TWI666212B - 作為類鐸受體7(toll-like receptor 7)促效劑之化合物及組合物 - Google Patents
作為類鐸受體7(toll-like receptor 7)促效劑之化合物及組合物 Download PDFInfo
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- TWI666212B TWI666212B TW104113993A TW104113993A TWI666212B TW I666212 B TWI666212 B TW I666212B TW 104113993 A TW104113993 A TW 104113993A TW 104113993 A TW104113993 A TW 104113993A TW I666212 B TWI666212 B TW I666212B
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Abstract
本發明提供化合物、包含該等化合物之免疫原性組合物及醫藥組合物以及使用該等化合物治療與類鐸受體7(Toll-Like Receptor 7)活性相關之疾病或病症之方法。
Description
本申請案主張於2014年5月1日提出申請的美國臨時申請案第61,987,321號之權益,該申請案之全文以引用方式併入本文中。
本發明係關於為類鐸受體7(Toll-Like Receptor 7,TLR7)促效劑之化合物、含有該等化合物之組合物及使用該等化合物之方法。
在模式識別受體(pattern recognition receptors;PRRs)之幫助下,藉由先天性免疫系統可以完成早期特定病原體種類之偵測。所偵測的病原體包括病毒、細菌、原生動物及真菌,且各自組成型表現一組種類特異性突變抗性分子,稱為病原體相關之分子模式(pathogen-associated molecular patterns;PAMPs)。該等分子標記物可由蛋白質、碳水化合物、脂質、核酸或其組合構成,且可定位於內部或外部。PAMP之實例包括細菌碳水化合物(脂多糖或LPS、甘露糖)、核酸(細菌或病毒DNA或RNA)、肽聚糖及脂磷壁酸(來自革蘭氏陽性細菌(Gram positive bacteria))、N-甲醯基甲硫胺酸、脂蛋白及真菌葡聚糖。
模式識別受體已進化以利用三種PAMP特性。第一,組成型表現
使得宿主可以偵測病原體而無關乎病原體之生命週期階段。第二,PAMP具有種類特異性,此使得宿主可以區分病原體且由此調整宿主的反應。第三,突變抗性使得宿主可以識別病原體而無關乎特定的菌株。
模式識別受體不僅僅經由其PAMP參與病原體之識別。結合後,模式識別受體往往立即成簇,將其他細胞外及細胞內蛋白質招募至複合物,並起始信號傳導級聯,其最終影響轉錄。另外,模式識別受體參與因應病原體偵測之補體活化、凝血、吞噬作用、發炎及細胞凋亡功能。
模式識別受體(PRR)可分成胞吞PRR或信號傳導PRR。信號傳導PRR包括膜結合類鐸受體(TLR)及細胞質NOD樣受體之大家族,而胞吞PRR促進吞噬細胞對微生物之附著、吞食及破壞而不轉遞細胞內信號,發現於所有吞噬細胞上且介導凋亡細胞之移除。另外,胞吞PRR識別碳水化合物且包括巨噬細胞之甘露糖受體、存在於所有吞噬細胞上之葡聚糖受體及識別帶電配體之清除劑受體。
本文提供為類鐸受體7(TLR7)之促效劑之化合物及其醫藥組合物。該等TLR7促效劑係免疫增強劑。本文亦提供含有該等TLR7促效劑之免疫原性組合物。
在一個態樣中,該等化合物及其醫藥上可接受之鹽、個別異構物及異構物之混合物具有式(I)之結構:
其中:
R1係-NHR6或-NHCHR6R9;R3係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH或四唑基;R4係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH或四唑基;其中,當R3係H時,則R4係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH或四唑基;或當R4係H時,則R3係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH或四唑基;L1係-(CH2)m-;L2係-(CH2)m-;L7=-(CH2)m(CHR11CH2)m(CH2)n-;R6係-C3-C6烷基;R7係-C1-C3烷基;R9係L1OH;每一R11獨立地選自-OH;R12係a)未經取代之四唑基;b)經-L1C(=O)OH取代之四唑基;或
c)5-6員雜環烷基,其具有1至2個獨立地選自N及O之雜原子且經-C(=O)OH取代;每一m獨立地選自1、2、3及4,且每一n獨立地選自0、1、2、3及4。
在某些實施例中,式(I)化合物係式(Ia)或式(Ib)之化合物:
在式(I)化合物之某些實施例中,R1係-NHR6或-NHCHR6R9;R3係H、-OL2C(=O)OH或四唑基;R4係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH或四唑基;其中,當R3係H時,則R4係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH或四唑基;或當R4係H時,則R3係-OL2C(=O)OH或四唑基;L1係-(CH2)m-;L2係-(CH2)m-;L7=-(CH2)m(CHR11CH2)m(CH2)n-;R6係-C3-C6烷基;R7係-C1-C3烷基;甲基
R9係L1OH;每一R11獨立地選自-OH;R12係a)未經取代之四唑基;b)經-L1C(=O)OH取代之四唑基;或c)5-6員雜環烷基,其具有1至2個獨立地選自N及O之雜原子且經-C(=O)OH取代;每一m獨立地選自1、2、3及4,且每一n獨立地選自0、1、2、3及4。
在式(Ia)或式(Ib)化合物之某些實施例中,R1係-NHR6或-NHCHR6R9;R3係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH、或
;l;R4係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-
C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH、或
;其中,當R3係H時,則R4係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-
CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-
OL2C(=O)OH、或;或當R4係H時,則R3係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-
OL2C(=O)OH、、;L1係-(CH2)m-;L2係-(CH2)m-;L7=-(CH2)m(CHR11CH2)m(CH2)n-;R6係-C3-C6烷基;R7係-C1-C3烷基;R9係L1OH;每一R11獨立地選自-OH;
R12係a)或
b)
或
c)、或
每一m獨立地選自1、2、3及4,且每一n獨立地選自0、1、2、3及4。
在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,
R1係-NHR6或-NHCHR6R9;
R3係H、-OL2C(=O)OH、或;l;R4係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-
C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、或;其中,當R3係H時,則R4係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-
CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、或
;
或當R4係H時,則R3係-OL2C(=O)OH、、;L1係-(CH2)m-;L2係-(CH2)m-;L7=-(CH2)m(CHR11CH2)m(CH2)n-;R6係-C3-C6烷基;R7係-C1-C3烷基;R9係L1OH;每一R11獨立地選自-OH;R12係
a)或
b)
或
c)、或;每一m獨立地選自1、2、3及4,且每一n獨立地選自0、1、2、3及4。
在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,L1係-CH2-;L2係-CH2-或-CH2CH2-;L7=-(CH2)2(CHR11CH2)2-;R6係-C4烷基或-C5烷基;R7係甲基、乙基或丙基,且R11係OH。
在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,R1係-NHR6;R3係H;R4係-L2R12;L2係-(CH2)m-;R6係-C3-C6烷基;R12係a)未經取代之四唑基;b)經-L1C(=O)OH取代之四唑基;或c)5-6員雜環烷基,其具有1至2個獨立地選自N及O之雜原子且經-C(=O)OH取代,且每一m獨立地選自1、2、3及4。
在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,R1係-NHR6;R3係H;R4係-L2R12;L2係-CH2-或-CH2CH2-;R6係-C5烷基;且R12係
a)或
b)
或
c)、或。
在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,R1係-NHR6;R3係H;R4係-L2R12;L2係-CH2-或-CH2CH2-;R6係-C5烷基;且R12係
a)或
或
b)、或。
在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,R1係-NHR6;R3係H;R4係-L2C(=O)OH;L2係-CH2-或-CH2CH2-;且R6係-C5烷基。
在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,化合物係選自:5-(5-((1H-四唑-5-基)甲氧基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;5-(5-((1H-四唑-5-基)甲基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;(S)-2-((5-(5-((1H-四唑-5-基)甲基)-2-甲氧基苄基)-2-胺基-5H-吡咯并[3,2-d]嘧啶-4-基)胺基)己-1-醇;(S)-2-((5-(5-((1H-四唑-5-基)甲基)-2-甲氧基苄基)-2-胺基-5H-吡咯并[3,2-d]嘧啶-4-基)胺基)戊-1-醇;
5-(5-(2-(1H-四唑-5-基)乙基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;N4-己基-5-(2-甲氧基-5-(1H-四唑-5-基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;(S)-2-((2-胺基-5-(2-甲氧基-5-(1H-四唑-5-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-基)胺基)己-1-醇;2-(5-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苄基)-2H-四唑-2-基)乙酸;5-(2-甲氧基-4-(1H-四唑-5-基)苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;5-(2-甲氧基-5-(1H-四唑-5-基)苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;5-(5-(2-(1H-四唑-5-基)丙-2-基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;(S)-2-((5-(5-(2-(1H-四唑-5-基)丙-2-基)-2-甲氧基苄基)-2-胺基-5H-吡咯并[3,2-d]嘧啶-4-基)胺基)己-1-醇;5-(5-(二氟(1H-四唑-5-基)甲基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;2-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)-2,2-二氟乙酸;(3R,5R)-7-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)-3,5-二羥基庚酸;2-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)乙酸;(S)-2-(3-((2-胺基-4-((1-羥基己-2-基)胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)乙酸;
3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯甲酸;(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)膦酸;(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)膦酸氫甲酯;(E)-3-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)丙烯酸;3-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)丙酸;(S)-3-(3-((2-胺基-4-((1-羥基己-2-基)胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)丙酸;(S)-1-(4-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-3-甲氧基苄基)吡咯啶-2-甲酸;(R)-1-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苄基)吡咯啶-2-甲酸,及2-(4-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-3-甲氧基苯氧基)乙酸。
在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,化合物係選自:2-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)乙酸;3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯甲酸;5-(5-((1H-四唑-5-基)甲基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;
5-(5-(2-(1H-四唑-5-基)乙基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;(S)-1-(4-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-3-甲氧基苄基)吡咯啶-2-甲酸,及(R)-1-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苄基)吡咯啶-2-甲酸。
本文提供之另一態樣係使用式(I)、式(Ia)及式(Ib)化合物之方法及包含該等式(I)、式(Ia)及式(Ib)化合物之醫藥組合物。
本文提供之另一態樣係包括治療有效量之式(I)、式(Ia)或式(Ib)化合物及醫藥上可接受之載劑之醫藥組合物。在該等醫藥組合物之某些實施例中,醫藥組合物經調配用於靜脈內投與、玻璃體內投與、肌內投與、口服投與、直腸投與吸入、經鼻投與、局部投與、經眼投與或經耳投與。在其他實施例中,醫藥組合物呈以下形式:錠劑、丸劑、膠囊、液體、吸入劑、鼻噴霧溶液、栓劑、溶液、乳液、軟膏劑、滴眼劑或滴耳劑。在其他實施例中,該等醫藥組合物進一步包括一或多種其他治療劑。
本文提供之另一態樣係用於治療患有與TLR7受體活性相關之疾病或病症之患者的藥劑,且該等藥劑包括治療有效量之式(I)、式(Ia)或式(Ib)化合物。
本文提供之另一態樣係式(I)、式(Ia)或式(Ib)化合物之用途,其用於製造用來治療與TLR7活性相關之疾病或病症的藥劑。在該等用途之某些實施例中,疾病係傳染病、病毒性傳染病、發炎性疾病、呼吸疾病、皮膚病、自體免疫疾病、細胞增生性疾病或癌症。在該等用途之某些實施例中,疾病係氣喘、慢性阻塞性肺病(COPD)、成人呼吸窘迫症候群(ARDS)、潰瘍性結腸炎、克隆氏病(Crohn’s disease)、支氣管炎、皮炎、日光性角化症、基底細胞癌、膀胱癌、過敏性鼻
炎、牛皮癬、硬皮症、蕁麻疹、類風濕性關節炎、多發性硬化、癌症、乳癌、HIV、肝炎、C型肝炎或狼瘡。在該等用途之某些實施例中,疾病係B型肝炎、C型肝炎、結腸直腸癌或肝細胞癌。
本文提供之另一態樣係活化TLR7受體之方法,其中該方法包括向有需要之系統或個體投與治療有效量之式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽或醫藥組合物,由此活化TLR受體。在該等方法之某些實施例中,該等方法包括將化合物投與細胞或組織系統或人類或動物個體。
本文提供之另一態樣係治療與TLR7活性相關之疾病或病症之方法,其中該方法包括向需要該治療之系統或個體投與有效量之式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽,由此治療該疾病或病症。在該等方法之某些實施例中,該等方法包括將化合物投與細胞或組織系統或人類或動物個體。在該等方法之某些實施例中,疾病或病況係傳染病、病毒性傳染病、發炎性疾病、呼吸疾病、皮膚病、自體免疫疾病、細胞增生性疾病或癌症。在該等方法之某些實施例中,疾病或病況係氣喘、慢性阻塞性肺病(COPD)、成人呼吸窘迫症候群(ARDS)、潰瘍性結腸炎、克隆氏病、支氣管炎、皮炎、日光性角化症、基底細胞癌、膀胱癌、過敏性鼻炎、牛皮癬、硬皮症、蕁麻疹、類風濕性關節炎、多發性硬化、癌症、乳癌、HIV、肝炎、C型肝炎或狼瘡。在該等方法之某些實施例中,疾病係B型肝炎、C型肝炎、結腸直腸癌或肝細胞癌。
本文提供之另一態樣係治療細胞增生性疾病之方法,其包含向需要該治療之系統或個體投與有效量之式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽;其中細胞增生性疾病係膀胱癌、淋巴瘤、骨肉瘤、黑色素瘤或乳房腫瘤、腎腫瘤、前列腺腫瘤、結腸直腸腫瘤、甲狀腺腫瘤、卵巢腫瘤、胰臟腫瘤、神經元腫瘤、肺腫瘤、子宮腫瘤
或胃腸腫瘤。在該等方法之某些實施例中,細胞增生性疾病係結腸直腸癌或肝細胞癌。在該等方法之某些實施例中,細胞增生性疾病係結腸直腸癌。在該等方法之某些實施例中,細胞增生性疾病係肝細胞癌。
