TW202017929A - 吡咯并〔2,3-d〕嘧啶化合物的製造方法與中間產物及其用途 - Google Patents
吡咯并〔2,3-d〕嘧啶化合物的製造方法與中間產物及其用途 Download PDFInfo
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- TW202017929A TW202017929A TW108123441A TW108123441A TW202017929A TW 202017929 A TW202017929 A TW 202017929A TW 108123441 A TW108123441 A TW 108123441A TW 108123441 A TW108123441 A TW 108123441A TW 202017929 A TW202017929 A TW 202017929A
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- compound
- following structure
- salt
- group
- pyrrolo
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- -1 pyrimidine compound Chemical class 0.000 title claims description 42
- 238000004519 manufacturing process Methods 0.000 title abstract description 7
- 239000000543 intermediate Substances 0.000 title abstract 2
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- IUEWXNHSKRWHDY-UHFFFAOYSA-N N-[3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl]propane-1-sulfonamide Chemical compound C1C(NS(=O)(=O)CCC)CC1N(C)C1=NC=NC2=C1C=CN2 IUEWXNHSKRWHDY-UHFFFAOYSA-N 0.000 claims abstract description 32
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 5
- 125000006532 (C3-C5) alkyl group Chemical group 0.000 claims description 4
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- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
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- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical class [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical class OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本發明是關於用於製備N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶或非結晶型之製造方法與中間產物。本發明亦是關於包括該結晶型的鹽形式與醫藥組成物,以及關於使用從結晶型製備的化合物於治療各種疾病的方法。
Description
本發明是關於製備N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶或非結晶型的製造方法與中間產物。本發明亦是關於包括該結晶型的醫藥組成物以及關於使用該結晶型於治療各種疾病的方法。
N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的製備合成描述於共同讓渡的US9,035,074中,其內容全文藉由引用而併入本文。N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺游離鹼(free base)的結晶型有用於作為蛋白質激酶(例如Janus Kinase(JAK)酶)的抑制劑,因此也在治療上有用於作為免疫抑制劑,用於器官移植、異種移植、狼瘡、多發性硬化症、類風濕性關節炎、牛皮癬、第I型糖尿病和糖尿病併發症、癌症、氣喘、異位性皮膚炎、自身免疫性甲狀腺疾病、潰瘍性結腸炎、克隆氏症、阿茲海默症、白血病和其他需要免疫抑制的適應症。本發明是關於製備N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶或非結晶型的製造方法與中間產物,因而該結型提供某些改良的性質,用於製造藥物劑量形式,特別是用於口服和局部劑量形式。
本發明是針對N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺游離鹼的結晶或非結晶型的製備方法。本發明亦是針對組成物,其包含醫藥組成物,含有結晶3-((3R,4R)-4-甲基-3- [甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺基]-哌啶-1-基)-3-側氧基丙腈游離鹼。本發明亦提供治療哺乳動物疾病的方法,包括對於有需要的哺乳動物投予治療有效量的結晶N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺或其醫藥上可接受的鹽或是醫藥組成物,該疾病係選自於類風濕關節炎、狼瘡、牛皮癬、異位性皮膚炎,白斑病(vitiligo)和炎症性腸病。
本發明提供一種有用於製造具有以下結構之N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺化合物:
其中R1
是選自:氫、經取代或未經取代的苯基、經取代或未經取代的吡啶基、經取代或未經取代的咪唑基、(C1
-C6
)烷基、(C3
-C10
)環烷基,其可任選地被1、2或3個獨立地選自鹵素、(C1
-C3
)烷基和(C1
-C3
)烷氧基的基團取代;或選自由鈉、鉀、鋰、鎂和鈣所組成之群組之其鹽。在特別的方面,本發明提供R1
是氫的該化合物,或其鹽。
本發明進一步提供具有以下結構的化合物:
其中R2
是選自(C3
-C5
)烷基和(C3
-C4
)環烷基;以及X和Y獨立地選自CR3
和N,其中R3
是選自:氫和(C1
-C6
)烷基。在一些方面,本發明提供該化合物,其中X和Y皆為N;以及R2
是(C3
-C5
)烷基。在一些方面,本發明提供該化合物,其中R2
是直鏈或支鏈丙基。在一些其他方面,本發明提供該化合物,其中R2
是直鏈丙基。在一些其他方面,本發明提供該化合物,其中X是CR3
,其中R3
是氫;以及Y是N,以及進一步其中R2
是直鏈或支鏈丙基。在特定方面,本發明提供該化合物,其中R2
是直鏈丙基。據此,本發明提供具有以下結構之1-(丙基磺醯基)-1H-1,2,4-三唑化合物:。
本發明進一步提供具有以下結構之化合物的鹽:
該鹽選自由鹽酸鹽、磷酸(單、雙、三)酸鹽、(1S)-(+)-10-樟腦磺酸鹽、1,2-乙二磺酸鹽、二苯甲醯基-L-酒石酸鹽、二苯甲醯基-D-酒石酸鹽、檸檬酸鹽、琥珀酸鹽、富馬酸鹽、馬來酸鹽、草酸鹽、對甲苯磺酸鹽、L-(+)-酒石酸鹽、D-(-)-酒石酸鹽、氫溴酸鹽、酸鹽,甲磺酸鹽和丙二酸鹽所組成之群組。在特定方面,本發明提供該化合物的磷酸鹽。
本發明亦提供具有以下結構之化合物的酸鹽:
