TW201943704A - 新穎化合物 - Google Patents
新穎化合物Info
- Publication number
- TW201943704A TW201943704A TW108114167A TW108114167A TW201943704A TW 201943704 A TW201943704 A TW 201943704A TW 108114167 A TW108114167 A TW 108114167A TW 108114167 A TW108114167 A TW 108114167A TW 201943704 A TW201943704 A TW 201943704A
- Authority
- TW
- Taiwan
- Prior art keywords
- salt
- disease
- hexahydro
- isopropyl
- pyrazole
- Prior art date
Links
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- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本發明係關於N-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H-吡唑-3-磺醯胺之鈉鹽及其水合物、溶劑合物及多晶型。本發明進一步係關於包含此化合物之醫藥組合物及此化合物在治療及預防醫學病症及疾病(最尤其藉由NLRP3抑制)中之用途。
Description
本發明係關於N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺之鈉鹽及其水合物、溶劑合物及多晶型。本發明進一步係關於包含此化合物之醫藥組合物及此化合物在治療及預防醫學病症及疾病(最尤其藉由NLRP3抑制)中之用途。
NOD樣受體(NLR)家族之含熱蛋白結構域之蛋白質3 (NLRP3)發炎體係發炎過程之組分，且其異常活性係遺傳病症(諸如隱熱蛋白相關週期性症候群(CAPS))及複雜疾病(諸如多發性硬化、2型糖尿病、阿茲海默氏病(Alzheimer’s disease)及動脈粥樣硬化)之致病機制。
NLRP3係感測多種病原體源、環境及宿主源因子之細胞內信號傳導分子。活化時，NLRP3結合至含有半胱天冬酶活化及募集結構域之細胞凋亡相關之斑點樣蛋白質(ASC)。接著ASC聚合以形成大的聚集物，稱為ASC斑點。聚合之ASC進而與半胱胺酸蛋白酶半胱天冬酶-1相互作用以形成複合物，稱作發炎體。此引起半胱天冬酶-1之活化，該半胱天冬酶-1裂解促炎性細胞介素IL-1β及IL-18之前體形式(分別稱作Pro-IL-1β及Pro-IL-18)以藉此使該等細胞介素活化。半胱天冬酶-1亦介導一種類型之發炎細胞死亡(稱為細胞焦亡)。ASC斑點亦可募集且活化半胱天冬酶-8，其可加工Pro-IL-1β及Pro-IL-18且觸發細胞凋亡性細胞死亡。
半胱天冬酶-1將Pro-IL-1β及Pro-IL-18裂解為其活性形式，該等活性形式係自細胞分泌。活性半胱天冬酶-1亦裂解gasdermin-D以觸發細胞焦亡。半胱天冬酶-1經由其對細胞焦亡性細胞死亡路徑之控制，亦介導警報素(alarmin)分子(諸如IL-33及高遷移率族蛋白1 (high mobility group box 1 protein，HMGB1))之釋放。半胱天冬酶-1亦裂解細胞內IL-1R2，從而引起其降解且容許IL-1α之釋放。在人類細胞中，半胱天冬酶-1亦可控制IL-37之加工及分泌。多種其他半胱天冬酶-1受質(諸如細胞骨架及醣解路徑之組分)可促進半胱天冬酶-1依賴性發炎。
NLRP3依賴性ASC斑點釋放至細胞外環境中，在此其可使半胱天冬酶-1活化，誘導半胱天冬酶-1受質之加工且傳播發炎。
源自NLRP3發炎體活化之活性細胞介素係發炎之重要驅動子，且與其他細胞介素路徑相互作用以形成對感染及損傷之免疫反應。舉例而言，IL-1β信號傳導誘導促發炎細胞介素IL-6及TNF之分泌。IL-1β及IL-18與IL-23協同作用以誘導在不存在T細胞受體接合下由記憶CD4 Th17細胞及γδ T細胞產生IL-17。IL-18及IL-12亦協同作用以誘導自驅動Th1反應之記憶T細胞及NK細胞產生IFN-γ。
遺傳CAPS疾病穆-韋二氏症候群(Muckle-Wells syndrome，MWS)、家族性寒冷自體發炎性症候群(FCAS)及新生兒發作型多系統發炎性疾病(NOMID)係由NLRP3之功能獲得型突變引起，由此將NLRP3定義為發炎過程之關鍵組分。NLRP3亦參與多種複雜疾病(尤其包括代謝病症，諸如2型糖尿病、動脈粥樣硬化、肥胖症及痛風)之致病機制。
NLRP3在中樞神經系統疾病中之作用正在顯現，且亦已顯示肺病受NLRP3影響。此外，NLRP3在肝病、腎病及衰老之發生中起作用。許多該等相關性係使用Nlrp3−/−
小鼠來定義，但亦瞭解該等疾病中NLRP3之特異性活化。在2型糖尿病(T2D)中，胰島類澱粉多肽在胰臟中之沈積使NLRP3及IL-1β信號傳導活化，從而導致細胞死亡及發炎。
若干種小分子已顯示抑制NLRP3發炎體。格列苯脲(glyburide)因應NLRP3而非NLRC4或NLRP1之活化以微莫耳濃度抑制IL-1β產生。其他先前經表徵之弱NLRP3抑制劑包括小白菊內酯(parthenolide)、3,4-亞甲基二氧基-β-硝基苯乙烯及二甲亞碸(DMSO)，但該等劑具有有限之功效且係非特異性的。
針對NLRP3有關疾病之當前治療包括靶向IL-1之生物劑。該等生物劑係重組IL-1受體拮抗劑阿那白滯素(anakinra)、中和IL-1β抗體卡那單抗(canakinumab)及可溶性誘餌IL-1受體利納西普(rilonacept)。已證明該等方法在CAPS之治療中係成功的，且該等生物劑已用於針對其他IL-1β相關疾病之臨床試驗中。
一些含二芳基磺醯脲之化合物已鑑別為細胞介素釋放抑制性藥物(CRID) (Perregaux等人；J. Pharmacol. Exp. Ther. 299, 187-197, 2001)。CRID係一類抑制IL-1β之轉譯後加工之含二芳基磺醯脲之化合物。IL-1β之轉譯後加工伴隨半胱天冬酶-1之活化及細胞死亡。CRID阻滯活化之單核球，從而使得半胱天冬酶-1保持無活性且質膜潛伏期得以保留。
亦揭示某些含磺醯脲之化合物為NLRP3之抑制劑(例如，參見Baldwin等人，J. Med. Chem., 59(5), 1691-1710, 2016；及WO 2016/131098 A1、WO 2017/129897 A1、WO 2017/140778 A1、WO 2017/184604 A1、WO 2017/184623 A1、WO 2017/184624 A1及WO 2018/015445 A1)。WO 2016/131098 A1揭示N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺。