本文提供之另一態樣係用於醫學治療之方法中之化合物,其中醫學治療之方法用於治療與TLR7受體活性相關之疾病,其中疾病係選自傳染病、病毒性傳染病、發炎性疾病、呼吸疾病、皮膚病、自體免疫疾病、細胞增生性疾病或癌症,且其中化合物係式(I)、式(Ia)或式(Ib)化合物。在該等方法之某些實施例中,疾病或病況係氣喘、慢性阻塞性肺病(COPD)、成人呼吸窘迫症候群(ARDS)、潰瘍性結腸炎、克隆氏病、支氣管炎、皮炎、日光性角化症、基底細胞癌、膀胱癌、過敏性鼻炎、牛皮癬、硬皮症、蕁麻疹、類風濕性關節炎、多發性硬化、癌症、乳癌、HIV、肝炎、C型肝炎或狼瘡。在該等方法之某些實施例中,疾病係B型肝炎、C型肝炎、結腸直腸癌或肝細胞癌。
如本文所用之術語「烷基」係指飽和具支鏈或直鏈烴。在某些實施例中,該等烷基視情況經取代。如本文所用之術語「C1-C3烷基」、「C1-C4烷基」、「C1-C5烷基」、「C1-C6烷基」、「C1-C7烷基」及「C1-C8烷基」分別係指含有至少1個且至多3個、4個、5個、6個、7個或8個碳原子之烷基。若無另外說明,則烷基通常係C1-C6烷基。如本文所用烷基之非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊基、異戊基、己基、庚
基、辛基、壬基、癸基及諸如此類。
如本文所用之術語「雜原子」係指氮(N)、氧(O)或硫(S)原子。
如本文所用之術語「雜環烷基」係指飽和3-6員單環烴環結構、飽和5-6員單環烴環結構、飽和6-9員稠合二環烴環結構或飽和10-14員稠合三環烴環結構,其中烴環結構之1至4個環碳經1至4個獨立地選自-O-、-NR-或-S-之基團替代,其中R係氫、C1-C4烷基或胺基保護基團。
如本文所用雜環烷基之非限制性實例包括氮丙啶基、氮丙啶-1-基、氮丙啶-2-基、氮丙啶-3-基、環氧乙烷基、環氧乙烷-2-基、環氧乙烷-3-基、硫雜環丙基、硫雜環丙-2-基、硫雜環丙-3-基、氮雜環丁烷基、氮雜環丁烷-1-基、氮雜環丁烷-2-基、氮雜環丁烷-3-基、氧雜環丁基、氧雜環丁-2-基、氧雜環丁-3-基、氧雜環丁-4-基、硫雜環丁基、硫雜環丁烷-2-基、硫雜環丁烷-3-基、硫雜環丁烷-4-基、吡咯啶基、吡咯啶-1-基、吡咯啶-2-基、吡咯啶-3-基、吡咯啶-4-基、吡咯啶-5-基、四氫呋喃基、四氫呋喃-2-基、四氫呋喃-3-基、四氫呋喃-4-基、四氫呋喃-5-基、四氫噻吩基、四氫噻吩-2-基、四氫噻吩-3-基、四氫噻吩-4-基、四氫噻吩-5-基、六氫吡啶基、六氫吡啶-1-基、六氫吡啶-2-基、六氫吡啶-3-基、六氫吡啶-4-基、六氫吡啶-5-基、六氫吡啶-6-基、四氫吡喃基、四氫吡喃-2-基、四氫吡喃-3-基、四氫吡喃-4-基、四氫吡喃-5-基、四氫吡喃-6-基、四氫噻喃基、四氫噻喃-2-基、四氫噻喃-3-基、四氫噻喃-4-基、四氫噻喃-5-基、四氫噻喃-6-基、六氫吡嗪基、六氫吡嗪-1-基、六氫吡嗪-2-基、六氫吡嗪-3-基、六氫吡嗪-4-基、六氫吡嗪-5-基、六氫吡嗪-6-基、嗎啉基、嗎啉-2-基、嗎啉-3-基、嗎啉-4-基、嗎啉-5-基、嗎啉-6-基、硫嗎啉基、硫嗎啉-2-基、硫嗎啉-3-基、硫嗎啉-4-基、硫嗎啉-5-基、硫嗎啉-6-基、氧硫雜環己烷基、氧硫雜環己烷-2-基、氧硫雜環己烷-3-基、氧硫雜環己烷-5-
基、氧硫雜環己烷-6-基、二噻烷基、二噻烷-2-基、二噻烷-3-基、二噻烷-5-基、二噻烷-6-基、氮雜環庚烷基、氮雜環庚烷-1-基、氮雜環庚烷-2-基、氮雜環庚烷-3-基、氮雜環庚烷-4-基、氮雜環庚烷-5-基、氮雜環庚烷-6-基、氮雜環庚烷-7-基、氧雜環庚烷基、氧雜環庚烷-2-基、氧雜環庚烷-3-基、氧雜環庚烷-4-基、氧雜環庚烷-5-基、氧雜環庚烷-6-基、氧雜環庚烷-7-基、硫雜環庚烷基、硫雜環庚烷-2-基、硫雜環庚烷-3-基、硫雜環庚烷-4-基、硫雜環庚烷-5-基、硫雜環庚烷-6-基、硫雜環庚烷-7-基、二氧戊環基、二氧戊環-2-基、二氧戊環-4-基、二氧戊環-5-基、噻噁烷基、噻噁烷-2-基、噻噁烷-3-基、噻噁烷-4-基、噻噁烷-5-基、二硫戊環基、二硫戊環-2-基、二硫戊環-4-基、二硫戊環-5-基、吡咯啉基、吡咯啉-1-基、吡咯啉-2-基、吡咯啉-3-基、吡咯啉-4-基、吡咯啉-5-基、咪唑啉基、咪唑啉-1-基、咪唑啉-3-基、咪唑啉-4-基、咪唑啉-5-基、咪唑啶基、咪唑啶-1-基、咪唑啶-2-基、咪唑啶-3-基、咪唑啶-4-基、咪唑啶-4-基、吡唑啉基、吡唑啉-1-基、吡唑啉-3-基、吡唑啉-4-基、吡唑啉-5-基、吡唑啶基、吡唑啶-1-基、吡唑啶-2-基、吡唑啶-3-基、吡唑啶-4-基、吡唑啶-5-基、六氫-1,4-二氮呯基、二氫呋喃基二氫吡喃基、1,2,3,6-四氫吡啶基、2H-吡喃基、4H-吡喃基、二氫吡喃基、二氫噻吩基、二氫呋喃基、3-氮雜二環[3.1.0]己基、3-氮雜二環[4.1.0]庚基、吡咯啶基-2-酮、六氫吡啶基-3-酮六氫吡啶基-2-酮、六氫吡啶基-4-酮及2H-吡咯基
如本文所用之關於調配物、組合物或成份之術語「可接受」意指對所治療個體之總體健康狀況無持久有害效應。
術語向個體「投與(administration)」或「投與(administering)」化合物意指向需要治療之個體提供式(I)化合物或其醫藥上可接受之鹽。
如本文所用之術語「癌症」係指往往以不受控方式增殖且在一些情形下轉移(擴散)之異常細胞生長。癌症之類型包括(但不限於)實
體腫瘤(例如以下彼等腫瘤:膀胱腫瘤、腸腫瘤、腦腫瘤、乳房腫瘤、子宮內膜腫瘤、心臟腫瘤、腎腫瘤、肺腫瘤、淋巴組織腫瘤(淋巴瘤)、卵巢腫瘤、胰臟腫瘤或其他內分泌器官(甲狀腺)腫瘤、前列腺腫瘤、皮膚腫瘤(黑素瘤))或血液腫瘤(例如白血病)。
如本文所用之術語「載劑」係指幫助本文所述之化合物納入細胞或組織中之化學化合物或藥劑。
如本文所用之術語「共投與」或「組合投與」或類似用語意欲涵蓋向單一患者投與所選治療劑,且意欲包括該等藥劑無需以相同投與途經或同時投與之治療方案。
如本文所用之術語「皮膚(dermatological)病症」係指皮膚(skin)病症。該等皮膚病症包括(但不限於)皮膚之增生性或發炎病症,例如異位性皮炎、大皰病症、膠原病、接觸性皮炎濕疹、川崎病(Kawasaki Disease)、酒渣鼻、休格連-拉森症候群(Sjogren-Larsso Syndrome)、日光性角化症、基底細胞癌及蕁麻疹。
如本文所用之術語「稀釋劑」係指用於在遞送之前稀釋本文所述化合物之化學化合物。稀釋劑亦可用於穩定本文所述化合物。
如本文所用術語「有效量」或「治療有效量」係指所投與之本文所述化合物將在一定程度上減輕所治療疾病或病況之一或多種症狀之足夠量。結果可為降低及/或減輕疾病之體徵、症狀或病因或生物系統之任何其他期望變化。例如,對於治療用途而言,「有效量」係使疾病症狀在臨床上顯著減輕所需之包含如本文所揭示化合物之組合物的量。在任何個別情形中之適當「有效」量可使用諸如劑量遞增研究等技術來測定。
如本文所用術語「增強(enhance或enhancing)」意指增加或延長期望效應之功效或持續時間。因此,關於增強治療劑之效應,術語「增強」係指增加或延長其他治療劑對系統之效應的功效或持續時
間。如本文所用之「增強有效量」係指足以增強期望系統中另一治療劑之效應之量。
術語「賦形劑」係指可以成品劑型存在之任何基本輔助物質。舉例而言,術語「賦形劑」包括媒劑、黏合劑、崩解劑、填充劑(稀釋劑)、潤滑劑、懸浮/分散劑及諸如此類。
如本文所用術語「纖維化」或「纖維化病症」係指以下病況:跟隨急性或慢性發炎且與細胞及/或膠原之異常累積相關,並包括(但不限於)個別器官或組織(例如心臟、腎、關節、肺或皮膚)之纖維化,且包括諸如特發性肺纖維化及隱原性纖維化肺泡炎等病症。
如本文所用術語「醫原性」意指因醫學或手術療法產生或惡化之病況、病症或疾病。
如本文所用術語「免疫有效量」意指向個體投與可有效地治療或預防免疫疾病或病症之呈單一劑量或作為一系列之一部分的足夠量。此量端視欲治療個體之健康及身體狀況、年齡、欲治療個體(例如非人類靈長類動物、靈長類動物等)之分類群、個體之免疫系統合成抗體之能力、期望保護度、治療醫師對醫學情況之評價及其他相關要素而定。預期該量將在可經由常規試驗測定之相對較寬之範圍內。
如本文所用針對抗原或組合物之「免疫性反應」或「免疫反應」係指在個體中發生針對抗原或組合物之體液及/或細胞免疫反應。
免疫反應包括先天性及適應性免疫反應。先天性免疫反應係為免疫系統提供第一線防禦之速效反應。相比之下,適應性免疫性利用具有體細胞重組受體基因(例如,T細胞及B細胞受體)的免疫細胞之選擇及選殖擴增,該等基因識別來自給定病原體或病症(例如,腫瘤)之抗原,由此提供特異性及免疫記憶。先天性免疫反應在其許多效應中尤其引起發炎細胞介素之快速突發及抗原呈遞細胞(APC)(例如巨噬
細胞及樹突狀細胞)之活化。為區分病原體與自身組份,先天性免疫系統利用眾多種偵測病原體特徵之相對不變之受體,稱為病原體相關之分子模式或PAMP。已報導免疫反應之此增強背後之機制涉及在眾多種免疫細胞上差異表現之模式識別受體(PRR),該等細胞包括嗜中性球細胞、巨噬細胞、樹突狀細胞、天然殺傷細胞、B細胞及一些非免疫細胞(例如上皮及內皮細胞)。PRR之接合使得該等細胞中之一些活化及其細胞介素及趨化介素之分泌以及其他細胞之成熟及遷移。協同地,此產生可建立適應性免疫反應之發炎環境。PRR包括非吞噬受體(例如類鐸受體(TLR)及核苷酸結合寡聚結構域(NOD)蛋白)及誘導吞噬作用之受體(例如清除劑受體、甘露糖受體及β-葡聚糖受體)。樹突狀細胞識別為用於起始原初CD4+輔助T(TH)細胞之引發並誘導CD8+ T細胞分化成殺傷細胞之一些最重要細胞類型。已報導TLR信號傳導在確定該等輔助T細胞反應之品質方面具有重要作用,例如利用TLR信號之性質確定所觀察到之特定類型之TH反應(例如,TH1對TH2反應)。抗體(體液)及細胞免疫性之組合係作為TH1型反應之一部分產生,而TH2型反應主要係抗體反應。
「體液免疫反應」係指由抗體分子介導之免疫反應,而「細胞免疫反應」係指由T淋巴球及/或其他白血球介導之免疫反應。細胞免疫性之一個重要態樣涉及藉由細胞溶解性T細胞(「CTL」)之抗原特異性反應。CTL具有針對與由主要組織相容性複合物(MHC)編碼之蛋白質一起呈遞且在細胞表面上表現之肽抗原之特異性。CTL幫助誘導及促進細胞內微生物之細胞內破壞或感染該等微生物之細胞之溶解。細胞免疫性之另一態樣涉及藉由輔助T細胞之抗原特異性反應。輔助T細胞用於幫助刺激針對顯示肽抗原及其表面上之MHC分子之細胞的非特異性效應細胞之功能並集中其活性。「細胞免疫反應」亦係指產生細胞介素、趨化介素及由活化T細胞及/或其他白血球(包括源自
CD4+及CD8+ T細胞之彼等)產生之其他該等分子。
如本文所用術語「發炎病症」係指特徵在於以下體徵中之一或多者之彼等疾病或病況:疼痛(痛,來自有毒物質之產生及神經之刺激)、發熱(灼熱,來自血管擴張)、充血(發紅,來自血管擴張及血流增加)、腫脹(腫瘤,來自體液之過量流入或限制性流出)及功能損失(機能喪失,其可為部分或完全的、短暫或永久的)。發炎具有多種形式且包括(但不限於)為以下中之一或多者之發炎:急性、黏連性、萎縮性、多泌性、慢性、硬變性、瀰漫性、散播性、滲出性、纖維蛋白性、纖維性、局灶性、肉芽腫性、增生性、肥厚性、間質性、轉移性、壞死性、阻塞性、實質性、塑性、新生性、增殖性、假膜性、化膿性、硬化性、漿液組織形成性、漿液性、單純性、特異性、亞急性、催膿性、毒性、創傷性及/或潰瘍性。發炎病症進一步包括(但不限於)彼等侵襲血管(多發性動脈炎、暫時性關節炎);關節(關節炎:結晶性關節炎、骨關節炎、牛皮癬性關節炎、反應性關節炎、類風濕性關節炎、萊特氏關節炎(Reiter's arthritis));胃腸道(疾病);皮膚(皮炎);或多種器官及組織(全身性紅斑狼瘡)。
如本文所用術語「眼疾病」或「眼部疾病」係指侵襲眼亦及可能周圍組織之疾病。眼或眼部疾病包括(但不限於)結膜炎、視網膜炎、鞏膜炎、眼色素層炎、過敏性結膜炎、春季結膜炎、乳頭狀結膜炎及巨細胞病毒(CMV)視網膜炎。
如本文所用術語「醫藥上可接受」係指並不消除本文所述化合物之生物活性或性質之材料,例如載劑或稀釋劑。向個體投與該等材料而不引起不期望生物效應或以有害方式與含有其之組合物之任一組份相互作用。
如本文所用術語「醫藥上可接受之鹽」係指不會對其投與之生物體造成明顯刺激且不會消除本文所述化合物之生物活性及性質之化
合物的調配物。
如本文所用術語「組合」或「醫藥組合」意指自混合或組合一種以上之活性成份產生且包括活性成份之固定及非固定組合二者的產品。術語「固定組合」意指將活性成份(例如,式(I)化合物)及另一治療劑二者以單一實體或劑量之形式同時投與患者。術語「非固定組合」意指將活性成份(例如式(I)化合物)與另一治療劑二者作為單獨實體同時、同步或相繼且無特定時間限制地投與患者,其中該投與可在患者體內提供該2種化合物之治療有效含量。後者亦適用於聯合療法,例如投與3種或更多種活性成份。
如本文所用術語「組合物」或「醫藥組合物」係指式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽與至少一種及視情況一種以上之其他醫藥上可接受之化學組份(例如載劑、穩定劑、稀釋劑、分散劑、懸浮劑、增稠劑及/或賦形劑)的混合物。
如本文所用術語「呼吸疾病」係指侵襲參與呼吸之器官(例如鼻、咽喉、喉、氣管、支氣管及肺)之疾病。呼吸疾病包括(但不限於)氣喘、成人呼吸窘迫症候群及過敏性(外源性)氣喘、非過敏性(內源性)氣喘、急性重度氣喘、慢性氣喘、臨床氣喘、夜間氣喘、過敏原引起之氣喘、阿司匹林(aspirin)敏感性氣喘、運動引起之氣喘、二氧化碳換氣過度(isocapnic hyperventilation)、兒童期發作性氣喘、成人期發作性氣喘、咳嗽變異性氣喘、職業性氣喘、類固醇抵抗性氣喘、季節性氣喘、季節性過敏性鼻炎、常年性過敏性鼻炎、慢性阻塞性肺病(包括慢性支氣管炎或肺氣腫、肺動脈高血壓、間質性肺纖維化及/或氣道發炎及囊性纖維化)以及低氧。
如本文所用術語「個體」或「患者」涵蓋哺乳動物及非哺乳動物。哺乳動物之實例包括(但不限於)人類、黑猩猩、猿、猴子、牛、馬、綿羊、山羊、豬;兔、狗、貓、大鼠、小鼠、豚鼠及諸如此類。
非哺乳動物之實例包括(但不限於)鳥、魚及諸如此類。通常,個體係人類,且可係已經診斷需要治療本文所揭示疾病或病症之人類。
如本文所用術語「TLR7促效劑」係指活化TLR7受體之化合物。
如本文所用術語「TLR7疾病」或「與TLR7活性相關之疾病或病症」係指與類鐸受體相關之任何疾病況態。該等疾病或病症包括(但不限於)傳染病、病毒性傳染病、發炎性疾病、呼吸疾病、皮膚病、自體免疫疾病、細胞增生性疾病及癌症,例如(僅舉例而言)氣喘、慢性阻塞性肺病(COPD)、成人呼吸窘迫症候群(ARDS)、潰瘍性結腸炎、克隆氏病、支氣管炎、皮炎、日光性角化症、基底細胞癌、膀胱癌、過敏性鼻炎、牛皮癬、硬皮症、蕁麻疹、類風濕性關節炎、多發性硬化、癌症、乳癌、淋巴瘤、骨肉瘤、黑色素瘤、乳癌、腎癌、前列腺癌、結腸直腸癌、甲狀腺癌、卵巢癌、胰臟癌、神經元癌症、肺、子宮癌、胃腸癌症、HIV、肝炎、B型肝炎、C型肝炎、肝細胞癌或狼瘡。
如本文所用術語「治療有效量」係指與未接受該量之相應個體相比,可改良治療、治癒、預防或改善疾病、病症或副作用或降低疾病或病症之進展速率之化合物之任一量。該術語在其範疇內亦包括可有效地增強正常生理功能之量。
如本文所用術語「治療」(「treat」、「treating」或「treatment」)係指以預防及/或治療方式減輕、減弱或改善疾病或病況症狀、預防額外症狀、改善或預防症狀之潛在代謝病因、抑制疾病或病況、阻止疾病或病況之發展、減輕疾病或病況、使疾病或病況消退、減輕由疾病或病況所引起之病況或終止疾病或病況之症狀。
化合物名稱係使用ChemDraw Ultra 10.0版(CambridgeSoft®)或JChem 5.2.2版(ChemAxon)來獲得。
本文提供為類鐸受體-7(TLR7)之促效劑之化合物及其醫藥組合物。本文亦提供用於治療與TLR7活性相關之疾病及/或病症之化合物、醫藥組合物及方法。
本發明之TLR7促效劑係具有式(I)結構之化合物及其醫藥上可接受之鹽、個別異構物及異構物之混合物:
其中:R1係-NHR6或-NHCHR6R9;R3係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH或四唑基;R4係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH或四唑基;其中,當R3係H時,則R4係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH或四唑基;或當R4係H時,則R3係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH或四唑基;L1係-(CH2)m-;
L2係-(CH2)m-;L7=-(CH2)m(CHR11CH2)m(CH2)n-;R6係-C3-C6烷基;R7係-C1-C3烷基;R9係L1OH;每一R11獨立地選自-OH;R12係a)未經取代之四唑基;b)經-L1C(=O)OH取代之四唑基;或c)5-6員雜環烷基,其具有1至2個獨立地選自N及O之雜原子且經-C(=O)OH取代;每一m獨立地選自1、2、3及4,且每一n獨立地選自0、1、2、3及4。
在某些實施例中,本發明之TLR7促效劑係具有式(Ia)或式(Ib)結構之化合物:
其中R1、R3及R4係如本文所定義。
本文所提供之式(I)、式(Ia)及式(Ib)化合物及其醫藥上可接受之鹽亦包括該等化合物及醫藥上可接受之鹽之所有適宜同位素變化形式。化合物或其醫藥上可接受之鹽之同位素變化形式定義為其中至少一個原子經具有相同原子序數但原子質量不同於通常或主要在自然界
中發現之原子質量的原子替代者。可納入化合物及其醫藥上可接受之鹽中之同位素之實例包括(但不限於)氫、碳、氮及氧之同位素,例如2H、3H、11C、13C、14C、15N、17O、18O、35S、18F、36Cl及123I。化合物及其醫藥上可接受之鹽之某些同位素變化形式(例如其中納入放射性同位素(例如3H或14C)之彼等)可用於藥物及/或受質組織分佈研究中。在具體實例中,3H及14C同位素可因其易於製備及可檢測性而使用。在其他實例中,使用同位素(例如2H)取代可提供某些治療優點,此歸因於較強代謝穩定性,例如增加的活體內半衰期或降低的劑量需求。化合物及其醫藥上可接受之鹽及異構物之同位素變化形式係藉由習用程序使用適宜試劑之適宜同位素變化形式來製備。
用於製備式(I)及其子式之化合物之一般程序闡述於下文實例中。在所述反應中,倘若反應性官能基(例如羥基、胺基、亞胺基、硫基或羧基)在最終產物中合意,則可對該等基團進行保護以避免其於反應中之不期望參與。習用保護基團可根據標準實踐來使用(例如,參見T.W.Greene及P.G.M.Wuts,「Protective Groups in Organic Chemistry」,John Wiley and Sons,1991)。
在某些實施例中,藉由使式(I)、式(Ia)或式(Ib)化合物之游離鹼形式與醫藥上可接受之有機酸或無機酸反應將式(I)及其子式之化合物製備成醫藥上可接受之酸加成鹽。在其他實施例中,藉由使式(I)、式(Ia)或式(Ib)化合物之游離酸形式與醫藥上可接受之有機鹼或無機鹼反應來製備式(I)、式(Ia)或式(Ib)化合物之醫藥上可接受之鹼加成鹽。或者,使用起始材料或中間體之鹽來製備式(I)、式(Ia)或式(Ib)化合物之鹽形式。在某些實施例中,式(I)、式(Ia)或式(Ib)化合物呈其他鹽形式,包括(但不限於)草酸鹽及三氟乙酸鹽。在某些實施例中,形成酸與鹼之半鹽,例如半硫酸鹽及半鈣鹽。