其中該酸鹽是選自由鹽酸鹽、磷酸鹽、琥珀酸鹽、檸檬酸鹽、對甲苯磺酸鹽、甲磺酸鹽、半硫酸鹽、半富馬酸鹽和丙二酸鹽所組成之群組。在一方面,本發明提供具有以下結構之化合物的酸鹽:
其中該酸鹽為鹽酸鹽。
本發明進一步提供具有以下結構的化合物:
其是從選自由鹽酸鹽、磷酸鹽、琥珀酸鹽、對甲苯磺酸鹽、甲磺酸鹽、半硫酸鹽、檸檬酸鹽、半富馬酸鹽和丙二酸鹽所組成之群組的酸鹽所製備。在特定方面,本發明提供在合適的鹼性條件下由該化合物之鹽酸鹽所製備的該化合物。更特別地,本發明提供該化合物,其具有粉末X射線繞射圖,該粉末X射線繞射圖包括以2θ計在13.0°、14.8°和23.3° 2θ ± 0.2° 2θ處的峰。
本發明亦提供具有以下結構之化合物:
其中Ra
是選自氫、(C1
-C6
)烷基、(C3
-C10
)環烷基、和經取代或未經取代的苯基,其中該烷基和環烷基可任選地被1、2或3個獨立地選自鹵素、(C1
-C3
)烷基、和(C1
-C3
)烷氧基的基團取代;或其鹽。在特別的方面,本發明提供上述化合物,其中Ra
是氫。在另一特別的方面,本發明提供上述化合物,其中Ra
是甲基或異丙基。
此外,本發明提供製備具有以下結構之化合物的方法:
其包括(a)在合適的條件下製備該化合物之該鹽酸鹽,以及而後(b)將該鹽與合適的鹼在合適的條件下反應以形成該化合物,其中該合適的鹼是選自碳酸鈉、碳酸鉀、碳酸氫鈉、碳酸氫鉀、氫氧化鈉、氫氧化鉀或三乙胺。在一方面,本發明提供該方法,其中該合適的鹼是碳酸氫鈉或碳酸氫鉀。
本發明亦提供製備具有以下結構之化合物的方法:
其包括(a)製備具有以下結構的羥胺化合物:
(b)在合適的條件下使該羥胺化合物反應以製備具有以下結構之胺基化合物:
以及而後(c)在合適的條件下用合適的正丙基磺化試劑處理該胺基化合物以形成該化合物。在一些方面,本發明提供該方法,其中該正丙基磺化試劑是具有以下結構的化合物:
其中R2
是正丙基;以及X和Y是獨立地選自CR3
和N,其中R3
是選自氫和(C1
-C6
)烷基。在特別的方面,本發明提供該方法,其中X和Y皆為N。在其他方面,本發明進一步提供該方法,其中該正丙基磺化試劑是具有以下結構之1-(丙基磺醯基)-1H-1,2,4-三唑化合物:。
在另一方面,本發明提供該方法,其中具有以下結構之該化合物:
是N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶型,其具有粉末X射線繞射圖,該粉末X射線繞射圖包括以2θ計在13.0°、14.8°和23.3° 2θ ± 0.2° 2θ處的峰。
本發明另提供製備具有以下結構之化合物的方法:
其包括(a)製備具有以下結構之胺基化合物:
以及而後(b)在合適的條件下用合適的正丙基磺化試劑處理該胺基化合物以形成該化合物。在一些方面,本發明提供該方法,其中該正丙基磺化試劑是具有以下結構的化合物:
其中R2
是正丙基;以及X和Y是獨立地選自CR3
和N,其中R3
是選自氫和(C1
-C6
)烷基。在一些方面,本發明提供該方法,其中X和Y皆為N。在其他方面,本發明提供該方法,其中該正丙基磺化試劑是具有以下結構之1-(丙基磺醯基)-1H-1,2,4-三唑化合物:。
本發明進一步提供該方法,其中具有以下結構之該化合物:
是N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶型,其具有粉末X射線繞射圖,該粉末X射線繞射圖包括以2θ計在13.0°、14.8°和23.3° 2θ ± 0.2° 2θ處的峰。
此外,本發明提供具有以下結構之化合物的醫藥組成物:
其中該組成物是從該化合物所製備,該化合物之結晶型具有包括以2θ計在13.0°、14.8°和23.3° 2θ ± 0.2° 2θ處的峰之粉末X射線繞射圖;以及進一步包括醫藥上可接受的載體。在一些方面,本發明提供一種醫藥組成物,其包括自乳膏、穿皮貼劑、軟膏、滴眼劑、洗劑和凝膠的局部製劑(topical formulation)。特別地,本發明提供該醫藥組成物,其中該局部製劑含有從約0.1%至約5.0%(w/v)的N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺。
本發明進一步提供治療哺乳動物疾病的方法,包括對有需要的哺乳動物投予治療有效量的本文上述所揭露之醫藥組成物,其中該疾病是選自於由狼瘡、類風濕性關節炎、IBD、潰瘍性結腸炎、克隆氏症、白斑病、脫髮、牛皮癬和異位性皮膚炎所組成之群組。
本發明亦提供局部治療哺乳動物疾病的方法,其包括對於有需要的哺乳動物以局部投予模式投予治療有效量的本文上述所揭露之醫藥組成物,其中該疾病是選自由白斑病(vitiligo)、脫髮、牛皮癬和異位性皮膚炎(atopic dermatitis)所組成之群組。
本發明進一步提供本文上述所揭露之醫藥組成物做為藥物。
本發明另提供本文上述所揭露之醫藥組成物用於治療選自由以下所組成之群組的疾病:狼瘡、類風濕性關節炎、IBD、潰瘍性結腸炎、克隆氏症、白斑病、脫髮、牛皮癬和異位性皮膚炎。
本發明亦提供本文上述所揭露之醫藥組成物用於製備治療選自由狼瘡、類風濕性關節炎、IBD、潰瘍性結腸炎、克隆氏症、白斑病、脫髮、牛皮癬和異位性皮膚炎所組成之群組的疾病的用途。
儀器與分析方法:
計算的粉末圖案:
使用包含XFOG (SHELXTL,Bruker AXS,XFOG,版本5.100,1997)和XPOW (SHELXTL,Bruker AXS,XPOW,版本5.102,1997-2000)的SHELXTL程式包,從單晶X射線數據計算粉末圖案。使用XCH文件交換程式(SHELXTL,Bruker AXS,XCH,版本5.0.4,1995-2001)添加覆蓋圖形所需的適當波長。
粉末
X
射線繞射:
使用配備有Cu輻射源的Bruker AXS D8 Advance繞射儀進行粉末X射線繞射分析,該輻射源配備有利用gobel鏡的雙初級反射鏡。藉由具有電動狹縫的LYNXEYE_EX檢測器檢測繞射輻射。初級和二級皆配備有2.5焊縫狹縫。X射線管的電壓和安培數分別設定為40kV和40mA。在Theta-Theta測角儀中,在Cu K-alpha波長為3.0至40.0度的2-Theta的鎖定耦合掃描中以1204步進行收集數據,掃描速度為每步0.50秒。藉由放置在低矽背景樣品架中製備樣品,並在收集過程中旋轉樣品。使用Bruker DIFFRAC Plus軟體收集數據。藉由EVA diffract plus軟體進行分析。峰值搜索之前未處理PXRD數據文件。使用EVA軟體中的峰值搜索演算法,將閾值選擇為1的峰用於進行初步峰分配。為了確保有效性,手動進行調整;目視檢查自動分配的輸出,並將峰位置調整為最大峰。通常選擇相對強度≥2%的峰。不選擇未分辨或與雜訊一致的峰。在USP中,與PXRD的峰值位置相關的典型誤差高達+/- 0.2° 2-θ (USP-941)。
PXRD 反射分配:
使用Eva Application 9.0軟體,視化和評估PXRD圖譜。在給定反射的最大強度下分配峰值。下表中包含展現出大於10%之相對強度的所有反射。
本發明提供從N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶型所製備之醫藥組成物,該結晶型可藉由一種或多種固態分析方法鑑定。
表1顯示23℃時結晶型的PXRD峰列表。表 1 :
結晶型1的PXRD峰列表。峰位置代表N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺(結晶型1無水游離鹼)的特徵峰。
b) 定義為峰高。強度可以依據CPMAS實驗參數的實際設定和樣品的熱歷史而變化。CPMAS強度為非必須定量。*峰肩
據此,本發明提供從結晶型所製備之醫藥組成物,以及製備該結晶型的方法,以及用於藥物用途及用於治療諸如狼瘡、類風濕性關節炎、IBD、潰瘍性結腸炎、克隆氏症、白斑病、脫髮、牛皮癬和異位性皮膚炎等疾病的醫藥組成物。本發明亦提供該醫藥組成物於製造用於治療如狼瘡、類風濕性關節炎、IBD、潰瘍性結腸炎、克隆氏症、白斑病、脫髮、牛皮癬和異位性皮膚炎等疾病的藥物之用途。