業內需要提供具有改良之藥理學及/或生理及/或物理化學性質之化合物及/或提供已知化合物之有用替代物之彼等化合物。
本發明之第一態樣提供N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺之鈉鹽，或其水合物或溶劑合物。
本發明之第二態樣提供N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺之鈉鹽或其水合物或溶劑合物之多晶型。
在某些實施例中，第二態樣之多晶型係N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺單鈉鹽一水合物之多晶型物。此等多晶型物之實例包括本文中稱為形式1之多晶型物。
在某些實施例中，第二態樣之多晶型係N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺單鈉鹽無水物之多晶型物。此等多晶型物之實例包括本文中稱為形式2之多晶型物。
本發明之第三態樣提供用於製備N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺之鈉鹽之製程，其包含：
(a) 使N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺游離酸與鈉離子源在一或多種極性溶劑存在下接觸以形成混合物；及
(b) 自該混合物獲得N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺之固體鈉鹽。
(a) 使N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺游離酸與鈉離子源在一或多種極性溶劑存在下接觸以形成混合物；及
(b) 自該混合物獲得N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺之固體鈉鹽。
本發明之第四態樣提供醫藥組合物，其包含本發明之第一態樣之鹽、水合物或溶劑合物或本發明之第二態樣之多晶型以及醫藥學上可接受之賦形劑。
本發明之其他態樣提供治療或預防疾病、病症或病狀(最尤其藉由NLRP3抑制)之醫學用途及方法。
活性醫藥化合物之鹽形式之間的差異會對該化合物之固體形式之性質具有顯著效應。舉例而言，與非成鹽化合物及相同化合物之其他鹽形式相比，物質之固體形式之結晶度、溶解度、固有溶解速率、儲存下之穩定性及於水性介質中之穩定性會出現差異。本發明之鹽提供N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺之形式且特定而言鈉鹽，其具有優於其他鹽且優於游離酸自身之某些優點。
本發明之第一態樣提供N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺之鈉鹽，或其水合物或溶劑合物。N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺(亦稱為游離酸)具有下式：
。
。
本發明之第一態樣之鹽涵蓋具有游離酸對鈉離子之共軛鹼之任一比率之鹽，例如單鈉鹽、二鈉鹽及半鈉鹽。在一個實施例中，N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺之鈉鹽係單鈉鹽。
本發明之第一態樣之鹽可係無水的或呈水合物(例如半水合物、一水合物、二水合物或三水合物)或其他溶劑合物之形式。此等溶劑合物可利用常見有機溶劑形成，該等有機溶劑包括(但不限於)醇系溶劑，例如甲醇、乙醇或異丙醇。在一個實施例中，N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺之鈉鹽係一水合物或無水物。在一個實施例中，N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺之鈉鹽係一水合物。
本發明之第一態樣之鹽、水合物及溶劑合物可呈任何結晶型或非晶型，或可作為結晶型及非晶型之任何混合物存在。在其中本發明之第一態樣之鹽、水合物及/或溶劑合物係作為結晶型及非晶型之混合物存在之實施例中，鹽、水合物及/或溶劑合物可具有結晶度。如本文所用，結晶度係呈一或多種結晶型之本發明之第一態樣之鹽、水合物及/或溶劑合物之重量百分比，其表示為該鹽、水合物及/或溶劑合物之總重量之百分比。
本發明之第一態樣之鹽、水合物及溶劑合物較佳具有50%或更大(例如60%或更大、70%或更大、80%或更大、90%或更大、95%或更大或99%或更大)之結晶度。更佳地，本發明之第一態樣之鹽、水合物及溶劑合物係結晶的。如本文所用，若本發明之第一態樣之鹽、水合物及/或溶劑合物具有90%或更大(例如95%或更大或99%或更大)之結晶度，則其通常稱為結晶的。
在一個實施例中，N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺之鈉鹽係結晶的。在一個實施例中，N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺之鈉鹽係結晶的N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺單鈉鹽一水合物。
本發明之第一態樣之結晶鹽、水合物及/或溶劑合物可以一或多種多晶型存在。多型性係指固體物質以一或多種不同晶體結構存在之能力(亦即在晶格中相對於彼此具有一或多種不同之分子排列)。物質之不同多晶型物可具有不同物理性質，諸如溶解度、固有溶解速率及量熱行為(例如熔點)。不同的多晶型物亦可展現穩定性之差異(例如關於轉化成其他結晶型或非晶型之穩定性差異)。活性醫藥成分之物理性質可影響藥物產品安全性效能及性能。因此，有利的係鑑別原料藥中具有醫藥學上可接受之性質之多晶型。
因此，本發明之第二態樣提供N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺之鈉鹽或其水合物或溶劑合物之多晶型。
本發明之第一態樣之鹽、水合物及溶劑合物及本發明之第二態樣之多晶型可含有任何穩定同位素，包括(但不限於)12
C、13
C、1
H、2
H (D)、14
N、15
N、16
O、17
O、18
O、19
F及127
I，及任何放射性同位素，包括(但不限於)11
C、14
C、3
H (T)、13
N、15
O、18
F、123
I、124
I、125
I及131
I。
在某些實施例中，第二態樣之多晶型係N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺單鈉鹽一水合物之多晶型物。此等多晶型物之實例包括本文中稱為形式1之多晶型物。
形式1多晶型物可藉由包括X射線粉末繞射(XRPD)、差示掃描量熱法(DSC)及/或熱重分析(TGA)在內之技術來表徵。