式(I)、式(Ia)或式(Ib)化合物之該等醫藥上可接受之酸加成鹽包括(但不限於)氫溴酸鹽、鹽酸鹽、硫酸鹽、硝酸鹽、琥珀酸鹽、馬來酸鹽、甲酸鹽、乙酸鹽、己二酸鹽、苯磺酸鹽、碳酸氫鹽/碳酸鹽、丙酸鹽、富馬酸鹽、檸檬酸鹽、酒石酸鹽、乳酸鹽、苯甲酸鹽、柳酸鹽、麩胺酸鹽、天冬胺酸鹽、對甲苯磺酸鹽、苯磺酸鹽、甲烷磺酸鹽、乙烷磺酸鹽、萘磺酸鹽(例如2-萘磺酸鹽)、己酸鹽、重硫酸鹽/硫酸鹽、硼酸鹽、樟腦磺酸鹽、環己胺磺酸鹽、乙二磺酸鹽、乙磺酸鹽、葡庚糖酸鹽、葡萄糖酸鹽、葡糖醛酸鹽、六氟磷酸鹽、海苯酸鹽、鹽酸鹽/氯化物、氫溴酸鹽/溴化物、氫碘酸鹽/碘化物、羥乙磺酸鹽、乳酸鹽、蘋果酸鹽、丙二酸鹽、甲磺酸鹽、甲基硫酸鹽、萘酸鹽、2-萘磺酸鹽、菸鹼酸鹽、乳清酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、磷酸鹽/氫磷酸鹽/磷酸二氫鹽、焦麩胺酸鹽、葡萄糖二酸鹽、硬脂酸鹽、鞣酸鹽、甲苯磺酸鹽、三氟乙酸鹽及昔萘酸鹽。
用於形成式(I)、式(Ia)或式(Ib)化合物之某些醫藥上可接受之酸加成鹽之有機酸或無機酸包括(但不限於)氫溴酸、鹽酸、硫酸、硝酸、磷酸、琥珀酸、馬來酸、甲酸、乙酸、丙酸、富馬酸、檸檬酸、酒石酸、乳酸、苯甲酸、柳酸、麩胺酸、天冬胺酸、對甲苯磺酸、苯磺酸、甲烷磺酸、乙烷磺酸、萘磺酸(例如2-萘磺酸)或己酸。
式(I)、式(Ia)或式(Ib)化合物之該等醫藥上可接受之鹼加成鹽包括(但不限於)鋁鹽、精胺酸鹽、苄星青黴素鹽、鈣鹽、膽鹼鹽、二乙胺鹽、二醇胺鹽、甘胺酸鹽、離胺酸鹽、鎂鹽、葡甲胺鹽、醇胺鹽、鉀鹽、鈉鹽、胺丁三醇鹽及鋅鹽。
在某些實施例中,式(I)化合物之游離酸或游離鹼形式係分別自相應的鹼加成鹽或酸加成鹽形式製備。例如,呈酸加成鹽形式之式(I)、式(Ia)或式(Ib)化合物藉由用適宜鹼(僅舉例而言,氫氧化銨溶液、氫氧化鈉及諸如此類)處理轉化成相應的游離鹼。舉例而言,呈
鹼加成鹽形式之式(I)、式(Ia)或式(Ib)化合物藉由用適宜酸(僅舉例而言,鹽酸)處理轉化成相應的游離酸。
在某些實施例中,使用彼等熟習此項技術者已知之方法將式(I)、式(Ia)或式(Ib)化合物製備成受保護衍生物。適於產生保護基團及其移除之技術之詳細描述可參見T.W.Greene,「Protecting Groups in Organic Chemistry」,第3版,John Wiley and Sons公司,1999。
在某些實施例中,將化合物製備成其個別立體異構物。在其他實施例中,藉由使化合物之外消旋混合物與光學活性解析劑反應以成一對非鏡像異構物化合物、分離該等非鏡像異構物並回收光學純鏡像異構物將式(I)、式(Ia)及式(Ib)化合物製備成其個別立體異構物。在某些實施例中,使用式(I)、式(Ia)或式(Ib)化合物之共價非鏡像異構物衍生物或藉由使用可解離複合物(例如,結晶非鏡像異構物鹽)來實施鏡像異構物之解析。非鏡像異構物具有不同的物理性質(例如,熔點、沸點、溶解度、反應性等)且容易地藉由利用該等相異性來分離。在某些實施例中,非鏡像異構物係藉由層析或藉由分離/解析技術基於溶解度差異來分離。然後藉由不會引起消旋之任何實踐方式回收光學純鏡像異構物以及解析劑。適用於自化合物之外消旋混合物解析其立體異構物之技術的更詳細描述可參見Jean Jacques、Andre Collet、Samuel H.Wilen,「Enantiomers,Racemates and Resolutions」,John Wiley and Sons公司,1981。
用於製備式(I)化合物之合成反應圖之非限制性實例圖解說明於下文反應圖(I)中。
反應圖(I)圖解說明自市售4-氯-5H-吡咯并[3,2-d]嘧啶-2-胺開始使用兩步反應圖之式(I)吡咯并嘧啶之合成。N-5位置處藉由苄基溴(或苄基氯)類似物之烷基化給出相應的5-苄基衍生物,其中R3及R4係如本文所定義。隨後藉由烷基胺衍生物SNAr取代氯基團提供相應的4,5-二取代之吡咯并嘧啶,其中R係R6或-CHR6R9,且R6及R9係如本文所定義。
當外源抗原激發免疫系統時,其會啟動保護反應作為回應,該保護反應的特徵在於先天及獲得性免疫系統二者之協同相互作用。這兩個相互依賴之系統會滿足兩個特有的要求:速度(由先天性系統貢獻)及特異性(由適應性系統貢獻)。
先天性免疫系統是抵禦侵襲性病原體之第一道防線,阻止病原體的同時使適應性反應成熟,其會在感染數分鐘內因應病原體中之廣泛保守模式(儘管其不具非特異性,但可區分自身與病原體)以抗原獨立性方式觸發。主要地,其亦會產生增強適應性免疫系統且引向(或使其極化)最適於抵抗傳染原之細胞或體液反應之發炎及共刺激環境(有時稱為危險信號)。已綜述用於治療性靶向先天免疫性之TLR調節劑之研發(參見Nature Medicine,2007,13,552-559;Drug Discovery Today:Therapeutic Stategies,2006,3,343-352及Journal of Immunology,2005,174,1259-1268)。
適應性反應經數天或數週會發揮效果,但最終會提供完全消除病原體及產生免疫記憶所需之精細抗原特異性。其主要係由已經歷種系基因重組且特徵在於特異性及長效記憶之T細胞及B細胞來調介。然而,其亦涉及招募先天性免疫系統之要件,包括吞噬細菌且甚至相對較大之原生動物寄生蟲之專職吞噬細胞(巨噬細胞、嗜中性球細胞等)及顆粒球細胞(嗜鹼性球細胞、嗜酸性球細胞等)。一旦適應性免疫
反應成熟,隨後暴露於病原體即可引起其快速消除,此乃因已產生在隨後暴露於其同源抗原下後快速活化之高度特異性記憶細胞。
自體免疫疾病係藉由以下各項來定義:(i)針對自身抗原(僅舉例而言,使用針對TSH受體之抗體之葛瑞夫茲原發性甲狀腺功能亢進症(Graves' primary hyperthyroidism))之體液或自體抗體反應,或(ii)其中免疫細胞破壞衍生出自身抗原之非免疫細胞(僅舉例而言,甲狀腺細胞(橋本氏甲狀腺炎(Hashimoto's thyroiditis))或胰臟β-胰島細胞(1型糖尿病)之細胞反應。許多自體免疫疾病係兩種現象之組合,例如橋本氏及1型糖尿病亦具有自體抗體、抗甲狀腺過氧化酶(TPO)或抗麩胺酸去羧酶(GAD)/胰島細胞。自體免疫疾病通常具有發炎組份,包括(但不限於)黏附分子(僅舉例而言,血管細胞黏附分子-1(VCAM-1)增加及對脈管系統之白血球黏附改變,例如(僅舉例而言)結腸炎、全身性狼瘡、全身性硬化及糖尿病之血管併發症。
類鐸受體(TLR)係I型跨膜蛋白,其特徵在於細胞外N末端富含白胺酸之重複(LRR)結構域,其後為富含半胱胺酸之區域、TM結構域及含有保守區域(稱為鐸/IL-1受體(TIR)結構域)之細胞內(細胞質)尾。TLR係主要在免疫細胞上表現之模式識別受體(PRR),該等免疫細胞包括(但不限於)樹突狀細胞、T淋巴球、巨噬細胞、單核球細胞及天然殺傷細胞。LLR結構域對於配體結合及相關信號傳導至關重要且係PRR之共同特徵。TIR結構域在蛋白質-蛋白質相互作用中至關重要且與先天免疫性相關。TIR結構域亦結合由三個亞群構成之較大IL-1R/TLR超家族。第一群之成員在其細胞外區域中具有免疫球蛋白結構域且包括IL-1及IL-18受體及輔助蛋白以及ST2。第二群涵蓋TLR。第三群包括對信號傳導至關重要之細胞內銜接蛋白。
TLR係一群模式識別受體,該等可結合至來自細菌、真菌、原生動物及病毒之病原體相關分子模式(PAMP)且係作為抵禦侵襲性病原
體之第一道防線。TLR為誘導參與發炎反應之基因之表現所必需,且TLR及先天性免疫系統係發展抗原特異性獲得性免疫性之關鍵步驟。
適應性(體液或細胞介導之)免疫性與先天免疫性之TLR信號機制相關。先天免疫性係快速發揮抵抗環境傷害(包括(但不限於)細菌或病毒劑)之功能之保護性免疫細胞反應。適應性免疫性係較緩慢反應,其涉及原初T淋巴球至T輔助1(Th1)或T輔助2(Th2)細胞類型之分化及活化。Th1細胞主要促進細胞免疫性,而Th2細胞主要促進體液性免疫性。儘管是一種主要的宿主保護系統,但自TLR路徑所發出之先天免疫性信號之病理表現也參與啟動自體免疫發炎性疾病。
所有TLR似乎是以同二聚體或異二聚體發揮識別存在於病原性生物體上之特異性分子決定子或其集合的功能,該等特異性分子決定子包括細菌細胞表面脂多糖、脂蛋白、細菌鞭毛蛋白、來自細菌及病毒二者之DNA及病毒RNA。針對TLR活化之細胞反應涉及活化一或多種轉錄因子,從而產生並分泌細胞介素及共刺激分子,例如干擾素、TNF-、介白素、MIP-1及MCP-1,該等有助於殺死及清除病原性入侵。
TLR空間表現與宿主之環境界面一致。儘管於果蠅屬(Drosophila)中僅已選殖少數其他類鐸蛋白,但人類TLR家族係由至少11個成員TLR1至TLR11構成,由於其起始之細胞表現及信號傳導路徑不同而會引發重疊但不同的生物反應。每一TLR係在不同白血球亞組上表現,且每一TLR之表現模式及PAMP敏感性具有特異性,且可以藉由免疫系統使得警醒地監督偵測到之不同病原體亞組。
TLR7對應位置至人類染色體Xp22,且TLR7序列編碼含有27個N末端LRR之1049(aa)蛋白質,其計算分子量為121kDa。TLR7與TLR8及TLR9最密切相關,其分別具有43%及36%總體(aa)序列一致性。
在活體內,TLR7 mRNA表現於肺、胎盤、脾、淋巴結及扁桃體中。TLR7 mRNA會表現在單核球細胞、B細胞及漿細胞樣樹突狀細胞中最高。活體外,THP-1細胞經PMA誘導之分化後,TLR7 mRNA表現會上調。TLR7會因暴露於IL-6而大幅度上調,而暴露於自泌素IFN-γ、IL-1β則上調程度稍低。暴露於革蘭氏陽性及革蘭氏陰性細菌二者後,THP-1細胞中之TLR7 mRNA表現會升高。離體下,暴露於革蘭氏陽性及革蘭氏陰性細菌二者後,單核球細胞中之TLR7表現會升高,且在顆粒球細胞升高較大的程度。TLR7會在胞內體中表現。TLR7之作用係偵測細胞內「外源」單鏈RNA之存在,是為對病毒入侵反應的一種工具。TLR7係結構高度保守之蛋白質,其可識別來自病毒(例如人類免疫缺陷病毒、水泡性口炎病毒及流行性感冒病毒)之富含鳥苷或尿苷之單鏈RNA(ssRNA)。因此,經由活化樹突狀細胞及其他抗原呈遞細胞,預期TLR7接合及所得細胞介素產生會活化不同的先天及獲得性免疫反應機制,從而破壞病原體、所感染細胞或腫瘤細胞。
式(I)、式(Ia)或式(Ib)化合物、其醫藥上可接受之鹽及異構物醫藥組合物及/或組合係類鐸受體7活性之促效劑,且用於治療與該等TLR7受體相關之疾病及/或病症。
在某些實施例中,式(I)、式(Ia)或式(Ib)化合物、其醫藥上可接受之鹽及異構物、醫藥組合物及/或組合用於治療呼吸疾病及/或病症,包括(但不限於)氣喘、支氣管性氣喘、過敏性氣喘、內源性氣喘、外源性氣喘、運動引起之氣喘、藥物引起之氣喘(包括阿斯匹林及NSAID引起之氣喘)及粉塵引起之氣喘、慢性阻塞性肺病(COPD);支氣管炎,包括傳染性及嗜酸性球性支氣管炎;肺氣腫;支氣管擴張症;囊性纖維化;類肉瘤病;農夫肺及相關疾病;過敏性肺炎;肺纖維化,包括隱原性纖維肺泡炎、特發性間質性肺炎、纖維化併發性抗腫瘤療法及慢性感染,包括結核病及麯黴病及其他真菌感染;肺移植
之併發症;肺脈管系統之血管炎及血栓病症以及肺高血壓;鎮咳活性,包括治療與氣道之發炎及分泌病況相關之慢性咳嗽及醫原性咳嗽;急性及慢性鼻炎,包括藥物性鼻炎及血管運動性鼻炎;常年性及季節性過敏性鼻炎,包括神經性鼻炎(花粉熱);鼻息肉病;急性病毒感染,包括普通感冒及因呼吸道融合病毒、流行性感冒病毒、冠狀病毒(包括SARS)及腺病毒所致之感染。
在某些實施例中,式(I)、式(Ia)或式(Ib)化合物、其醫藥上可接受之鹽及異構物、醫藥組合物及/或組合用於治療皮膚病症,包括(但不限於)牛皮癬、異位性皮炎、接觸性皮炎或其他濕疹性皮膚病及延遲型過敏反應;植物性及光照性皮炎;脂溢性皮炎、皰疹樣皮炎、扁平苔蘚、硬化萎縮苔蘚、壞疽性膿皮病、皮膚類肉瘤、基底細胞癌、日光性角化症、盤狀紅斑狼瘡、天皰瘡、類天皰瘡、大皰性表皮鬆懈、蕁麻疹、血管水腫、血管炎、毒性紅斑、皮膚嗜酸性球增多症、斑禿、男性型禿髮、史維特症候群(Sweet's syndrome)、偉柯二氏症候群(Weber-Christian syndrome)、多形性紅斑;傳染性及非傳染性蜂巢組織炎二者;脂層炎;皮膚淋巴瘤、非黑色素瘤皮膚癌及其他發育不良病灶;藥物引起之病症,包括固定型藥疹。
在某些實施例中,式(I)、式(Ia)或式(Ib)化合物、其醫藥上可接受之鹽及異構物、醫藥組合物及/或組合用於治療眼疾病及/或病症,包括(但不限於)眼瞼炎;結膜炎,包括常年性及春季過敏性結膜炎;虹膜炎;前及後眼色素層炎;脈絡膜炎;侵襲視網膜之自體免疫、變性或發炎病症;眼炎,包括交感性眼炎;類肉瘤病;感染,包括病毒、真菌及細菌感染。
在某些實施例中,式(I)、式(Ia)或式(Ib)化合物、其醫藥上可接受之鹽及異構物、醫藥組合物及/或組合用於治療其他自體免疫及過敏病症,包括(但不限於)類風濕性關節炎、腸躁激症候群、全身性紅
斑狼瘡、多發性硬化、橋本氏甲狀腺炎、克隆氏病、發炎性腸病(IBD)、格雷氏病(Graves' disease)、愛迪生病(Addison's disease)、糖尿病、特發性血小板減少性紫癜、嗜酸性球筋膜炎、高IgE症候群、抗磷脂症候群及塞紮萊症候群(Sazary syndrome)。
在某些實施例中,式(I)、式(Ia)或式(Ib)化合物、其醫藥上可接受之鹽及異構物及醫藥組合物用於治療癌症,包括(但不限於)膀胱癌、前列腺癌、乳癌、結腸直腸癌、肝癌、肝細胞癌、肺癌、卵巢癌、胰臟癌、腸及結腸癌、胃癌、皮膚癌及腦瘤以及侵襲骨髓(包括白血病)及淋巴增生性系統之惡性病,例如霍奇金氏(Hodgkin's)及非霍奇金氏淋巴瘤;包括預防及治療轉移性疾病及腫瘤復發以及腫瘤相關症候群。在某些實施例中,式(I)、式(Ia)或式(Ib)化合物、其醫藥上可接受之鹽及異構物及醫藥組合物可用作類鐸受體活性之調節劑,且用於治療贅瘤形成,包括(但不限於)基底細胞癌、鱗狀細胞癌、日光性角化症、黑色素瘤、癌、肉瘤、白血病、腎細胞癌、卡波氏肉瘤(Kaposi's sarcoma)、骨髓性白血病、慢性淋巴球性白血病及多發性骨髓瘤。
在某些實施例中,式(I)、式(Ia)或式(Ib)化合物、其醫藥上可接受之鹽及異構物、醫藥組合物及/或組合用於治療傳染病,包括(但不限於)病毒性傳染病,例如尖銳濕疣、普通疣、掌疣、呼吸道融合病毒(RSV)、B型肝炎、C型肝炎、登革熱病毒、單純皰疹病毒(僅舉例而言,HSV-I、HSV-II、CMV或VZV)、傳染性軟疣、痘瘡、天花、慢病毒、人類免疫缺陷病毒(HIV)、人類乳頭瘤病毒(HPV)、巨細胞病毒(CMV)、水痘帶狀皰狀病毒(VZV)、鼻病毒、腸病毒、腺病毒、冠狀病毒(例如,SARS)、流行性感冒病毒、副流行性感冒病毒、流行性腮腺炎病毒、麻疹病毒、乳多泡病毒、嗜肝性DNA病毒、黃病毒、反轉錄病毒、沙狀病毒(僅舉例而言,LCM、胡寧病毒(Junin virus)、馬
秋波病毒(Machupo virus)、瓜納瑞托病毒(Guanarito virus)及拉薩熱(Lassa Fever))及絲狀病毒(僅舉例而言,伊波拉病毒(ebola virus)或馬堡病毒(marbug virus))。
在某些實施例中,式(I)、式(Ia)或式(Ib)化合物、其醫藥上可接受之鹽及異構物、醫藥組合物及/或組合用於治療細菌、真菌及原生動物感染,包括(但不限於)結核病及雞結核桿菌、麻風;肺囊蟲肺炎、隱孢子蟲病、組織漿菌症、弓蟲症、錐蟲感染、利什曼體病(leishmaniasis)、由以下各屬之細菌引起之感染:大腸桿菌屬(Escherichia)、腸桿菌屬(Enterobacter)、沙門桿菌屬(Salmonella)、葡萄球菌屬(Staphylococcus)、克留氏菌屬(Klebsiella)、變形桿菌屬(Proteus)、假單胞菌屬(Pseudomonas)、鏈球菌屬(Streptococcus)及衣原體屬(Chlamydia),及真菌感染,例如念珠菌病、麯黴病、組織漿菌症、隱球菌腦膜炎。
對於式(I)、式(Ia)及式(Ib)化合物或其醫藥上可接受之鹽及異構物之治療用途,該等化合物係以治療有效量單獨或作為醫藥組合物之一部分來投與。因此,該等醫藥組合物包含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽及一或多種醫藥上可接受之載劑、稀釋劑或賦形劑。另外,該等化合物及組合物係單獨或與一或多種其他治療劑組合投與。投與該等化合物及組合物之方法包括(但不限於)口服投與、直腸投與、非經腸、靜脈內投與、玻璃體內投與、肌內投與、吸入、鼻內投與、局部投與、經眼投與或經耳投與。
治療有效量將尤其端視所指疾病、疾病之嚴重程度、個體之年齡及相關健康狀況、所投與化合物之功效、投與模式及期望治療而變化。在某些實施例中,指示式(I)、式(Ia)或式(Ib)化合物之日劑量在約0.03mg至2.5mg/kg體重之日劑量下以全身性方式獲得令人滿意的
結果。在某些實施例中,藉由吸入投與之式(I)、式(Ia)或式(Ib)化合物之日劑量介於0.05微克/公斤體重(μg/kg)至100微克/公斤體重(μg/kg)範圍內。在某些實施例中,藉由吸入投與之每劑量之式(I)、式(Ia)或式(Ib)化合物之量介於10ng至500ng範圍內。在其他實施例中,口服投與之式(I)、式(Ia)或式(Ib)化合物之日劑量介於0.01微克/公斤體重(μg/kg)至100毫克/公斤體重(mg/kg)範圍內。較大型哺乳動物(例如人類)之所指示日劑量介於約0.5mg至約100mg式(I)化合物範圍內,其係便捷地例如以分開劑量每天至多四次或以控制釋放形式投與。在某些實施例中,用於口服投與之單位劑型包含約1mg至50mg式(I)、式(Ia)或式(Ib)化合物。
本文提供之其他態樣係用於製備包含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物的製程。在某些實施例中,該等製程包括混合式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽與一或多種醫藥上可接受之載劑、稀釋劑或賦形劑。在某些實施例中,醫藥組合物包含呈游離形式或呈醫藥上可接受之鹽形式之式(I)、式(Ia)或式(Ib)化合物以及至少一種醫藥上可接受之載劑、稀釋劑或賦形劑,該等醫藥組合物係藉由混合、造粒及/或塗覆方法來製造。在其他實施例中,該等組合物視情況含有賦形劑,例如防腐劑、穩定劑、潤濕劑或乳化劑、促溶劑、調節滲透壓之鹽及/或緩衝劑。在其他實施例中,該等組合物係無菌的。
在某些實施例中,含有式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物係作為離散劑型口服投與,其中該等劑型包括(但不限於)膠囊、明膠膠囊、囊片、錠劑、可咀嚼錠劑、粉末、顆粒、糖漿、矯味糖漿、呈水性或非水性液體之溶液或懸浮液、可食用泡沫或攪打物(whips)及水包油液體乳液或油包水液體乳液。
用於口服投與式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之膠囊、明膠膠囊、囊片、錠劑、可咀嚼錠劑、粉末或顆粒係藉由使用習用醫藥化合技術將式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽以及至少一種賦形劑複合在一起來製備。以本文所述口服劑型使用之賦形劑之非限制性實例包括(但不限於)黏合劑、填充劑、崩解劑、潤滑劑、吸收劑、著色劑、矯味劑、防腐劑及甜味劑。
該等黏合劑之非限制性實例包括(但不限於)玉米澱粉、馬鈴薯澱粉、澱粉糊、預膠凝澱粉或其他澱粉、糖、明膠、天然及合成樹膠(例如阿拉伯樹膠)、海藻酸鈉、海藻酸、其他海藻酸鹽、黃蓍膠、瓜爾膠、纖維素及其衍生物(僅舉例而言,乙基纖維素、乙酸纖維素、羧基甲基纖維素鈣、羧基甲基纖維素鈉、甲基纖維素、羥基丙基甲基纖維素及微晶纖維素)、矽酸鎂鋁、聚乙烯基吡咯啶酮及其組合。