應理解本文列出的疾病和症候群的治療方法涉及對需要這種治療的個體投予治療有效量之根據本發明的方法所製備的多晶型物的醫藥組成物。如本文所用,關於疾病的術語「治療」是指預防、抑制和/或改善疾病。
如本文所用,術語「個體」或「患者」可互換使用,是指任何動物,包含哺乳動物,較佳為小鼠、大鼠、其他囓齒動物、兔子、狗、貓、豬、牛、綿羊、山羊、馬或靈長類動物,並且最佳為人類。如本文所用,短語「治療有效量」是指引起研究人員、獸醫、醫師或其他臨床醫師所尋求在組織、系統、動物、個體或人類中的生物學或醫學反應的活性化合物或藥劑之量,該反應包含以下一項或多項:
(1)預防疾病;例如,預防可能易患該疾病、病症或失調但尚未經歷或未表現出該疾病的病理或症狀的個體中的疾病、病症或失調;
(2)抑制疾病;例如,抑制正在經歷或表現出該疾病、病症或失調的病理或症狀的個體中的疾病、病症或失調(亦即,阻止或減緩該病理和/或症狀的進一步發展);以及
(3) 改善疾病;例如,改善正在經歷或顯示出該疾病、病症或失調的病理或症狀(亦即逆轉該病理和/或症狀)的個體的疾病、病症或失調。
劑量與製劑
本發明亦包含本文所述之藥物組成物,其包含一種或多種醫藥上可接受的載體、賦形劑、媒介物等。以有效量投予本發明的醫藥組成物以治療本文所述之病症,並且可由結晶化合物本身或者作為其藥學上可接受的鹽製備本發明的醫藥組成物。
藉由任何合適的途徑以適合於該途徑的組成物的形式投予本發明的醫藥組成物,並且以對預期治療有效的劑量投予。本發明的化合物可用口服、直腸、陰道、腸胃外或局部投予。
可口服投予本發明之醫藥組成物。口服投予可能涉及吞嚥,從而使化合物進入胃腸道,或者可通過頰或舌下投予使化合物直接從口腔進入血流。
在另一實施例中,本發明之醫藥組成物亦可直接投予至血流中、肌肉中、或內臟中。腸胃外投予的合適方式包含靜脈內、動脈內、腹膜內、鞘內、心室內、尿道內、胸骨內、顱內、肌肉內和皮下投予。腸胃外投予的合適裝置包含針頭(包括微針頭)注射器、無針頭注射器和輸注技術。
在另一實施例中,本發明之醫藥組成物亦可局部投予至皮膚或黏膜,亦即經皮膚或穿皮投予。在另一實施例中,亦可鼻內或藉由吸入投予本發明之醫藥組成物。在另一實施例中,可藉由直腸或陰道投予本發明之化合物。在另一實施例中,亦可將本發明之醫藥組成物直接投予至眼或耳。
本發明之醫藥組成物的劑量方案基於多種因素,包含患者的類型、年齡、體重、性別和醫療狀況;以及病情嚴重程度;投予途徑;以及所用特定化合物之活性。因此,劑量方案變化範圍很大。在一實施例中,化合物用於治療本文所述之病症的每日總劑量通常自約0.01至約100 mg/kg (亦即,每kg體重之本發明化合物mg)。在另一實施例中,化合物的每日總劑量是從約0.1至約50 mg/kg,以及在另一實施例中,從約0.5至約30 mg/kg。
關於口服投予,依症狀調整劑量,可用含有0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、75.0、100、125、150、175、200、250和500毫克活性成分的片劑形式提供組成物給患者。藥物通常包含約0.01 mg至約500 mg的活性成分,或在另一實施例中,包含約1 mg至約100 mg的活性成分。在恆定速率輸注期間,靜脈內劑量範圍可為約0.01至約10 mg/ kg/分鐘。
根據本發明之合適的受試者包含哺乳動物個體。根據本發明之哺乳動物包含犬、貓、牛、山羊、馬、綿羊、豬、囓齒動物、兔形動物、靈長類動物等,並且包括子宮內的哺乳動物。在一實施例中,人是合適的個體。人類個體可為任何性別,也可以是處於發展的任何階段。
在另一實施例中,本發明包括含有化合物與醫藥上可接受的載體之醫藥組成物。亦可存在其他醫藥上的活性物質。如本文所使用,「醫藥上可接受的載體」包含任何和所有溶劑、分散媒介、塗覆、抗細菌和抗真菌劑、等張和吸收延遲劑、以及生理上可相容的類似物。醫藥上可接受的載體之實例包含水、鹽水、磷酸鹽緩衝鹽水、右旋糖、甘油、乙醇等,及其組合中的一種或多種,並且可包含等張劑,例如糖、氯化鈉或多元醇(例如甘露醇或山梨糖醇)於組成物中。藥學上可接受的物質(例如潤濕劑)或少量輔助物質(例如潤濕劑或乳化劑、防腐劑或緩衝液),其延長抗體或抗體部分的保質期或有效性。
本發明之組成物可為多種形式。這些包含例如液體、半固體和固體劑量形式,例如液體溶液(例如可注射的和可輸注的溶液)、分散液或懸浮液、片劑、丸劑、粉末、脂質體和栓劑。形式取決於預期的投予模式和治療應用。
典型的組成物為可注射或可輸注溶液的形式,例如類似於通常用於以抗體被動免疫人的那些組成物。一種投予模式是腸胃外投予(例如靜脈內、皮下、腹膜內或肌肉內)。在另一實施例中,藉由靜脈內輸注或是注射而投予抗體。在另一實施例中,藉由肌肉內或是皮下注射而投予抗體。
固體劑量形式的口服投予可為例如以離散單位存在,例如硬膠囊或軟膠囊、丸劑、扁囊劑、錠劑或片劑,每個均含有預定量的至少一種本文所述之化合物。在另一實施例中,口服投予可為粉末或是顆粒形式。在另一實施中,口服劑量形式為舌下的,例如口含錠(lozenge)。在此固體劑量形式中,結晶化合物通常與一種或多種佐劑結合。此膠囊或片劑可含有控制釋放製劑。在膠囊、片劑與丸劑的情況下,劑量形式一可包括緩衝劑或是可用腸溶衣製備。
在另一實施例中,口服投予可為液體劑量形式。用於口服投予的液體劑量形式包含例如醫藥上可接受的乳液、溶液、懸浮液、糖漿和含有該技術中常用的惰性稀釋劑(例如水)之酏劑(elixir)。此組成物亦可包括佐劑,例如潤濕劑、乳化劑、懸浮劑、調味劑(例如甜味劑)和/或加香劑。
在另一實施例中,本發明包括腸胃外投予的劑量形式。「腸胃外投予」包含例如皮下注射、靜脈內注射、腹膜內、肌肉內注射、胸骨內注射和輸注。可根據已知技術使用合適的分散劑、濕潤劑和/或懸浮劑調配可注射的製備劑(亦即無菌注射用水或油性懸浮液)。
在另一實施例中,本發明包括局部劑量形式。「局部投予」包含例如穿皮投予,例如經由透皮貼劑或離子電滲法裝置、眼內投予或鼻內或吸入投予。局部投予的組成物亦包含例如局部凝膠、噴劑、軟膏和乳霜。局部製劑可包含結晶化合物,其促進活性成分經由皮膚或其他受影響區域的吸收或滲透。當本發明的結晶化合物藉由穿皮裝置而投予時,將使用儲庫和多孔膜類型或固體基質種類的貼劑來完成投予。用於此目的之典型製劑包含凝膠、水膠、洗劑、溶液、乳霜、軟膏、粉劑、敷料、泡沫、薄膜、皮膚貼劑、糯米紙(wafer)、植入物、海綿、纖維、繃帶和微乳化劑。亦可使用脂質體。典型的載體包含醇、水、礦物油、液體凡士林、白凡士林、甘油、聚乙二醇和丙二醇。可併入滲透促進劑,參閱例如B. C. Finnin and T. M. Morgan, J. Pharm. Sci., vol. 88, pp. 955-958, 1999。
據此,可使用這樣的製備劑,包括所有習知橫跨體表和包含上皮和黏膜組織在內的身體通道內層的投予方法,包含經皮、表皮、頰、肺、眼、鼻內、陰道和直腸投予模式,投予根據本發明之方法的從N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶或非結晶型所製備的局部製劑。典型的載體包含醇、水、礦物油、液體凡士林、白凡士林、甘油、聚乙二醇和丙二醇。可與其他藥學上可接受的賦形劑組合製備這樣的局部製劑。對於臨床療效所必須的賦形劑是一種或多種滲透促進劑,例如一種或多種飽和或順式不飽和的C10-C18脂肪醇。這些脂肪醇包含C16-C18脂肪醇,以及最佳為C18脂肪醇。順式不飽和C16-C18脂肪醇的實例包含油醇、亞油醇、γ-次亞麻醇(γ-linolenyl alcohol)和次亞麻醇(linolenyl alcohol)。可用作為滲透促進劑的飽和的C10-C18脂肪醇包含癸醇、月桂醇、肉荳蔻醇(myristyl alcohol)、鯨蠟醇(cetyl alcohol)和硬脂醇。或者,可用於製備局部製劑的其他滲透促進劑包含C10-C18脂肪酸,當其飽和時,可包含癸酸、月桂酸、肉荳蔻酸、棕櫚酸、硬脂酸和花生酸。或者,滲透促進劑可有用地是順式不飽和脂肪酸,例如棕櫚油酸(順-9-十六碳烯酸)、油酸(順-9-十八碳烯酸)、順-十八烯酸(順-11-十八烯酸)、亞麻油酸(順-9,12-十八碳二烯酸)、γ-次亞麻油酸(順-6,9,12-十八碳三烯酸)、次亞麻油酸(順-9,12,15-十八碳三烯酸)、以及花生油酸(順-5,8,11,14-二十碳四烯酸)。滲透促進劑,例如選自C10-C18脂肪醇的一種,以約0.1至約5%(w/v),較佳為1至約4%,更佳為1至約3%(w/v)範圍的量使用。