如本文所用，XRPD數據通常係可在20℃下使用CuKα輻射獲得之彼等數據。如本文所用，術語「近似」或「大約」在結合XRPD峰之位置使用時通常係指所述位置±0.2 °2θ。
形式1多晶型物通常具有包含在大約以下各處之峰的XRPD光譜：4.3 °2θ、8.7 °2θ及20.6 °2θ。更通常地，形式1多晶型物具有包含在大約以下各處之峰的XRPD光譜：4.3 °2θ、7.3 °2θ、8.7 °2θ、16.5 °2θ及20.6 °2θ。仍更通常地，形式1多晶型物具有包含在大約以下各處之峰的XRPD光譜：4.3 °2θ、6.7 °2θ、7.3 °2θ、8.7 °2θ、15.8 °2θ、16.5 °2θ及20.6 °2θ。仍進一步通常地，形式1多晶型物具有包含在大約以下各處之峰的XRPD光譜：4.3 °2θ、6.7 °2θ、7.3 °2θ、8.7 °2θ、9.0 °2θ、15.8 °2θ、16.5 °2θ、18.0 °2θ及20.6 °2θ。
形式1多晶型物通常具有如下XRPD光譜：其中10個最強峰包括5個或更多個(例如6個或更多個、7個或更多個、8個或更多個、9個或更多個或10個)具有選自以下之近似2θ值之峰：4.3 °2θ、6.2 °2θ、6.7 °2θ、7.3 °2θ、8.7 °2θ、9.0 °2θ、12.1 °2θ、15.8 °2θ、16.5 °2θ、18.0 °2θ、18.1 °2θ、20.6 °2θ、21.6 °2θ及24.5 °2θ。更通常地，形式1多晶型物具有如下XRPD光譜：其中10個最強峰包括5個或更多個(例如6個或更多個、7個或更多個、8個或更多個、9個或更多個或10個)具有選自以下之近似2θ值之峰：4.3 °2θ、6.2 °2θ、6.7 °2θ、7.3 °2θ、8.7 °2θ、9.0 °2θ、12.1 °2θ、15.8 °2θ、16.5 °2θ、18.0 °2θ、20.6 °2θ及21.6 °2θ。仍更通常地，形式1多晶型物具有如下XRPD光譜：其中10個最強峰包括5個或更多個(例如6個或更多個、7個或更多個、8個或更多個、9個或更多個或10個)具有選自以下之近似2θ值之峰：4.3 °2θ、6.2 °2θ、6.7 °2θ、7.3 °2θ、8.7 °2θ、9.0 °2θ、15.8 °2θ、16.5 °2θ、18.0 °2θ及20.6 °2θ。
形式1多晶型物可具有大約如下表1中所列之XRPD光譜：
表 1
表 1
形式1多晶型物通常具有包含在20℃與100℃之間約4.6%至約5.0%之重量損失(例如約4.7%至約4.9%之重量損失或約4.8%之重量損失)之TGA曲線。
形式1多晶型物通常具有包含第一吸熱及第二吸熱之DSC曲線。形式1多晶型物之第一吸熱通常在約41℃至約45℃範圍內之溫度下(例如在約42℃至約44℃範圍內之溫度下或在約43℃之溫度下)開始。形式1多晶型物之第一吸熱通常在約72℃至約76℃範圍內之溫度下(例如在約73℃至約75℃範圍內之溫度下或在約74℃之溫度下)具有峰值。形式1多晶型物之第一吸熱通常具有約69 J/g至約73 J/g (例如約70 J/g至約72 J/g或約71 J/g)之焓變。形式1多晶型物之第二吸熱通常在約177℃至約181℃範圍內之溫度下(例如在約178℃至約180℃範圍內之溫度下或在約179℃之溫度下)開始。形式1多晶型物之第二吸熱通常在約188℃至約192℃範圍內之溫度下(例如在約189℃至約191℃範圍內之溫度下或在約190℃之溫度下)具有峰值。形式1多晶型物之第二吸熱通常具有約13 J/g至約17 J/g (例如約14 J/g至約16 J/g或約15 J/g)之焓變。
形式1多晶型物可藉由包含以下之製程來獲得：
(a) 使N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺游離酸與鈉離子源在水及視情況極性非質子有機溶劑存在下接觸以形成溶液；或將N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺單鈉鹽溶解於包含水及視情況極性非質子有機溶劑之溶劑混合物中以形成溶液；及
(b) 自該溶液獲得結晶的N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺單鈉鹽一水合物作為形式1多晶型物。
(a) 使N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺游離酸與鈉離子源在水及視情況極性非質子有機溶劑存在下接觸以形成溶液；或將N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺單鈉鹽溶解於包含水及視情況極性非質子有機溶劑之溶劑混合物中以形成溶液；及
(b) 自該溶液獲得結晶的N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺單鈉鹽一水合物作為形式1多晶型物。
在較佳實施例中，步驟(a)中所用之溶劑混合物包含水及極性非質子有機溶劑。在較佳實施例中，該極性非質子有機溶劑係丙酮。水對極性非質子有機溶劑之體積比通常為1:35至1:1 (例如1:20至1:1、或1:15至1:4、或1:13至1:6、或1:11至1:8或約1:9)。在較佳實施例中，將N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺游離酸用水及極性非質子有機溶劑之溶劑混合物處理，之後添加鈉離子源以形成溶液。
在較佳實施例中，在步驟(b)中，結晶的N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺單鈉鹽一水合物形式1多晶型物可藉由添加適宜反溶劑或藉由添加適宜反溶劑及添加晶種之組合自溶液獲得。較佳之反溶劑係二乙醚、二異丙醚及第三丁基甲醚。尤佳者係第三丁基甲醚。
獲得形式1多晶型物之其他較佳製程包括其中極性非質子有機溶劑、鈉離子源、獲得固體鈉鹽之方式及該製程之其他特徵係如本文關於本發明之第三態樣之製程所述之彼等製程。
在某些實施例中，第二態樣之多晶型係N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺單鈉鹽無水物之多晶型物。此等多晶型物之實例包括本文中稱為形式2之多晶型物。
形式2多晶型物通常具有包含在大約以下各處之峰的XRPD光譜：5.1 °2θ、21.7 °2θ及22.7 °2θ。更通常地，形式2多晶型物具有包含在大約以下各處之峰的XRPD光譜：5.1 °2θ、17.9 °2θ、18.7 °2θ、21.7 °2θ及22.7 °2θ。仍更通常地，形式2多晶型物具有包含在大約以下各處之峰的XRPD光譜：5.1 °2θ、17.1 °2θ、17.9 °2θ、18.7 °2θ、20.1 °2θ、21.7 °2θ及22.7 °2θ。仍進一步通常地，形式2多晶型物具有包含在大約以下各處之峰的XRPD光譜：5.1 °2θ、8.9 °2θ、17.1 °2θ、17.9 °2θ、18.7 °2θ、20.1 °2θ、20.6°2θ、21.7 °2θ及22.7 °2θ。