該等填充劑之非限制性實例包括(但不限於)滑石、碳酸鈣(例如顆粒或粉末)、微晶纖維素、粉末狀纖維素、右旋糖、高嶺土、甘露醇、矽酸、山梨醇、澱粉、預膠凝澱粉及其混合物。在某些實施例中,醫藥組合物中之黏合劑或填充劑係以佔醫藥組合物或劑型約50重量%至約99重量%存在。
該等崩解劑之非限制性實例包括(但不限於)瓊脂-瓊脂、海藻酸、海藻酸鈉、碳酸鈣、碳酸鈉、微晶纖維素、交聯羧甲纖維素鈉、交聯聚維酮、波拉克林鉀(polacrilin potassium)、羥乙酸澱粉鈉、馬鈴薯或樹薯澱粉、預膠凝澱粉、其他澱粉、黏土、其他藻膠、其他纖維素、樹膠及其組合。在某些實施例中,用於醫藥組合物中之崩解劑之量為約0.5重量%至約15重量%之崩解劑,而在其他實施例中,該量為約1重量%至約5重量%之崩解劑。
該等潤滑劑之非限制性實例包括(但不限於)硬脂酸鈉、硬脂酸鈣、硬脂酸鎂、硬脂酸、礦物油、輕礦物油、甘油、山梨醇、甘露
醇、聚乙烯二醇、其他二醇、月桂基硫酸鈉、滑石、氫化植物油(僅舉例而言,花生油、棉籽油、向日葵油、芝麻油、橄欖油、玉米油及大豆油)、硬脂酸鋅、油酸鈉、油酸乙酯、月桂酸乙酯、瓊脂、二氧化矽、syloid矽膠(AEROSIL 200,由Baltimore,Md.之W.R.Grace公司製造)、合成二氧化矽之凝聚型氣溶膠(由Plano,Tex.之Degussa公司出售)、CAB-O-SIL(致熱二氧化矽產品,由Boston,Mass.之Cabot公司出售)及其組合。在某些實施例中,用於醫藥組合物中之潤滑劑之量係小於醫藥組合物或劑型之約1重量%之量。
該等稀釋劑之非限制性實例包括(但不限於)乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纖維素、甘胺酸或其組合。
在某些實施例中,錠劑及膠囊係藉由以下方式來製備:均勻地混合式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽與液體載劑、精細固體載劑或二者,且然後若需要使產物形成期望表現形式。在某些實施例中,錠劑係藉由壓縮來製備。在其他實施例中,錠劑係藉由模製來製備。
在某些實施例中,式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽係以控制釋放劑型口服投與。該等劑型用於提供式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之緩慢或控制釋放。控制釋放係使用例如羥基丙基甲基纖維素、其他聚合物基質、凝膠、滲透膜、滲透系統、多層包衣、微粒子、脂質體、微球或其組合獲得。在某些實施例中,控制釋放劑型用於延長式(I)化合物之活性、減少劑量頻率及增加患者順從性。
作為口服液(例如溶液、糖漿及酏劑)之式(I)化合物之投與係以單位劑型製備,使得給定量之溶液、糖漿或酏劑含有預定量之式(I)化合物。糖漿係藉由將化合物溶解於經適宜矯味之水溶液中來製備,而酏劑係經由使用無毒醇媒劑來製備。懸浮液係藉由將化合物分散於無毒
媒劑中來調配。用於作為口服液口服投與之賦形劑之非限制性實例包括(但不限於)增溶劑、乳化劑、矯味劑、防腐劑及著色劑。增溶劑及乳化劑之非限制性實例包括(但不限於)水、二醇、油、醇、乙氧基化異十八烷醇及聚氧乙烯山梨醇醚。防腐劑之非限制性實例包括(但不限於)苯甲酸鈉。矯味劑之非限制性實例包括(但不限於)薄荷油或天然甜味劑或糖精或其他人工甜味劑。
在某些實施例中,含有式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物係藉由多種途徑非經腸投與,該等途徑包括(但不限於)皮下、靜脈內(包括濃注注射)、肌內及動脈內。
該等非經腸劑型係以無菌或無菌可注射溶液、懸浮液、備用於溶解或懸浮於醫藥上可接受之注射用媒劑之乾燥及/或凍乾產品(可重構粉末)及乳液形式來投與。用於該等劑型中之媒劑包括(但不限於)USP注射用水;水性媒劑,例如(但不限於)氯化鈉注射液、林格氏注射液(Ringer's Injection)、右旋糖注射液、右旋糖及氯化鈉注射液及乳酸化林格氏注射液;水可混溶媒劑,例如(但不限於)乙醇、聚乙二醇及聚丙二醇;及非水性媒劑,例如(但不限於)玉米油、棉籽油、花生油、芝麻油、油酸乙酯、肉豆蔻酸異丙酯及苯甲酸苄基酯。
在某些實施例中,含有式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物係經皮投與。該等經皮劑型包括「儲層型」或「基質型」貼片,其施用至皮膚且佩戴特定時間段以允許期望量之式(I)化合物滲透。僅舉例而言,該等經皮裝置呈繃帶形式,該繃帶包含背襯部件、含有該化合物(視情況含有載劑)之儲層、視情況以受控且預定速率經延長時間段將該化合物遞送至宿主皮膚之速率控制障壁以及將該裝置固定至皮膚的構件。在其他實施例中,使用基質經皮調
配物。
用於經皮遞送式(I)化合物之調配物包括有效量之式(I)化合物、載劑及可選稀釋劑。載劑包括(但不限於)幫助穿過宿主皮膚之可吸收性藥理上可接受之溶劑,例如水、丙酮、乙醇、乙二醇、丙二醇、丁烷-1,3-二醇、肉豆蔻酸異丙酯、棕櫚酸異丙酯、礦物油及其組合。
在某些實施例中,該等經皮遞送系統包括有助於將一或多種式(I)化合物遞送至組織之滲透促進劑。該等滲透促進劑包括(但不限於)丙酮;各種醇,例如乙醇、油烯基及四氫呋喃基;烷基亞碸,例如二甲基亞碸;二甲基乙醯胺;二甲基甲醯胺;聚乙烯二醇;吡咯啶酮,例如聚乙烯基吡咯啶酮;Kollidon級(帕維酮(Povidone)、聚維酮(Polyvidone));尿素;及各種水溶性或不溶性糖酯,例如Tween 80(聚山梨醇酯80)及Span 60(去水山梨醇單硬脂酸酯)。
在其他實施例中,調節此一經皮醫藥組合物或劑型或施用該醫藥組合物或劑型之組織之pH以改良一或多種式(I)化合物之遞送。在其他實施例中,調節溶劑載劑之極性、其離子強度或滲透性以改良遞送。在其他實施例中,添加諸如硬脂酸鹽等化合物以有利地改變一或多種式(I)化合物之親水性或親脂性以改良遞送。在某些實施例中,該等硬脂酸鹽用作調配物之脂質媒劑、乳化劑或表面活性劑及遞送增強或滲透增強劑。在其他實施例中,使用式(I)化合物之不同鹽、水合物來進一步調節所得組合物之性質。
在某些實施例中,式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽係藉由局部施用含有式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物,以洗液、凝膠、軟膏劑溶液、乳液、懸浮液或乳霜形式來投與。適於局部施用至皮膚之調配物係水溶液、軟膏劑、乳霜或凝膠,而用於經眼投與之調配物係水溶液。該等調配物視
情況含有增溶劑、穩定劑、增滲劑、緩衝劑及防腐劑。
該等局部調配物包括至少一種載劑及視情況至少一種稀釋劑。該等載劑及稀釋劑包括(但不限於)水、丙酮、乙醇、乙二醇、丙二醇、丁烷-1,3-二醇、肉豆蔻酸異丙酯、棕櫚酸異丙酯、礦物油及其組合。
在某些實施例中,該等局部調配物包括有助於將一或多種式(I)化合物遞送至組織之滲透促進劑。該等滲透促進劑包括(但不限於)丙酮;各種醇,例如乙醇、油烯基及四氫呋喃基;烷基亞碸,例如二甲基亞碸;二甲基乙醯胺;二甲基甲醯胺;聚乙烯二醇;吡咯啶酮,例如聚乙烯基吡咯啶酮;Kollidon級(帕維酮、聚維酮);尿素;及各種水溶性或不溶性糖酯,例如Tween 80(聚山梨醇酯80)及Span 60(去水山梨醇單硬脂酸酯)。
在某些實施例中,含有式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物係藉由吸入來投與。可將用於吸入投與之劑型調配成氣溶膠或乾燥粉末。用於吸入投與之氣溶膠調配物包含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽於醫藥上可接受之水性或非水性溶劑中之溶液或精細懸浮液。另外,該等醫藥組合物視情況包含粉末基底(例如乳糖、葡萄糖、海藻糖、甘露醇或澱粉)及視情況性能改質劑(例如L-白胺酸或另一胺基酸)及/或硬脂酸之金屬鹽(例如硬脂酸鎂或硬脂酸鈣)。
在某些實施例中,式(I)化合物係藉由吸入使用利用含有適宜低沸點推進劑(例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他適宜氣體)之筒之計量劑量吸入器(「MDI」)或使用突發性氣體在容器內部產生一團乾燥粉末、然後由患者吸入之乾燥粉末吸入器(DPI)裝置直接投與至肺。在某些實施例中,用於吸入器或吹入器中之膠囊及明膠柱經調配含有式(I)化合物及粉末基質(例如乳糖或澱
粉)之粉末混合物。在某些實施例中,式(I)化合物係使用液體噴霧裝置遞送至肺,其中該等裝置使用極小噴嘴孔以氣霧化液體藥物調配物,該調配物隨後可直接吸入肺中。在其他實施例中,式(I)化合物係使用噴霧器裝置遞送至肺,其中噴霧器藉由使用超音波能產生液體藥物調配物之氣溶膠以形成可易於吸入之精細粒子。在其他實施例中,式(I)化合物係使用電流體動力學(「EHD」)氣溶膠裝置遞送至肺,其中該等EHD氣溶膠裝置使用電能氣霧化液體藥物溶液或懸浮液。
在某些實施例中,本文所述含有式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物亦含有一或多種吸收增強劑。在某些實施例中,該等吸收增強劑包括(但不限於)肝膽酸鈉、癸酸鈉、N-月桂基-β-D-麥芽吡喃糖苷、EDTA及混合膠束。
在某些實施例中,含有式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物係經鼻投與。將用於經鼻投與之劑型方便地調配成氣溶膠、溶膠、滴劑、凝膠或乾燥粉末。
在某些實施例中,含有式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物係以栓劑、灌腸劑、軟膏劑、乳霜、直腸泡沫或直腸凝膠形式經直腸投與。在某些實施例中,該等栓劑係自脂肪乳液或懸浮液、可可油或其他甘油酯製備。
在某些實施例中,含有式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物係作為滴眼劑經眼投與。該等調配物係視情況含有增溶劑、穩定劑、增滲劑、緩衝劑及防腐劑之水溶液。
在某些實施例中,含有式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物係作為滴耳劑經耳投與。該等調配物係視情況含有增溶劑、穩定劑、增滲劑、緩衝劑及防腐劑之水溶液。
在某些實施例中,將含有式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物調配成儲積製劑。該等調配物係藉由植入
(例如,經皮下或肌內)或藉由肌內注射來投與。在某些實施例中,該等調配物包括聚合或疏水材料(例如呈可接受油中之乳液形式)或離子交換樹脂或呈微溶衍生物(例如呈微溶鹽)。
在另一實施例中,包含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物適於口服投與來治療病毒性傳染病及/或與TLR7活性相關之病症。
在另一實施例中,包含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物適於肌內投與來治療病毒性傳染病及/或與TLR7相關之病症。
在另一實施例中,包含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物適於口服投與來治療傳染病及/或與TLR7相關之病症。
在另一實施例中,包含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物適於口服投與來治療細菌疾病及/或與TLR7相關之病症。
在另一實施例中,包含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物適於口服投與來治療真菌疾病及/或與TLR7相關之病症。
在另一實施例中,包含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物適於口服投與來治療與TLR7相關之癌症。
在另一實施例中,包含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物適於靜脈內投與來治療與TLR7相關之癌症。
在另一實施例中,包含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物適於作為滴眼劑投與來治療眼部疾病及/或與TLR7相關之病症。
在另一實施例中,包含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物適於局部投與來治療皮膚病及/或與TLR7相關之病症。
在另一實施例中,包含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物適於局部投與來治療日光性角化症。在另一實施例中,包含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物適於作為乳霜局部投與來治療日光性角化症。
在另一實施例中,包含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物適於局部投與來治療基底細胞癌。在另一實施例中,包含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物適於作為乳霜局部投與來治療基底細胞癌。
在另一實施例中,包含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物適於藉由吸入投與來治療呼吸疾病及/或與TLR7相關之病症。在某些實施例中,呼吸疾病係過敏性氣喘。
本文提供式(I)、式(Ia)或式(Ib)化合物及其醫藥上可接受之鹽及含有式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽及/或其醫藥上可接受之鹽之醫藥組合物,其用於活化TLR7活性,且由此用於預防或治療與TLR7活性相關之疾病及/或病症。該等式(I)化合物及其醫藥上可接受之鹽及醫藥組合物係TLR7之促效劑。
本文亦提供用於治療患有與TLR7活性相關之疾病及/或病症之個體的方法,其中該方法包括向個體投與有效量之單獨或作為醫藥組合物之一部分之式(I)化合物或其醫藥上可接受之鹽,如本文所述。
本文提供式(I)化合物或其醫藥上可接受之鹽之用途,其用於製備用來治療與TLR7活性相關之疾病或病症之藥劑。
在某些實施例中,式(I)化合物或其醫藥上可接受之鹽或含有式
(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物係單獨(不含另一治療劑)投與來治療一或多種本文所述與TLR7活性相關之疾病及/或病症。
在其他實施例中,式(I)化合物或其醫藥上可接受之鹽或含有式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物係與一或多種其他治療劑組合投與來治療一或多種本文所述與TLR7活性相關之疾病及/或病症。
在其他實施例中,式(I)化合物或其醫藥上可接受之鹽或含有式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物係與一或多種其他治療劑組合調配及投與來治療一或多種本文所述與TLR7活性相關之疾病及/或病症。
在其他實施例中,式(I)化合物或其醫藥上可接受之鹽或含有式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物係與一或多種其他治療劑依序投與來治療一或多種本文所述與TLR7活性相關之疾病及/或病症。
在其他實施例中,組合治療包括在投與一或多種其他治療劑之前投與式(I)化合物或其醫藥上可接受之鹽或含有式(I)化合物之醫藥組合物,來治療一或多種本文所述與TLR7活性相關之疾病及/或病症。
在其他實施例中,組合治療包括在投與一或多種其他治療劑之後投與式(I)化合物或其醫藥上可接受之鹽或含有式(I)化合物之醫藥組合物,來治療一或多種本文所述與TLR7活性相關之疾病及/或病症。
在某些實施例中,組合治療包括同步投與式(I)化合物或其醫藥上可接受之鹽或含有式(I)化合物之醫藥組合物與一或多種其他治療劑,來治療一或多種本文所述與TLR7活性相關之疾病及/或病症。
在某些實施例中,組合治療包括投與式(I)化合物或其醫藥上可接受之鹽或含有與一或多種其他治療劑調配在一起之式(I)化合物之醫藥組合物,來治療一或多種本文所述與TLR7活性相關之疾病及/或病症。
在之某些實施例中,本文所述之組合療法、式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽及另一(些)治療劑以加和方式起作用。在本文所述組合療法之某些實施例中,式(I)化合物或其醫藥上可接受之鹽及另一(些)治療劑協同作用。
在其他實施例中,將式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽或含有式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物投與先前尚未經歷或當前未經歷另一治療劑治療之患者。
與式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽組合使用之其他治療劑包括(但不限於)抗生素或抗細菌劑、止吐劑、抗真菌劑、抗發炎劑、抗病毒劑、病毒酶抑制劑或抗癌劑。
在某些實施例中,含有式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之醫藥組合物係免疫原性組合物。
在其他實施例中,式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽係免疫增強劑,且在投與後與不含式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽之調配物相比賦予免疫刺激效應。
本文所提及之免疫刺激效應通常係增強免疫原性組合物之效應。在某些實施例中,相對於在免疫增強劑不存在下之免疫原性組合物,免疫原性組合物之效能增強至少10%。在某些實施例中,相對於在免疫增強劑不存在下之免疫原性組合物,免疫原性組合物之效能增強至少20%。在某些實施例中,相對於在免疫增強劑不存在下之免疫原性組合物,免疫原性組合物之效能增強至少30%。在某些實施例
中,相對於在免疫增強劑不存在下之免疫原性組合物,免疫原性組合物之效能增強至少40%。在某些實施例中,相對於在免疫增強劑不存在下之免疫原性組合物,免疫原性組合物之效能增強至少50%。在某些實施例中,相對於在免疫增強劑不存在下之免疫原性組合物,免疫原性組合物之效能增強至少60%。在某些實施例中,相對於在免疫增強劑不存在下之免疫原性組合物,免疫原性組合物之效能增強至少70%。在某些實施例中,相對於在免疫增強劑不存在下之免疫原性組合物,免疫原性組合物之效能增強至少80%。在某些實施例中,相對於在免疫增強劑不存在下之免疫原性組合物,免疫原性組合物之效能增強至少90%。在某些實施例中,相對於在免疫增強劑不存在下之免疫原性組合物,免疫原性組合物之效能增強至少100%。
如本文所揭示之免疫原性組合物可用於增加或增強哺乳動物中之免疫反應之方法中,其包含投與有效量之如本文所揭示之免疫原性組合物之步驟。免疫反應較佳具有保護性且較佳涉及抗體及/或細胞介導之免疫性。
在某些實施例中,本文所揭示之免疫原性組合物可用作藥劑,例如用於增加或增強哺乳動物中之免疫反應。
