(econazole)、芬替康唑(fenticonazole)、非律平(filipin)、氟康唑(fluconazole)、異康唑(isoconazole)、伊曲康唑(itraconazole)、酮康唑(ketoconazole)、米卡芬淨(micafungin)、咪康唑(miconazole)、萘替芬(naftifine)、遊黴素(natamycin)、制黴菌素(nystatin)、奧昔康唑(oxyconazole)、雷夫康唑(ravuconazole)、泊沙康唑(posaconazole)、龜裂殺菌素(rimocidin)、舍他康唑(sertaconazole)、硫康唑(sulconazole)、特比萘芬(terbinafine)、特康唑(terconazole)、噻康唑(tioconazole)及伏立康唑(voriconazole);(9)消炎劑,例如非類固醇消炎劑,諸如醋氯芬酸(aceclofenac)、阿西美辛(acemetacin)、阿莫匹靈(amoxiprin)、阿司匹靈(aspirin)、阿紮丙宗(azapropazone)、貝諾酯(benorilate)、溴芬酸(bromfenac)、卡洛芬(carprofen)、塞內昔布(celecoxib)、膽鹼水楊酸鎂(choline magnesium salicylate)、雙氯芬酸(diclofenac)、二氟尼柳(diflunisal)、依託度酸(etodolac)、依託昔布(etoricoxib)、法伊西明(faislamine)、芬布芬(fenbufen)、非諾洛芬(fenoprofen)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、吲哚美辛(indometacin)、酮基布洛芬(ketoprofen)、酮咯酸(ketorolac)、氯諾昔康(lornoxicam)、洛索洛芬(loxoprofen)、盧米羅可(lumiracoxib)、甲氯芬那酸(meclofenamic acid)、甲芬那酸(mefenamic acid)、美儂西康(meloxicam)、安乃近(metamizole)、水楊酸甲酯(methyl salicylate)、水楊酸鎂(magnesium salicylate)、萘丁美酮(nabumetone)、萘普生(naproxen)、尼美舒利(nimesulide)、羥布宗(oxyphenbutazone)、帕瑞昔布(parecoxib)、苯基丁氮酮(phenylbutazone)、吡羅昔康(piroxicam)、雙水楊酯(salicyl salicylate)、舒林酸(sulindac)、苯磺唑酮(sulfinpyrazone)、舒洛芬(suprofen)、替諾昔康(tenoxicam)、噻洛芬酸(tiaprofenic acid)及托美丁(tolmetin);(10)抗代謝物,諸如葉酸鹽拮抗劑、嘌呤類似物及嘧啶類似物;(11)抗血小板劑,諸如GPIIb/IIIa阻斷劑(例如阿昔單抗、埃替菲巴肽及替羅非班)、P2Y(AC)拮抗劑(例如氯吡格雷、噻氯匹定及CS-747)及阿司匹靈;(12)抗增生劑,諸如甲胺喋呤(methotrexate)、FK506(他克莫司(tacrolimus))及黴酚酸嗎啉乙酯(mycophenolate mofetil);(13)抗TNF抗體或可溶性TNF受體,諸如依那西普(etanercept)、雷帕黴素(rapamycin)及來氟米特(leflunimide);(14)aP2抑制劑;(15)β-腎上腺素激導性藥劑,諸如卡維地洛(carvedilol)及美托洛爾(metoprolol);(16)膽汁酸錯隔劑,諸如降膽敏(questran);(17)鈣通道阻斷劑,諸如苄磺酸胺氯地平(amlodipine besylate);(18)化學治療劑;(19)環加氧酶-2(COX-2)抑制劑,諸如塞內昔布(celecoxib)及羅非昔布(rofecoxib);(20)環孢素(cyclosporin);(21)細胞毒性藥,諸如硫唑嘌呤(azathioprine)及環磷醯胺(cyclophosphamide);(22)利尿劑,諸如氯噻嗪(chlorothiazide)、氫氯噻嗪(hydrochlorothiazide)、氟甲噻嗪(flumethiazide)、氫氟噻嗪(hydroflumethiazide)、苄氟噻嗪(bendroflumethiazide)、甲氯噻嗪(methylchlorothiazide)、三氯噻嗪(trichloromethiazide)、多噻嗪(polythiazide)、苯并噻嗪(benzothiazide)、依他尼酸(ethacrynic acid)、替尼酸(ticrynafen)、氯噻酮(chlorthalidone)、呋喃苯胺酸(furosenide)、莫唑胺(muzolimine)、布美他尼(bumetanide)、胺苯喋啶(triamterene)、胺氯吡脒(amiloride)及螺內酯(spironolactone);(23)內皮素轉化酶(ECE)抑制劑,諸如磷胺米酮(phosphoramidon);(24)酶,諸如L-天冬醯胺酶;(25)因子VIIa抑制劑及因子Xa抑制劑;(26)法呢基(farnesyl)-蛋白質轉移酶抑制劑;(27)纖維酸酯;(28)生長因子抑制劑,諸如PDGF活性之調節劑;(29)生長激素促泌素;(30)HMG CoA還原酶抑制劑,諸如普伐他汀(pravastatin)、洛伐他汀(lovastatin)、阿托伐他汀(atorvastatin)、辛伐他汀(simvastatin)、NK-104(亦稱為伊伐他汀(itavastatin)、尼伐他汀(nisvastatin)或尼巴他汀(nisbastatin))及ZD-4522(亦稱為羅素他汀(rosuvastatin)、阿托伐他汀(atavastatin)或維薩他汀(visastatin));中性肽鏈內切酶(NEP)抑制劑;(31)激素劑,諸如糖皮質激素(例如可的松(cortisone))、雌激素/抗雌激素、雄激素/抗雄激素、助孕素及促黃體素釋放激素拮抗劑及乙酸奧曲肽(octreotide acetate);(32)免疫抑制劑;(33)鹽皮質素受體拮抗劑,諸如螺內酯及依普利酮(eplerenone);(34)微管破壞劑,諸如海鞘素(ecteinascidin);(35)微管穩定劑,諸如太平洋紫杉醇(pacitaxel)、多西他賓(docetaxel)及埃坡黴素(epothilone)A-F;(36)MTP抑制劑;(37)煙酸;(38)磷酸二酯酶抑制劑,諸如PDE III抑制劑(例如西洛他唑(cilostazol))及PDE V抑制劑(例如西地那非(sildenafil)、他達那非(tadalafil)及伐地那非(vardenafil));(39)植物來源之產物,諸如長春花生物鹼(vinca alkaloid)、表鬼臼素(epipodophyllotoxin)及紫杉烷(txane);(40)血小板活化因子(PAF)拮抗劑;(41)鉑配位錯合物,諸如順鉑(cisplatin)、撒塔鉑(satraplatin)及卡鉑(carboplatin);(42)鉀通道開啟劑;(43)異戊二烯基-蛋白質轉移酶抑制劑;(44)蛋白質酪胺酸激酶抑制劑;(45)腎素抑制劑;(46)角鯊烯合成酶抑制劑;(47)類固醇,諸如醛固酮、倍氯米松(beclometasone)、倍他米松(betamethasone)、乙酸去氧皮質酮(deoxycorticosterone acetate)、氟氫可的松(fludrocortisone)、氫皮質酮(hydrocortisone)(皮質醇)、潑尼龍(prednisolone)、潑尼松(prednisone)、甲潑尼龍(methylprednisolone)、地塞米松(dexamethasone)及曲安西龍(triamcinolone);(48)TNF-α抑制劑,諸如替尼達普(tenidap);(49)凝血酶抑制劑,諸如水蛭素(hirudin);(50)溶血栓藥,諸如阿尼普酶(anistreplase)、瑞替普酶(reteplase)、替奈普酶(tenecteplase)、組織血纖維蛋白溶酶原活化劑(tPA)、重組tPA、鏈激酶、尿激酶、尿激酶原及對甲氧苯甲醯基化血纖維蛋白溶酶原鏈激酶活化劑複合物(APSAC);(51)血栓素受體拮抗劑,諸如伊非曲班(ifetroban);(52)拓撲異構酶抑制劑;(53)血管肽酶(vasopeptidase)抑制劑(雙重NEP-ACE抑制劑),諸如奧帕曲拉(omapatrilat)及古莫曲拉(gemopatrilat);及(54)其他藥劑,諸如羥基脲、丙卡巴肼(procarbazine)、米托坦(mitotane)、六甲蜜胺(hexamethylmelamine)及金化合物。
該等其他藥劑或藥物可藉由其常用途徑及量,與本文所提供之化合物(例如式I化合物,包括其單一對映異構體、對映異構體之混合物或非對映異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物或前藥)同時或依序投與。當本文所提供之化合物與一或多種其他藥物同時使用時,可利用除本文所提供之化合物外亦含該等其他藥物之醫藥組合物,但並非必需。因此,本文所提供之醫藥組合物包括除本文所提供之化合物外亦含有一或多種其他活性成分或治療劑的醫藥組合物。
本文所提供之化合物與第二活性成分的重量比可改變且將視各成分之有效劑量而定。通常,將使用每一者之有效劑量。因此,舉例而言,當本文所提供之化合物與NSAID組合時,化合物與NSAID之重量比可在約1,000:1至約1:1,000或約200:1至約1:200之範圍內。本文所提供之化合物與其他活性成分的組合通常亦在上述範圍內,但在各種情況下,應使用各活性成分之有效劑量。
本文所提供之化合物亦可以使用熟習此項技術者所熟知之包裝材料的製品形式提供。參見例如美國專利第5,323,907號;第5,052,558號;及第5,033,252號。醫藥包裝材料之實例包括(但不限於)發泡包裝、瓶子、試管、吸入器、泵、袋、小瓶、容器、注射器及任何適合於所選調配物及預定投藥及治療模式之包裝材料。
本文亦提供套組,當由醫師使用時,其可使向個體投與適量活性成分變得簡單。在某些實施例中,本文所提供之套組包括容器及本文所提供化合物(包括其單一對映異構體或非對映異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物或前藥)之劑型。
在某些實施例中,該套組包括包含本文所提供化合物(包括其單一對映異構體或非對映異構體之混合物;或其醫藥學上可接受之鹽、溶劑合物或前藥)之劑型的容器,在容器中包含一或多種本文所述之其他治療劑。
本文所提供之套組可進一步包括用於投與活性成分之裝置。該等裝置之實例包括(但不限於)注射器、無針注射器滴液袋、貼片及吸入器。本文所提供之套組亦可包括用於投與活性成分之保險套。
本文所提供之套組可進一步包括可用於投與一或多種活性成分之醫藥學上可接受之媒劑。舉例而言,若活性成分以必須復原以供非經腸投與之固體形式提供,則套組可包含具有適合媒劑之密封容器,活性成分可溶解於該媒劑中以形成適合於非經腸投與之無微粒無菌溶液。醫藥學上可接受之媒劑的實例包括(但不限於):水性媒劑,包括(但不限於)注射用水USP、氯化鈉注射液、林格氏注射液、右旋糖注射液、右旋糖及氯化鈉注射液、及乳酸鹽林格氏注射液;水可混溶性媒劑,包括(但不限於)乙醇、聚乙二醇及聚丙二醇;及非水性媒劑,包括(但不限於)玉米油、棉籽油、花生油、芝麻油、油酸乙酯、十四烷酸異丙酯及苯甲酸苯甲酯。
本發明將進一步藉由以下非限制性實例來瞭解。
實例
如本文中所使用,此等方法、流程及實例中所用之符號及慣例無論是否具體定義特定縮寫,均與當代科學文獻(例如Journal of the American Chemical Society或Journal of Biological Chemistry)中所用之彼等縮寫一致。具體而言(但不限於),以下縮寫可用於實例及整個說明書中:g(公克);mg(毫克);mL(毫升);μL(微升);mM(毫莫耳濃度);μM(微莫耳濃度);Hz(赫茲);MHz(兆赫);mmol(毫莫耳);hr或hrs(小時);min(分鐘);MS(質譜法);ESI(電噴霧電離);TLC(薄層層析);HPLC(高壓液相層析);THF(四氫呋喃);CDCl3
(氘化三氯甲烷);DMSO(二甲亞碸);DMSO-d 6
(氘化二甲亞碸);EtOAc(乙酸乙酯);及MeOH(甲醇)。
對於所有以下實例,可利用熟習此項技術者已知之標準處理及純化方法。除非另有指示,否則所有溫度均以℃(攝氏度)表示。除非另作說明,否則所有反應均於室溫下進行。本文所說明之合成方法意欲經由使用特定實例來例示適用化學且並不指示本發明之範疇。
實例1製備4-(3,5-二甲基苯氧基)-3-(4-丙醯基哌嗪-1-基磺醯基)苯甲腈57
如流程2中所示合成化合物57
。
4-(3,5-二甲基苯氧基)-3-硝基苯甲腈21
。向4-氯-3-硝基苯甲腈(12.00 g,65.75 mmol)之THF溶液中添加碳酸鉀(45.58 g,328.70 mmol)及3,5-二甲基苯酚(9.658 g,78.88 mmol)。使反應混合物回流17小時,隨之起始物質耗盡(TLC,25% EtOAc之己烷溶液)。接著使反應混合物冷卻至室溫,且過濾碳酸鉀並用大量EtOAc洗滌。依序用飽和碳酸氫鈉溶液、水及飽和氯化鈉溶液洗滌濾液,經無水MgSO4
乾燥,過濾,且於真空中濃縮,得到呈黃色固體狀之粗產物。用己烷濕磨固體且過濾,得到呈帶白色黃色粉末狀之化合物21
。(15.022 g,85.2%產率,100% HPLC純度)。1
H NMR(500 MHz,DMSO-d 6