形式2多晶型物通常具有如下XRPD光譜：其中10個最強峰包括5個或更多個(例如6個或更多個、7個或更多個、8個或更多個、9個或更多個或10個)具有選自以下之近似2θ值之峰：5.1 °2θ、6.6 °2θ、7.7 °2θ、8.9 °2θ、9.3 °2θ、10.3 °2θ、16.2 °2θ、17.1 °2θ、17.9 °2θ、18.7 °2θ、20.1 °2θ、20.6°2θ、21.7 °2θ及22.7 °2θ。更通常地，形式2多晶型物具有如下XRPD光譜：其中10個最強峰包括5個或更多個(例如6個或更多個、7個或更多個、8個或更多個、9個或更多個或10個)具有選自以下之近似2θ值之峰：5.1 °2θ、6.6 °2θ、8.9 °2θ、10.3 °2θ、16.2 °2θ、17.1 °2θ、17.9 °2θ、18.7 °2θ、20.1 °2θ、20.6 °2θ、21.7 °2θ及22.7 °2θ。仍更通常地，形式2多晶型物具有如下XRPD光譜：其中10個最強峰包括5個或更多個(例如6個或更多個、7個或更多個、8個或更多個、9個或更多個或10個)具有選自以下之近似2θ值之峰：5.1 °2θ、8.9 °2θ、16.2 °2θ、17.1 °2θ、17.9 °2θ、18.7 °2θ、20.1 °2θ、20.6°2θ、21.7 °2θ及22.7 °2θ。
形式2多晶型物可具有大約如下表2中所列之XRPD光譜：
表 2
表 2
形式2多晶型物通常具有包含在20℃與160℃之間約8.5%至約8.9%之重量損失(例如約8.6%至約8.8%之重量損失或約8.7%之重量損失)之TGA曲線。
形式2多晶型物通常具有包含第一吸熱、第二吸熱及第三吸熱之DSC曲線。形式2多晶型物之第一吸熱通常在約61℃至約65℃範圍內之溫度下(例如在約62℃至約64℃範圍內之溫度下或在約63℃之溫度下)開始。形式2多晶型物之第一吸熱通常在約73℃至約77℃範圍內之溫度下(例如在約74℃至約76℃範圍內之溫度下或在約75℃之溫度下)具有峰值。形式2多晶型物之第一吸熱通常具有約1 J/g至約5 J/g (例如約2 J/g至約4 J/g或約3 J/g)之焓變。形式2多晶型物之第二吸熱通常在約93℃至約97℃範圍內之溫度下(例如在約94℃至約96℃範圍內之溫度下或在約95℃之溫度下)開始。形式2多晶型物之第二吸熱通常在約99℃至約103℃範圍內之溫度下(例如在約100℃至約102℃範圍內之溫度下或在約101℃之溫度下)具有峰值。形式2多晶型物之第二吸熱通常具有約0.5 J/g至約4 J/g (例如約1 J/g至約3 J/g或約2 J/g)之焓變。形式2多晶型物之第三吸熱通常在約180℃至約184℃範圍內之溫度下(例如在約181℃至約183℃範圍內之溫度下或在約182℃之溫度下)開始。形式2多晶型物之第三吸熱通常在約196℃至約200℃範圍內之溫度下(例如在約197℃至約199℃範圍內之溫度下或在約198℃之溫度下)具有峰值。形式2多晶型物之第三吸熱通常具有約25 J/g至約29 J/g (例如約26 J/g至約28 J/g或約27 J/g)之焓變。
形式2多晶型物可藉由包含以下之製程來獲得：
(a) 使N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺游離酸與鈉離子源在水及極性質子有機溶劑存在下接觸以形成溶液；或將N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺單鈉鹽溶解於包含水及極性質子有機溶劑之溶劑混合物中以形成溶液；及
(b) 自該溶液獲得結晶的N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺單鈉鹽無水物作為形式2多晶型物。
(a) 使N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺游離酸與鈉離子源在水及極性質子有機溶劑存在下接觸以形成溶液；或將N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺單鈉鹽溶解於包含水及極性質子有機溶劑之溶劑混合物中以形成溶液；及
(b) 自該溶液獲得結晶的N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺單鈉鹽無水物作為形式2多晶型物。
在較佳實施例中，在步驟(a)中，將N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺單鈉鹽溶解於包含水及極性質子有機溶劑之溶劑混合物中以形成溶液。
在較佳實施例中，步驟(a)中所用之極性質子有機溶劑係異丙醇。水對極性質子有機溶劑之體積比通常為1:35至1:1 (例如1:20至1:1、或1:15至1:4、或1:13至1:6、或1:11至1:8或約1:10)。
獲得形式2多晶型物之其他較佳製程包括其中極性質子有機溶劑、鈉離子源、獲得固體鈉鹽之方式及該製程之其他特徵係如本文關於本發明之第三態樣之製程所述之彼等製程。
本發明之第三態樣提供用於製備本發明之第一態樣之鹽、水合物或溶劑合物或本發明之第二態樣之多晶型之製程，該製程包含：
(a) 使N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺游離酸與鈉離子源在一或多種極性溶劑存在下接觸以形成混合物；及
(b) 自該混合物獲得N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺之固體鈉鹽。
(a) 使N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺游離酸與鈉離子源在一或多種極性溶劑存在下接觸以形成混合物；及
(b) 自該混合物獲得N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺之固體鈉鹽。
在某些實施例中，步驟(a)中所用之一或多種極性溶劑係極性溶劑之混合物，例如水及極性有機溶劑之混合物。在此等實施例中，水對極性有機溶劑之體積比通常為1:35至1:1 (例如1:20至1:1、或1:15至1:4、或1:13至1:6、或1:11至1:8、或約1:10或約1:9)。
極性溶劑之混合物可係(例如)水及極性質子有機溶劑之混合物或水及極性非質子有機溶劑之混合物。適宜極性質子有機溶劑包括諸如甲酸及乙酸等酸及諸如甲醇、乙醇、異丙醇及正丁醇等醇。較佳極性質子有機溶劑係異丙醇。適宜極性非質子有機溶劑包括N
-甲基吡咯啶酮、四氫呋喃、2-甲基四氫呋喃、乙酸乙酯、乙酸甲酯、丙酮、二甲基甲醯胺、乙腈、二甲亞碸及碳酸丙二酯。較佳極性非質子有機溶劑係丙酮。