在某些實施例中,本文所揭示之免疫原性組合物可用於製造用來增加哺乳動物中之免疫反應之藥劑。哺乳動物較佳係人類,但可係例如牛、豬、雞、貓或狗。
檢查治療性治療之效能之一種方式涉及在投與本文所揭示之免疫原性組合物後監測病原體感染。檢查預防性治療之效能之一種方式涉及在投與免疫原性組合物(及抗原,若單獨投與)後,以全身性方式(例如監測IgG1及IgG2a產生量)及/或黏膜方式(例如監測IgA產生量)監測針對包括於本文所揭示之免疫原性組合物中或與其結合投與之抗原的免疫反應。通常,抗原特異性血清抗體反應係在免疫後但激發前測
定,而抗原特異性黏膜抗體反應係在免疫後及激發後測定。
評價抗原為蛋白質之本文所揭示免疫原性組合物之免疫原性之另一方式係重組表現蛋白質以藉由免疫印跡及/或微陣列篩選患者血清或黏膜分泌物。蛋白質與患者樣品之間之陽性反應指示患者已引發針對所討論蛋白質之免疫反應。此方法亦可用於鑑別蛋白質抗原內之免疫顯性抗原及/或表位。
免疫原性組合物之效能亦可在活體內藉由激發所關注病原體感染之適宜動物模型來測定。
本文所揭示之免疫原性組合物通常將直接投與個體。直接遞送可藉由陽性方式來實現:非經腸注射(例如,皮下、腹膜內、靜脈內、肌內或至組織之間質性空間)或黏膜,例如藉由直腸、口服(例如,錠劑、噴霧劑)、陰道、局部、經皮或穿皮、鼻內、眼、耳、肺或其他黏膜投與。
免疫原性組合物可用於引發全身性及/或黏膜免疫性,較佳引發增強的全身性及/或黏膜免疫性。
較佳地,增強的全身性及/或黏膜免疫性係以增強的TH1及/或TH2免疫反應來反映。較佳地,增強的免疫反應包括IgG1及/或IgG2a及/或IgA之產生增加。
在所列舉實施例之以下列表中提供本發明之某些態樣及實例。應認識到,在每一實施例中指定之特徵可與其他指定特徵組合以提供本發明之其他實施例。
1.化合物及其醫藥上可接受之鹽、個別異構物及異構物之混合物具有式(I)之結構:
式(I)
R1係-NHR6或-NHCHR6R9;R3係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH或四唑基;R4係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH或四唑基;其中,當R3係H時,則R4係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH或四唑基;或當R4係H時,則R3係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH或四唑基;L1係-(CH2)m-;L2係-(CH2)m-;L7=-(CH2)m(CHR11CH2)m(CH2)n-;R6係-C3-C6烷基;R7係-C1-C3烷基;R9係L1OH;每一R11獨立地選自-OH;R12係a)未經取代之四唑基;b)經-L1C(=O)OH取代之四唑基;
或c)5-6員雜環烷基,其具有1至2個獨立地選自N及O之雜原子且經-C(=O)OH取代;每一m獨立地選自1、2、3及4,且每一n獨立地選自0、1、2、3及4。
2.在某些實施例中,式(I)化合物係式(Ia)或式(Ib)之化合物:
3.在式(I)化合物之某些實施例中,R1係-NHR6或-NHCHR6R9;R3係H、-OL2C(=O)OH或四唑基;R4係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH或四唑基;其中,當R3係H時,則R4係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH或四唑基;或當R4係H時,則R3係-OL2C(=O)OH或四唑基;L1係-(CH2)m-;L2係-(CH2)m-;L7=-(CH2)m(CHR11CH2)m(CH2)n-;R6係-C3-C6烷基;
R7係-C1-C3烷基;甲基R9係L1OH;每一R11獨立地選自-OH;R12係a)未經取代之四唑基;b)經-L1C(=O)OH取代之四唑基;或c)5-6員雜環烷基,其具有1至2個獨立地選自N及O之雜原子且經-C(=O)OH取代;每一m獨立地選自1、2、3及4,且每一n獨立地選自0、1、2、3及4。
4.在式(I)、式(Ia)或式(Ib)化合物之某些實施例中,R1係-NHR6或-NHCHR6R9;R3係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-
C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH、或
;l;
R4係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-
C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH、或
;其中,當R3係H時,則R4係-L2R12、-OL2R12、-C(CH3)2R12、-
P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-
OL2C(=O)OH、或;
或當R4係H時,則R3係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-
OL2C(=O)OH、、;
L1係-(CH2)m-;L2係-(CH2)m-;L7=-(CH2)m(CHR11CH2)m(CH2)n-;R6係-C3-C6烷基;R7係-C1-C3烷基;R9係L1OH;每一R11獨立地選自-OH;
R12係、、、、或每一m獨立地選自1、2、3及4,且每一n獨立地選自0、1、2、3及4。
5.在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,R1係-NHR6或-NHCHR6R9;
R3係H、-OL2C(=O)OH、或;l;
R4係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-
P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-
C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、或;
其中,當R3係H時,則R4係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-
CH=CHC(=O)OH、-C(=O)OH、-L2C(=O)OH、-L7C(=O)OH、或
;
或當R4係H時,則R3係-OL2C(=O)OH、、;L1係-(CH2)m-;L2係-(CH2)m-;L7=-(CH2)m(CHR11CH2)m(CH2)n-;R6係-C3-C6烷基;R7係-C1-C3烷基;R9係L1OH;每一R11獨立地選自-OH;
R12係、、、、或
;
每一m獨立地選自1、2、3及4,且每一n獨立地選自0、1、2、3及4。
6.在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,L1係-CH2-;
L2係-CH2-或-CH2CH2-;L7=-(CH2)2(CHR11CH2)2-;R6係-C4烷基或-C5烷基;R7係甲基、乙基或丙基,且R11係OH。
7.在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,R1係-NHR6;R3係H;R4係-L2R12;L2係-(CH2)m-;R6係-C3-C6烷基;R12係a)未經取代之四唑基;b)經-L1C(=O)OH取代之四唑基;或c)5-6員雜環烷基,其具有1至2個獨立地選自N及O之雜原子且經-C(=O)OH取代,且每一m獨立地選自1、2、3及4。
8.在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,R1係-NHR6;R3係H;R4係-L2R12;L2係-CH2-或-CH2CH2-;R6係-C5烷基;且
R12係、、、、或
。
9.在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,R1係-NHR6;R3係H;R4係-L2R12;L2係-CH2-或-CH2CH2-;R6係-C5烷基;且
R12係、、、或。
10.在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,R1係-NHR6;R3係H;R4係-L2R12;L2係-CH2-或-CH2CH2-;R6係-C5烷基;且
R12係或。
11.在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,R1係-NHR6;R3係H;R4係-L2R12;L2係-CH2-或-CH2CH2-;R6係-C5烷基;且
R12係、或。
12.在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,R1係-NHR6;R3係H;R4係-L2C(=O)OH;L2係-CH2-或-CH2CH2-;且R6係-C5烷基。
13.在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,
R12係或。
14.在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,
R12係、或。
15.在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,化合物係選自:5-(5-((1H-四唑-5-基)甲氧基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;5-(5-((1H-四唑-5-基)甲基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;(S)-2-((5-(5-((1H-四唑-5-基)甲基)-2-甲氧基苄基)-2-胺基-5H-吡咯并[3,2-d]嘧啶-4-基)胺基)己-1-醇;(S)-2-((5-(5-((1H-四唑-5-基)甲基)-2-甲氧基苄基)-2-胺基-5H-吡咯并[3,2-d]嘧啶-4-基)胺基)戊-1-醇;
5-(5-(2-(1H-四唑-5-基)乙基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;N4-己基-5-(2-甲氧基-5-(1H-四唑-5-基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;(S)-2-((2-胺基-5-(2-甲氧基-5-(1H-四唑-5-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-基)胺基)己-1-醇;2-(5-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苄基)-2H-四唑-2-基)乙酸;5-(2-甲氧基-4-(1H-四唑-5-基)苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;5-(2-甲氧基-5-(1H-四唑-5-基)苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;5-(5-(2-(1H-四唑-5-基)丙-2-基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;(S)-2-((5-(5-(2-(1H-四唑-5-基)丙-2-基)-2-甲氧基苄基)-2-胺基-5H-吡咯并[3,2-d]嘧啶-4-基)胺基)己-1-醇;5-(5-(二氟(1H-四唑-5-基)甲基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;2-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)-2,2-二氟乙酸;(3R,5R)-7-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)-3,5-二羥基庚酸;2-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)乙酸;(S)-2-(3-((2-胺基-4-((1-羥基己-2-基)胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)乙酸;
3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯甲酸;(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)膦酸;(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)膦酸氫甲酯;(E)-3-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)丙烯酸;3-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)丙酸;(S)-3-(3-((2-胺基-4-((1-羥基己-2-基)胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)丙酸;(S)-1-(4-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-3-甲氧基苄基)吡咯啶-2-甲酸;(R)-1-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苄基)吡咯啶-2-甲酸,及2-(4-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-3-甲氧基苯氧基)乙酸。
16.在式(I)、式(Ia)及式(Ib)化合物之某些實施例中,化合物係選自:2-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)乙酸;3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯甲酸;5-(5-((1H-四唑-5-基)甲基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;
5-(5-(2-(1H-四唑-5-基)乙基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;(S)-1-(4-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-3-甲氧基苄基)吡咯啶-2-甲酸,及(R)-1-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苄基)吡咯啶-2-甲酸。
17.另一實施例係使用式(I)、式(Ia)及式(Ib)化合物之方法及包含該等式(I)、式(Ia)及式(Ib)化合物之醫藥組合物。
18.另一實施例係包括治療有效量之式(I)、式(Ia)或式(Ib)化合物及醫藥上可接受之載劑之醫藥組合物。在該等醫藥組合物之某些實施例中,醫藥組合物經調配用於靜脈內投與、玻璃體內投與、肌內投與、口服投與、直腸投與吸入、經鼻投與、局部投與、經眼投與或經耳投與。在其他實施例中,醫藥組合物呈以下形式:錠劑、丸劑、膠囊、液體、吸入劑、鼻噴霧溶液、栓劑、溶液、乳液、軟膏劑、滴眼劑或滴耳劑。在其他實施例中,該等醫藥組合物進一步包括一或多種其他治療劑。
19.另一實施例係用於治療患有與TLR7受體活性相關之疾病或病症之患者的藥劑,且該等藥劑包括治療有效量之式(I)、式(Ia)或式(Ib)化合物。
20.另一實施例係式(I)、式(Ia)或式(Ib)化合物之用途,其用於製造用來治療與TLR7活性相關之疾病或病症的藥劑。
21.在式(I)、式(Ia)或式(Ib)化合物於製造藥劑之用途之某些實施例中,疾病係傳染病、病毒性傳染病、發炎性疾病、呼吸疾病、皮膚病、自體免疫疾病、細胞增生性疾病或癌症。
22.在式(I)、式(Ia)或式(Ib)化合物於製造藥劑之該用途之某些實施例中,疾病係氣喘、慢性阻塞性肺病(COPD)、成人呼吸窘迫症
候群(ARDS)、潰瘍性結腸炎、克隆氏病、支氣管炎、皮炎、日光性角化症、基底細胞癌、膀胱癌、過敏性鼻炎、牛皮癬、硬皮症、蕁麻疹、類風濕性關節炎、多發性硬化、癌症、乳癌、HIV、肝炎、C型肝炎或狼瘡。
23.在式(I)、式(Ia)或式(Ib)化合物於製造藥劑之該用途之某些實施例中,疾病之B型肝炎、C型肝炎、結腸直腸癌或肝細胞癌。
24.另一實施例係用於活化TLR7受體之方法,其中該方法包括向有需要之系統或個體投與治療有效量之式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽或醫藥組合物,由此活化TLR受體。
25.在用於活化TLR7受體之該等方法之某些實施例中,該等方法包括將化合物投與細胞或組織系統或人類或動物個體。
26.另一實施例係用於治療與TLR7活性相關之疾病或病症之方法,其中該方法包括向需要該治療之系統或個體投與有效量之式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽,由此治療該疾病或病症。
27.在用於治療與TLR7活性相關之疾病或病症之該等方法之某些實施例中,該等方法包括將化合物投與細胞或組織系統或人類或動物個體。
28.在用於治療與TLR7活性相關之疾病或病症之該等方法之某些實施例中,疾病或病況係傳染病、病毒性傳染病、發炎性疾病、呼吸疾病、皮膚病、自體免疫疾病、細胞增生性疾病或癌症。
29.在用於治療與TLR7活性相關之疾病或病症之該等方法之某些實施例中,疾病或病況係氣喘、慢性阻塞性肺病(COPD)、成人呼吸窘迫症候群(ARDS)、潰瘍性結腸炎、克隆氏病、支氣管炎、皮炎、日光性角化症、基底細胞癌、膀胱癌、過敏性鼻炎、牛皮癬、硬皮症、蕁麻疹、類風濕性關節炎、多發性硬化、癌症、乳癌、HIV、
肝炎、C型肝炎或狼瘡。
30.在用於治療與TLR7活性相關之疾病或病症之該等方法之某些實施例中,疾病或病況係B型肝炎、C型肝炎、結腸直腸癌或肝細胞癌。
31.另一實施例係用於治療細胞增生性疾病之方法,其包含向需要該治療之系統或個體投與有效量之式(I)、式(Ia)或式(Ib)化合物或其醫藥上可接受之鹽;其中細胞增生性疾病係膀胱癌、淋巴瘤、骨肉瘤、黑色素瘤或乳房腫瘤、腎腫瘤、前列腺腫瘤、結腸直腸腫瘤、甲狀腺腫瘤、卵巢腫瘤、胰臟腫瘤、神經元腫瘤、肺腫瘤、子宮腫瘤或胃腸腫瘤。
32.在用於治療細胞增生性疾病之該等方法之某些實施例中,細胞增生性疾病係結腸直腸癌或肝細胞癌。
33.另一實施例係用於醫學治療之方法中之化合物,其中醫學治療之方法用於治療與TLR7受體活性相關之疾病,其中疾病選自傳染病、病毒性傳染病、發炎性疾病、呼吸疾病、皮膚病、自體免疫疾病、細胞增生性疾病或癌症,且其中化合物係式(I)、式(Ia)或式(Ib)化合物。
34.在於醫學治療方法中之該用途之某些實施例中,疾病或病況係氣喘、慢性阻塞性肺病(COPD)、成人呼吸窘迫症候群(ARDS)、潰瘍性結腸炎、克隆氏病、支氣管炎、皮炎、日光性角化症、基底細胞癌、膀胱癌、過敏性鼻炎、牛皮癬、硬皮症、蕁麻疹、類風濕性關節炎、多發性硬化、癌症、乳癌、HIV、肝炎、C型肝炎或狼瘡。
35.在於醫學治療方法中之該用途之某些實施例中,疾病係B型肝炎、C型肝炎、結腸直腸癌或肝細胞癌。