):δ8.65(d,J
=2 Hz,1H),8.06(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.12(d,J
=9 Hz,1H),6.97(s,1H),6.84(s,2H),2.29(s,6H)。
3-胺基-4-(3,5-二甲基苯氧基)苯甲腈22
。向化合物21
(15.00 g,55.91 mmol)於THF(250 mL)中之溶液中添加亞硫酸氫鈉(58.41 g,335.5 mmol)於水(75 mL)中之溶液。於90℃下攪拌反應混合物。24小時後,如利用TLC(10% EtOAc之己烷溶液)所監測,起始物質耗盡,且不再加熱反應混合物。於真空中濃縮反應混合物直至產物在殘餘水中沈澱。經由真空過濾收集沈澱物且用水洗滌。於40℃下於真空中乾燥產物隔夜,得到化合物22
。(12.681 g,95.2%產率,99.9% HPLC純度)。1
H NMR(500 MHz,DMSO-d 6
):δ7.08(d,J
=2 Hz,1H),6.91(dd,J 1
=8 Hz,J 2
=2 Hz,1H),6.80(s,1H),6.73(d,J
=8 Hz,1H),6.63(s,2H),5.47(s,2H),2.24(s,6H)。
5-氰基-2-(3,5-二甲基苯氧基)苯-1-磺醯氯23
。於室溫下將化合物22
(12.00 g,50.36 mmol)添加至H2
O(50.0 mL)及濃HCl(100 mL)中。接著於冰浴中攪拌反應混合物。於0℃下將含亞硝酸鈉(10.434 g,151.1 mmol)之H2
O(50 mL)逐滴添加至反應混合物中。於冰浴中攪拌反應混合物1小時。在另一燒瓶中,使二氧化硫鼓泡穿過乙酸(430 mL)維持45分鐘。接著將二水合氯化銅(4.305 g,25.2 mmol)添加至此二氧化硫飽和溶液中,且再攪拌30分鐘。接著於冰浴中再攪拌此飽和二氧化硫溶液5分鐘。接著將含有化合物22
之反應混合物逐滴添加至氯化銅溶液中。添加完成後,再攪拌溶液1小時且接著緩慢傾倒於冰水漿料上並攪拌1小時。接著過濾所得沈澱物且用水清洗黃色固體,得到化合物23
(13.944 g,86.1%產率)。1
H NMR(500 MHz,DMSO-d 6
):δ 8、06(d,J
=2 Hz,1H),7.71(dd,J 1
=8 Hz,J 2
=2 Hz,1H),6.85(s,1H),6.81(d,J
=9 Hz,1H),6.66(s,2H),2.26(s,6H)。
4-(3,5-二甲基苯氧基)-3-(哌嗪-1-基磺醯基)苯甲腈24
。經兩天時間向在冰鹽水浴中攪拌之哌嗪(16.144 g,186.4 mmol)於CH2
Cl2
(80 mL)中之溶液中逐滴添加化合物23
(3.009 g,9.35 mmol)於CH2
Cl2
(270 mL)中之溶液。接著攪拌反應物74小時,隨之起始物質耗盡(TLC,5% MeOH之CH2
Cl2
溶液)。使反應混合物分配於CH2
Cl2
與水之間。接著用飽和氯化鈉溶液洗滌有機層且經無水MgSO4
乾燥。接著於真空中濃縮有機層,再溶解於最少量之CH2
Cl2
中,且進行正相二氧化矽層析(MeOH/CH2
Cl2
)。合併含有所需產物之溶離份且於真空中濃縮,得到淡黃色油狀物。接著該油狀物用CH2
Cl2
/二異丙醚濕磨且真空過濾,得到呈白色粉末狀之化合物24
(2.032 g,58.5%產率,95.5% HPLC純度)。1
H NMR(500 MHz,DMSO-d 6
):δ 8.21(d,J
=2 Hz,1H),8.03(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.01(m,1H),6.96(d,J
=11 Hz,1H),6.80(d,J
=9 Hz,2H),3.19(m,2H),3.11(m,2H),2.70(m,2H),2.46(m,2H),2.30(s,1H),2.27(s,6H)。
4-(3,5-二甲基苯氧基)-3-(4-丙醯基哌嗪-1-基磺醯基)苯甲腈57
。向化合物24
(0.102 g,0.27 mmol)於CH2
Cl2
(2 mL)中之溶液中添加丙醯氯(0.035 g,0.38 mmol)及三乙胺(0.039 g,0.38 mmol)。於室溫下攪拌反應混合物20小時,隨之起始物質耗盡(TLC,1% MeOH之CH2
Cl2
溶液)。於真空中濃縮反應混合物,再溶解於最少量之CH2
Cl2
中,且進行正相二氧化矽層析(MeOH/CH2
Cl2
)。合併含有所需產物之溶離份且於真空中濃縮,得到白色粉末,接著該白色粉末用CH2
Cl2
/二異丙醚濕磨且真空過濾,得到呈粉末狀之所需產物。將該粉末再溶解於CH2
Cl2
中且進行第二次正相二氧化矽層析(MeOH/CH2
Cl2
)。合併含有所需產物之溶離份且於真空中濃縮,得到白色粉末。該粉末用二異丙醚濕磨且真空過濾,得到化合物57
(0.061 g,52.1%產率,96.6% HPLC純度)。1
H NMR(500 MHz,CDCl3
):8.27(d,J=
2 Hz,1H),7.67(dd,J 1
=9 Hz,J 2
=2 Hz,1H),6.94(s,1H),6.90(d,J
=9 Hz,1H),6.68(s,2H),3.71(m,2H),3.54(m,2H),3.35(m,4H),2.34(s,6H),2.32(m,2H),1.13(t,J
=7 Hz,3H);MS(ESI,EI+
):m/z
=428(MH+
)。
根據如本實例中所述之程序製備以下化合物。
4-(3,5-二甲基苯氧基)-3-(4-(4-(三氟甲基)苯甲醯基)哌嗪-1-基磺醯基)苯甲腈54
。HPLC純度:96.6%;1
H NMR(500 MHz,DMSO-d 6
): 8.23(d,J
=2 Hz,1H),8.05(dd,J 1
=9Hz,J 2
=2 Hz,1H),7.80(d,J
=8 Hz,2H),7.62(d,J
=8 Hz,2H),7.03(d,J
=9 Hz,1H),6.97(s,1H),6.86(s,2H),3.71(m,2H),3.35(m,4H),3.26(m,2H),2.30(s,6H);MS(ESI,EI+
):m/z
=544(MH+
)。
3-(4-苯甲醯基哌嗪-1-基磺醯基)-4-(3,5-二甲基苯氧基)苯甲腈55
。HPLC純度:95.5%;1
H NMR(500 MHz,DMSO-d 6
): 8.23(d,J
=2 Hz,1H),8.05(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7、42(m,5H),7.02(d,J
=9 Hz,1H),6.97(s,1H),6.87(s,2H),3.68(m,2H),3.38(m,2H),3.30(m,4H),2.30(s,6H);MS(ESI,EI+
):m/z
=478(MH+
)。
3-(4-(2,2-二甲基丁醯基)哌嗪-1-基磺醯基)-4-(3,5-二甲基苯氧基)苯甲腈59
。HPLC純度:92.2%;1
H NMR(500 MHz,CDCl3
):8.27(d,J
=2 Hz,1H),7.67(dd,J 1
=9 Hz,J 2
=2 Hz,1H),6.93(s,1H),6.90(d,J
=9 Hz,1H),6.67(s,2H),3.72(m,4H),3.34(m,4H),2.33(s,6H),1.60(m,2H),1.21(s,6H),0.85(t,J
=7 Hz,3H);MS(ESI,EI+
):m/z=
470(MH+
)。
4-(3,5-二甲基苯氧基)-3-(4-特戊醯基哌嗪-1-基磺醯基)苯甲腈63
。HPLC純度:98.8%;1
H NMR(500 MHz,CDCl3
): 8.27(d,J
=2 Hz,1H),7.67(dd,J 1
=9 Hz,J 2
=2 Hz,1H),6.93(s,1H),6.90(d,J
=9 Hz,1H),6.68(s,2H),3.72(m,4H),3.34(m,4H),2.33(s,6H),1.25(s,9H);MS(ESI,EI+
):m/z
=456(MH+
)。
3-(4-(環丁烷羰基)哌嗪-1-基磺醯基)-4-(3,5-二甲基苯氧基)苯甲腈64
。HPLC純度:97.4%;1
H NMR(500 MHz,CDCl3
): 8.26(d,J
=2 Hz,1H),7.67(dd,J 1
=9 Hz,J 2
=2 Hz,1H),6.93(s,1H),6.90(d,J
=9 Hz,1H),6.67(s,2H),3.69(m,2H),3.42(m,2H),3.30(m,4H),3.21(m,1H),2.33(s,6H),2.29(m,2H),2.12(m,2H),1.96(m,1H),1.85(m,1H);MS(ESI,EI+
): m/z=454(MH+
)。
3-(4-(環己烷羰基)哌嗪-1-基磺醯基)-4-(3,5-二甲基苯氧基)苯甲腈65
。HPLC純度:97.9%;1
H NMR(500 MHz,CDCl3
): 8.27(d,J
=2 Hz,1H),7.67(dd,J 1
=9 Hz,J 2
=2 Hz,1H),6.94(s,1H),6.90(d,J
=9 Hz,1H),6.68(s,2H),3.70(m,2H),3.57(m,2H),3.34(m,4H),2.41(m,1H),2.33(s,6H),1.79(m,2H),1.66(m,3H),1.50(m,2H),1.24(m,3H);MS(ESI,EI+
): m/z=482(MH+
)。
4-(3,5-二甲基苯氧基)-3-(4-(3-甲基丁醯基)哌嗪-1-基磺醯基)苯甲腈66
。HPLC純度:100%;1
H NMR(500 MHz,CDCl3
): 8.27(d,J
=2 Hz,1H),7.67(dd,J 1
=9 Hz,J 2
=2 Hz,1H),6.94(s,1H),6.90(d,J
=9 Hz,1H),6.68(s,2H),3.72(m,2H),3.55(m,2H),3.34(m,4H),2.33(s,6H),2.19(d,J
=7 Hz,2H),2.09(m,1H),0.95(d,J
=7 Hz,6H);MS(ESI,EI+
): m/z=456(MH+
)。
3-(4-(3,3-二甲基丁醯基)哌嗪-1-基磺醯基)-4-(3,5-二甲基苯氧基)苯甲腈67
。HPLC純度:98.5%;1
H NMR(500 MHz,CDCl3
): 8.27(d,J
=2 Hz,1H),7.67(dd,J 1
=9 Hz,J 2
=2 Hz,1H),6.94(s,1H),6.90(d,J
=9 Hz,1H),6.68(s,2H),3.73(m,2H),3.58(m,2H),3.35(m,4H),2.33(s,6H),2.24(s,2H),1.03(s,9H)。
3-(4-(環戊烷羰基)哌嗪-1-基磺醯基)-4-(3,5-二甲基苯氧基)苯甲腈68
。HPLC純度:95.3%;1
H NMR(500 MHz,CDCl3
):8.27(d,J
=2 Hz,1H),7.67(dd,J 1
=9 Hz,J 2
=2 Hz,1H),6.94(s,1H),6.90(d,J
=9 Hz,1H),6.68(s,2H),3.72(m,2H),3.60(m,2H),3.34(m,4H),2.84(m,1H),2.33(s,6H),1.78(m,4H),1.70(m,2H),1.58(m,2H);MS(ESI,EI+
):m
/z
=468(MH+
)。
4-(3,5-二氯苯氧基)-3-(4-(4-(三氟甲基)苯甲醯基)哌嗪-1-基磺醯基)苯甲腈69
。HPLC純度:99.1%;1
H NMR(500 MHz,CDCl3
): 8.29(d,J
=2 Hz,1H),7.81(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.70(d,J
=8 Hz,2H),7.50(d,J
=8 Hz,2H),7.30(t,J
=2 Hz,1H),7.04(d,J
=9 Hz,1H),6.98(s,2H),3.89(m,2H),3.48(m,4H),3.29(m,2H);MS(ESI,EI+
):m
/z
=589(MH+
)。
3-(4-苯甲醯基哌嗪-1-基磺醯基)-4-(3,5-二氯苯氧基)苯甲腈70
。HPLC純度:96.8%;1
H NMR(500 MHz,CDCl3
): 8.29(d,J
=2 Hz,1H),7.80(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.45(m,3H),7.37(m,2H),7.30(s,1H),7.04(d,J
=9 Hz,1H),6.99(s,2H),3.85(m,2H),3.64(m,2H),3.36(m,4H);MS(ESI,EI+
):m
/z
=517(MH+
)。
4-(3,5-二氯苯氧基)-3-(4-(3,3-二甲基丁醯基)哌嗪-1-基磺醯基)苯甲腈71
。HPLC純度:99.3%;1
H NMR(500MHz,CDCl3
):8.30(d,J
=2 Hz,1H),7.80(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.29(s,1H),7.02(d,J
=9 Hz,1H),6.97(s,2H),3.73(m,2H),3.59(m,2H),3.31(m,4H),2.24(s,2H),1.03(s,9H);MS(ESI,EI+
):m/z
=511(MH+
)。
4-(3,5-二氯苯氧基)-3-(4-(3-甲基丁醯基)哌嗪-1-基磺醯基)苯甲腈72。HPLC純度:99.1%;1
H NMR(500 MHz,CDCl3
):8.30(d,J