局部製劑含有治療有效量的N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺,其可每日一次或兩次投予至有需要的患者。這些量的範圍從約0.1%至約5.0% (w/v),更佳為從 0.1%至約3.0% (w/v)。促進這些製劑穩定性的其他賦形劑包含醛清除劑(如甘油和丙二醇)以及抗氧化劑,例如丁基羥基甲氧苯(butyl hydroxyanisole,BHA)、二丁基羥基甲苯(butyl hydroxytoluene,BHT)、沒食子酸丙酯、抗壞血酸(維生素C)、多酚、生育酚(維生素E)及其衍生物。
適合局部投予至眼的製劑包含例如眼藥水,其中本發明之化合物溶解或懸浮在合適的載體中。適合用於眼或耳部投予的典型製劑可為在等張的、經pH調節的無菌鹽水中的微粉化懸浮液或溶液的滴劑形式。適合用於眼或耳部投予的其他製劑包含軟膏、生物可降解的(亦即可吸收的凝膠海綿、膠原蛋白)和非生物可降解的(亦即聚矽氧)植入物、糯米紙(wafer)、透鏡和顆粒或泡狀(vesicular)系統,例如類脂囊泡(niosome)或脂質體。可將諸如交聯的聚丙烯酸、聚乙烯醇、透明質酸的聚合物,例如羥基丙基甲基纖維素、羥基乙基纖維素或甲基纖維素的纖維素聚合物、或例如多醣膠的雜多醣聚合物與防腐劑(例如苯扎氯銨)合併在一起。這樣的製劑亦可藉由離子電滲法(iontophoresis)遞送。
關於鼻內投予或藉由吸入投予,本發明之結晶化合物以溶液或懸浮液的形式由患者擠壓或泵送的泵噴霧容器中方便地遞送,或使用合適的推進劑從加壓容器或霧化器中以氣溶膠噴霧劑呈現。適用於鼻內投予的製劑通常以來自乾粉吸入器的乾粉形式(單獨使用,或例如與乳糖進行乾混的混合物,或者作為例如與磷脂(例如磷脂醯膽鹼)混合使用之混合成分顆粒)或來自加壓容器、泵、噴霧器、原子化器(atomizer)(較佳為使用電動流體力學產生細霧的原子化器)或霧化器的氣溶膠噴霧劑形式投予,可使用或不使用合適的推進劑,例如1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷。關於鼻內使用,粉末可包括生物黏著劑,例如幾丁聚醣或環糊精。
在另一實施例中,本發明包括從根據本發明之N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶或非結晶型所製備的直腸劑型。此直腸劑型可為例如栓劑的形式。可可脂是傳統的栓劑基料,但可酌情使用各種替代品。
亦可使用醫藥領域已知的其他載體材料和投予模式。本發明的醫藥組成物可藉由任何眾所周知的藥學技術來製備,例如有效的製劑和投予程序。關於有效製劑和投予程序的上述考量是本領域眾所周知的,並且描述於標準教科書中。例如,Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975;Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980;以及Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999中討論藥物的製劑。
根據本發明之方法的N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶或非結晶型可被單獨使用,或是與其他治療劑組合使用。本發明提供本文所定義之任何用途、方法或組成物,其中本文的結晶或非結晶型或該化合物之醫藥上可接受的溶劑化物與本文所述的一種或多種其他治療劑組合使用。
兩種或多種化合物的「組合」投予是指所有化合物的投予時間都足夠緊密,以至於一種化合物的存在會改變任何其他化合物的生物學作用。可同時、並行或依序投予二種或多種化合物。此外,可藉由在投予前混合化合物或在相同的時間點以分開的劑型在相同或不同的投予部位來進行同時投予。
用語「並行投予」、「共同投予」、「同時投予」和「同時地投予」是指組合投予化合物。
在另一實施例,本發明提供治療的方法,其包含投予根據本發明之方法的N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶或非結晶型組合一種或多種其他的治療劑,其中該一種或多種其他的治療劑可選自本文所述之藥劑。
這些藥劑和根據本發明之方法的N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶或非結晶型可與醫藥上可接受的載體(例如鹽水、林格氏溶液、右旋糖溶液等)組合。特定的劑量方案(亦即劑量、時間和重複)將取決於特定個體以及該個體的病史。
可接受的載體、賦形劑或穩定劑在使用的劑量和濃度下對接受者無毒,並且可包括緩衝液(例如磷酸鹽、檸檬酸鹽和其他有機酸);鹽(例如氯化鈉);抗氧化劑(包含抗壞血酸和甲硫胺酸);防腐劑(例如十八烷基二甲基苄基氯化銨;氯化六烴季銨(hexamethonium chloride);苯扎氯銨(benzalkonium chloride)、氯化苯索寧(benzethonium chloride);苯酚、丁醇或苯甲醇;對羥基苯甲酸烷酯(例如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯);兒茶酚;間苯二酚;環己醇;3-戊醇;以及間甲酚);低分子量(小於約10個殘基)多肽;蛋白質(例如血清白蛋白、明膠或Ig);親水性聚合物(例如聚乙烯吡咯烷酮);胺基酸(例如甘胺酸、麩醯胺酸、天冬醯胺、組胺酸、精胺酸或離胺酸);單醣、二醣和其他碳水化合物(包含葡萄糖、甘露糖或糊精);螯合劑(例如EDTA);糖(例如蔗糖、甘露醇、海藻糖或山梨糖醇);成鹽的抗衡離子(例如鈉);金屬錯合物(例如Zn-蛋白質錯合物);以及/或非離子性界面活性劑(例如TWEENTM
、PLURONICSTM
或聚乙二醇(PEG)。
藉由本技藝已知的方法(例如美國專利第4,485,045號和第4,544,545號所述之方法)製備含有這些試劑和/或本發明之化合物的脂質體。美國專利第5,013,556號揭露具有延長循環時間的脂質體。可藉由反相蒸發法用包括卵磷脂、膽固醇和PEG-衍生的磷脂醯乙醇胺(PEG-derivatized phosphatidylethanolamine,PEG-PE)的脂質組成物產生特別有用的脂質體。經由具有定義的孔徑之過濾器擠出脂質體,以產生具有所需直徑的脂質體。
根據本發明之方法的這些試劑和/或N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶或非結晶形式亦可包埋在例如藉由凝聚技術或藉由界面聚合作用製備的微膠囊中,例如,分別在膠體藥物遞送系統(例如脂質體、白蛋白微球、微乳劑、奈米顆粒和奈米膠囊)或大乳劑中的羥基甲基纖維素或明膠微膠囊和聚(甲基丙烯酸甲酯)微膠囊。這些技術亦揭露於Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing (2000)。
可使用緩釋製劑。緩釋製劑之合適的實例包含固體疏水性聚合物的半透性基質,其含有本發明之抗體/化合物,該基質是成形物體的形式,例如薄膜或微膠囊。緩釋基質的實例包含聚酯、水膠(例如聚(甲基丙烯酸2-羥基乙酯)、或聚(乙烯醇))、聚乳酸(美國專利第3,773,919號)、L-麩胺酸和7乙基-L-麩胺酸酯的共聚物、不可降解的乙烯乙酸乙烯酯、可降解的乳酸-乙醇酸共聚物(例如用於LUPRON DEPOTTM