以下實例說明某些實例性式(I)化合物之製備。表1給出使用該等
實例性化合物獲得之人類TLR7 EC50(nM)值。
向含有於CH2Cl2(0.3M)中之4-甲氧基-3-甲基苯甲醛(1當量)之圓底燒瓶中添加於CH2Cl2(0.2M)中之m-CPBA(1.2當量)。在室溫下將反應物攪拌16小時,用過量飽和硫代硫酸鈉(水溶液)驟冷,且用過量2N NaOH(水溶液)處理。在室溫下攪拌16小時後,用NaHCO3將pH調節至7且用CH2Cl2萃取水層。經Na2SO4乾燥有機物且在真空下濃縮。標題化合物(2)係以粗製物形式用於下一步驟中。
向含有來自先前步驟之4-甲氧基-3-甲基酚(2,1當量)、Cs2CO3(2.5當量)及DMF(0.25M)之圓底燒瓶中添加溴乙腈(2當量)。在室溫下將反應物攪拌16小時,用水驟冷且用乙酸乙酯萃取。經Na2SO4乾燥有機物且在真空下濃縮。藉由矽膠層析純化殘餘物,以提供腈產物3。
向含有來自先前步驟之2-(4-甲氧基-3-甲基苯氧基)乙腈(3,1當量)、(PhCO2)2(0.01當量)及CCl4(0.25M)之圓底燒瓶中添加NBS(1當量)。在75℃下將反應物攪拌1小時,在真空下濃縮,且藉由矽膠層析純化,以提供溴化物4。
向含有市售4-氯-5H-吡咯并[3,2-d]嘧啶-2-胺5(1當量)、DMF(0.25M)及Cs2CO3(1.2當量)之圓底燒瓶中添加來自先前步驟之2-(3-(溴甲基)-4-甲氧基苯氧基)乙腈(4,1當量),在室溫下將反應物攪拌16小時,用水驟冷且用乙酸乙酯萃取。經Na2SO4乾燥有機物且在真空下濃縮。標題化合物(6)係以粗製物形式用於下一步驟中。
向含有來自先前步驟之2-(3-((2-胺基-4-氯-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯氧基)乙腈(6,1當量)、Cs2CO3(2當量)及DMF(0.25M)之圓底燒瓶中添加戊基胺(2當量)。在90℃下將反應物攪拌16小時,用水驟冷且用乙酸乙酯萃取。經Na2SO4乾燥有機物且在真空下濃縮。藉由矽膠層析純化殘餘物,以提供標題產物7。
向含有來自先前步驟之2-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯氧基)乙腈(7,1當量)、Bu2SnO(2當量)及NMP(0.25M)之圓底燒瓶中添加TMSN3(10當量)。在125℃下將反應物攪拌16小時,用水驟冷且用乙酸乙酯萃取。經Na2SO4乾燥有機物且在真空下濃縮。藉由反相HPLC純化殘餘物,以提供四唑產物8。1H NMR(d-DMSO):δ 7.39(d,1H),7.05(d,1H),6.97(d,1H),6.22
(s,1H),6.17(d,1H),5.48(s,2H),4.95(s,2H),3.77(s,3H),3.47-3.42(m,2H),1.51-1.43(m,2H),1.26-1.21(m,2H),1.15-1.09(m,2H),0.82(t,3H)。LRMS[M+H]=438.2。
向含有2-(4-甲氧基-3-甲基苯基)乙腈9(1當量)、AIBN(0.07當量)及CCl4(0.25M)之圓底燒瓶中添加NBS(1.1當量)。在75℃下將反應物攪拌1小時,在真空下濃縮,且藉由矽膠層析純化,以提供產物10。
向市售2,4-二氯-5H-吡咯并[3,2-d]嘧啶11(1當量)、Cs2CO3(4當量)於DMF(0.3M)中之溶液中添加來自先前步驟之2-(3-(溴甲基)-4-甲氧基苯基)乙腈(10)(1.1當量)。在室溫下將反應混合物攪拌5小時,然後用戊基胺(3當量)處理。將反應混合物加熱至100℃並保持16小時,用水驟冷且用乙酸乙酯萃取。用鹽水洗滌有機層,經Na2SO4乾燥並在真空下濃縮。經由矽膠管柱層析純化殘餘物,以提供產物12。
向含有來自先前步驟之2-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)乙腈(12)(1當量)、Bu2SnO(2當量)及NMP(0.25M)之圓底燒瓶中添加TMSN3(10當量)。在125℃下將反應物攪拌16小時,用水驟冷且用乙酸乙酯萃取。經Na2SO4乾燥有機物且在真空下濃縮。藉由反相HPLC純化殘餘物,以提供四唑產物13。1H NMR(400MHz,DMSO-d 6):δ 7.25(d,J=3.2Hz,1H),7.16(dd,J=2.0,8.4Hz,1H),6.97(d,J=8.8Hz,1H),6.73(d,J=2.0Hz,1H),6.70(br s,1H),6.62(br s,2H),6.04(d,J=3.2Hz,1H),5.42(s,2H),3.91(s,2H),3.78(s,3H),3.42-3.36(m,2H),1.45-1.41(m,2H),1.29-1.20(m,2H),1.17-1.09(m,2H),0.83(t,J=7.2Hz,3H);LRMS[M+H]=422.3。
向5-(5-((2H-四唑-5-基)甲基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺(13)(實例2)於DMSO(0.15M)中之溶液中添加2-溴乙酸乙酯(0.95當量)及K2CO3(4.0當量)。在室溫下將懸浮液攪拌90分鐘,且然後用反相HPLC純化,以提供白色固體。
向上述白色固體於EtOH/THF(1:1,v/v 0.02M)中之溶液中添加2.0N NaOH(2.0當量)。在室溫下將溶液攪拌1小時,且然後用製備型
HPLC純化,以提供標題化合物。TFA鹽=1H NMR(400MHz,DMSO-d 6):δ 7.38-7.37(m,3H),7.27(t,J=5.6Hz,1H),7.22(dd,J=2.4,8.4Hz,1H),7.02(d,J=8.4Hz,1H),6.49(d,J=1.6Hz,1H),6.19(d,J=3.2Hz,1H),5.53(s,2H),5.50(s,2H),4.06(s,2H),3.80(s,3H),3.44-3.39(m,2H),1.46-1.38(m,2H),1.26-1.16(m,2H),1.09-1.02(m,2H),0.80(t,J=7.2Hz,3H);LRMS[M+H]=480.2。
將2-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)乙腈(12)(實例2,步驟2)懸浮於EtOH:4N NaOH(v/v=1:2,0.1M)中。在80℃下將反應混合物攪拌過夜。用1N HCl中和後,藉由過濾收集白色固體狀標題化合物。1H NMR(400MHz,DMSO-d 6):δ(d-DMSO):δ 7.38(d,1H),7.25(br s,2H),7.19(d,1H),7.01(d,1H),6.64(s,1H),6.56(s,1H),6.17(d,1H),5.50(s,2H),3.81(s,3H),3.52-3.42(m,2H),3.38(s,2H),1.50-1.43(m,2H),1.29-1.20(m,2H),1.16-1.07(m,2H),0.82(t,3H)。LRMS[M+H]=398.2。
(S)-2-(3-((2-胺基-4-((1-羥基己-2-基)胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)乙酸係使用與實例4相同之方案來製備。使用(S)-2-胺基己-1-醇替代戊基胺。1H NMR(d-DMSO):δ 12.23(s,1H),7.51(d,1H),7.36(br,2H),7.21(d,1H),7.04(d,1H),6.57(s,1H),6.23(d,1H),6.21(d,1H),5.61(d,1H),5.45(d,1H),4.32-4.24(m,1H),3.83(s,3H),3.38(s,2H),3.38-3.33(m,2H),1.52-1.43(m,1H),1.24-1.08(m,3H),1.00-0.85(m,2H),0.76(t,3H)。LRMS[M+H]=428.2。
(S)-2-((5-(5-((1H-四唑-5-基)甲基)-2-甲氧基苄基)-2-胺基-5H-吡咯并[3,2-d]嘧啶-4-基)胺基)己-1-醇係遵循與實例2類似之方案製備。使用(S)-2-胺基己-1-醇替代正戊基胺。1H NMR(400MHz,DMSO-d 6):δ 7.36(d,J=3.2Hz,1H),7.14(dd,J=2.0,8.4Hz,1H),6.97(d,J=8.8Hz,1H),6.69(d,J=1.6Hz,1H),6.34(br s,2H),6.07(d,J=2.8Hz,1H),5.63(d,J=8.4Hz,1H),5.46(d,J=16.8Hz,1H),5.34(d,J=
16.8Hz,1H),4.28-4.20(m,1H),3.88(d,J=15.2Hz,1H),3.83(d,J=15.2Hz,1H),3.80(s,3H),3.42-3.31(m,2H),1.52-1.41(m,1H),1.27-1.12(m,3H),1.05-0.95(m,2H),0.78(t,J=7.6Hz,3H);LRMS[M+H]=452.3。
(S)-2-((5-(5-((1H-四唑-5-基)甲基)-2-甲氧基苄基)-2-胺基-5H-吡咯并[3,2-d]嘧啶-4-基)胺基)戊-1-醇係遵循與實例2類似之方案製備。使用(S)-2-胺基戊-1-醇替代戊基胺。1H NMR(400MHz,DMSO-d 6):δ 7.45(d,J=3.2Hz,1H),7.21(dd,J=2.0,8.4Hz,1H),6.34(br s,2H),7.03(d,J=8.4Hz,1H),6.62(d,J=2.0Hz,1H),6.18(d,J=3.2Hz,1H),6.06(d,J=8.4Hz,1H),5.55(d,J=16.8Hz,1H),5.41(d,J=16.8Hz,1H),4.32-4.24(m,1H),3.99(s,2H),3.81(s,3H),3.41-3.34(m,2H),1.44-1.36(m,1H),1.23-1.13(m,1H),1.01-0.89(m,2H),0.73(t,J=7.2Hz,3H);LRMS[M+H]=438.2。
5-(2-甲氧基-5-(1H-四唑-5-基)苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺係遵循與實例2、步驟2-3類似之方案製備。在步驟2中使用3-(氯甲基)-4-甲氧基苯甲腈(McKillop,A.等人,Tetrahedron Lett.,1983,24,1933-36)替代2-(3-(溴甲基)-4-甲氧基苯基)乙腈(10)。1H NMR(400MHz,DMSO-d 6):δ 7.87(dd,J=2.0,8.4Hz,1H),7.35(d,J=2.0Hz,1H),7.28(d,J=3.2Hz,1H),7.09(d,J=8.8Hz,1H),5.98(d,J=2.8Hz,1H),5.61(br s,1H),5.48(br s,2H),5.42(s,2H),3.88(s,3H),3.30-3.26(m,2H),1.42-1.34(m,2H),1.24-1.15(m,2H),1.11-1.04(m,2H),0.79(t,J=7.6Hz,3H);LRMS[M+H]=408.2。
N4-己基-5-(2-甲氧基-5-(1H-四唑-5-基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4-二胺係遵循與實例2、步驟2-3類似之方案製備。在步驟2中使用3-(氯甲基)-4-甲氧基苯甲腈(McKillop,A.等人,Tetrahedron Lett.,1983,24,1933-36)替代2-(3-(溴甲基)-4-甲氧基苯基)乙腈(10),且使用
N-己基胺替代正戊基胺。TFA鹽=1H NMR(400MHz,DMSO-d 6):δ 12.3(br s,1H),7.98(d,1H),7.51(d,1H),7.40(br s,2H),7.35(s,1H),7.3(dd,2H),6.27(d,1H),5.65(s,2H),3.93(s,3H),3.51-3.40(m,2H),1.42-1.31(m,2H),1.10-0.94(m,6H),0.74(t,3H);LRMS[M+H]=422.3。
(S)-2-((2-胺基-5-(2-甲氧基-5-(1H-四唑-5-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-基)胺基)己-1-醇係遵循與實例2、步驟2-3類似之方案製備。在步驟2中使用3-(氯甲基)-4-甲氧基苯甲腈(McKillop,A.等人,Tetrahedron Lett.,1983,24,1933-36)替代2-(3-(溴甲基)-4-甲氧基苯基)乙腈(10),且使用(S)-2-胺基己-1-醇替代正戊基胺。LRMS[M+H]=438.2。
向2-(3-(羥基甲基)-4-甲氧基苯基)-2-甲基丙腈(14,1當量)(Shetty,R.;Moffett,K.K.Tetrahedron Lett. 2006,47,8021)於CH2Cl2中之0℃溶液中添加Et3N(3當量)及MsCl(1.2當量)。將反應混合物攪拌2小時,用水驟冷,且用CH2Cl2萃取。經Na2SO4乾燥有機物且在真空下濃縮。殘餘物係以粗製物形式用於下一反應中。
標題化合物係使用與實例2、步驟2-3類似之方案來製備。使用來自先前步驟之甲烷磺酸5-(2-氰基丙-2-基)-2-甲氧基苄基酯(15)替代2-(3-(溴甲基)-4-甲氧基苯基)乙腈(10)。1H NMR(400MHz,DMSO-d 6):δ 7.22(d,J=2.8Hz,1H),7.10(dd,J=2.4,8.8Hz,1H),7.01(br s,1H),6.96(br s,2H),6.95(d,J=8.8Hz,1H),6.53(d,J=2.4Hz,1H),6.03(d,J=3.2Hz,1H),5.43(s,2H),3.77(s,3H),3.43-3.36(m,2H),1.56(s,6H),1.48-1.41(m,2H),1.28-1.18(m,2H),1.13-1.06(m,2H),0.82(t,J=7.2Hz,3H);LRMS[M+H]=450.3。
(S)-2-((5-(5-(2-(1H-四唑-5-基)丙-2-基)-2-甲氧基苄基)-2-胺基-5H-吡咯并[3,2-d]嘧啶-4-基)胺基)己-1-醇係遵循與實例11類似之方案
製備。使用(S)-2-胺基己-1-醇替代正戊基胺。1H NMR(400MHz,DMSO-d 6):δ 7.37(d,1H),7.16(dd,1H),7.12(br s,2H),7.01(d,1H),6.25(d,1H),6.15(d,1H),6.07(d,1H),5.56(d,1H),5.44(d,1H),4.26-4.16(m,1H),3.81(s,3H),3.35(d,2H),1.58(s,3H),1.53(s,3H),1.39-1.24(m,1H),1.24-1.08(m,3H),1.00-0.84(m,2H),0.75(t,3H);LRMS[M+H]=480.3。
3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯甲酸甲酯(17)係遵循與實例2、步驟2-3相同之方案來製備。使用3-(氯甲基)-4-甲氧基苯甲酸甲酯替代2-(3-(溴甲基)-4-甲氧基苯基)乙腈(10)。
向3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯甲酸甲酯(來自先前步驟之17,1當量)於EtOH(0.1M)中之溶液中添加2N NaOH(2當量)。在80℃下將反應混合物攪拌過夜且經由反相HPLC純化全部反應物,以提供產物。TFA鹽=1H NMR(400MHz,DMSO-d 6):δ 7.90(d,1H),7.50(d,1H),7.41(s,2H),7.37(t,1H),
7.15(d,1H),7.13(d,1H),6.24(d,1H),5.60(s,2H),3.91(s,3H),3.44(q,2H),1.46-1.38(m,2H),1.20-1.10(m,2H),1.03-0.95(m,2H),0.76(t,3H)。LRMS[M+H]=384.2。
向市售2,4-二氯-5H-吡咯并[3,2-d]嘧啶(1當量)、Cs2CO3(4當量)於DMF(0.3M)中之溶液中添加市售4-(溴甲基)-3-甲氧基苯甲腈(1.1當量)。在室溫下將反應混合物攪拌5小時,然後用戊基胺(3當量)處理。將反應混合物加熱至100℃並保持16小時,用水驟冷且用乙酸乙酯萃取。用鹽水洗滌有機層,經Na2SO4乾燥並在真空下濃縮。經由矽膠管柱層析純化殘餘物,以提供產物19。
將來自先前步驟之4-((2-氯-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-3-甲氧基苯甲腈(19)(1當量)、ZnCl2(10當量)及NaN3(15當量)於NMP(0.3M)中之漿液加熱至150℃並保持4小時,然後冷卻至
室溫且用水稀釋,此後產物20發生沈澱。藉由真空過濾分離產物20且以粗製物形式用於下一步驟中。
將粗2-疊氮基-5-(2-甲氧基-4-(1H-四唑-5-基)苄基)-正戊基-5H-吡咯并[3,2-d]嘧啶-4-胺(20,來自先前步驟,1當量)及Zn粉(30當量)於AcOH(0.3M)中之漿液加熱至80℃並保持15小時,然後冷卻至室溫,用10% MeOH/CH2Cl2稀釋且經由矽藻土墊過濾。在真空下濃縮濾液且藉由反相HPLC純化,以提供產物21。TFA鹽=1H NMR(400MHz,DMSO-d 6):δ 12.4(br s,1H),7.71(d,J=1.6Hz,1H),7.55(dd,J=1.2,7.6Hz,1H),7.51(d,J=3.2Hz,1H),7.45(br s,2H),7.35(t,J=6.0Hz,1H),6.62(d,J=5.6Hz,1H),6.26(d,J=2.8Hz,1H),5.66(s,2H),3.96(s,3H),3.43(q,J=6.4Hz,2H),1.45-1.37(m,2H),1.17-1.08(m,2H),1.02-0.95(m,2H),0.67(t,J=7.2Hz,3H);LRMS[M+H]=408.2。
在0℃下,向5-碘-2-甲氧基苯甲酸甲酯22(1當量)於THF(0.3M)中之溶液中添加DIBAL(2.1當量)。將反應混合物升溫至室溫並保持1
小時,然後冷卻至0℃,且用飽和Na2SO4(水溶液)驟冷直至形成精細白色固體。添加過量固體Na2SO4,且經由矽藻土墊過濾反應混合物並用醚洗滌。在真空下濃縮濾液,以提供白色固體。將白色固體溶解於CH2Cl2(0.3M)中,冷卻至0℃且用Et3N(2當量)及MsCl(1.2當量)處理。將反應混合物攪拌3小時,用水驟冷且用CH2Cl2萃取。經Na2SO4乾燥有機物且在真空下濃縮。殘餘物係以粗製物形式用於下一反應中。
向市售2,4-二氯-5H-吡咯并[3,2-d]嘧啶(1當量)、Cs2CO3(4當量)於DMF(0.3M)中之溶液中添加上述殘餘物(1.1當量)。在室溫下將反應混合物攪拌5小時,然後用戊基胺(3當量)處理。將反應混合物加熱至100℃並保持16小時,用水驟冷且用乙酸乙酯萃取。用鹽水洗滌有機層,經Na2SO4乾燥並在真空下濃縮。經由矽膠管柱層析純化殘餘物,以提供產物23。
向來自先前步驟之5-(5-碘-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺(23)於DMF(1.0M)中之溶液中添加乙酸鈀(0.3當量)、三乙胺(1.3當量)及丙烯腈(1.0當量)。在100℃下用微波將反應混合物加熱40分鐘。將其冷卻至室溫且用反相HPLC純化,以提供用於下一反應之產物。