=2 Hz,1H),7.80(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.30(t,J
=2 Hz,1H),7.02(d,J
=9 Hz,1H),6.98(d,J
=2 Hz,2H),3.72(m,2H),3.57(m,2H),3.31(m,4H),2.19(d,J
=7 Hz,2H),2.09(m,1H),0.95(d,J
=7 Hz,6H);MS(ESI,EI+
):m/z
=497(MH+
)。
3-(4-(環丁烷羰基)哌嗪-1-基磺醯基)-4-(3,5-二氯苯氧基)苯甲腈73
。HPLC純度:96.6%;1
H NMR(500 MHz,CDCl3
):8.29(d,J
=2 Hz,1H),7.79(dd,J 1
=8 Hz,J 2
=2 Hz,1H),7.30(t,J
=2 Hz,1H),7.02(d,J
=9 Hz,1H),6.97(d,J
=2 Hz,2H),3.70(m,2H),3.43(m,2H),3.28(m,4H),3.22(m,1H),2.32(m,2H),2.14(m,2H),1.97(m,1H),1.86(m,1H);MS(ESI,EI+
):m/z
=495(MH+
)。
3-(4-(環戊烷羰基)哌嗪-1-基磺醯基)-4-(3,5-二氯苯氧基)苯甲腈74
。HPLC純度:97.5%;1
H NMR(500 MHz,CDCl3
):8.30(d,J
=2 Hz,1H),7.80(dd,J 1
=8 Hz,J 2
=2 Hz,1H),7.30(t,J
=2 Hz,1H),7.03(d,J
=9 Hz,1H),6.98(d,J
=2 Hz,2H),3.72(m,2H),3.61(m,2H),3.31(m,4H),2.84(m,1H),1.80(m,4H),1.74(m,2H),1.57(m,2H);MS(ESI,EI+
):m/z
=509(MH+
)。
3-(4-(4-氯苯甲醯基)哌嗪-1-基磺醯基)-4-(3,5-二氯苯氧基)苯甲腈78
。HPLC純度:94.4%;1
H NMR(500 MHz,CDCl3
): 8.29(d,J
=2 Hz,1H),7.81(dd,J 1
=8 Hz,J 2
=2 Hz,1H),7.40(m,2H),7.33(m,2H),7.30(t,J
=2 Hz,1H),7.04(d,J
=9 Hz,1H),6.98(s,2H),3.70(m,4H),3.35(m,4H);MS(ESI,EI+
):m/z
=551(MH+
)。
3-(4-(3-氯苯甲醯基)哌嗪-1-基磺醯基)-4-(3,5-二氯苯氧基)苯甲腈81
。HPLC純度:92.5%;1
H NMR(500 MHz,CDCl3
): 8.30(d,J
=2 Hz,1H),7.81(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.42(m,1H),7.35(m,2H),7.30(t,J
=2 Hz,1H),7.26(m,1H),7.04(d,J
=9 Hz,1H),6.99(d,J
=2 Hz,2H),3.85(m,2H),3.55(m,2H),3.38(m,4H);MS(ESI,EI+
):m/z
=551(MH+
)。
4-(3,5-二氯苯氧基)-3-(4-(4-甲基苯甲醯基)哌嗪-1-基磺醯基)苯甲腈82
。HPLC純度:91.7%;1
H NMR(500 MHz,CDCl3
): 8.29(d,J
=2 Hz,1H),7.80(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.29(m,3H),7.21(d,J
=8 Hz,2H),7.03(d,J
=9 Hz,1H),6.98(d,J
=2 Hz,2H),3.70(m,4H),3.33(m,4H),2.38(s,3H);MS(ESI,EI+
):m/z
=531(MH+
)。
4-(3,5-二氯苯氧基)-3-(4-(2-甲基苯甲醯基)哌嗪-1-基磺醯基)苯甲腈83
。HPLC純度:90.1%;1
H NMR(500 MHz,CDCl3
): 8.29(d,J
=2 Hz,1H),7.80(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.30(m,2H),7.22(m,2H),7.11(d,J
=7 Hz,1H),7.03(d,J
=9 Hz,1H),6.98(d,J
=2 Hz,2H),3.99(m,1H),3.83(m,1H),3.47(m,1H),3.36(m,3H),3.22(m,2H),2.27(s,3H);MS(ESI,EI+
):m/z
=531(MH+
)。
3-(4-(2-氯苯甲醯基)哌嗪-1-基磺醯基)-4-(3,5-二氯苯氧基)苯甲腈84
。HPLC純度:98.6%;1
H NMR(500 MHz,CDCl3
): 8.30(d,J
=2 Hz,1H),7.80(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.41(m,1H),7.35(m,3H),7.26(m,1H),7.02(d,J
=9 Hz,1H),6.99(d,J
=2 Hz,2H),4.11(m,1H),3.73(m,1H),3.53(m,1H),3.33(m,5H);MS(ESI,EI+
):m/z
=551(MH+
)。
4-(3,5-二氯苯氧基)-3-(4-(2-氟苯甲醯基)哌嗪-1-基磺醯基)苯甲腈85
。HPLC純度:98.6%;1
H NMR(500 MHz,CDCl3
): 8.30(d,J
=2 Hz,1H),7.80(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.43(m,1H),7.41(m,1H),7.30(s,1H),7.23(m,1H),7.10(t,J
=9 Hz,1H),7.03(d,J
=9 Hz,1H),7.00(d,J
=2 Hz,2H),3.90(m,2H),3.43(m,4H),3.33(m,2H);MS(ESI,EI+
):m/z
=535(MH+
)。
4-(3,5-二氯苯氧基)-3-(4-(3-氟苯甲醯基)哌嗪-1-基磺醯基)苯甲腈86
。HPLC純度:98%;1
H NMR(500 MHz,CDCl3
): 8.29(d,J
=2 Hz,1H),7.81(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.41(m,1H),7.30(s,1H),7.16(m,2H),7.09(d,J
=9 Hz,1H),7.04(d,J
=9 Hz,1H),6,99(s,2H),3.85(m,2H),3.55(m,2H),3.36(m,4H);MS(ESI,EI+
):m/z
=535(MH+
)。
4-(3,5-二氯苯氧基)-3-(4-(4-氟苯甲醯基)哌嗪-1-基磺醯基)苯甲腈87
。HPLC純度:98%;1
H NMR(500 MHz,CDCl3
):8.29(d,J
=2 Hz,1H),7.81(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.40(m,2H),7.30(s,1H),7.11(t,J
=9 Hz,2H),7.04(d,J
=9 Hz,1H),6.98(s,2H),3.71(m,4H),3.35(m,4H);MS(ESI,EI+
):m/z
=535(MH+
)。
4-(3,5-二甲基苯硫基)-3-(4-(4-(三氟甲基)苯甲醯基)哌嗪-1-基磺醯基)苯甲腈88
。HPLC純度:98.9%;1
H NMR(500 MHz,CDCl3
): 8.18(d,J
=2 Hz,1H),7.70(d,J
=8 Hz,2H),7.52(d,J
=8 Hz,2H),7.48(dd,J 1
=8 Hz,J 2
=2 Hz,1H),7.15(m,3H),6.95(d,J
=8 Hz,1H),3.92(m,2H),3.54(m,2H),3.48(m,2H),3.36(m,2H),2.36(s,6H);MS(ESI,EI+
):m/z
=560(MH+
)。
3-(4-苯甲醯基哌嗪-1-基磺醯基)-4-(3,5-二甲基苯硫基)苯甲腈89
。HPLC純度:98.7%;1
H NMR(500 MHz,CDCl3
): 8.18(d,J
=2 Hz,1H),7.47(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.42(m,5H),7.14(s,3H),6.95(d,J
=8 Hz,1H),3.90(m,2H),3.60(m,2H),3.40(m,4H),2.36(s,6H);MS(ESI,EI+
):m/z
=492(MH+
)。
4-(3,5-二甲基苯硫基)-3-(4-(4-甲基苯甲醯基)哌嗪-1-基磺醯基)苯甲腈90
。1
H NMR(500 MHz,CDCl3
): 8.17(d,J
=2 Hz,1H),7.47(dd,J 1
=8 Hz,J 2
=2 Hz,1H),7.29(d,J
=8 Hz,2H),7.22(d,J
=8 Hz,1H),7.15(m,3H),6.94(d,J
=8 Hz,1H),3.77(m,4H),3.39(m,4H),2.37(d,J
=8 Hz,9H);MS(ESI,EI+
):m/
z=506(MH+
)。
4-(3,5-二甲基苯硫基)-3-(4-(3-甲基苯甲醯基)哌嗪-1-基磺醯基)苯甲腈91
。1
H NMR(500 MHz,CDCl3
):8.18(d,J
=2 Hz,1H),7.47(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.26(m,3H),7.15(m,4H),6.95(d,J
=8 Hz,1H),3.88(m,2H),3.60(m,2H),3.40(m,4H),2.36(s,9H);MS(ESI,EI+
):m/z
=506(MH+
)。
4-(3,5-二甲基苯硫基)-3-(4-(2-甲基苯甲醯基)哌嗪-1-基磺醯基)苯甲腈92
。1
H NMR(500 MHz,CDCl3
):8.18(d,J
=2 Hz,1H),7.48(dd,J 1
=8 Hz,J 2
=2 Hz,1H),7.29(m,1H),7.23(m,2H),7.14(m,4H),6.96(d,J
=8 Hz,1H),4.02(m,1H),3.87(m,1H),3.52(m,1H),3.37(m,4H),3.26(m,1H),2.36(s,6H),2.29(s,3H);MS(ESI,EI+
):m/z
=506(MH+
)。
實例2製備4-(5-氰基-2-(3,5-二甲基苯氧基)苯基磺醯基)-N
-異丙基哌嗪-1-甲醯胺58
如流程3中所示合成化合物58
。
4-(5-氰基-2-(3,5-二甲基苯氧基)苯基磺醯基)-N
-異丙基哌嗪-1-甲醯胺58
。向化合物24
(0.100 g,0.27 mmol)於CH2
Cl2
(3 mL)中之溶液中添加異氰酸異丙酯(0.032 g,0.38 mmol)及三乙胺(0.039 g,0.38 mmol)。於室溫下攪拌反應物20小時,隨之起始物質耗盡(TLC,1% MeOH之CH2
Cl2
溶液)。接著於真空中濃縮反應混合物,再溶解於最少量之CH2
Cl2
中,且進行正相二氧化矽層析(MeOH/CH2
Cl2
)。合併含有所需產物之溶離份且於真空中濃縮,得到白色粉末,接著該白色粉末用CH2
Cl2
/己烷濕磨且真空過濾,得到粉末。將該粉末再溶解於CH2
Cl2
中且進行第二次正相二氧化矽層析(MeOH/CH2
Cl2
)。合併含有所需產物之溶離份且於真空中濃縮,得到白色粉末,接著該白色粉末用己烷濕磨且真空過濾,得到呈白色粉末狀之化合物58
(0.014 g,11.3%產率,99.1% HPLC純度)。1
H NMR(500 MHz,CDCl3
): 8.27(d,J
=2 Hz,1H),7.67(dd,J 1
=9 Hz,J 2
=2 Hz,1H) 6.93(s,1H),6.89(s,J
=9 Hz,1H),6.69(s,2H),4.17(m,1H),3.95(m,1H),3.44(m,4H),3.35(m,4H),2.34(s,6H),1.14(d,J
=7 Hz,6H);MS(ESI,EI+
):m
/z
=457(MH+
)。
根據如本實例中所述之程序製備以下化合物。
4-(5-氰基-2-(3,5-二甲基苯氧基)苯基磺醯基)-N
-(3-氟苯基)哌嗪-1-甲醯胺61
。HPLC純度:99.2%;1
H NMR(500 MHz,CDCl3
): 8.28(d,J
=2 Hz,1H),7.68(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.25(m,1H),7.20(m,1H),6.97(dd,J 1
=8 Hz,J 2
=2 Hz,1H),6.94(s,1H),6.91(d,J
=9 Hz,1H),6.74(m,1H),6.70(s,2H),6.43(s,1H),3.59(m,4H),3.42(m,4H),2.33(s,6H);MS(ESI,EI+
):m/z
=509(MH+
)。
4-(5-氰基-2-(3,5-二甲基苯氧基)苯基磺醯基)-N
-(4-乙基苯基)哌嗪-1-甲醯胺62
。HPLC純度:98.7%;1
H NMR(500 MHz,CDCl3
): 8.28(d,J
=2 Hz,1H),7.68(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.20(m,2H),7.11(d,J