在一些實施例中，極性溶劑之混合物可係水及異丙醇之混合物。在一些實施例中，極性溶劑之混合物可係水及丙酮之混合物。
鈉離子源通常係鈉鹽。在一些實施例中，鈉鹽係固體鈉鹽。在其他實施例中，鈉鹽係含鈉離子之化合物之溶液。適宜固體鈉鹽包括NaCl、NaOH、Na2
CO3
及NaHCO3
。含鈉離子之化合物之適宜溶液包括甲醇鈉(NaOMe)、乙醇鈉(NaOEt)及第三丁醇鈉(NaO t
Bu)，其全部均於乙醇、四氫呋喃或丙酮或該等溶劑中之任一者與水之混合物中。含鈉離子之化合物之其他適宜溶液包括於水中之NaCl、NaOH、Na2
CO3
及NaHCO3
。較佳鈉離子源係於乙醇中之乙醇鈉(NaOEt)或於水中之NaOH。更佳鈉離子源係於乙醇中之乙醇鈉(NaOEt)。
在一些實施例中，在步驟(a)中，所形成之反應混合物係溶液。在一些實施例中，在步驟(a)中，將N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺游離酸用極性溶劑或極性溶劑之混合物處理，之後添加鈉離子源以形成溶液。
在一些實施例中，步驟(a)係在5℃至100℃範圍內、或10℃至60℃範圍內、或15℃至30℃範圍內之溫度下實施。
在一些實施例中，在步驟(b)中，N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺之固體鈉鹽可藉由蒸發溶劑或溶劑混合物自反應混合物獲得。在一些實施例中，N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺之固體鈉鹽可藉由添加適宜反溶劑自反應混合物獲得。在此等實施例中，溶劑或溶劑混合物對反溶劑之體積比通常為1:1至1:10 (例如1:1.5至1:8、或1:2至1:6、或約1:3或約1:5)。在一些實施例中，N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺之固體鈉鹽可藉由添加晶種自反應混合物獲得。在一些實施例中，N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺之固體鈉鹽可藉由添加適宜反溶劑及添加晶種之組合自反應混合物獲得。
適宜反溶劑包括非極性溶劑，諸如己烷、庚烷、環己烷、甲苯、苯、1,4-二噁烷、氯仿、二氯甲烷、二乙醚、二異丙醚及第三丁基甲醚。二乙醚、二異丙醚及第三丁基甲醚較佳。尤佳者係第三丁基甲醚。
在一些實施例中，步驟(b)係在5℃至100℃範圍內、或10℃至60℃範圍內、或15℃至30℃範圍內之溫度下實施。
本發明之第四態樣提供醫藥組合物，其包含本發明之第一態樣之鹽、水合物或溶劑合物或本發明之第二態樣之多晶型以及醫藥學上可接受之賦形劑。
用於選擇及製備適宜醫藥調配物之習用程序闡述於(例如)「Aulton’s Pharmaceutics - The Design and Manufacture of Medicines」, M. E. Aulton及K. M. G. Taylor, Churchill Livingstone Elsevier，第4版，2013中。
可用於本發明之醫藥組合物中之包括佐劑、稀釋劑或載劑在內之醫藥學上可接受之賦形劑係醫藥調配領域所習用採用之彼等賦形劑，且包括(但不限於)糖、糖醇、澱粉、離子交換劑、氧化鋁、硬脂酸鋁、卵磷脂、血清蛋白(諸如人類血清白蛋白)、緩衝物質(諸如磷酸鹽)、甘油、山梨酸、山梨酸鉀、飽和植物脂肪酸之偏甘油酯混合物、水、鹽或電解質(諸如硫酸魚精蛋白、磷酸氫二鈉、磷酸氫鉀、氯化鈉、鋅鹽、膠質二氧化矽、三矽酸鎂)、聚乙烯基吡咯啶酮、基於纖維素之物質、聚乙二醇、羧甲基纖維素鈉、聚丙烯酸酯、蠟、聚乙烯-聚氧基丙烯嵌段聚合物、聚乙二醇及羊毛脂。
在一個實施例中，本發明之第四態樣之醫藥組合物另外包含一或多種其他活性劑。
在另一實施例中，本發明之第四態樣之醫藥組合物可作為多部分套組之一部分提供，其中該多部分套組包含本發明之第四態樣之醫藥組合物及一或多種其他醫藥組合物，其中該一或多種其他醫藥組合物各自包含醫藥學上可接受之賦形劑及一或多種其他活性劑。
本發明之第五態樣提供本發明之第一態樣之鹽、水合物或溶劑合物、本發明之第二態樣之多晶型或本發明之第四態樣之醫藥組合物，其用於醫藥中及/或用於治療或預防疾病、病症或病狀。通常，該用途包含向個體投與該鹽、水合物、溶劑合物、多晶型或醫藥組合物。在一個實施例中，該用途包含共投與一或多種其他活性劑。
如本文所用之術語「治療」同樣係指治癒性療法及改善或姑息性療法。該術語包括獲得有益或期望之生理結果，其可在臨床上確立或不可在臨床上確立。有益或期望之臨床結果包括(但不限於)可偵測或不可偵測地緩和症狀、預防症狀、降低疾病程度、穩定病狀(亦即不惡化)、延遲或減慢病狀/症狀之進展/惡化、改善或減緩病狀/症狀及緩解(部分或全部)。如本文所用之術語「減緩」及其變化形式意指與不投與本發明之鹽、水合物、溶劑合物、多晶型或醫藥組合物相比，生理病狀或症狀之程度及/或不期望之臨床表現減輕及/或進展之時程減慢或延長。如本文關於疾病、病症或病狀所用之術語「預防」係指預防性(prophylactic或preventative)療法，以及降低發生該疾病、病症或病狀之風險之療法。術語「預防」包括避免疾病、病症或病狀之發生及延遲疾病、病症或病狀之發作二者。如藉由對照臨床試驗所量測之任何統計學上顯著(p ≤ 0.05)之避免發生、延遲發作或降低風險均可視為對疾病、病症或病狀之預防。適於預防之個體包括如由遺傳或生物化學標記物所鑑別之疾病、病症或病狀之風險增加之彼等個體。通常，遺傳或生物化學標記物適於所考慮之疾病、病症或病狀，且可包括(例如)在發炎情形下之發炎性生物標記物，諸如C-反應蛋白(CRP)及單核球趨化蛋白1 (MCP-1)；在NAFLD及NASH情形下之總膽固醇、甘油三酯、胰島素抗性及C-肽；及更一般而言在對NLRP3抑制有反應之疾病、病症或病狀情形下之IL1β及IL18。
本發明之第六態樣提供本發明之第一態樣之鹽、水合物或溶劑合物或本發明之第二態樣之多晶型之用途，其用於製造用於治療或預防疾病、病症或病狀之藥劑。通常，治療或預防包含向個體投與該鹽、水合物、溶劑合物、多晶型或藥劑。在一個實施例中，治療或預防包含共投與一或多種其他活性劑。
本發明之第七態樣提供治療或預防疾病、病症或病狀之方法，該方法包括投與有效量之本發明之第一態樣之鹽、水合物或溶劑合物、本發明之第二態樣之多晶型或第四態樣之醫藥組合物之步驟，以藉此治療或預防該疾病、病症或病狀。在一個實施例中，該方法進一步包括共投與有效量之一或多種其他活性劑之步驟。通常，投與係針對有需要之個體。