向上述產物於MeOH(0.1M)中之溶液中添加碳載鈀(10% wt.,0.3當量),且在室溫下在氫下將懸浮液攪拌1小時。過濾出觸媒且濃縮濾液用於矽膠管柱層析,以提供產物。向上述產物於NMP(0.1M)中之溶液中添加氯化鋅(7.0當量)及疊氮化鈉(7.0當量)。將懸浮液加熱至150℃並保持20小時且冷卻用於反相HPLC純化,以提供5-(5-(2-(2H-四唑-5-基)乙基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-
2,4-二胺(24)。TFA鹽=1H NMR(400MHz,DMSO-d 6):δ 12.16,(s,1H),7.36(s,2H),7.31(d,J=2.8,1H),7.28(t,J=5.6Hz,1H),7.17(dd,J=2.0,8.4Hz,1H),6.99(d,J=8.4Hz,1H),6.56(d,J=1.6Hz,1H),6.19(d,J=2.8Hz,1H),5.47(s,2H),3.78(s,3H),3.48-3.43(m,2H),3.04(t,J=7.2Hz,2H),2.88(t,J=7.2Hz,2H),1.50-1.43(m,2H),1.26-1.19(m,2H),1.13-1.07(m,2H),0.81(t,J=7.2Hz,3H);LRMS[M+H]=436.3。
向4-碘-1-甲氧基-2-甲苯(1當量)及2-溴-2,2-二氟乙酸乙酯(2當量)於DMF(0.3M)中之溶液中添加Cu粉末(3當量)。將反應漿液加熱至80℃並保持1.5天,用飽和NaH2PO4(水溶液)驟冷且用乙酸乙酯萃取。經Na2SO4乾燥有機物且在真空下濃縮。經由矽膠管柱層析純化殘餘物,以提供產物26。
用甲醇(5當量)中之7N氨處理來自先前步驟之2,2-二氟-2-(4-甲氧
基-3-甲基苯基)乙酸乙酯(26)。在室溫下將反應混合物攪拌2小時,然後在真空下濃縮,以提供白色固體。將白色固體溶解於CCl4(0.3M)中,且用AIBN(0.08當量)及NBS(1.2當量)處理。在70℃下將反應漿液攪拌15小時。藉由真空過濾移除固體。在真空下濃縮濾液,且殘餘物係以粗製物形式用於下一反應中。
向市售2,4-二氯-5H-吡咯并[3,2-d]嘧啶(1當量)、Cs2CO3(4當量)於DMF(0.3M)中之溶液中添加上述殘餘物(1.1當量)。在室溫下將反應混合物攪拌5小時,然後用戊基胺(3當量)處理。將反應混合物加熱至100℃並保持16小時,用水驟冷且用乙酸乙酯萃取。用鹽水洗滌有機層,經Na2SO4乾燥並在真空下濃縮。經由矽膠管柱層析純化殘餘物,以提供產物27。
在0℃下,向於CH2Cl2(0.1M)中之來自先前步驟之2-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)-2,2-二氟乙醯胺(27)中添加吡啶(10當量),然後添加三氟乙酸酐(1.3當量)。3小時後,再添加三氟乙酸酐(1.3當量)。將反應混合物再攪拌3小時,用飽和NaHCO3(水溶液)驟冷且用CH2Cl2萃取。用鹽水洗滌有機層,經Na2SO4乾燥並在真空下濃縮。將殘餘物溶解於NMP(0.3M)中,且用NaN3(7當量)及ZnCl2(7當量)處理。將反應混合物加熱至100℃並保持16小時。藉由反相HPLC純化反應混合物,以提供5-(5-(二氟(1H-四唑-5-基)甲基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺(28)。TFA鹽=1H NMR(400MHz,DMSO-d 6):δ 12.22(s,1H),7.53(dd,1H),7.44(d,1H),7.42-7.35(m,3H),7.20(d,1H),6.76(d,1H),6.22(d,1H),5.59(s,2H),3.88(s,3H),3.45-3.35(m,2H),1.44-1.31(m,2H),1.24-1.11(m,2H),1.08-0.93(m,2H),0.77(t,3H);LRMS
[M+H]=458.2。
將2,2-二氟-2-(4-甲氧基-3-甲基苯基)乙酸乙酯(26)(來自實例16,步驟1)溶解於CCl4(0.3M)中。添加NBS(1.0當量)及AIBN(0.05當量),且在80℃下將反應混合物攪拌2小時。將其冷卻至室溫並濃縮。用矽膠管柱層析純化殘餘物,以提供無色油狀物。
向市售4-氯-5H-吡咯并[3,2-d]嘧啶-2-胺(1.0當量)及Cs2CO3(1.3當量)於DMF中之溶液中添加上述油狀物(1.0當量)。在室溫下將反應混合物攪拌5小時。將其用水驟冷且用10% MeOH/DCM(v/v)萃取。濃縮合併之有機萃取物且藉由矽膠管柱層析純化,以提供白色固體狀化合物(29)。
向來自先前步驟之2-(3-((2-胺基-4-氯-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)-2,2-二氟乙酸乙酯(29)於水/MeOH(1:1 v/v,0.3M)中之溶液中添加LiOH(1.4當量),且在室溫下將其攪拌10分
鐘。將其用1N HCl(1.0當量)驟冷。濃縮溶液,且殘餘物係以粗製物形式用於下一反應中。
向上述殘餘物於NMP(0.1M)中之溶液中添加戊基胺(3.0當量)。在100℃下將溶液加熱2小時且冷卻至室溫用於反相HPLC純化,以提供白色固體狀2-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)-2,2-二氟乙酸(30)。1H NMR(400MHz,DMSO-d 6):δ 7.47-7.44(m,3H),7.41(d,J=2.8Hz,1H),7.23(s,1H),7.09(d,J=8.4Hz,1H),7.00(d,J=1.6Hz,1H),6.10(d,J=3.2Hz,1H),5.54(s,2H),3.85(s,3H),3.47-3.41(m,2H),1.51-1.44(m,2H),1.27-1.20(m,2H),1.15-1.10(m,2H),0.82(t,J=7.2Hz,3H);LRMS[M+H]=434.1。
向市售3-(羥基甲基)-4-甲氧基苯甲酸甲酯(31)(1當量)之DMF(0.3M)溶液中添加Et3N(3當量)及TBSCl(1.4當量)。在室溫下將反應混合物攪拌15小時,用水驟冷且用乙酸乙酯萃取。用鹽水洗滌有機層,經Na2SO4乾燥並在真空下濃縮。將殘餘物溶解於THF(0.3M)中,且添加至LAH(1當量)之0℃ THF(0.3M)漿液中。將反應物升溫至室溫並保持1小時,冷卻至0℃且用飽和Na2SO4(水溶液)驟冷直至形成精細白色固體。添加過量固體Na2SO4,且經由矽藻土墊過濾反應混合物並用醚洗滌。在真空下濃縮濾液,以提供澄清油狀物。將澄清油狀物溶解於1,4-二噁烷(0.6M)中,且用MnO2(2.1當量)處理。將反應混合物回流1h,用乙酸乙酯稀釋且經由矽藻土墊過濾。濃縮濾液且經由矽膠管柱層析純化殘餘物,以提供醛產物32。
向來自先前步驟之醛32(1當量)及市售碸33(1.3當量)之-78℃ THF(0.3M)溶液中添加LHMDS(2.6當量)。在-78℃下將反應混合物攪拌1小時,用飽和NaHCO3(水溶液)驟冷且用乙酸乙酯萃取。用鹽水洗滌有機層,經Na2SO4乾燥並在真空下濃縮。經由矽膠管柱層析純化殘餘物,以提供烯烴產物34。
向來自先前步驟之烯烴34(1當量)之THF(0.3M)溶液中添加1M TBAF/THF(1.5當量)。在室溫下將反應混合物攪拌1小時,用水驟冷且用乙酸乙酯萃取。用鹽水洗滌有機層,經Na2SO4乾燥並在真空下濃縮。將殘餘物溶解於CH2Cl2(0.3M)中,冷卻至0℃且用Et3N(2當量)及
MsCl(1.2當量)處理。將反應混合物攪拌3小時,用水驟冷且用CH2Cl2萃取。經Na2SO4乾燥有機物且在真空下濃縮。殘餘物係以粗製物形式用於下一反應中。
向市售2,4-二氯-5H-吡咯并[3,2-d]嘧啶(1當量)、Cs2CO3(4當量)於DMF(0.3M)中之溶液中添加上述殘餘物(1.1當量)。在室溫下將反應混合物攪拌5小時,然後用戊基胺(3當量)處理。將反應混合物加熱至100℃並保持16小時,用水驟冷且用乙酸乙酯萃取。用鹽水洗滌有機層,經Na2SO4乾燥並在真空下濃縮。經由矽膠管柱層析純化殘餘物,以提供產物35。
經由用氫氣球鼓泡將來自先前步驟之2-((4R,6S)-6-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯乙烯基)-2,2-二甲基-1,3-二噁烷-4-基)乙酸第三丁基酯(35)(1當量)及10%碳載Pd(1當量)之乙酸乙酯(0.3M)漿液吹掃15分鐘。在氫氣氛下將反應混合物攪拌3小時,用乙酸乙酯稀釋且經矽藻土墊過濾。濃縮濾液且將殘餘物溶解於MeCN(0.03M)中,並用0.1M HCl(3當量)處理。在室溫下將反應混合物攪拌15小時,且用1M NaOH(11當量)處理。將反應混合物攪拌15小時,將pH調節至7-8且經由反相HPLC純化全部反應物,以提供產物36。1H NMR(400MHz,CD3OD):δ 7.41(d,1H),7.17(dd,1H),6.99(d,1H),6.45(d,1H),6.24(d,1H),5.54-5.45(m,2H),4.05-3.96(m,1H),3.90(s,3H),3.66-3.58(m,1H),3.55-3.42(m,2H),2.64-2.54(m,1H),2.54-2.45(m,1H),2.33-2.22(m,2H),1.62-1.40(m,6H),1.33-1.21(m,2H),1.15-1.05(m,2H),0.87(t,3H);LRMS[M+H]=500.3。
及
在微波管中,將4-碘-1-甲氧基-2-甲苯37(1當量,市售)、亞磷酸三甲酯(1.1當量)及乙酸鈀(0.1當量)添加至乙腈(0.4M),且在攪拌的同時在160℃下照射1小時。ISCO純化(二氧化矽管柱)提供無色油狀標題產物38。
(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)膦酸二甲酯(39)係遵循與實例2、步驟1-2相同之方案、在步驟1中使用(4-甲氧基-3-甲基苯基)膦酸二甲酯(38)替代2-(4-甲氧基-3-甲基苯基)乙腈(9)來製備。
用TMSI處理來自先前步驟之(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基-苯基)膦酸二甲酯(39),以提供(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)膦酸(40a)LRMS[M+H]=420.2,及(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)膦酸氫甲酯(40b)1H NMR(DMSO-d6):δ 12.38(s,1H),7.62(dd,1H),7.46(d,1H),7.44(s,2H),7.39(t,1H),7.18(dd,1H),6.83(d,1H),6.23(d,1H),5.60(s,2H),3.87(s,3H),3.43(q,2H),3.35(d,3H),1.48-1.38(m,2H),1.24-1.16(m,2H),1.10-1.01(m,2H),0.80(t,3H)。LRMS[M+H]=434.2
將4-溴-1-甲氧基-2-甲苯(市售,1.0當量)溶解於氯仿(0.1M)中,且用N-溴琥珀醯亞胺(1.1當量)及偶氮二異丁腈(AIBN,催化量)處理。在回流下將反應混合物攪拌過夜。冷卻至室溫後,藉由ISCO(矽膠管柱,EtOAc/己烷)純化反應混合物,以提供白色固體狀4-溴-2-(溴甲基)-1-甲氧基苯(41)。
將4-氯-5H-吡咯并[3,2-d]嘧啶-2-胺(市售,1當量)溶解於NMP(0.1M)中,且在室溫下在N2下攪拌。添加碳酸鉀(1當量),然後添加4-溴-2-(溴甲基)-1-甲氧基苯41(來自先前步驟,1當量)以獲得懸浮液。在室溫下將反應物攪拌18小時,且LCMS展示完全轉化。添加正戊基胺(2當量),然後添加碳酸鉀(1當量)。在60℃下將反應混合物攪拌過夜。冷卻至室溫後,在真空中濃縮反應混合物,且藉由ISCO層析(0-100% EtOAc於己烷中)純化,以提供白色固體狀產物5-(5-溴-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺42。
將5-(5-溴-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺42(來自先前步驟,1當量)、(E)-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)丙烯酸乙酯(1.5當量)、參(二亞苄基丙酮)二鈀(0)(0.1當量)、2-二環己基膦基-2',6'-二甲氧基聯苯(Sphos,0.2當量)及K3PO4(2當量)溶解於4:1正丁醇:水(0.1M)中。用N2脫氣後,將容器密封且在100℃下加熱過夜。冷卻至室溫後,用等體積之飽和碳酸氫鈉水溶液驟冷反應混合物,且用DCM萃取。合併有機層且經無水硫酸鈉乾燥,並在真空中濃縮。藉由反相製備型HPLC純化粗製物,以提供白色固體狀標題化合物(43)。
將(E)-3-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)丙烯酸乙酯(43)(來自先前步驟,1當量)及10%碳載鈀(0.1當量)懸浮於乙醇(0.1M)中。在攪拌的同時在H2氣氛下將混合物攪拌過夜。在真空下移除溶劑,且藉由ISCO(DCM-EtOAc,矽膠)純化粗製物,以提供白色固體狀產物(44)。
將3-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)-丙酸乙酯(44)(來自先前步驟,1當量)溶解於EtOH中,且添加2N NaOH(2當量)。在80℃下將反應混合物攪拌過夜。經由反相HPLC純化全部反應物以提供產物45。1H NMR(MeOD)δ 7.37(d,1H),7.22(1H),7.01(d,1H),6.67(s,1H),6.22(d,1H),5.49(s,2H),3.89(s,3H),3.53(t,2H),2.76(t,2H),2.46(t,2H),1.52-1.45(m,2H),1.36-1.24(m,2H),1.18-1.10(m,2H),0.88(t,J=7.3,3H)。LRMS[M+H]=412.2
(E)-3-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲
基)-4-甲氧基苯基)丙烯酸係使用與實例21、步驟5類似之方案來製備。使用(E)-3-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)丙烯酸乙酯(43,來自實例20、步驟3)替代3-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)丙酸乙酯(44)。1H NMR(MeOD):δ 7.61(d,1H),7.51(d,1H),7.40(d,1H),7.13(d,1H),6.95(s,1H),6.26(d,1H),6.18(d,1H),5.56(s,2H),3.94(s,3H),3.55(t,2H),1.52-1.44(m,2H),1.30-1.21(m,2H),1.14-1.07(m,2H),0.84(t,J=7.3,3H)。LRMS[M+H]=410.2
(S)-3-(3-((2-胺基-4-((1-羥基己-2-基)胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)丙酸係使用與實例21類似之方案來製備。在步驟2中使用(S)-2-胺基己-1-醇替代正戊基胺。1H NMR(d-DMSO):δ 7.31(d,1H),7.14(d,1H),6.99(d,1H),6.45(s,1H),6.01(d,1H),5.70(br,2H),5.47(d,1H),5.29(d,1H),5.15(d,1H),4.18-4.12(m,1H),3.82(s,3H),3.36-3.25(m,2H),2.60(t,2H),2.32(t,2H),1.49-1.40(m,1H),1.17-1.08(m,3H),0.95-0.88(m,2H),0.75(t,3H)。LRMS[M+H]=442.2。
在0℃下,向3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯甲酸甲酯(來自實例13,步驟1)於THF(0.1M)中之溶液中添加DIBAL(4當量)。將反應混合物升溫至室溫並保持1小時,冷卻至0℃且用飽和Na2SO4(水溶液)驟冷直至形成精細白色固體。添加過量固體Na2SO4且經由矽藻土墊過濾反應混合物。在真空下濃縮濾液且藉由ISCO(矽膠管柱,MeOH/DCM)純化,以提供白色固體。
在0℃下,向(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)甲醇(46)(來自先前步驟,1當量)於氯仿(0.1M)中之溶液中添加SOCl2(6當量)。將反應混合物升溫至室溫,並在室溫下攪拌過夜。然後冷卻至0℃,用飽和NaHCO3(水溶液)驟冷,且用DCM萃取。用鹽水洗滌有機層,經Na2SO4乾燥並在真空下濃縮。殘餘物未經純化即用於下一步驟。
在室溫下,向5-(5-(氯甲基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺(47,來自先前步驟,1當量)於DCM(0.1M)中之溶液中添加(R)-吡咯啶-2-甲酸第三丁基酯(4當量)。在室溫下將反應混合物攪拌過夜。在真空下濃縮反應混合物。藉由反相製備型HPLC純化粗製物,以提供白色固體狀標題化合物。
在室溫下,向(R)-1-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苄基)吡咯啶-2-甲酸第三丁基酯(48,來自先前步驟,1當量)於DCM(0.5M)中之溶液中添加TFA(10當量)。在室溫下將反應混合物攪拌6小時。在真空下濃縮反應混合物後,藉由反相製備型HPLC純化粗製物,以提供白色固體狀標題化合物49。1H NMR(d-DMSO):δ 12.58(s,1H),7.48(br,2H),7.47(d,1H),7.36(t,1H),7.32(d,1H),7.16(d,1H),6.77(s,1H),6.21(d,1H),5.54(s,2H),4.19-4.13(m,2H),3.84(s,3H),3.46-3.41(m,2H),3.31-3.25(m,1H),3.10-3.04(m,1H),2.41-2.32(m,2H),2.02-1.93(m,2H),1.88-1.75(m,1H),1.50-1.42(m,2H),1.29-1.20(m,2H),1.15-1.07(m,2H),0.81(t,3H)。LRMS[M+H]=467.3
(S)-1-(4-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-3-甲氧基苄基)吡咯啶-2-甲酸係使用與實例13及24類似之方案來製備。使用4-(氯甲基)-3-甲氧基苯甲酸酯替代實例13、步驟1中之3-(氯甲基)-4-甲氧基苯甲酸甲酯。使用(S)-吡咯啶-2-甲酸第三丁基酯替代實例24、步驟3中之(R)-吡咯啶-2-甲酸第三丁基酯。1H NMR(d-DMSO):δ 12.76(s,1H),7.54(br,2H),7.40-7.36(m,2H),7.22(s,1H),6.97(d,1H),6.58(d,1H),6.20(d,1H),5.56(s,2H),4.14-4.37(m,2H),3.86(s,3H),3.47-3.42(m,2H),3.36-3.30(m,2H),3.14-3.08(m,1H),2.39-2.32(m,1H),2.04-1.95(m,2H),1.87-1.80(m,1H),1.49-1.41(m,2H),1.26-1.18(m,2H),1.12-1.05(m,2H),0.81(t,3H)。[M+H]+=467.3。