=8 Hz,2H),6.93(s,1H),6.90(d,J
=9 Hz,1H),6.70(s,2H),6.28(s,1H),3.57(m,4H),3.41(m,4H),2.59(q,J 1
=15 Hz,J 2
=8 Hz,2H),2.33(s,6H),1.20(t,J
=8 Hz,3H);MS(ESI,EI+
):m/z
=519(MH+
)。
4-(5-氰基-2-(3,5-二氯苯氧基)苯基磺醯基)-N
-(3-氟苯基)哌嗪-1-甲醯胺75
。HPLC純度:97%;1
H NMR(500 MHz,CDCl3
): 8.31(d,J
=2 Hz,1H),7.80(dd,J 1
=9 Hz,J 2
=2 Hz,1H) 7.30(t,J
=2 Hz,1H),7.27(m,1H),7.23(m,1H),7.03(d,J
=9 Hz,1H),7.00(d,J
=2 Hz,2H),6.97(m,1H),6.75(m,1H),6.37(s,1H),3.61(m,4H),3.40(m,4H);MS(ESI,EI+
):m/z
=550(MH+
)。4-(5-氰基-2-(3,5-二氯苯氧基)苯基磺醯基)-N
-異丙基哌嗪-1-甲醯胺80
。HPLC純度:99.4%;1
H NMR(500 MHz,CDCl3
): 8.30(d,J
=2 Hz,1H),7.79(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.29(t,J
=2 Hz,1H),7.02(d,J
=9 Hz,1H),6.98(d,J
=2 Hz,2H),4.18(d,J
=7 Hz,1H),3.95(m,1H),3.45(m,4H),3.32(m,4H),1.15(d,J
=7 Hz,6H);MS(ESI,EI+
):m
/z
=498(MH+
)。4-(5-氰基-2-(3,5-二氯苯硫基)苯基磺醯基)哌嗪-1-甲酸乙酯94
。1
H NMR(500 MHz,CDCl3
): 8.29(d,J
=2 Hz,1H),7.79(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.29(t,2 Hz,1H),7.02(d,J
=9 Hz,1H),6.98(s,2H),4.14(m,2H),3.57(m,4H),3.30(m,4H),1.25(t,J
=7 Hz,3H);MS(ESI,EI+
):m
/z
=525(MH+
)。
實例3製備4-(3,5-二甲基苯氧基)-3-(4-(4-(三氟甲基)苯基磺醯基)哌嗪-1-基磺醯基)苯甲腈60
如流程4中所示合成化合物60
。4-(3,5-二甲基苯氧基)-3-(4-(4-(三氟甲基)苯基磺醯基)哌嗪-1-基磺醯基)苯甲腈60
。向化合物24
(0.099 g,0.27 mmol)於CH2
Cl2
(3 mL)中之溶液中添加4-(三氟甲基)苯磺醯氯(0.093 g,0.38 mmol)及三乙胺(0.039 g,0.38 mmol)。於室溫下攪拌反應混合物18小時,隨之起始物質耗盡(TLC,1% MeOH之CH2
Cl2
溶液)。接著於真空中濃縮反應混合物,再溶解於最少量之CH2
Cl2
中,且進行正相二氧化矽層析(MeOH/CH2
Cl2
)。合併含有所需產物之溶離份且於真空中濃縮,得到白色固體。固體用二異丙醚/己烷濕磨且真空過濾,得到呈白色粉末狀之化合物60
。(0.065 g,42.2%產率,95.7% HPLC純度)。1
H NMR(500 MHz,CDCl3
): 8.23(d,J
=2 Hz,1H),7.86(m,4H),7.67(dd,J 1
=9 Hz,J 2
=2 Hz,1H),6.95(s,1H),6.89(d,J
=9 Hz,1H),6.68(s,2H),3.48(m,4H),3.15(m,4H),2.35(s,6H);MS(ESI,EI+
):m/z
=580(MH+
)。
根據如本實例中所述之程序製備以下化合物。
3-(4-((7,7-二甲基雙環[2.2.1]庚-1-基)甲磺醯基)哌嗪-1-基磺醯基)-4-(3,5-二甲基苯氧基)苯甲腈51
。HPLC純度:99.3%;1
H NMR(500 MHz,CDCl3
):δ
8.27(d,J
=2 Hz,1H),7.68(dd,J 1
=9 Hz,J 2
=2 Hz,1H),6.94(s,1H),6.90(d,J
=9 Hz,1H),6.71(s,2H),3.43(m,5H),3.32(d,J
=15Hz,1H),2.75(d,J
=15 Hz,1H),2.41(m,4H),2.34(s,6H),2.12(t,J
=4 Hz,1H),2.05(m,1H),1.94(d,J
=19 Hz,1H),1.63(m,1H),1.56(s,1H),1.43(m,1H),1.10(s,3H),0.87(s,3H);MS(ESI,EI+
):m/z
=586(MH+
)。
4-(3,5-二甲基苯氧基)-3-(4-(甲磺醯基)哌嗪-1-基磺醯基)苯甲腈52
。HPLC純度:97.2%;1
H NMR(500 MHz,DMSO-d 6
):δ8.25(d,J
=2 Hz,1H),8.04(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.00(d,J
=9 Hz,1H),6.98(s,1H),6.87(s,2H),3、36(t,J
=4 Hz,4H),3.19(t,J
=5 Hz,4H),2.90(s,3H),2.30(s,6H);MS(ESI,EI+
):m/z
=450(MH+
)。4-(3,5-二甲基苯氧基)-3-(4-甲苯磺醯基哌嗪-1-基磺醯基)苯甲腈53
。HPLC純度:98.2%;1
H NMR(500 MHz,DMSO-d 6
):δ8.19(d,J
=2 Hz,1H),8.01(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.60(d,J
=8 Hz,2H),7.45(d,J=8 Hz,2H),6.94(d,J
=9 Hz,2H),6.77(s,2H),3.35(m,4H),2.92(m,4H),2.41(s,3H),2.29(s,6H);MS(ESI,EI+
):m/z
=526(MH+
)。4-(3,5-二甲基苯氧基)-3-(4-(異丁基磺醯基)哌嗪-1-基磺醯基)苯甲腈56
。HPLC純度:97.9%;1
H NMR(500MHz,CDCl3
): 8.26(d,J
=2 Hz,1H),7.68(dd,J 1
=9 Hz,J 2
=2 Hz,1H),6.94(s,1H),6.90(d,J
=9 Hz,1H),6.70(s,2H),3.46(m,4H),3.35(m,4H),2.75(d,J
=7 Hz,2H),2.34(s,6H),2.28(m,1H),1.11(s,J
=7 Hz,6H);MS(ESI,EI+
):m/z
=492(MH+
)。4-(3,5-二氯苯氧基)-3-(4-(甲磺醯基)哌嗪-1-基磺醯基)苯甲腈76
。HPLC純度:88.5%;1
H NMR(500 MHz,CDCl3
):8.30(d,J
=2 Hz,1H),7.81(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.31(s,1H),7.03(d,J
=9 Hz,1H),7.00(d,J
=2 Hz,2H),3.46(m,4H),3.35(m,4H),2.82(s,3H);MS(ESI,EI+
):m/z
=491(MH+
)。4-(3,5-二氯苯氧基)-3-(4-甲苯磺醯基哌嗪-1-基磺醯基)苯甲腈77。HPLC純度:91.7%;1
H NMR(500 MHz,CDCl3
):8.25(d,J
=2 Hz,1H),7.78(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.61(d,J
=8 Hz,2H),7.36(d,J
=8 Hz,2H),7.30(t,J
=2 Hz,1H),7.00(d,J
=9 Hz,1H),6.97(dJ
=2 Hz,2H),3.43(m,4H),3.09(m,4H),2.46(s,3H);MS(ESI,EI+
):m/z
=567(MH+
)。4-(3,5-二氯苯氧基)-3-(4-(3-甲基苯甲醯基)哌嗪-1-基磺醯基)苯甲腈79。HPLC純度:90.2%;1
H NMR(500 MHz,CDCl3
):8.29(d,J
=2 Hz,1H),7.80(dd,J 1
=9 Hz,J 2
=2 Hz,1H),7.30(m,1H),7.25(m,2H),7.19(s,1H)7.14(d,J
=7 Hz,1H),7.04(d,J
=9 Hz,1H),6.99(d,J
=2 Hz,2H),3.85(m,2H),3.57(m,2H),3.36(m,4H),2.37(s,3H);MS(ESI,EI+
):m/z
=531(MH+
)。4-(3,5-二甲基苯硫基)-3-(4-(3-氟苯甲醯基)哌嗪-1-基磺醯基)苯甲腈93
。1
H NMR(500 MHz,CDCl3
):8.18(d,J
=2 Hz,1H),7.48(dd,J 1
=8 Hz,J2
=2 Hz,1H),7.28(s,1H),7.23(m,1H),7.14(s,3H),6.98(m,1H),6.94(d,J
=8 Hz,1H),6.75(m,1H),6.42(s,1H),3.64(m,4H),3.44(m,4H),2.36(s,6H);MS(ESI,EI+
):m/z
=525(MH+
)。
實例4製備1-(2-(2,5-二氯苯氧基)-5-硝基苯基磺醯基)哌嗪
如流程5中所示合成化合物40
。
2-氯-5-硝基苯-1-磺醯氯37
。向冰浴冷卻之濃HCl溶液(100 mL)中逐份添加2-氯-5-硝基苯胺(10 g)。當達成完全溶解時,逐滴添加亞硝酸鈉水溶液(6.0 g,於50 mL水中)且於0℃下攪拌所得反應混合物1小時。接著將以上所獲得之重氮鎓離子溶液小心地添加至冰浴冷卻之用二氧化硫氣體預飽和的二水合氯化銅(5 g)於乙酸(500 mL)中之混合物中。於0℃下攪拌所得反應混合物1小時後,在有力攪拌下將其小心地逐份添加至冰水漿料中。藉由抽吸收集分離之固體,用水清洗,且於真空下乾燥,產生呈乳白色粉末狀之所需產物37
(8.2 g,55%)。1
H NMR(500 MHz,DMSO-d 6
):δ8.61(d,J
=3 Hz,1H),8.16(dd,J 1
=9 Hz,J 2
=3 Hz,1H),7.70(d,J
=9 Hz,1H)。
4-(2-氯-5-硝基苯基磺醯基)哌嗪-1-甲酸第三丁酯38
。向化合物37
(0.600 g,2.34 mmol)於DCM(20.00 mL)中之溶液中添加1-哌嗪甲酸第三丁酯(0.566 g,3.04 mmol)及TEA(0.422 mL,3.04 mmol)。藉由TCL(25% EtOAc之己烷溶液,Rf
=0.53)監測反應。如藉由不存在起始物質(TLC)所指示,於室溫下攪拌1小時後反應混合物完成反應。添加水且用DCM萃取水層兩次。依序用水及鹽水洗滌合併之萃取物,經MgSO4
乾燥,過濾,且於真空中蒸發,得到黃色固體。用DCM及己烷濕磨固體,且接著過濾,得到呈黃色固體狀之化合物38
(0.789 g,100% HPLC純度,83%產率)。1
H NMR(500 MHz,DMSO-d 6
):δ8.60(d,J
=3 Hz,1H),8.47(dd,J 1
=3 Hz,J 2
=8 Hz,1H),8.01(d,J
=8 Hz,1H),3.37(m,4H),3.23(m,4H),1.37(s,9H)。
4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺醯基)哌嗪-1-甲酸第三丁酯39
。向於冰浴中攪拌之2,5-二氯苯酚(0.414 g,2.54 mmol)於THF(20.00 mL)中之溶液中緩慢添加NaH(0.101 g,2.54 mmol)。添加後,攪拌混合物5分鐘。接著添加化合物38
(0.790 g,1.95 mmol)且將所得反應混合物加熱至75℃隔夜。藉由HPLC監測反應。然而,16小時(HPLC)後反應並未完成,因此蒸發THF且添加18-冠-6(1.057 g,4.00 mmol)、DMF(15 mL)及K2
CO3
(0.553 g,4.00 mmol)。將反應混合物再加熱至100℃維持16小時,此時HPLC藉由不存在起始物質指示反應完成。使反應混合物冷卻至室溫且添加水(0.250 mL)。用EtOAc萃取反應混合物三次。依序用1 N NaOH、水及鹽水洗滌合併之萃取物,經MgSO4
乾燥,過濾,且於真空中蒸發。將殘餘物溶解於最少量之DCM中且藉由層析法使用5%至30% EtOAc之己烷溶液梯度純化。合併純溶離份且於真空中蒸發。用DCM及己烷濕磨所得固體,且接著過濾,得到呈白色/黃色粉末狀之化合物39
(0.120 g,100% HPLC純度,10.0%產率)。1
H NMR(500 MHz,DMSO-d 6
):δ8.59(d,J
=2 Hz,1H),8.42(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.76(d,J
=8 Hz,1H),7.66(d,J
=3 Hz,1H),7.50(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.10(d,J
=8 Hz,1H),3.40(m,4H),3.25(m,4H),1.37(s,9H)。
1-(2-(2,5-二氯苯氧基)-5-硝基苯基磺醯基)哌嗪40
。向化合物39