的那些)(乳酸-乙醇酸共聚物和乙酸亮丙瑞林(leuprolide acetate)組成的可注射微球)、蔗糖乙酸酯異丁酸酯(sucrose acetate isobutyrate)、以及聚-D-(-)-3-羥基丁酸。
用於靜脈內投予的製劑必須是無菌的。這很容易藉由例如通過無菌濾膜的過濾而完成。通常將根據本發明之方法的N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶或非結晶型放置在具有無菌通道的容器中,例如,具有可被皮下注射針刺穿的塞子的靜脈內溶液袋或小瓶。
可使用可商購的脂肪乳液,例如IntralipidTM
、LiposynTM
、InfonutrolTM
、LipofundinTM
和LipiphysanTM
來製備合適的乳液。活性成分可溶解在預混合的乳液組合物中,或者可溶解在油(例如大豆油、紅花油、棉籽油、芝麻油、玉米油或杏仁油)以及與磷脂(例如,卵磷脂、大豆磷脂或大豆卵磷脂)和水混合形成的乳液中。應當理解,可添加其他成分,例如甘油或葡萄糖,以調節乳液的張力(tonicity)。合適的乳液通常將含有至多20%的油,例如5至20%。脂肪乳液可包括0.1至1.0 μm,特別是0.1至0.5 μm的脂肪滴,並且具有5.5至8.0的pH。
製備根據這些教示之本發明之方法的N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶或非結晶型所使用的試劑可以商購獲得或可藉由文獻中描述的標準程序製備。例如,可根據以下實例中所述之方法來製備本發明之結晶或非結晶型。
本發明的描述利用熟習本技術人士公知的各種縮寫,包含:
aq.:水性的
CH3
CN:乙腈
DCM:二氯甲烷
DMF:N,N-二甲基甲醯胺
DMSO:二甲基亞碸
EtOAc:乙酸乙酯
EtOH:乙醇
FT-IR:傅立葉轉換紅外線
HOAc:乙酸
MeOH:甲醇
PXRD:粉末X射線繞射
ss13
C NMR:固態13
C核磁共振
THF:四氫呋喃
TLC:薄層色層分析
實例
提出以下非限制性實施例僅用於說明本發明。熟習本技術人士將理解有許多未例示的等效形式和變異,但仍構成本教示的一部分。
實例
1
N-((1S,3S)-3-(
甲基
(7H-
吡咯并
[2,3-d]
嘧啶
-4-
基
)
胺基
)
環丁基
)
丙烷
-1-
磺醯胺晶型
I
的製備
根據美國專利第9,035,074號的實例2製備標題化合物。將粗物質以10倍體積(100mg/ml)的2:1EtOH/水加熱至80ºC(直至完全溶解),而後進行拋光過濾,緩慢冷卻直至產品結晶。過濾後,將材料在真空下於45-55℃乾燥。
實例
2
N-((1S,3S)-3-(
甲基
(7H-
吡咯并
[2,3-d]
嘧啶
-4-
基
)
胺基
)
環丁基
)
丙烷
-1-
磺醯胺的替代製備
3-
側氧基環丁烷
-1-
羧酸異丙酯
(A)
將市售的3-環丁酮羧酸(175 g)溶解在2-丙醇(1050 mL)中,並且加入對甲苯磺酸單水合物(11.85 g,4mol%)。將該溶液加熱至80℃並且攪拌19小時。藉由UPLCMS確認反應完成,並將反應冷卻。將反應濃縮至淺黃色油,並且用1000 mL的MTBE稀釋。用300 mL的飽和碳酸氫鈉洗滌並分離溶液。丟棄水層,並且用另外的200 mL的飽和碳酸氫鈉洗滌。分離各層,並且丟棄水層。MTBE層先用200 mL的鹽水乾燥,而後用硫酸鎂乾燥。而後將MTBE溶液濃縮成淡黃色油。1
H NMR (400 MHz, DMSO-d 6
) δ 4.95 (hept, J =6.3 Hz, 1H), 3.38-3.18 (m, 5H), 1.22 (d, J = 6.3 Hz, 6H)。
(1s,3s)-3-(
甲基胺基
)
環丁烷
-1-
羧酸異丙酯
(
游離鹼
)(B)
將甲胺水溶液(75 mL,40 wt%) 加入反應器中,而後加入由磷酸二氫鉀和磷酸氫二鉀組成的磷酸鹽緩衝液(700 mL,pH 7.2,100 mM)。藉由緩慢加入濃鹽酸而將溶液的pH調節至8.8。而後加入NADP+ (700 mg)、GDH (350 mg)和葡萄糖(150 g)。將IRED酶(50 mL的裂解物)加入反應器中。將3-側氧基環丁烷-1-羧酸異丙酯受質(100 g)用DMSO(25 mL)稀釋並且裝入。將反應溫熱至30℃,並使用pH探針和計量裝置(2N氫氧化鈉)將pH保持在7.5。藉由GC和UPLC分析監測反應。當確認反應完成時,將混合物經由Celite™ (50 g)過濾,並且用水(100 mL)洗滌Celite™濾餅。將水溶液加入到分液漏斗中,加入MTBE(500 mL)並且搖動。分離並丟棄MTBE層。而後用氫氧化鈉(50%水溶液)將水層鹼化至pH為12。而後加入MTBE(1 L),並且搖動漏斗。分離各相,收集MTBE並且放在一旁。用另外的MTBE (700 mL)再次萃取水層,並分離各層。丟棄水層,將MTBE溶液各自通過另外的Celite™(36.5 g)過濾。而後合併MTBE溶液,並且用無水硫酸鈉乾燥。1
H NMR (400 MHz, DMSO-d 6
) δ 4.86 (hept,J
= 6.3 Hz, 1H), 2.96 (tt,J
= 8.7, 7.0 Hz, 1H), 2.67 (tt,J
= 9.7, 8.1 Hz, 1H), 2.41 - 2.26 (m, 2H), 2.15 (s, 3H), 1.78 (dtd,J
= 9.8, 8.8, 2.6 Hz, 2H), 1.17 (d,J
= 6.2 Hz, 6H)。
(1s,3s)-3-(
甲基胺基
)
環丁烷
-1-
羧酸異丙酯
(
琥珀酸鹽
)(B
琥珀酸鹽
)
將粗生物催化反應(1125 mL)濃縮至約一半體積(530 mL)。在一個個別的反應器中裝入琥珀酸(75.6 g)和2MeTHF (1100 mL),並且加熱至60℃以溶解酸。將溶液冷卻至50℃,並且加入約一半的胺溶液。將所得渾濁溶液保持30分鐘,為稀漿液。而後加入其餘的胺溶液。將溶液冷卻至20ºC,而後加溫至50ºC,形成漿液。將漿液在50ºC保持30分鐘,而後冷卻至20 ºC並且攪拌過夜。將漿液過濾並用兩份2-MeTHF(各100 mL)洗滌,並且將材料在烘箱中乾燥。分離出95.7g (52%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ 4.88 (hept,J
= 6.2 Hz, 1H), 3.30 (tt,J
= 8.8, 7.3 Hz, 1H), 2.82 (tt,J
= 9.8, 8.2 Hz, 1H), 2.43 - 2.34 (m, 2H), 2.31 (d,J
= 2.5 Hz, 7H), 2.13 - 2.00 (m, 2H), 1.18 (d,J
= 6.3 Hz, 6H)。
(1s,3s)-3-(
甲基胺基
)
環丁烷
-1-
羧酸異丙酯
(B HCl
鹽
)
將粗胺(8 g)溶解在MTBE(80 mL)中,並且加熱至50℃。而後加入二㗁烷中的鹽酸(11 mL,4M)。觀察到可攪拌的漿液,並且將反應在50℃保持1小時。將漿液冷卻至20℃,而後過濾並用兩份MTBE(各20 mL)洗滌。而後將材料在真空下乾燥。分離出8.7g (96%產率)。1
H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 2H), 4.89 (hept, J = 6.3 Hz, 1H), 3.52 (tt, J = 9.0, 7.5 Hz, 1H), 2.92 (tt, J = 9.8, 8.2 Hz, 1H), 2.45 - 2.35 (m, 5H), 2.34 - 2.24 (m, 2H), 1.18 (d, J = 6.3 Hz, 6H)。
(1s,3s)-3-(
甲基
(7H-
吡咯并
[2,3-d]
嘧啶
-4-
基
)
胺基
)
環丁烷
-1-
羧酸異丙酯
(C
;
CSNAr)