本發明之第八態樣提供本發明之第一態樣之鹽、水合物或溶劑合物、本發明之第二態樣之多晶型或本發明之第四態樣之醫藥組合物，其用於治療或預防個體之疾病、病症或病狀，其中該個體在NLRP3中具有生殖系或體細胞非沈默突變。該突變可係(例如)功能獲得型突變或使得NLRP3活性增加之其他突變。通常，該用途包含向個體投與該鹽、水合物、溶劑合物、多晶型或醫藥組合物。在一個實施例中，該用途包含共投與一或多種其他活性劑。該用途亦可包含診斷在NLRP3中具有生殖系或體細胞非沈默突變之個體，其中基於對突變之陽性診斷向個體投與該鹽、水合物、溶劑合物、多晶型或醫藥組合物。通常，可藉由任何適宜遺傳或生物化學手段鑑別個體之NLRP3中之突變。
本發明之第九態樣提供本發明之第一態樣之鹽、水合物或溶劑合物或本發明之第二態樣之多晶型之用途，其用於製造用於治療或預防個體之疾病、病症或病狀之藥劑，其中該個體在NLRP3中具有生殖系或體細胞非沈默突變。該突變可係(例如)功能獲得型突變或使得NLRP3活性增加之其他突變。通常，治療或預防包含向個體投與該鹽、水合物、溶劑合物、多晶型或藥劑。在一個實施例中，治療或預防包含共投與一或多種其他活性劑。治療或預防亦可包含診斷在NLRP3中具有生殖系或體細胞非沈默突變之個體，其中基於對突變之陽性診斷向個體投與該鹽、水合物、溶劑合物、多晶型或藥劑。通常，可藉由任何適宜遺傳或生物化學手段鑑別個體之NLRP3中之突變。
本發明之第十態樣提供治療或預防疾病、病症或病狀之方法，該方法包括診斷在NLRP3中具有生殖系或體細胞非沈默突變之個體及向診斷為陽性之個體投與有效量之本發明之第一態樣之鹽、水合物或溶劑合物、本發明之第二態樣之多晶型或本發明之第四態樣之醫藥組合物之步驟，以藉此治療或預防該疾病、病症或病狀。在一個實施例中，該方法進一步包括共投與有效量之一或多種其他活性劑之步驟。通常，投與係針對有需要之個體。
在一般實施例中，疾病、病症或病狀可係免疫系統、心血管系統、內分泌系統、胃腸道、腎系統、肝系統、代謝系統、呼吸系統、中樞神經系統之疾病、病症或病狀，可係癌症或其他惡性病，及/或可由病原體引起或與病原體相關。
應瞭解，根據疾病、病症及病狀之寬類別定義之該等一般實施例不相互排斥。就此而言，可根據上述一般實施例中之一者以上對任何特定疾病、病症或病狀進行分類。非限制性實例係I型糖尿病，其係自體免疫疾病及內分泌系統之疾病。
在本發明之第五、第六、第七、第八、第九或第十態樣之一個實施例中，疾病、病症或病狀對NLRP3抑制有反應。如本文所用，術語「NLRP3抑制」係指完全或部分降低NLRP3之活性水準，且包括(例如)抑制活性NLRP3及/或抑制NLRP3之活化。
有證據表明NLRP3誘導之IL-1及IL-18在與多種不同病症相關或由於多種不同病症而發生之發炎性反應中之作用(Menu等人，Clinical and Experimental Immunology, 166: 1-15, 2011；Strowig等人，Nature, 481:278-286, 2012)。
NLRP3已參與多種自體發炎性疾病，包括家族性地中海熱(FMF)、TNF受體相關週期性症候群(TRAPS)、高免疫球蛋白血症D及週期性發熱症候群(HIDS)、化膿性關節炎、壞疽性膿皮症及痤瘡(PAPA)、斯威特氏症候群(Sweet’s syndrome)、慢性非細菌性骨髓炎(CNO)及尋常性痤瘡(Cook等人，Eur. J. Immunol., 40: 595-653, 2010)。特定而言，已發現NLRP3突變係一組稱為CAPS之罕見自體發炎性疾病之原因(Ozaki等人，J. Inflammation Research, 8:15-27, 2015；Schroder等人，Cell, 140: 821-832, 2010；及Menu等人，Clinical and Experimental Immunology, 166: 1-15, 2011)。CAPS係特徵在於反復發熱及發炎之可遺傳疾病，且包含三種形成臨床連續體之自體發炎性病症。該等疾病按照嚴重程度增加之順序係家族性寒冷自體發炎性症候群(FCAS)、穆-韋二氏症候群(MWS)及慢性嬰兒皮膚神經關節症候群(CINCA；亦稱為新生兒發作型多系統發炎性疾病，NOMID)，且全部已顯示係由於NLRP3基因之功能獲得型突變而引起，此導致IL-1β之分泌增加。
已顯示多種自體免疫疾病涉及NLRP3，特定而言包括多發性硬化、1型糖尿病(T1D)、牛皮癬、類風濕性關節炎(RA)、貝賽特氏病(Behcet's disease)、施尼茨勒氏症候群(Schnitzler syndrome)、巨噬細胞活化症候群(Masters Clin. Immunol. 2013；Braddock等人，Nat. Rev. Drug Disc. 2004 3: 1-10；Inoue等人，Immunology 139: 11-18；Coll等人，Nat. Med. 2015 21(3):248-55；及Scott等人，Clin. Exp. Rheumatol 2016 34(1): 88-93)、全身性紅斑狼瘡(Lu等人，J Immunol. 2017 198(3): 1119-29)及全身性硬化(Artlett等人，Arthritis Rheum. 2011;63(11): 3563-74)。亦已顯示NLRP3在多種肺病中起作用，包括慢性阻塞性肺病症(COPD)、氣喘(包括耐受類固醇之氣喘)、石棉肺及矽肺病(De Nardo等人，Am. J. Pathol., 184: 42-54, 2014及Kim等人，Am J Respir Crit Care Med. 2017 196(3): 283-97)。亦已提出NLRP3在多種中樞神經系統病狀中具有作用，包括帕金森氏病(Parkinson's disease，PD)、阿茲海默氏病(AD)、失智症、亨庭頓氏病(Huntington's disease)、腦型瘧疾、肺炎球菌腦膜炎所致之腦損傷(Walsh等人，Nature Reviews, 15: 84-97, 2014及Dempsey等人，Brain. Behav. Immun. 2017 61: 306-316)、顱內動脈瘤(Zhang等人，J. Stroke & Cerebrovascular Dis. 2015 24;5: 972-979)及創傷性腦損傷(Ismael等人，J Neurotrauma. 2018年1月2日)。亦已顯示NRLP3活性與各種代謝疾病有關，包括2型糖尿病(T2D)、動脈粥樣硬化、肥胖症、痛風、假性痛風、代謝症候群(Wen等人，Nature Immunology, 13: 352-357, 2012；Duewell等人，Nature, 464: 1357-1361, 2010；Strowig等人，Nature, 481: 278-286, 2012)及非酒精性脂肪性肝炎(Mridha等人，J Hepatol. 2017 66(5): 1037-46)。亦已在以下中提出NLRP3經由IL-1β之作用：動脈粥樣硬化、心肌梗塞(van Hout等人，Eur. Heart J. 2017 38(11): 828-36)、心臟衰竭(Sano等人，J AM. Coll. Cardiol. 