(0.100 g,0.19 mmol)於DCM(6.00 mL)中之溶液中添加1 N HCl之1,4-二噁烷溶液(0.570 mL)。藉由TCL(25% EtOAc之己烷溶液,Rf
=0.0)監測反應。如藉由不存在起始物質(TLC)所指示,於室溫下攪拌16小時後反應完成。濃縮反應混合物且將殘餘物再溶解於MeOH(2.00 mL)中。接著添加Et2
O(4.00 mL)且攪拌混合物直至形成沈澱物(10分鐘)。藉由過濾收集固體,得到呈白色固體狀之化合物40
(0.080 g,100% HPLC純度,83%產率)。1
H NMR(500 MHz,DMSO-d 6
):δ
9.39(s,2H),8.61(d,J
=2 Hz,1H),8.45(dd,J 1
=3 Hz,J 2
=9 Hz,1H),7.78(d,J
=9 Hz,1H),7.73(d,J
=2 Hz,1H),7.53(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.12(d,J
=8 Hz,1H),3.57(m,4H),3.16(m,4H)。
根據如本實例中所述之程序製備以下化合物,且隨後如本文(例如實例1至3中)所述進行改質。1-(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)哌嗪-1-基)乙酮151
。HPLC純度:99.5%;1
H NMR(500 MHz,DMSO-d 6
):δ
8.51(d,J
=2 Hz,1H),8.28(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.00(d,J
=2 Hz,1H),7.81(d,J
=8 Hz,1H),7.74(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.01(d,J
=8 Hz,1H),3.54(m,4H),3.35(m,2H),3.25(m,2H),1.99(s,3H);熔點:190-193℃。1-(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)哌嗪-1-基)-3-甲基丁-1-酮152
。HPLC純度:100%;1
H NMR(500 MHz,DMSO-d 6
):δ
8.51(d,J
=2 Hz,1H),8.28(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.00(d,J
=2 Hz,1H),7.81(d,J
=8 Hz,1H),7.74(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.01(d,J
=8 Hz,1H),3.57(m,4H),3.34(m,2H),3.25(m,2H),2.17(d,J
=8 Hz,2H),1.93(m,1H),0.86(d,J
=8 Hz,6H);熔點:180-183℃。(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)哌嗪-1-基)(4-(三氟甲基)苯基)甲酮153
。HPLC純度:100%;1
H NMR(500 MHz,DMSO-d 6
):δ8.51(d,J
=2 Hz,1H),8.30(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.01(d,J
=2 Hz,1H),7.83(s,1H),7、80(d,J
=8 Hz,2H),7.74(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.62(d,J
=8 Hz,2H),7.03(d,J
=8 Hz,1H),3.75(m,2H),3.35-3.40(m,6H);熔點:190-193℃。4-氯-1-(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)哌嗪-1-基)丁-1-酮160
。HPLC純度:98.5%;1
H NMR(500 MHz,DMSO-d 6
):δ8.51(d,J
=2 Hz,1H),8.28(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.00(d,J
=2 Hz,1H),7.81(d,J
=8 Hz,1H),7.74(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.01(d,J
=8 Hz,1H),3.63(t,J
=8 Hz,2H),3.56(m,4H),3.33(m,2H),3.27(m,2H),2.45(m,2H),1.91(m,2H);熔點:179-182℃。環丁基(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)哌嗪-1-基)甲酮161
。HPLC純度:99.6%;1
H NMR(500 MHz,DMSO-d 6
):δ8.50(d,J
=2 Hz,1H),8.28(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.99(d,J
=2 Hz,1H),7.81(d,J
=8 Hz,1H),7.73(dd,J1
=2 Hz,J 2
=8 Hz,1H),7.01(d,J
=8 Hz,1H),3.54(m,2H),3.42(m,2H),3.24-3.31(m,5H),2.12(m,2H),2.06(m,2H),1.85(m,1H),1.69(m,1H);熔點:189-192℃。環己基(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)哌嗪-1-基)甲酮162
。HPLC純度:99.3%;1
H NMR(500 MHz,DMSO-d 6
):δ8.51(d,J
=2 Hz,1H),8.28(dd,J 1
=2 Hz,J 2
=8Hz,1H),8.00(d,J
=2 Hz,1H),7.80(d,J
=8 Hz,1H),7.73(dd,J1
=2 Hz,J 2
=8 Hz,1H),7.01(d,J
=8 Hz,1H),3.59(m,4H),3.25(m,2H),2.53(m,1H),1.65(m,2H),1.59(m,3H),1.25(m,4H),1.13(m,1H);熔點:207-210℃。
(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)哌嗪-1-基)(苯基)甲酮163
。HPLC純度:99%;1
H NMR(500 MHz,DMSO-d 6
):δ8.51(d,J
=2 Hz,1H),8.29(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.02(d,J
=2 Hz,1H),7.82(d,J
=8 Hz,1H),7.74(dd,J1
=2 Hz,J 2
=8 Hz,1H),7.44(m,3H),7.39(m,2H),7.02(d,J
=8 Hz,1H),3.72(m,2H),3.38(m,6H)。(4-氯苯基)(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)-哌嗪-1-基)甲酮164
。HPLC純度:100%;1
H NMR(500 MHz,DMSO-d 6
):δ8.51(d,J
=2 Hz,1H),8.29(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.01(d,J
=2 Hz,1H),7.82(d,J
=8 Hz,1H),7.74(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.48(d,J
=8 Hz,2H),7.42(d,J
=8 Hz,2H),7.02(d,J
=8 Hz,1H),3.71(m,2H),3.37(m,6H);熔點:172-175℃。(4-甲氧基苯基)(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)-哌嗪-1-基)甲酮165
。HPLC純度:100%;1
H NMR(500 MHz,DMSO-d 6
):δ8.51(d,J
=2 Hz,1H),8.29(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.02(d,J
=2 Hz,1H),7.82(d,J
=8 Hz,1H),7.74(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.35(d,J
=8 Hz,1H),7.02(d,J
=8 Hz,1H),6.95(d,J
=8 Hz,2H),3.78(s,3H),3.60(m,4H),3.37(m,4H);熔點:185-188℃。(4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)哌嗪-1-基)(呋喃-2-基)甲酮166
。HPLC純度:99%;1
H NMR(500 MHz,DMSO-d 6
):δ8.52(d,J
=2 Hz,1H),8.28(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.02(d,J
=2 Hz,1H),7.82(d,J
=2 Hz,1H),7、80(s,1H),7.73(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.00(m,2H),6.62(m,1H),3.78(m,4H),3.40(m,4H);熔點:199-202℃。1-(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺醯基)哌嗪-1-基)乙酮167
。HPLC純度:99%;1
H NMR(500 MHz,DMSO-d 6
):δ8.50(d,J
=2 Hz,1H),8.26(dd,J1
=2 Hz,J 2
=8 Hz,1H),7.47(s,1H),7.41(d,J
=8Hz,1H),7.35(d,J
=8 Hz,1H),6.81(d,J
=8 Hz,1H),3.55(m,4H),3.35(m,2H),3.24(m,2H),2.32(s,3H),2.24(s,3H),2.00(s,3H);熔點:151-153℃。(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺醯基)哌嗪-1-基)(4-(三氟甲基)苯基)甲酮168
。HPLC純度:99%;1
H NMR(500 MHz,DMSO-d 6
):δ8.50(d,J
=2 Hz,1H),8.27(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.81(d,J
=8 Hz,2H),7.63(d,J
=8 Hz,2H),7.48(s,1H),7.42(d,J
=8 Hz,1H),7.36(d,J
=8 Hz,1H),6.82(d,J
=8 Hz,1H),3.76(m,2H),3.35-3.41(m,6H),2.33(s,3H),2.26(s,3H);熔點:200-203℃。1-(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺醯基)哌嗪-1-基)-3-甲基丁-1-酮169
。HPLC純度:99%;1
H NMR(500 MHz,DMSO-d 6
):b8.50(d,J
=2 Hz,1H),8.25(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.47(s,1H),7.42(d,J
=8 Hz,1H),7.35(d,J
=8 Hz,1H),6.81(d,J
=8 Hz,1H),3.57(m,4H),3.32(m,2H),3.25(m,2H),2.32(s,3H),2.23(s,3H),2.19(d,J
=8 Hz,2H),1.94(m,1H),0.87(d,J
=8 Hz,6H);熔點:157-160℃。
4-氯-1-(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺醯基)哌嗪-1-基)丁-1-酮170
。HPLC純度:99%;1
H NMR(500 MHz,DMSO-d 6
):δ8.50(d,J
=2 Hz,1H),8.26(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.47(s,1H),7.41(d,J
=8 Hz,1H),7.35(d,J
=8 Hz,1H),6.81(d,J
=8 Hz,1H),3.64(t,J 1
=J 2
=7
Hz,2H),3.57(m,4H),3.33(m,2H),3.27(m,2H),2.46(t,J1
=J 2
=7
Hz,2H),2.32(s,3H),2.24(s,3H),1.93(m,2H);熔點:156-159℃。
環己基(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺醯基)哌嗪-1-基)甲酮171
。HPLC純度:100%;1
H NMR(500 MHz,DMSO-d 6
):δ8.50(d,J
=2 Hz,1H),8.26(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.47(s,1H),7.42(d,J
=8 Hz,1H),7.35(d,J