在0℃下,將2-(4-(羥基甲基)-3-甲氧基苯氧基)乙酸(市售,1當量)於甲醇(0.5M)中攪拌。以逐滴方式添加三甲基矽基重氮甲烷(1.2當量)。將反應混合物升溫至室溫且在室溫下攪拌1小時,冷卻至0℃,用水驟冷,且用乙酸乙酯萃取。用鹽水洗滌有機層,經Na2SO4乾燥並
在真空下濃縮。殘餘物未經純化即用於下一步驟。
在0℃下,將來自先前步驟之2-(4-(羥基甲基)-3-甲氧基苯氧基)乙酸甲酯(50,1當量)於二氯甲烷(1M)中攪拌。以逐滴方式添加三乙胺(2.4當量)及甲烷磺醯氯(1.2當量)。在0℃下將反應混合物再攪拌1小時,然後將其用水驟冷且用乙酸乙酯萃取。合併有機相,乾燥(Na2SO4)並濃縮。粗產物直接用於下一步驟中。
2-(4-((2-氯-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-3-甲氧基苯氧基)乙酸甲酯(52)係遵循與實例14、步驟1相同之方案、使用2-(3-甲氧基-4-(((甲基磺醯基)氧基)甲基)苯氧基)乙酸甲酯(51,來自先前步驟)替代4-(溴甲基)-3-甲氧基苯甲腈來製備。
在微波管中,向2-(4-((2-氯-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-3-甲氧基苯氧基)乙酸甲酯(52,1當量,來自先前步驟)於NMP(1M)中之溶液中添加NH4OH(與NMP等體積),然後添加氧化銅(I)(0.1當量)。蓋住管口,且在110℃下將懸浮液加熱過夜。冷卻至室溫後,藉由反相製備型HPLC純化反應混合物,以提供白色固體狀標題化合物。1H NMR(CDCl3-CD3OD):δ 7.22(s,1H),6.73(d,1H),6.65(d,1H),6.45(d,1H),6.16(d,1H),5.34(s,2H),4.55(s,2H),3.88(s,3H),3.46(t,2H),1.50-1.43(m,2H),1.31-1.24(m,2H),1.19-1.13(m,2H),0.86(t,3H)。LRMS[M+H]=414.2。
分析式(I)化合物以量測其作為類鐸受體7促效劑之能力。
根據經機構審議委員會批準之指導方針,在人類末梢血分析(人類PBMC)中使用一組獨立的正常人類供體測試式(I)化合物之生物活性。使用Ficoll密度梯度(GE healthcare 17-1440-03)自新鮮末梢血分離人類PBMC。使30-35mL人類末梢血於50ml尖底管中之15mL Ficoll上分層,然後在室溫下在1800rpm(Eppendorf Centrifuge 5810R,在管用吊桶上方具有biohazard蓋)下離心30分鐘,其中無加速且無制動。然後收集血沉棕黃層且轉移至新50ml尖底管上並於由以下組成之完全培養基中洗滌兩次:RPMI 1640(11875085,來自Invitrogen公司,Carlsbad,California),補充有10%熱失活胎牛血清(Gibco 10099-141)、1%青黴素-鏈黴素(Gibco編號15140-122)、1mM非必需胺基酸(Gibco編號11140-050)、1mM丙酮酸鈉(Gibco編號11360-070)、2mM L-麩醯胺酸(Gibco編號25030-081)及1mM HEPES(Gibco編號15630-080)。然後使用台盼藍(trypan blue)染色對活細胞進行計數,以2×105個細胞/孔平鋪於96孔平底板(Becton Dickinson編號353070)中之總體積為200μl之完全培養基中。然後以自100μM開始3倍稀釋之10點劑量反應格式添加化合物。使陰性對照孔接受等濃度之DMSO。在37℃、5% CO2下培育18-24小時後收集培養物上清液,儲存在-20℃下直至進一步使用。
使用Luminex套組(Biorad)量測培養物上清液中之IL-6含量。使用來自GraphPad(San Diego,CA)之Prism軟體實施數據分析。產生每一化合物之劑量反應曲線,且根據給出50%最大信號之濃度確定EC50值。
使用人類TLR7及NF-kB驅動之螢光素酶報導基因載體(pNifty-螢
光素酶)穩定轉染人類胚腎293(HEK 293)細胞。作為對照分析,使用經pNifty-Luc轉染之正常Hek293。將細胞培養於補充有2mM L-麩醯胺酸、10%熱失活FBS、1%青黴素及鏈黴素、2μg/ml嘌呤黴素(InvivoGen編號ant-pr-5)及5μg/ml殺稻瘟菌素(Invitrogen編號46-1120)之DMEM中。Bright-GloTM螢光素酶分析緩衝劑及受質係由Promega編號E263B及編號E264B(分別為分析受質及緩衝劑)供應。384孔透明底板係由Greiner bio-one(編號789163-G)供應且係定製條形碼板。
將細胞以25,000個細胞/孔平鋪於384孔板中之最終體積為50μl之培養基中。在37℃及5% CO2下過夜(18小時)培養後容許細胞黏著至板。然後將連續稀釋實驗及陽性對照化合物分配至每一孔,且在37℃及5% CO2下培育7小時。經單獨DMSO刺激之細胞亦用作陰性對照。培育後,根據製造商之說明書,將30μl預混合分析緩衝劑及受質緩衝劑添加至每一孔中。在CLIPR機器上讀取發光信號,其中每板之積分時間為20秒。
產生每一化合物之劑量反應曲線,且根據給出50%最大信號之濃度確定EC50值。
呈游離形式或醫藥上可接受之鹽形式之各種式(I)化合物展現藥理學性質,例如如藉由本申請案中所述之活體外測試所指示。彼等實驗中之EC50值係根據所討論測試化合物之引起基線與最大反應之間之中途之反應的濃度給出。在其他實例中,式(I)化合物之EC50值介於1nM至2μM範圍內。在其他實例中,式(I)化合物之EC50值介於1nM至1μM範圍內。在其他實例中,式(I)化合物之EC50值介於1nM至500nM範圍內。在其他實例中,式(I)化合物之EC50值介於1nM至250nM範圍內。在其他實例中,式(I)化合物之EC50值介於1nM至100nM範圍內。在其他實例中,式(I)化合物之EC50值介於1nM至50nM範圍內。
在其他實例中,式(I)化合物之EC50值介於1nM至25nM範圍內。在其他實例中,式(I)化合物之EC50值介於1nM至10nM範圍內。該等EC50值係相對於設定為100%之雷西莫特(resiquimod)活性來獲得。
僅舉例而言,藉由某些式(I)化合物之TLR-7刺激之EC50列示於表1中。
應理解,本文所述實例及實施例僅出於說明之目的,且基於其之各種修改或變化應為熟習此項技術者所瞭解且欲包括在本申請案之精神與範圍內及隨附申請專利範圍之範疇內。出於所有目的,本文所引用之所有公開案、專利及專利申請案皆以引用方式併入本文中。
Claims (20)
- 一種具有式(I)結構之化合物或其醫藥鹽,其中:R1係-NHR6或-NHCHR6R9;R3係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH或四唑基;R4係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH或四唑基;其中,當R3係H時,則R4係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH或四唑基;或當R4係H時,則R3係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH或四唑基;L1係-(CH2)m-;L2係-(CH2)m-;L7=-(CH2)m(CHR11CH2)m(CH2)n-;R6係-C3-C6烷基;R7係-C1-C3烷基;R9係L1OH;每一R11獨立地選自-OH;R12係a)未經取代之四唑基;b)經-L1C(=O)OH取代之四唑基;或c)5至6員雜環烷基,其具有1至2個獨立地選自N及O之雜原子且經-C(=O)OH取代;每一m獨立地選自1、2、3及4,且每一n獨立地選自0、1、2、3及4。
- 如請求項1或2之化合物,其中:R1係-NHR6或-NHCHR6R9;R3係H、-OL2C(=O)OH或四唑基;R4係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-L2C(=O)OH、-L7C(=O)OH或四唑基;其中,當R3係H時,則R4係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-L2C(=O)OH、-L7C(=O)OH或四唑基;或當R4係H時,則R3係-OL2C(=O)OH或四唑基;L1係-(CH2)m-;L2係-(CH2)m-;L7=-(CH2)m(CHR11CH2)m(CH2)n-;R6係-C3-C6烷基;R7係-C1-C3烷基;R9係L1OH;每一R11獨立地選自-OH;R12係a)未經取代之四唑基;b)經-L1C(=O)OH取代之四唑基;或c)5至6員雜環烷基,其具有1至2個獨立地選自N及O之雜原子且經-C(=O)OH取代;每一m獨立地選自1、2、3及4,且每一n獨立地選自0、1、2、3及4。
- 如請求項1或2之化合物,其中:R1係-NHR6或-NHCHR6R9;R3係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH、或;R4係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH、或;其中,當R3係H時,則R4係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH、或當R4係H時,則R3係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-L2C(=O)OH、-L7C(=O)OH、-OL2C(=O)OH、、;L1係-(CH2)m-;L2係-(CH2)m-;L7=-(CH2)m(CHR11CH2)m(CH2)n-;R6係-C3-C6烷基;R7係-C1-C3烷基;R9係L1OH;每一R11獨立地選自-OH;R12係a)或b)或c)、或每一m獨立地選自1、2、3及4,且每一n獨立地選自0、1、2、3及4。
- 如請求項1或2之化合物,其中:R1係-NHR6或-NHCHR6R9;R3係H、-OL2C(=O)OH、或;l;R4係H、-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-L2C(=O)OH、-L7C(=O)OH、或;其中,當R3係H時,則R4係-L2R12、-OL2R12、-C(CH3)2R12、-P(=O)(OH)2、-P(=O)OH(OR7)、-CF2R12、-CF2C(=O)OH、-CH=CHC(=O)OH、-L2C(=O)OH、-L7C(=O)OH、或或當R4係H時,則R3係-OL2C(=O)OH、、;L1係-(CH2)m-;L2係-(CH2)m-;L7=-(CH2)m(CHR11CH2)m(CH2)n-;R6係-C3-C6烷基;R7係-C1-C3烷基;R9係L1OH;每一R11獨立地選自-OH;R12係a)或b)或c)、或;每一m獨立地選自1、2、3及4,且每一n獨立地選自0、1、2、3及4。
- 如請求項1或2之化合物,其中:L1係-CH2-;L2係-CH2-或-CH2CH2-;L7=-(CH2)2(CHR11CH2)2-;R6係-C4烷基或-C5烷基;R7係甲基、乙基或丙基,且R11係OH。
- 如請求項1或2之化合物,其中:R1係-NHR6;R3係H;R4係-L2R12;L2係-(CH2)m-;R6係-C3-C6烷基;R12係a)未經取代之四唑基;b)經-L1C(=O)OH取代之四唑基;或c)5至6員雜環烷基,其具有1至2個獨立地選自N及O之雜原子且經-C(=O)OH取代,且每一m獨立地選自1、2、3及4。
- 如請求項1或2之化合物,其中:R1係-NHR6;R3係H;R4係-L2C(=O)OH;L2係-CH2-或-CH2CH2-;且R6係-C5烷基。
- 如請求項1之化合物,其中該化合物係選自:5-(5-((1H-四唑-5-基)甲氧基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;5-(5-((1H-四唑-5-基)甲基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;(S)-2-((5-(5-((1H-四唑-5-基)甲基)-2-甲氧基苄基)-2-胺基-5H-吡咯并[3,2-d]嘧啶-4-基)胺基)己-1-醇;(S)-2-((5-(5-((1H-四唑-5-基)甲基)-2-甲氧基苄基)-2-胺基-5H-吡咯并[3,2-d]嘧啶-4-基)胺基)戊-1-醇;5-(5-(2-(1H-四唑-5-基)乙基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;N4-己基-5-(2-甲氧基-5-(1H-四唑-5-基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;(S)-2-((2-胺基-5-(2-甲氧基-5-(1H-四唑-5-基)苄基)-5H-吡咯并[3,2-d]嘧啶-4-基)胺基)己-1-醇;2-(5-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苄基)-2H-四唑-2-基)乙酸;5-(2-甲氧基-4-(1H-四唑-5-基)苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;5-(2-甲氧基-5-(1H-四唑-5-基)苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;5-(5-(2-(1H-四唑-5-基)丙-2-基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;(S)-2-((5-(5-(2-(1H-四唑-5-基)丙-2-基)-2-甲氧基苄基)-2-胺基-5H-吡咯并[3,2-d]嘧啶-4-基)胺基)己-1-醇;5-(5-(二氟(1H-四唑-5-基)甲基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;2-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)-2,2-二氟乙酸;(3R,5R)-7-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)-3,5-二羥基庚酸;2-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)乙酸;(S)-2-(3-((2-胺基-4-((1-羥基己-2-基)胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)乙酸;3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯甲酸;(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)膦酸;(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)膦酸氫甲酯;(E)-3-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)丙烯酸;3-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)丙酸;(S)-3-(3-((2-胺基-4-((1-羥基己-2-基)胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)丙酸;(S)-1-(4-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-3-甲氧基苄基)吡咯啶-2-甲酸;(R)-1-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苄基)吡咯啶-2-甲酸,及2-(4-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-3-甲氧基苯氧基)乙酸。
- 如請求項1之化合物,其中該化合物係選自:2-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯基)乙酸;3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苯甲酸;5-(5-((1H-四唑-5-基)甲基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;5-(5-(2-(1H-四唑-5-基)乙基)-2-甲氧基苄基)-N4-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺;(S)-1-(4-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-3-甲氧基苄基)吡咯啶-2-甲酸,及(R)-1-(3-((2-胺基-4-(戊基胺基)-5H-吡咯并[3,2-d]嘧啶-5-基)甲基)-4-甲氧基苄基)吡咯啶-2-甲酸。
- 一種醫藥組合物,其包含治療有效量之如請求項1至12中任一項之化合物及醫藥上可接受之載劑。
- 一種如請求項1至12中任一項之化合物之用途,其用於製造用來治療與TLR7活性相關之疾病或病症的藥劑。
- 如請求項14之用途,其中該疾病係傳染病、病毒性傳染病、發炎性疾病、呼吸疾病、皮膚病、自體免疫疾病、細胞增生性疾病或癌症。
- 如請求項14之用途,其中該疾病或病況係氣喘、慢性阻塞性肺病(COPD)、成人呼吸窘迫症候群(ARDS)、潰瘍性結腸炎、克隆氏病(Crohn’s disease)、支氣管炎、皮炎、日光性角化症、基底細胞癌、膀胱癌、過敏性鼻炎、牛皮癬、硬皮症、蕁麻疹、類風濕性關節炎、多發性硬化、癌症、乳癌、HIV、肝炎、C型肝炎或狼瘡。
- 如請求項14之用途,其中該疾病或病況係B型肝炎、C型肝炎、結腸直腸癌或肝細胞癌。
- 一種用於醫學治療之方法中之化合物,其中該醫學治療之方法用於治療與TLR7受體活性相關之疾病,其中該疾病係傳染病、病毒性傳染病、發炎性疾病、呼吸疾病、皮膚病、自體免疫疾病、細胞增生性疾病或癌症,且其中該化合物係如請求項1至12中任一項之化合物。
- 如請求項18之化合物,其中該疾病係氣喘、慢性阻塞性肺病(COPD)、成人呼吸窘迫症候群(ARDS)、潰瘍性結腸炎、克隆氏病、支氣管炎、皮炎、日光性角化症、基底細胞癌、膀胱癌、過敏性鼻炎、牛皮癬、硬皮症、蕁麻疹、類風濕性關節炎、多發性硬化、癌症、乳癌、HIV、肝炎、C型肝炎或狼瘡。
- 如請求項18之化合物,其中該疾病或病況係B型肝炎、C型肝炎、結腸直腸癌或肝細胞癌。
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