2018 71(8): 875-66)、主動脈瘤及剝離(Wu等人，Arterioscler. Thromb. Vasc. Biol. 2017 37(4): 694-706)及其他心血管事件(Ridker等人，N Engl J Med., doi: 10.1056/ NEJMoa1707914, 2017)。已顯示其中涉及NLRP3之其他疾病包括：眼部疾病，諸如濕型及乾型年齡相關性黃斑退化二者(Doyle等人，Nature Medicine, 18: 791-798, 2012及Tarallo等人 Cell 2012 149(4): 847-59)、糖尿病視網膜病變(Loukovaara等人，Acta Ophthalmol. 2017; 95(8): 803-808)及視神經損害(Puyang等人，Sci Rep. 2016年2月19日;6:20998)；肝病，包括非酒精性脂肪性肝炎(NASH) (Henao-Meija等人，Nature, 482: 179-185, 2012)；肺及皮膚中之發炎性反應(Primiano等人，J Immunol. 2016 197(6): 2421-33)，包括接觸性過敏(諸如大皰性類天疱瘡(Fang等人，J Dermatol Sci. 2016;83(2): 116-23))、異位性皮膚炎(Niebuhr等人，Allergy 2014 69(8): 1058-67)、化膿性汗腺炎(Alikhan等人，2009 J Am Acad Dermatol 60(4): 539-61)、尋常性痤瘡(Qin等人，J Invest. Dermatol. 2014 134(2): 381-88)及類肉瘤病(Jager等人，Am J Respir Crit Care Med 2015 191: A5816)；關節中之發炎性反應(Braddock等人，Nat. Rev. Drug Disc., 3: 1-10, 2004)；肌肉萎縮性脊髓側索硬化症(Gugliandolo等人，Inflammation 2018 41(1): 93-103)；囊性纖維化(Iannitti等人，Nat. Commun. 2016 7: 10791)；中風(Walsh等人，Nature Reviews, 15: 84-97, 2014)；慢性腎病(Granata等人，PLoS One 2015 10(3): e0122272)；及發炎性腸病，包括潰瘍性結腸炎及克羅恩氏病(Crohn’s disease)(Braddock等人，Nat. Rev. Drug Disc., 3: 1-10, 2004，Neudecker等人，J Exp. Med. 2017 214(6): 1737-52及Lazaridis等人，Dig. Dis. Sci. 2017 62(9): 2348-56)。已發現NLRP3發炎體因應於氧化應激及UVB輻照而活化(Schroder等人，Science, 327: 296-300, 2010)。亦已顯示NLRP3與發炎性痛覺過敏有關(Dolunay等人，Inflammation, 40: 366-386, 2017)。
亦已提出發炎體、且具體而言NLRP3為各種病原體之調節靶標，該等病原體包括病毒，諸如DNA病毒(Amsler等人，Future Virol. (2013) 8(4), 357-370)。
NLRP3亦參與許多癌症之致病機制(Menu等人，Clinical and Experimental Immunology 166: 1-15, 2011；及Masters Clin. Immunol. 2013)。舉例而言，若干項先前研究已提出IL-1β在癌症侵襲性、生長及轉移中具有作用，且已顯示利用卡那單抗抑制IL-1β在隨機化、雙盲、安慰劑對照試驗中降低肺癌之發生率及總癌症死亡率(Ridker等人，Lancet, S0140-6736(17)32247-X, 2017)。亦已顯示抑制NLRP3發炎體或IL-1β抑制活體外肺癌細胞之增殖及遷移(Wang等人，Oncol Rep. 2016;35(4): 2053-64)。已提出NLRP3發炎體在骨髓發育不良症候群(Basiorka等人，Blood. 2016年12月22日;128(25):2960-2975)以及各種其他癌症之誘癌作用中之作用，該等其他癌症包括神經膠質瘤(Li等人，Am J Cancer Res. 2015;5(1): 442-449)、發炎誘導之腫瘤(Allen等人，J Exp Med. 2010; 207(5): 1045-56及Hu等人，PNAS. 2010; 107(50): 21635-40)、多發性骨髓瘤(Li等人，Hematology 2016 21(3): 144-51)及頭頸部鱗狀細胞癌(Huang等人，J Exp Clin Cancer Res. 2017 2;36(1): 116)。亦已顯示NLRP3發炎體之活化介導腫瘤細胞對5-氟尿嘧啶之化學抗性(Feng等人，J Exp Clin Cancer Res. 2017 21;36(1): 81)，且周圍神經中NLRP3發炎體之活化促成化學療法誘導之神經病性疼痛(Jia等人，Mol Pain. 2017;13: 1-11)。
亦已顯示NLRP3為有效控制病毒、細菌、真菌及蠕蟲病原體感染所必需(Strowig等人，Nature, 481:278-286, 2012)。
因此，可對NLRP3抑制有反應且可根據本發明之第五、第六、第七、第八、第九或第十態樣治療或預防之疾病、病症或病狀之實例包括：
(i) 發炎，包括由於發炎性病症(例如自體發炎性疾病)而發生之發炎、作為非發炎性病症之症狀發生之發炎、由於感染而發生之發炎或繼發於創傷、損傷或自體免疫之發炎；
(ii) 自體免疫疾病，諸如急性播散性腦炎、艾迪森氏病(Addison’s disease)、關節黏連性脊椎炎、抗磷脂抗體症候群(APS)、抗合成酶症候群、再生不良性貧血、自體免疫腎上腺炎、自體免疫肝炎、自體免疫卵巢炎、自體免疫多腺體衰竭、自體免疫甲狀腺炎、腹部疾病、克羅恩氏病、1型糖尿病(T1D)、古巴士德氏症候群(Goodpasture’s syndrome)、格雷夫氏病(Graves’ disease)、格林-巴利症候群(Guillain-Barré syndrome，GBS)、橋本氏病(Hashimoto’s disease)、特發性血小板減少紫斑症、川崎病(Kawasaki’s disease)、紅斑狼瘡(包括全身性紅斑狼瘡(SLE))、多發性硬化(MS)(包括原發進展性多發性硬化(PPMS)、繼發性進展型多發性硬化(SPMS)及復發緩解型多發性硬化(RRMS))、重症肌無力、斜視眼陣攣肌陣攣症候群(OMS)、視神經炎、沃德氏甲狀腺炎(Ord’s thyroiditis)、天疱瘡、惡性貧血、多發性關節炎、原發性膽汁性肝硬化、類風濕性關節炎(RA)、牛皮癬關節炎、幼年型特發性關節炎或斯蒂爾氏病(Still’s disease)、難治性痛風性關節炎、瑞特氏症候群(Reiter’s syndrome)、薛格連氏症候群(Sjögren’s syndrome)、全身性硬化(一種全身性結締組織病症)、高安氏動脈炎(Takayasu’s arteritis)、顳動脈炎、溫抗體型自體免疫溶血性貧血、韋格納氏肉芽腫病(Wegener’s granulomatosis)、普禿症、貝賽特氏病、恰加斯氏病(Chagas’ disease)、自主神經機能異常、子宮內膜異位症、化膿性汗腺炎(HS)、間質性膀胱炎、神經性肌強直、牛皮癬、類肉瘤病、硬皮症、潰瘍性結腸炎、施尼茨勒氏症候群、巨噬細胞活化症候群、布勞症候群(Blau syndrome)、白斑病或陰唇痛症；