=8 Hz,1H),6.81(d,J
=8 Hz,1H),3.62(s,2H),3.55(s,2H),3.24(s,2H),2.56(m,1H),2.32(s,3H),2.23(s,3H),1.67(m,2H),1.59(m,3H),1.27(m,4H),1.12(m,1H);熔點:170-173℃。
(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺醯基)哌嗪-1-基)(苯基)甲酮172
。HPLC純度:99.9%;1
H NMR(500 MHz,DMSO-d 6
):δ8.50(d,J
=2 Hz,1H),8.27(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.35-7.48(m,8H),6.82(d,J
=8 Hz,1H),3.70(m,2H),3.38(m,6H),2.33(s,3H),2.25(s,3H);熔點:190-193℃。
(4-氯苯基)(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺醯基)-哌嗪-1-基)甲酮173
。HPLC純度:100%;1
H NMR(500 MHz,DMSO-d 6
):δ8.50(d,J
=2 Hz,1H),8.27(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.49(t,J 1
=J 2
=8 Hz,3H),7.44(t,J 1
=J 2
=8 Hz,3H),7.35(d,J
=8 Hz,1H),6.82(d,J
=8 Hz,1H),3.71(m,2H),3.37(m,6H),2.33(s,3H),2.25(s,3H);熔點:205-207℃。
(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺醯基)哌嗪-1-基)(4-甲氧基苯基)甲酮174
。HPLC純度:100%;1
H NMR(500 MHz,DMSO-d 6
):δ8.50(d,J
=2 Hz,1H),8.27(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.48(s,1H),7.42(d,J
=8 Hz,1H),7.37(m,3H),6.97(d,J
=8 Hz,2H),5.82(d,J
=8 Hz,1H),3.78(s,3H),3.60(m,4H),3.36(m,4H),2.33(s,3H),2.25(s,3H);熔點:163-167℃。
(4-(2-(2,5-二甲基苯硫基)-5-硝基苯基磺醯基)哌嗪-1-基)(呋喃-2-基)甲酮175
。HPLC純度:96%;1
H NMR(500 MHz,DMSO-d 6
):δ8.51(d,J
=2 Hz,1H),8.26(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.83(s,1H),7.48(s,1H),7.41(d,J
=8 Hz,1H),7、36(d,J
=8 Hz,1H),7.02(d,J
=2 Hz,1H),6.81(d,J
=8 Hz,1H),6.62(dd,J 1
=2 Hz,J 2
=8 Hz,1H),3.79(m,4H),3.40(m,4H),2.32(s,3H),2.24(s,3H);熔點:160-163℃。
1-(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺醯基)哌嗪-1-基)乙酮176
。HPLC純度:98.7%;1
H NMR(500 MHz,DMSO-d 6
):δ
8.59(d,J
=2 Hz,1H),8.43(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.76(d,J
=8 Hz,1H),7.66(d,J
=2 Hz,1H),7.50(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.11(d,J
=8 Hz,1H),3.51(m,4H),3.31(m,2H),3.23(m,2H),1.98(s,3H);熔點:270-273℃。
1-(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺醯基)哌嗪-1-基)-3-甲基丁-1-酮177
。HPLC純度:100%;1
H NMR(500 MHz,DMSO-d 6
):δ
8.59(d,J
=2 Hz,1H),8.43(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.76(d,J
=8 Hz,1H),7.65(d,J
=2 Hz,1H),7.50(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.11(d,J
=8 Hz,1H),3.54(m,4H),3.29(m,2H),3.22(m,2H),2.16(d,J
=8 Hz,2H),1.92(m,1H),0.86(d,J
=8 Hz,6H);熔點:157-160℃。
(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺醯基)哌嗪-1-基)(4-(三氟甲基)苯基)甲酮178
。HPLC純度:99%;1
H NMR(500 MHz,DMSO-d 6
):δ
8.59(d,J
=2 Hz,1H),8.45(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.79(d,J
=8 Hz,2H),7.76(d,J
=8 Hz,1H),7.70(d,J
=2 Hz,1H),7.61(d,J
=8 Hz,2H),7.51(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.13(d,J
=8 Hz,1H),3.73(m,2H),3.30-3.60(m,6H);熔點:230-233℃。
4-氯-1-(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺醯基)哌嗪-1-基)丁-1-酮179
。HPLC純度:97.5%;1
H NMR(500 MHz,DMSO-d 6
):δ8.59(d,J
=2 Hz,1H),8.43(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.76(d,J
=8 Hz,1H),7.65(d,J
=2 Hz,1H),7.51(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.11(d,J
=8 Hz,1H),3.63(t,J 1
=J 2
=8 Hz,2H),3.53(m,4H),3.31(m,2H),3.24(m,2H),2.43(t,J 1
=J 2
=8 Hz,2H),1.91(m,2H);熔點:145-149℃。
環丁基(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺醯基)哌嗪-1-基)甲酮180
。HPLC純度:98%;1
H NMR(500 MHz,DMSO-d 6
):δ8.58(d,J
=2 Hz,1H),8.43(dd,J1
=2 Hz,J 2
=8 Hz,1H),7.76(d,J
=8 Hz,1H),7.65(d,J
=2 Hz,1H),7.50(dd,J1
=2 Hz,J 2
=8 Hz,1H),7.11(d,J
=8 Hz,1H),3.52(m,2H),3.39(m,2H),3.25(m,5H),2.10(m,2H),2.03(m,2H),1.84(m,1H),1.70(m,1H);熔點:237-241℃。
環己基(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺醯基)哌嗪-1-基)甲酮181
。HPLC純度:99%;1
H NMR(500 MHz,DMSO-d 6
):δ8.59(d,J
=2 Hz,1H),8.43(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.76(d,J
=8 Hz,1H),7.65(d,J
=2 Hz,1H),7.51(dd,J1
=2 Hz,J 2
=8 Hz,1H),7.11(d,J
=8 Hz,1H),3.55(d,J
=32 Hz,4H),3.24(d,J
=32 Hz,4H),2.52(m,1H),1.56-1.66(m,5H),1.27(m,4H),1.13(m,1H);熔點:200-203℃。
(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺醯基)哌嗪-1-基)(苯基)甲酮182
。HPLC純度:98%;1
H NMR(500 MHz,DMSO-d 6
):δ8.59(d,J
=2 Hz,1H),8.44(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.76(d,J
=8 Hz,1H),7.71(d,J
=2 Hz,1H),7.50(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.36-7.45(m,5H),7.13(d,J
=8 Hz,1H),3.70(m,2H),3.35(m,6H);熔點:206-209℃。
(4-氯苯基)(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺醯基)-哌嗪-1-基)甲酮183
。HPLC純度:97%;1
H NMR(500 MHz,DMSO-d 6
):δ8.59(d,J
=2 Hz,1H),8.45(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.76(d,J
=8 Hz,1H),7.70(d,J
=2 Hz,1H),7.50(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.48(d,J
=8 Hz,2H),7.42(d,J
=8 Hz,2H),7.13(d,J
=8 Hz,1H),3.69(m,2H),3.34(m,6H);熔點:226-229℃。
(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺醯基)哌嗪-1-基)(4-甲氧基苯基)甲酮184
。HPLC純度:97%;1
H NMR(500 MHz,DMSO-d 6
):δ8.59(d,J
=2 Hz,1H),8.44(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.76(d,J
=8 Hz,1H),7.69(d,J
=2 Hz,1H),7.50(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.36(d,J
=8 Hz,2H),7.12(d,J
=8 Hz,1H),6.95(d,J
=8 Hz,2H),3、78(s,3H),3.56(m,4H),3.29(m,4H);熔點:197-200℃。
(4-(2-(2,5-二氯苯氧基)-5-硝基苯基磺醯基)哌嗪-1-基)(呋喃-2-基)甲酮185
。HPLC純度:98%;1
H NMR(500 MHz,DMSO-d 6
):δ8.60(d,J
=2 Hz,1H),8.43(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.82(s,1H),7.75(d,J
=8 Hz,1H),7.67(d,J
=2 Hz,1H),7.50(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.10(d,J
=8 Hz,1H),6.99(d,J
=2 Hz,1H),6.61(d,J
=2 Hz,1H),3.75(m,4H),3.37(m,4H);熔點:236-240℃。
1-(4-(2-(2,5-二甲基苯氧基)-5-硝基苯基磺醯基)哌嗪-1-基)-3-甲基丁-1-酮187
。HPLC純度:97.3%;1
H NMR(500 MHz,DMSO-d 6
):δ8.59(d,J
=2 Hz,1H),8.41(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.31(d,J
=8 Hz,1H),7.11(d,J
=8 Hz,1H),7.01(s,1H),6.84(d,J
=8 Hz,1H),3.54(m,4H),3.29(m,2H),3.22(m,2H),2.30(s,3H),2.17(d,J
=8 Hz,2H),2.08(s,3H),1.93(m,1H),0.86(d,J
=8 Hz,6H);熔點:155-158℃。
(4-(2-(2,5-二甲基苯氧基)-5-硝基苯基磺醯基)哌嗪-1-基)(4-(三氟甲基)苯基)甲酮188
。HPLC純度:99%;1
H NMR(500 MHz,DMSO-d 6
):δ8.58(d,J
=2 Hz,1H),8.42(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.79(d,J
=8 Hz,2H),7.62(d,J
=8 Hz,2H),7.31(d,J
=8 Hz,1H),7.12(d,J