在反應器中合併胺的琥珀酸鹽(B琥珀酸鹽,75.4g)和氯吡咯并嘧啶(40.0 g)。加入2-丙醇(200 mL),得到漿液。加入二異丙基乙胺(114 mL),得到稀漿液。將反應加熱至80ºC,形成溶液。將反應保持在80℃,直到藉由UPLCMS確認反應完成(約48小時)。將反應冷卻至20℃並且變成漿液。過濾固體,並且用兩份2-丙醇(各80 mL)洗滌。分離出61克材料(81%)。1
H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.11 (s, 1H), 7.16 (dd, J = 3.6, 2.4 Hz, 1H), 6.62 (dd, J = 3.6, 1.9 Hz, 1H), 5.24 (tt, J = 9.4, 8.0 Hz, 1H), 4.91 (hept, J = 6.3 Hz, 1H), 3.25 (s, 3H), 2.87 (tt, J = 9.2, 8.0 Hz, 1H), 2.48 - 2.35 (m, 4H), 1.20 (d, J = 6.3 Hz, 6H)。
(1s,3s)-N- 羥基 -3-( 甲基 (7H- 吡咯并 [2,3-d] 嘧啶 -4- 基 ) 胺基 ) 環丁烷 -1- 羧醯胺 (D ;異羥肟醯胺 (hydroxamic amide))
在氮氣下向反應器中加入甲醇(500 mL)和甲醇鈉(sodium methoxide)的甲醇溶液(93.7mL,25質量%)。將鹽酸羥胺(15.1 g)加入到室溫反應中,造成輕微的吸熱。而後加入(1s,3s)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁烷-1-羧酸異丙酯(C;50 g),形成白色漿液。將反應溫熱至40℃,攪拌過夜,藉由UPLCMS確認反應完成。而後將稠漿加入鹽酸(1M)直至達到pH為7.0。而後將漿液過濾並且用甲醇(100 mL)沖洗。將材料在真空烘箱中乾燥過夜,得到42.7 g白色固體(94%產率)。1
H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 10.46 (s, 1H), 8.75 (s, 1H), 8.10 (s, 1H), 7.15 (dd, J = 3.6, 1.9 Hz, 1H), 6.61 (dd, J = 3.7, 1.4 Hz, 1H), 5.21 (p, J = 9.6 Hz, 1H), 3.28 (s, 3H), 2.60 (p, J = 8.3 Hz, 1H), 2.49 - 2.37 (m, 2H), 2.35 - 2.26 (m, 2H)。
(1s,3s)-N1-
甲基
-N1-(7H-
吡咯并
[2,3-d]
嘧啶
-4-
基
)
環丁烷
-1,3-
二胺
(E
;磷酸鹽
)
將異羥肟醯胺D (19.4 g)加入反應器中,而後加入2-MeTHF (388 mL),得到白色漿液。將漿液溫熱至30℃,並且加入羰基二咪唑(16.1 g)。將反應攪拌過夜。藉由UPLCMS確認反應完成。製備用水(78 mL)稀釋之磷酸溶液(14.7 M,在水中,25.5 mL),並且緩慢加至漿液。漿液溶解,將反應加熱至60℃並且保持數小時。反應經確認完成,加入氫氧化鈉(20質量%,在水中,16.4 m),以得到pH約為6。而後將反應溫熱至80℃,而後冷卻至25℃。緩慢加入2-丙醇(58 mL),並且過濾固體。濾餅用2-丙醇/水(1∶1,40 mL)洗滌,並在真空烘箱中乾燥,得到19.1 g(81%產率)。1
H NMR (600 MHz, 氧化氘, 35 ℃) δ 8.08 (s, 1H), 7.20 (d,J
= 3.6 Hz, 1H), 6.66 (d,J
= 3.6 Hz, 1H), 4.81 (tt,J
= 9.6, 7.4 Hz, 1H), 3.67 (tt,J
= 8.9, 7.3 Hz, 1H), 3.28 (s, 3H), 2.96 - 2.73 (m, 2H), 2.47 (qd,J
= 9.4, 2.9 Hz, 2H)。31
P NMR (243 MHz, 氧化氘, 35C) δ 0.31。
(1s,3s)-N1
-
甲基
-N1
-(7H-
吡咯并
[2,3-d]
嘧啶
-4-
基
)
環丁烷
-1,3-
二胺
(
游離胺
)
將胺基磷酸鹽(Amino phosphate) E(10 g)溶解於H2
O(30 mL)中。加入鹽酸(6N)直至pH為2,得到澄清溶液。用氫氧化鈉(50wt%)將pH升至12,得到濃稠的懸浮液。使用反相色層分析法(10:90 CH3
CN:H2
O 2CV,梯度至40:60 CH3
CN:H2
O,於4CV)純化漿液。收集適當的部分、合併、並且真空濃縮,得到胺游離鹼E,為白色固體(6.05 g,88%產率)。1
H NMR (400 MHz, 氧化氘) δ 7.78 (s, 1H), 6.91 (d,J
= 3.6 Hz, 1H), 6.24 (d,J
= 3.6 Hz, 1H), 4.25 (ddd,J
= 9.7, 7.4, 2.3 Hz, 1H), 3.08 (td,J
= 7.9, 7.1, 1.8 Hz, 1H), 2.95 (s, 3H), 2.58 - 2.39 (m, 2H), 1.86 (dd,J
= 9.4, 2.8 Hz, 2H)。
1-(
丙磺醯基
)-1H-1,2,4-
三唑
(
三唑試劑
)
將1,2,4-三唑(11.98 g)和THF(40 mL)裝入配備有塔頂攪拌器的反應器中。將懸浮液攪拌10分鐘,而後在20℃下加入1-丙磺醯氯(7.89 mL,68.0 mmol)。將所得漿液在20℃下攪拌直至藉由1
H NMR判斷原料被消耗。一旦完成,將反應過濾,並將濾液轉移至分液漏斗,在其中用水(20 mL)稀釋,並且用二氯甲烷(50 mL)萃取。分離各層,並且用水(2×20 mL)和鹽水(1×20 mL)洗滌DCM層。有機層用MgSO4
乾燥、過濾、並且真空濃縮,得到磺醯基三唑,為黏稠的透明無色油(10.66 g,89%產率)。1
H NMR (400 MHz, 氯仿-d
) δ 8.67 (s, 1H), 8.13 (s, 1H), 3.55 - 3.46 (m, 2H), 1.76 (h,J
= 7.5 Hz, 2H), 1.03 (t,J
= 7.5 Hz, 3H)。
實例
3
N-((1S,3S)-3-(
甲基
(7H-
吡咯并
[2,3-d]
嘧啶
-4-
基
)-
胺基
)
環丁基
)
丙烷
-1-
磺醯胺的替代製備
使用三唑試劑
1-(
丙磺醯基
)-1H-1,2,4-
三唑進行磺醯化
將水(18 mL)和胺磷酸鹽E(3g)加入反應器中,而後將氫氧化鈉水溶液(19M,1.5 mL)加入。反應稍微放熱,並且冷卻至25℃。將1-(丙磺醯基)-1H-1,2,4-三唑(4.3 g)溶解在THF(12 mL)中,並且加入至氫氧化物反應中。一旦確認反應完成,加入水(18 mL),將材料過濾並乾燥。獲得2.57 g (84%產率)。
原位
(In-situ
)
製備試劑
在20℃,將1,2,4-三唑的鋰鹽(1.0 g)和THF(8 mL)裝入反應器中。而後加入1-丙磺醯氯(1.47 mL)。將漿料在20℃下攪拌直至藉由H NMR判斷磺醯氯已被消耗。在另一個燒瓶中,將胺基磷酸鹽(2.0 g)在20℃溶於H2
O(12 mL),而後加入氫氧化鈉(1.0 mL,50wt%),保持溫度低於30℃。將水溶液冷卻至10℃,而後添加1-丙烷磺醯基-三唑試劑的THF溶液,保持溫度低於20℃。攪拌所得懸浮液直至根據UPCLMS保留<5%的胺,而後加入氫氧化鈉(0.67mL,50wt%),並且將反應加熱至50℃。一旦磺醯基三唑試劑被消耗後(藉UPLC),將反應冷卻至20℃,並使用鹽酸(6N)將pH調節至5-6。將所得的漿液冷卻至10℃且保持30分鐘並且過濾。用75:25 H2
O:THF (10 mL)沖洗濾餅,並在50℃將固體於真空烘箱中乾燥,得到期望的產物,為灰白色固體。
使用
1-
丙烷磺醯氯進行磺醯化