=8 Hz,1H),7.08(s,1H),6.86(d,J
=8 Hz,1H),3.73(m,2H),3.40(m,6H),2.32(s,3H),2.09(s,3H);熔點:177-180℃。
(4-(2-(2,5-二甲基苯氧基)-5-硝基苯基磺醯基)哌嗪-1-基)(4-甲氧基苯基)甲酮189
。HPLC純度:99.7%;1
H NMR(500 MHz,DMSO-d 6
):δ8.59(d,J
=2 Hz,1H),8.42(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.35(d,J
=8 Hz,2H),7.31(d,J
=8 Hz,1H),7.12(d,J
=8 Hz,1H),7.07(s,1H),6.95(d,J
=8 Hz,H),6.86(d,J
=8 Hz,1H),3.78(s,3H),3.57(m,4H),3.33(m,4H),2.32(s,3H),2.09(s,3H);熔點:161-164℃。
(4-(2-(2,5-二甲基苯氧基)-5-硝基苯基磺醯基)哌嗪-1-基)(呋喃-2-基)甲酮190
。HPLC純度:99.5%;1
H NMR(500 MHz,DMSO-d 6
):δ8.59(d,J
=2 Hz,1H),8.41(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.82(d,J
=2 Hz,1H),7.31(d,J
=8 Hz,1H),7.11(d,J
=8 Hz,1H),7.05(s,1H),6.99(d,J
=4 Hz,1H),6.84(d,J
=8 Hz,1H),6.62(d,J
=2 Hz,1H),3.75(m,4H),3.37(m,4H),2.29(s,3H),2.08(s,3H);熔點:170-174℃。
N
-烯丙基-4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)哌嗪-1-甲醯胺191
。HPLC純度:98.2%;1
H NMR(500 MHz,DMSO-d 6
):δ8.52(d,J
=2 Hz,1H),8.28(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.98(d,J
=2 Hz,1H),7.80(d,J
=8 Hz,1H),7.74(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.00(d,J
=8 Hz,1H),6.70(t,J
=4 Hz,1H),5.76(m,1H),5.06(d,J
=9 Hz,1H),4.97(d,J
=4 Hz,1H),3.62(m,2H),3.42(m,4H),3.26(m,4H);熔點:198-202℃。
4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)-N,N
-二乙基哌嗪-1-甲醯胺192
。HPLC純度:99%;1
H NMR(500 MHz,DMSO-d 6
):δ8.51(d,J
=2 Hz,1H),8.28(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.99(d,J
=2 Hz,1H),7.81(d,J
=8 Hz,1H),7.74(dd,J1
=2 Hz,J 2
=8 Hz,1H),7.01(d,J
=8 Hz,1H),3.32(m,4H),3.17(m,4H),3.09(m,4H),1.00(m,6H);熔點:160-163℃。
4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)-N
-對甲苯基哌嗪-1-甲醯胺193
。HPLC純度:97%;1
H NMR(500 MHz,DMSO-d 6
):δ8.53(m,2H),8.28(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.01(d,J
=2 Hz,1H),7.81(d,J
=8 Hz,1H),7.74(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.28(d,J
=8 Hz,2H),7.01(d,J
=8 Hz,3H),3.56(m,4H),3.35(m,4H),2.21(s,3H);熔點:231-234℃。
N
-(4-氰基苯基)-4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)-哌嗪-1-甲醯胺194
。HPLC純度:97.7%;1
H NMR(500 MHz,DMSO-d 6
):δ9.09(s,1H),8.53(d,J
=2 Hz,1H),8.28(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.00(d,J
=2 Hz,1H),7.81(d,J
=8 Hz,1H),7.74(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.68(d,J
=8 Hz,2H),7.62(d,J
=2 Hz,2H),7.01(d,J
=8 Hz,1H),3.60(m,4H),3.36(m,4H);熔點:232-235℃。
4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)-N
-(4-硝基苯基)-哌嗪-1-甲醯胺195
。HPLC純度:98.3%;1
H NMR(500 MHz,DMSO-d 6
):δ9.31(s,1H),8.53(d,J
=2 Hz,1H),8.28(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.14(d,J
=8 Hz,2H),8.00(d,J
=2 Hz,1H),7.81(d,J
=8 Hz,1H),7.75(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.67(d,J
=8 Hz,1H),7.02(d,J
=8 Hz,1H),3.62(m,4H),3.37(m,4H);熔點:242-246℃。
4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)-N
-異丙基哌嗪-1-硫代碳醯胺196
。HPLC純度:100%;1
H NMR(500 MHz,DMSO-d 6
):δ8.51(d,J
=2 Hz,1H),8.28(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.00(d,J
=2 Hz,1H),7.81(d,J
=8 Hz,1H),7.74(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.46(d,J
=6 Hz,1H),7.00(d,J
=8 Hz,1H),4.46(m,1H),3.90(s,4H),3.32(s,4H),1.10(d,6H);熔點:190-193℃。
N
-(3-氯苯甲基)-4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)-哌嗪-1-硫代碳醯胺197
。HPLC純度:100%;1
H NMR(500 MHz,DMSO-d 6
):δ8.52(d,J
=2 Hz,1H),8.41(t,J 1
=J 2
=4 Hz,1H),8.28(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.00(d,J
=2 Hz,1H),7.81(d,J
=8 Hz,1H),7.74(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.27(m,3H),7.21(d,J
=8 Hz,1H),7.01(d,J
=8 Hz,1H),4.75(d,J
=8 Hz,2H),3.97(m,4H),3.37(m,4H);熔點:170-174℃。
4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)-N
-(3-側氧基戊基)-哌嗪-1-硫代碳醯胺198
。HPLC純度:100%;1
H NMR(500 MHz,DMSO-d 6
):δ8.51(d,J
=2 Hz,1H),8.28(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.00(d,J
=2 Hz,1H),7.89(t,J 1
=J 2
=4 Hz,1H),7.81(d,J
=8 Hz,1H),7.74(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.00(d,J
=8 Hz,1H),4.02(q,J 1
=J 2
=8 Hz,2H),3.89(m,4H),3.67(m,2H),2.57(t,J 1
=J 2
=6 Hz,2H),1.15(t,J 1
=J 2
=6 Hz,3H);熔點:200-204℃。
4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)-N
-苯基哌嗪-1-硫代碳醯胺199
。HPLC純度:99.8%;1
H NMR(500 MHz,DMSO-d 6
):δ9.46(s,1H),8.54(d,J
=2 Hz,1H),8.29(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.02(d,J
=2 Hz,1H),7.82(d,J
=8 Hz,1H),7.74(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.26(m,4H),7.10(m,1H),7.02(d,J
=8 Hz,1H),4.03(m,4H),3.42(m,4H);熔點:198-201℃。
4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)-N
-(2-(N-嗎啉基)乙基)-哌嗪-1-硫代碳醯胺200
。HPLC純度:100%;1
H NMR(500 MHz,DMSO-d 6
):δ8.51(d,J
=2 Hz,1H),8.28(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.00(d,J
=2 Hz,1H),7.81(d,J
=8 Hz,1H),7.74(dd,J 1
=2 Hz,J 2
=8 Hz,2H),7.00(d,J
=8 Hz,1H),3.89(m,4H),3.58(m,2H),3.50(m,4H),2.43(t,J 1 =J 2
=6 Hz,2H),2.35(m,4H);熔點:130-136℃。
1-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)-4-(甲磺醯基)-哌嗪202
。HPLC純度:100%;1
H NMR(500 MHz,DMSO-d 6
):δ8.54(d,J
=8 Hz,2H),8.30(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.02(d,J=2 Hz,1H),7.82(d,J
=8 Hz,1H),7.74(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.02(d,J
=8 Hz,1H),3.44(m,4H),3.24(m,4H),2.92(s,3H);熔點:277-281℃。
4-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)-N,N-二甲基-哌嗪-1-磺醯胺203
。HPLC純度:100%;1
H NMR(500 MHz,DMSO-d 6
):δ8.53(d,J
=2 Hz,1H),8.29(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.00(d,J=
2 Hz,1H),7.82(d,J
=8 Hz,1H),7.74(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.03(d,J
=8 Hz,1H),3.39(m,4H),3.26(m,4H),2.74(s,6H);熔點:231-234℃。
1-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)-4-(苯基磺醯基)-哌嗪204
。HPLC純度:100%;1
H NMR(500 MHz,DMSO-d 6
):δ8.48(d,J
=2 Hz,1H),8.23(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.90(d,J
=2 Hz,1H),7.69-7.76(m,5H),7.60(m,2H),6.93(d,J
=8 Hz,1H),3.43(m,4H),2.99(m,4H);熔點:236-239℃。
1-(2-(2,5-二氯苯硫基)-5-硝基苯基磺醯基)-4-(4-(三氟甲基)苯基磺醯基)哌嗪205
。HPLC純度:100%;1
H NMR(500 MHz,DMSO-d 6
):δ8.51(d,J
=2 Hz,1H),8.23(dd,J 1
=2 Hz,J 2
=8 Hz,1H),8.01(d,J
=8 Hz,2H),7.94(d,J
=8 Hz,3H),7.74(dd,J 1