將胺磷酸鹽E(3.07 g)加入反應器,而後加入水(18 mL)。而後將氫氧化鈉(2.9 mL,10M)加入漿液中,並在室溫攪拌混合物。加入2-MeTHF (12 mL),並且將混合物冷卻至10℃。加入1-丙磺醯氯(1.6 mL),導致放熱。監測反應並且確認反應完成。而後加入水(18 mL),並且在10℃漿液製粒。將漿液過濾、用水(5 mL)洗滌、並且在真空下乾燥。分離出3.0 g淡黃色固體(96%產率)。
實例
4
向20 mL Schlenk管中加入胺基-醯胺鹽酸鹽(500 mg,3.04 mmol,1.0當量)和異丙醇(4 mL),然後加入氯-吡咯并嘧啶(1.03g,3.34 mmol,1.1當量)和DBU(0.97 g,6.38 mmol,2.1當量)。將所得的混合物加熱至85℃,並且攪拌直至由UPLC確認完成反應。一旦完成,將混合物冷卻至40℃,此時加水(20 mL),得到透明溶液。持續冷卻至20℃,造成反應沉澱出固體。過濾固體,並且用H2
O (30 mL)沖洗濾餅。藉由反相色層分析法(梯度4:6 MeOH:H2
O至100% MeOH,20 CV)純化粗固體(1.18 g)。合併所需的部分,並且真空除去甲醇,造成固體沉澱。過濾固體,用H2
O (10 mL)沖洗,並且在50℃於真空烘箱中乾燥,得到期望的SN
Ar產物,為白色固體(686 mg,57%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ 8.24 (s, 1H), 7.97 (d,J
= 8.4 Hz, 2H), 7.63 (d,J
= 4.1 Hz, 1H), 7.43 (d,J
= 8.6 Hz, 2H), 7.31 (s, 1H), 6.96 (d,J
= 4.1 Hz, 1H), 6.82 (s, 1H), 5.07 (p,J
= 8.6 Hz, 1H), 3.22 (s, 3H), 2.70 (p,J
= 8.6 Hz, 1H), 2.40 - 2.26 (m, 7H)。13
C NMR (101 MHz, DMSO-d 6
) δ 175.6, 157.1, 152.8, 151.7, 146.2, 134.9, 130.4, 128.2, 122.0, 106.9, 104.8, 47.3, 32.2, 31.7, 31.0, 21.6。
將氯吡咯并嘧啶(10.0 g)和胺基-醯胺草酸鹽(18.7 g)加入反應器中。加入IPA (100 mL),並且攪拌漿液。加入DBU (39 mL),並且將混合物加熱至80℃。一旦確認反應完成,加入水和氫氧化鈉,並且在80℃攪拌反應直至其變成稠漿液。加入IPA (60 mL),並且攪拌並過濾漿液。分離出26.39 g的酸-DBU加成物。在45℃,將10.0 g的DBU加成物溶於水(125 mL)。加入鹽酸(4mL,6M),並且將得到的沉澱物攪拌並過濾。用水(10 mL)洗滌固體。將固體乾燥(2.47g)。1
H NMR (400 MHz, DMSO-d 6
) δ 2.44 (d,J
= 8.8 Hz, 4H), 2.44 (d,J
= 8.8 Hz, 4H), 2.77-2.91 (m, 1H), 3.26 (s, 3H), 3.31-3.41 (m, 1H), 5.23 (t,J
= 8.7 Hz, 1H), 6.54-6.72 (m, 1H), 7.08-7.26 (m, 1H), 8.12 (s, 1H), 11.65 (br s, 1H), 12.13-12.43 (m, 1H)。
(1s,3s)-3-(
甲基
(7H-
吡咯並
[2,3-d]
嘧啶
-4-
基
)
胺基
)
環丁烷
-1-
羧酸甲酯的製備
將異丙酯:(1s,3s)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁烷-1-羧酸異丙酯(15.03g)加入具有甲醇(75 ml)的反應器並且在25℃攪拌。逐滴加入甲醇鈉(25質量%,在甲醇中,15 mL),攪拌反應直至藉由UPLCMS確認反應完成。過濾固體、用甲醇(20 mL)洗滌、並且在真空烘箱中乾燥,得到11.27 g白色固體。1
H NMR (400 MHz, 氯仿-d
) δ 11.48 (s, 1H), 8.33 (s, 1H), 7.09 (d,J
= 3.6 Hz, 1H), 6.58 (d,J
= 3.6 Hz, 1H), 5.58 - 5.23 (m, 1H), 3.72 (s, 3H), 3.39 (s, 3H), 2.88 (dq,J
= 10.0, 8.1 Hz, 1H), 2.69 - 2.52 (m, 4H)。13
C NMR (101 MHz, CDCl3
) δ 175.36, 157.64, 152.11, 150.87, 120.46, 103.41, 102.02, 52.06, 47.38, 32.03, 31.80, 31.20。
實例
5
化合物
E
成鹽的一般程序:
實例
6
磺醯基三唑的製備:
在250 mL燒瓶中,加入水(75 mL)和1,2,4-三唑(37.24 g,1.7當量),攪拌直至溶解。一旦溶液均質,將其轉移到含有THF(400 mL),並配備有頂置攪拌器的2 L容器中。將溶液溫熱至35℃,而後加入無水LiOH粉末(13.18 g,1.7當量)。將所得的懸浮液攪拌30分鐘,或直至所有固體溶解。一旦均質,緩慢加入1-丙烷磺醯氯(58.84 mL,1.6當量),保持內部溫度低於40℃。加完之後,繼續在35℃下攪拌溶液30分鐘,而後冷卻至0℃並保持直至胺磷酸鹽E的游離鹼完成。
由磷酸鹽
E
形成游離鹼
E
:
在配備有頂置攪拌器的1L容器中,加入水(300 mL)和THF (200 mL),而後加入11.5M KOH水溶液(82.75 mL,3.0當量)並且溫熱至25℃。分5批加入胺磷酸鹽E(100 g,1.0當量),並繼續攪拌直至所有固體溶解。停止攪拌並讓各相分離。丟棄水相(底部)。 繼續攪拌有機相,同時冷卻至8℃。
主要程序:
將冷卻的胺(游離鹼)溶液加入磺醯基三唑溶液中,保持內部溫度低於10℃。如有必要,用最少量的THF沖洗含胺容器。一旦轉移完成,以1℃/min的速度將所得的溶液溫熱至20℃。攪拌90分鐘,然後加入11.5 M KOH水溶液(13.8 mL,0.5當量)。持續攪拌直到剩餘<5%的胺E。當完成時,加水(1.14 L),而後加入11.5M KOH水溶液(110.3 mL,4當量)。將混合物加熱至40℃,保持4小時,而後冷卻至10℃。一旦冷卻,開始真空蒸餾(100 mbar),緩慢升溫至內部溫度45-50℃,此時最終溶液體積在1.65-1.70 L之間,表示蒸餾完成。將混合物冷卻至40℃,而後添加濃HCl (149 mL,5.7當量),目標pH值在2.0-3.0之間,內部溫度保持在40-45℃之間。將混合物溫熱至65℃,保持15分鐘,而後以0.5℃/min的速度冷卻至53℃。一旦達成,加入N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)-環丁基)丙烷-1-磺醯胺HCl晶種(500 mg,0.005 g/g)。冷卻至50℃並且攪拌30分鐘,而後以0.1℃/min的速度冷卻至10℃。在10℃攪拌1小時,而後經由600 mL粗燒結Buchner漏斗過濾。用冷卻至10℃(200 mL)的H2
O沖洗濾餅。將漏斗上的固體乾燥,以Karl Fisher滴定法使最終水含量為9.5%。1
H NMR (400 MHz, DMSO-d 6
) δ 12.81 (s, 1H), 8.34 (s, 1H), 7.64 (d,J
= 9.3 Hz, 1H), 7.52 - 7.43 (m, 1H), 7.00 (dd,J
= 3.7, 1.8 Hz, 1H), 4.75 (t,J
= 8.3 Hz, 1H), 3.63 (h,J
= 8.4 Hz, 1H), 3.00 - 2.90 (m, 2H), 2.73 (dtd,J
= 10.0, 7.4, 2.9 Hz, 2H), 2.35 (qd,J
= 9.1, 2.7 Hz, 2H), 1.68 (h,J
= 7.5 Hz, 2H), 0.98 (t,J
= 7.4 Hz, 3H)。13
C NMR (101 MHz, DMSO-d 6
) δ 152.2, 146.3, 143.2, 124.5, 105.0, 102.2, 54.2, 47.2, 41.3, 36.6, 34.0, 17.3, 13.2。
N-((1S,3S)-3-(
甲基
(7H-
吡咯并
[2,3-d]
嘧啶
-4-
基
)
胺基
)
環丁基
)
丙烷
-1-
磺醯胺
將N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺HCl (8 g)加入反應器中,而後加入異丙醇(56 mL)和水(20 mL)。將混合物加熱至60℃。製備碳酸氫鉀(2.4 g)的水(8 mL)溶液並將其添加至加熱的混合物中。將混合物加熱至80℃,而後冷卻至65℃。加入標題化合物的晶種(70 mg)。而後將反應器冷卻至20℃,而後研磨。將該材料真空過濾,並用2/1異丙醇/水洗滌兩次(每次14 mL)。將濾餅在真空下乾燥,得到6.09 g(87%產率)的標題化合物。1
H NMR (400 MHz, DMSO-d 6
) δ 11.65 (s, 1H), 8.13 (s, 1H), 7.50 (d,J
= 9.2 Hz, 1H), 7.15 (dd,J
= 3.6, 1.6 Hz, 1H), 6.63 (d,J
= 3.5 Hz, 1H), 4.91 (tt,J
= 9.6, 7.4 Hz, 1H), 3.70 - 3.47 (m, 1H), 3.26 (s, 3H), 3.04 - 2.87 (m, 2H), 2.61 (ddd,J
= 11.7, 8.9, 5.2 Hz, 2H), 2.24 (dt,J
= 11.8, 9.1 Hz, 2H), 1.79 - 1.55 (m, 2H), 0.98 (t,J
= 7.4 Hz, 3H)。
實例
7
N-((1S,3S)-3-(
甲基
(7H-
吡咯并
[2,3-d]
嘧啶
-4-
基
)
胺基
)
環丁基
)
丙烷
-1-
磺醯胺之鹽的一般製備
將N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺溶解於丙酮、乙醇、異丙醇、水或其混合物中。加入一定量的酸(鹽酸、甲磺酸、對甲苯磺酸、富馬酸或硫酸),並對樣品進行溫度循環。分離出固體用於定性。
在不脫離本教示的精神和基本特徵的情況下,熟習本技術人士將想到本文所述之內容的變化、修改和其他實施方式。據此,本教示的範圍不是由前述之說明性描述來定義,而是由以下的申請專利範圍來定義,並且落入申請專利範圍的均等含義和範圍內之所有變化皆包含在其中。
在本說明書中描述或引用的每個印刷出版物,包括但不限於專利、專利申請案、書籍、技術論文、商業出版物和期刊文章,藉由全文引用並出於所有目的而併入本文。
[圖1]描述N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶型之粉末X射線繞射圖。
[圖2]描述N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶型之Raman圖譜。
[圖3]描述N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶型之FT-IR圖譜。
[圖4]描述N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺的結晶型之固態13
C核磁共振圖譜。旋轉的邊帶標有星號。
[圖5]描述N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺A型無水單HCl(mono HCl anhydrous)的結晶型之粉末X射線繞射圖。
[圖6]描述N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺B型單HCl單水合物的結晶型之粉末X射線繞射圖。
[圖7]描述N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺C型無水單HCl(mono HCl anhydrous)的結晶型之粉末X射線繞射圖。
[圖8]描述N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺E型單HCl二水合物(mono HCl dihydrate)的結晶型之粉末X射線繞射圖。
[圖9]描述N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺G型無水單HCl的結晶型之粉末X射線繞射圖。
[圖10]描述N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺半硫酸鹽的結晶型之粉末X射線繞射圖。
[圖11]描述N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺甲磺酸鹽的結晶型之粉末X射線繞射圖。
[圖12]描述N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺對甲苯磺酸鹽的結晶型之粉末X射線繞射圖。
[圖13]描述N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺半富馬酸共晶體的結晶型之粉末X射線繞射圖。
Claims (37)
- 如申請專利範圍第1項之化合物或其鹽,其中R1 是氫。
- 如申請專利範圍第4項之化合物,其中X和Y皆為N;以及R2 是(C3 -C5 )烷基。
- 如申請專利範圍第4項之化合物,其中R2 是直鏈或支鏈丙基。
- 如申請專利範圍第4項之化合物,其中R2 是直鏈丙基。
- 如申請專利範圍第4項之化合物,其中X是CR3 ,其中R3 是氫;以及Y是N。
- 如申請專利範圍第8項之化合物,其中R2 是直鏈或支鏈丙基。
- 如申請專利範圍第8項之化合物,其中R2 是直鏈丙基。
- 如申請專利第12項之磷酸鹽。
- 如申請專利範圍第16項之化合物,其是在合適的鹼性條件下從該化合物之該鹽酸鹽所製備。
- 如申請專利範圍第16項之化合物,其具有粉末X射線繞射圖,該粉末X射線繞射圖包括以2θ計在13.0°、14.8°和23.3° 2θ ± 0.2° 2θ處的峰。
- 如申請專利範圍第19項之方法,其中該合適的鹼是碳酸氫鈉或碳酸氫鉀。
- 如申請專利範圍第21項之方法,其中X和Y皆為N。
- 如申請專利範圍第26項之方法,其中X和Y皆為N。
- 如申請專利範圍第31項之醫藥組成物,其包括選自乳膏、穿皮貼劑、軟膏、滴眼劑、洗劑和凝膠的局部製劑(topical formulation)。
- 如申請專利範圍第32項之醫藥組成物,其中該局部製劑含有從約0.1%至約5.0%(w/v)的N-((1S,3S)-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)環丁基)丙烷-1-磺醯胺。
- 一種如申請專利範圍第31-33項中任一項之醫藥組成物在製備用於局部治療哺乳動物中疾病的藥物之用途,其中該疾病是選自白斑病(vitiligo)、脫髮、牛皮癬和異位性皮膚炎(atopic dermatitis)所組成之群組。
- 如申請專利範圍第31-33項中任一項之醫藥組成物,其用作為藥物。
- 如申請專利範圍第31-33項中任一項之醫藥組成物,其用於治療選自由狼瘡(lupus)、類風濕性關節炎、IBD、潰瘍性結腸炎、克隆氏症(Crohn’s Disease)、白斑病、脫髮、牛皮癬和異位性皮膚炎所組成之群組的疾病。
- 一種如申請專利範圍第31-33項中任一項之醫藥組成物在製備用於治療選自由狼瘡、類風濕性關節炎、IBD、潰瘍性結腸炎、克隆氏症、白斑病、脫髮、牛皮癬和異位性皮膚炎所組成之群組的疾病之藥物的用途。
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