=2 Hz,J 2
=8 Hz,1H),7.64(d,J
=8 Hz,1H),6.92(d,J
=8 Hz,1H),3.44(m,4H),3.05(m,4H);熔點:264-267℃。
實例4CCR3受體結合檢定
細胞用PBS洗滌一次且再懸浮於結合緩衝液(25 mM HEPES(pH 7.6)、5 mM MgCl2
、1 mM CaCl2
、0.5% BSA、0.1% NaN3
)中。將100 mL細胞懸浮液(每孔2×105
個細胞)及0.1 nM經[125
I]標記之人類嗜酸性粒細胞趨化因子/CCL11(2000 Ci/mmol比活性)混合於96孔U型底聚丙烯板中,且於室溫下培育60分鐘以進行結合反應。接著將細胞懸浮液轉移至過濾板(#MAFB,Millipore),且用含有0.5 M NaCl之結合緩衝液洗滌3次,添加閃爍體,且於TopCount(Packard)上對放射性進行計數。對於測定非特異性結合,在500 nM未標記之人類嗜酸性粒細胞趨化因子/CCL11存在下培育細胞懸浮液及經[125
I]標記之人類嗜酸性粒細胞趨化因子/CCL11。參見Iino等人,「Molecular cloning and functional characterization of cynomolgus monkey(Macaca fascicularis
) CC chemokine receptor,CCR3,」Cytokine 2002
,19
,276-286。
生物學結果概述於表1中,其中A表示不大於50 nM之值;B表示大於50 nM但不大於500 nM之值;C表示大於500 nM但不大於5 μM之值;D表示大於5 μM之值。
1. 化合物係以鹽酸鹽形式測試。
提供上文所述之實例以給與一般技術者對如何製備及使用所主張之實施例的完整揭示及描述,且不欲限制本文所揭示之內容的範疇。對於熟習此項技術者顯而易見之修改意欲在以下申請專利範圍之範疇內。本說明書中所引用之所有公開案、專利及專利申請案以引用的方式併入本文中,仿佛特定地及個別地指示各個該公開案、專利或專利申請案以引用的方式併入本文中一般。
Claims (47)
- 一種式I化合物,
- 如請求項1之化合物,其中RYa 為-C(O)R1a 、-C(O)NR1b R1c 、-C(S)NR1b R1c 、-C(S)NR1a C(O)NR1b R1c 、-C(NNO2 )NR1b R1c 或-S(O)2 R1a 。
- 如請求項1之化合物,其中R1a 為(a)氫;(b)視情況經一 個、兩個或三個取代基取代之C1-6 烷基,該或該等取代基各獨立地選自氰基、鹵基、C3-7 環烷基、C6-14 芳基、雜芳基、雜環基、-C(O)Ra 、-C(O)ORa 及-SRa ,其中該環烷基、芳基、雜芳基及雜環基各進一步視情況經一個、兩個或三個取代基取代,該或該等取代基各獨立地為鹵基或C1-6 烷基;(c)視情況經C6-14 芳基取代之C2-6 烯基;(d)視情況經一或兩個C1-6 烷基取代之C3-7 環烷基;(e)視情況經一個、兩個或三個取代基取代之C6-14 芳基,該或該等取代基各獨立地選自鹵基、硝基、氰基、-ORa 、-C(O)Ra 及C1-6 烷基,其中該烷基進一步視情況經一個、兩個或三個鹵基取代;(f)視情況經一個、兩個或三個取代基取代之雜芳基,該或該等取代基各獨立地為鹵基或C1-6 烷基;或(g)雜環基。
- 如請求項1之化合物,其中R1a 為(a)氫;或(b)C1-6 烷基、C2-6 烯基、C3-7 環烷基、C6-14 芳基、雜芳基或雜環基,各視情況經一或兩個取代基取代,該或該等取代基各獨立地選自鹵基、氰基、硝基、C1-6 烷基、C3-7 環烷基、C6-14 芳基、雜芳基、雜環基、-ORa 、-SRa 及-C(O)Ra ,其中該烷基、環烷基、芳基、雜芳基及雜環基各視情況進一步經一或兩個取代基取代,該或該等取代基各獨立地為鹵基或C1-6 烷基。
- 如請求項1之化合物,其中R1a 為(a)氫;或(b)C1-6 烷基、C2-6 烯基、C3-7 環烷基、C6-14 芳基、雜芳基或雜環基,各視情況經一或兩個取代基取代,該或該等取代基各獨立 地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S ,2S ,4R )-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、乙醯基、丙醯基及乙氧羰基。
- 如請求項4之化合物,其中R1a 為(a)氫;(b)視情況經選自氯、氰基、乙氧基、甲硫基、(1S ,2S ,4R )-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、丙醯基及乙氧羰基之取代基取代之C1-6 烷基;(c)視情況經苯基取代之C2-6 烯基;(d)C3-7 環烷基;(e)視情況經一或兩個取代基取代之C6-14 芳基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基及乙醯基;(f)視情況經一或兩個甲基取代之雜芳基;或(g)雜環基。
- 如請求項6之化合物,其中R1a 為(a)氫;(b)甲基、乙基、丙基、丁基或戊基,各視情況經選自氯、氰基、乙氧基、甲硫基、(1S ,2S ,4R )-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、丙醯基及乙氧羰基之取代基取代;(c)乙烯基或烯丙基,各視情況經苯基取代;(d)環丁基、環戊基或環己基;(e)視情況經一或兩個取代基取代之苯基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基及乙醯基;(f)呋喃基、噻吩基、異噁唑基、吡唑基、1,2,3-噻二唑基、吡啶基、吡唑基、苯并呋喃基、苯并[c ][1,2,5]噁二唑基、苯并噻吩基或苯并噻唑基,各視情 況經一或兩個甲基取代;或(g)嗎啉基。
- 如請求項1之化合物,其中R1b 為氫或C1-6 烷基。
- 如請求項8之化合物,其中R1b 為氫、甲基或乙基。
- 如請求項1之化合物,其中R1c 為(a)氫;(b)視情況經一個、兩個或三個取代基取代之C1-6 烷基,該或該等取代基各獨立地選自氰基、鹵基、C3-7 環烷基、C6-14 芳基、雜芳基、雜環基、-C(O)Ra 、-C(O)ORa 及-SRa ,其中該環烷基、芳基、雜芳基及雜環基各進一步視情況經一個、兩個或三個取代基取代,該或該等取代基各獨立地為鹵基或C1-6 烷基;(c)視情況經C6-14 芳基取代之C2-6 烯基;(d)視情況經一或兩個C1-6 烷基取代之C3-7 環烷基;(e)視情況經一個、兩個或三個取代基取代之C6-14 芳基,該或該等取代基各獨立地選自鹵基、硝基、氰基、-ORa 、-C(O)Ra 及C1-6 烷基,其中該烷基進一步視情況經一個、兩個或三個鹵基取代;(f)視情況經一個、兩個或三個取代基取代之雜芳基,該或該等取代基各獨立地為鹵基或C1-6 烷基;或(g)雜環基。
- 如請求項1之化合物,其中R1c 為(a)氫;或(b)C1-6 烷基、C2-6 烯基、C3-7 環烷基、C6-14 芳基、雜芳基或雜環基,各視情況經一或兩個取代基取代,該或該等取代基各獨立地選自鹵基、氰基、硝基、C1-6 烷基、C3-7 環烷基、C6-14 芳基、雜芳基、雜環基、-ORa 、-SRa 及-C(O)Ra ,其中Ra 如本文所定義且該烷基、環烷基、芳基、雜芳基及雜環基各視情況進一步經一或兩個取代基取代,該或該 等取代基各獨立地為鹵基或C1-6 烷基。
- 如請求項10之化合物,其中R1c 為(a)氫;或(b)C1-6 烷基、C2-6 烯基、C3-7 環烷基、C6-14 芳基、雜芳基或雜環基,各視情況經一或兩個取代基取代,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基、乙氧基、甲硫基、(1S ,2S ,4R )-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、乙醯基、丙醯基及乙氧羰基。
- 如請求項12之化合物,其中R1c 為(a)氫;(b)視情況經選自氯、氰基、乙氧基、甲硫基、(1S ,2S ,4R )-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、丙醯基及乙氧羰基之取代基取代之C1-6 烷基;(c)視情況經苯基取代之C2-6 烯基;(d)C3-7 環烷基;(e)視情況經一或兩個取代基取代之C6-14 芳基,該或該等取代基各獨立地選自氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基及乙醯基;(f)視情況經一或兩個甲基取代之雜芳基;或(g)雜環基。
- 如請求項12之化合物,其中R1c 為(a)氫;(b)甲基、乙基、丙基、丁基或戊基,各視情況經選自氯、氰基、乙氧基、甲硫基、(1S ,2S ,4R )-7,7-二甲基雙環[2.2.1]-庚基、苯基、氯苯基、呋喃基、嗎啉基、丙醯基及乙氧羰基之取代基取代;(c)乙烯基或烯丙基,各視情況經苯基取代;(d)環丁基、環戊基或環己基;(e)視情況經一或兩個取代基取代之苯基,該或該等取代基各獨立地選自 氟、氯、氰基、硝基、甲基、三氟甲基、乙基、甲氧基及乙醯基;(f)呋喃基、噻吩基、異噁唑基、吡唑基、1,2,3-噻二唑基、吡啶基、吡唑基、苯并呋喃基、苯并[c ][1,2,5]噁二唑基、苯并噻吩基或苯并噻唑基,各視情況經一或兩個甲基取代;或(g)嗎啉基。
- 如請求項1之化合物,其中R1 、R2 、R3 、R4 及R5 各獨立地為氫、鹵基或C1-6 烷基。
- 如請求項15之化合物,其中R1 、R2 、R3 、R4 及R5 中之兩者為鹵基或C1-6 烷基,且其餘三者為氫。
- 如請求項15之化合物,其中R1 、R2 、R3 、R4 及R5 中之兩者為氯或甲基,且其餘三者為氫。
- 如請求項17之化合物,其中R1 、R3 及R5 為氫,且R2 及R4 為氯或甲基。
- 如請求項18之化合物,其中R2 及R4 為氯。
- 如請求項18之化合物,其中R2 及R4 為甲基。
- 如請求項17之化合物,其中R2 、R3 及R5 為氫,且R1 及R4 為氯或甲基。
- 如請求項21之化合物,其中R1 及R4 為氯。
- 如請求項21之化合物,其中R1 及R4 為甲基。
- 如請求項1之化合物,其中R6 為氰基或硝基。
- 如請求項1之化合物,其中R7 為C1-6 烷基。
- 如請求項1之化合物,其中m為1。
- 如請求項1之化合物,其中n為1或2。
- 如請求項1之化合物,其中p為0。
- 如請求項1之化合物,其中X為O。
- 如請求項1之化合物,其中X為S。
- 如請求項1之化合物,其係選自由以下組成之群:
- 如請求項1之化合物,其中該化合物為鹽酸鹽。
- 一種醫藥組合物,其包含如請求項1至32中任一項之化合物,或其醫藥學上可接受之鹽、立體異構體或互變異構體;及一或多種醫藥學上可接受之載劑或賦形劑。
- 如請求項33之醫藥組合物,其進一步包含第二治療劑。
- 如請求項33之醫藥組合物,其中該組合物經調配用於單次劑量投藥。
- 如請求項35之醫藥組合物,其中該組合物經調配成口服、非經腸或靜脈內劑型。
- 如請求項36之醫藥組合物,其中該口服劑型為錠劑或膠囊。
- 一種如請求項1至32中任一項之化合物或如請求項33至37中任一項之醫藥組合物之用途,其係用以製備用於治療或改善個體之CCR3介導之病症、疾病或病狀的一或多種症狀之藥物。
- 一種如請求項1至32中任一項之化合物或如請求項33至 37中任一項之醫藥組合物之用途,其係用以製備用於治療或改善個體之嗜酸性粒細胞相關性病症、疾病或病狀的一或多種症狀之藥物。
- 一種如請求項1至32中任一項之化合物或如請求項33至37中任一項之醫藥組合物之用途,其係用以製備用於治療或改善個體之嗜鹼性粒細胞相關性病症、疾病或病狀的一或多種症狀之藥物。
- 一種如請求項1至32中任一項之化合物或如請求項33至37中任一項之醫藥組合物之用途,其係用以製備用於治療或改善個體之肥大細胞相關性病症、疾病或病狀的一或多種症狀之藥物。
- 一種如請求項1至32中任一項之化合物或如請求項33至37中任一項之醫藥組合物之用途,其係用以製備用於治療或改善個體之發炎性疾病的一或多種症狀之藥物。
- 如請求項38至42中任一項之用途,其中該病症、疾病或病狀係選自由以下組成之群:哮喘、過敏性哮喘、運動誘發性哮喘、過敏性鼻炎、常年性過敏性鼻炎、季節性過敏性鼻炎、異位性皮膚炎、接觸性過敏反應、接觸性皮膚炎、結膜炎、過敏性結膜炎、嗜酸性粒細胞性支氣管炎、食物過敏、嗜酸性粒細胞性胃腸炎、發炎性腸病、潰瘍性結腸炎、克羅恩氏病(Crohn's disease)、肥大細胞增多症、高IgE症候群、全身性紅斑狼瘡、牛皮癬、痤瘡、多發性硬化症、同種異體移植排斥反應、再灌注損傷、慢性阻塞性肺病、徹奇-斯全司症候群 (Churg-Strauss syndrome)、竇炎、嗜鹼性白血病、慢性蕁麻疹、嗜鹼性白血球增多症、牛皮癬、濕疹、COPD(慢性阻塞性肺病)、關節炎、類風濕性關節炎、牛皮癬性關節炎、骨關節炎及心血管病症。
- 如請求項43之用途,其中該病症、疾病或病狀為哮喘、運動誘發性哮喘、過敏性鼻炎、異位性皮膚炎、慢性阻塞性肺病或過敏性結膜炎。
- 如請求項38之用途,其中該化合物係經口、非經腸或表面投與。
- 如請求項38之用途,其中該化合物係與第二治療劑組合投與。
- 一種如請求項1至32中任一項之化合物或如請求項33至37中任一項之醫藥組合物之用途,其係用以製備用於在體外調節CCR3活性之藥物。
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