(iii) 癌症，包括肺癌、胰臟癌、胃癌、骨髓發育不良症候群、白血病(包括急性淋巴球性白血病(ALL)及急性髓性白血病(AML))、腎上腺癌、肛門癌、基底及鱗狀細胞皮膚癌、膽管癌、膀胱癌、骨癌、腦及脊髓腫瘤、乳癌、子宮頸癌、慢性淋巴球性白血病(CLL)、慢性髓性白血病(CML)、慢性骨髓單核球性白血病(CMML)、結腸直腸癌、子宮內膜癌、食道癌、尤恩氏家族腫瘤(Ewing family of tumour)、眼癌、膽囊癌、胃腸類癌瘤、胃腸基質瘤(GIST)、妊娠滋養細胞病、神經膠質瘤、霍奇金氏淋巴瘤(Hodgkin lymphoma)、卡波西肉瘤(Kaposi sarcoma)、腎癌、喉及下咽癌、肝癌、肺類癌瘤、淋巴瘤(包括皮膚T細胞淋巴瘤)、惡性間皮瘤、黑色素瘤皮膚癌、默克爾細胞皮膚癌(Merkel cell skin cancer)、多發性骨髓瘤、鼻腔及鼻旁竇癌、鼻咽癌、神經胚細胞瘤、非霍奇金氏淋巴瘤、非小細胞肺癌、口腔及口咽癌、骨肉瘤、卵巢癌、陰莖癌、垂體瘤、前列腺癌、視網膜母細胞瘤、橫紋肌肉瘤、唾液腺癌、皮膚癌、小細胞肺癌、小腸癌、軟組織肉瘤、胃癌、睪丸癌、胸腺癌、甲狀腺癌(包括甲狀腺未分化癌)、子宮肉瘤、陰道癌、外陰癌、瓦登斯特隆巨球蛋白血症(Waldenstrom macroglobulinemia)及威爾姆氏瘤(Wilms tumour)；
(iv) 感染，包括病毒感染(例如來自流行性感冒病毒、人類免疫缺失病毒(HIV)、阿爾法病毒(alphavirus)(諸如屈公病病毒(Chikungunya virus)及羅氏河病毒(Ross River virus))、黃病毒(flavivirus)(諸如登革熱病毒(Dengue virus)及茲卡病毒(Zika virus))、疱疹病毒(諸如艾伯斯坦-巴爾病毒(Epstein Barr Virus)、巨細胞病毒(cytomegalovirus)、水痘帶狀疱疹病毒(Varicella-zoster virus)及KSHV)、痘病毒(諸如牛痘病毒(經改質之牛痘病毒安卡拉株(Modified vaccinia virus Ankara))及黏液瘤病毒)、腺病毒(諸如腺病毒5)或乳頭瘤病毒)、細菌感染(例如來自金黃色葡萄球菌(Staphylococcus aureus )、幽門螺旋桿菌(Helicobacter pylori )、炭疽桿菌(Bacillus anthracis )、百日咳博德特氏桿菌(Bordetella pertussis )、類鼻疽伯克氏菌(Burkholderia pseudomallei )、白喉棒狀桿菌(Corynebacterium diptheriae )、破傷風羧菌(Clostridium tetani )、肉毒桿菌(Clostridium botulinum )、肺炎鏈球菌(Streptococcus pneumoniae )、釀膿鏈球菌(Streptococcus pyogenes )、單核球增多性李氏菌(Listeria monocytogenes )、流行性感冒嗜血桿菌(Hemophilus influenzae )、多殺性巴氏桿菌(Pasteurella multicida )、痢疾志賀桿菌(Shigella dysenteriae )、結核分枝桿菌(Mycobacterium tuberculosis )、麻瘋分枝桿菌(Mycobacterium leprae )、肺炎支原體(Mycoplasma pneumoniae )、人型支原體(Mycoplasma hominis )、腦膜炎雙球菌(Neisseria meningitidis )、淋病雙球菌(Neisseria gonorrhoeae )、立氏立克次體(Rickettsia rickettsii )、嗜肺軍團菌(Legionella pneumophila )、克雷伯氏肺炎菌(Klebsiella pneumoniae )、綠膿桿菌(Pseudomonas aeruginosa )、痤瘡丙酸桿菌(Propionibacterium acnes )、梅毒密螺旋體(Treponema pallidum )、沙眼披衣菌(Chlamydia trachomatis )、霍亂弧菌(Vibrio cholerae )、鼠傷寒沙門氏菌(Salmonella typhimurium )、傷寒沙門桿菌(Salmonella typhi )、伯氏疏螺旋體(Borrelia burgdorferi )或鼠疫耶爾辛氏菌(Yersinia pestis ))、真菌感染(例如來自念珠菌屬(Candida)或麴菌屬(Aspergillus))、原生動物感染(例如來自瘧原蟲屬(Plasmodium)、巴貝蟲屬(Babesia)、梨形鞭毛蟲屬(Giardia)、阿米巴屬(Entamoeba)、利士曼原蟲屬(Leishmania)或錐體蟲屬(Trypanosomes))、蠕蟲感染(例如來自住血吸蟲屬(schistosoma)、蛔蟲、絛蟲或吸蟲)及普里昂蛋白(prion)感染；
(v) 中樞神經系統疾病，諸如帕金森氏病、阿茲海默氏病、失智症、運動神經元病、亨庭頓氏病、腦型瘧疾、肺炎球菌腦膜炎所致之腦損傷、顱內動脈瘤、創傷性腦損傷及肌肉萎縮性脊髓側索硬化症；
(vi) 代謝疾病，諸如2型糖尿病(T2D)、動脈粥樣硬化、肥胖症、痛風及假性痛風；
(vii) 心血管疾病，諸如高血壓、缺血、再灌注損傷(包括心肌梗塞後缺血性再灌注損傷)、中風(包括缺血性中風)、暫時性腦缺血發作、心肌梗塞(包括再發性心肌梗塞)、心臟衰竭(包括充血性心臟衰竭及射血分數保留性心臟衰竭)、栓塞、動脈瘤(包括腹主動脈瘤)及心包炎(包括德雷斯勒氏症候群(Dressler’s syndrome))；
(viii) 呼吸疾病，包括慢性阻塞性肺病症(COPD)、氣喘(諸如過敏性氣喘及耐受類固醇之氣喘)、石棉肺、矽肺病、奈米粒子誘發之發炎、囊性纖維化及特發性肺纖維化；
(ix) 肝病，包括非酒精性脂肪性肝病(NAFLD)及非酒精性脂肪性肝炎(NASH)(包括晚期纖維化階段F3及F4)、酒精性脂肪性肝病(AFLD)及酒精性脂肪性肝炎(ASH)；
(x) 腎病，包括慢性腎病、草酸鹽腎病變、腎鈣沈積病、腎小球性腎炎及糖尿病腎病變；
(xi) 眼部疾病，包括眼上皮之彼等疾病、年齡相關性黃斑退化(AMD) (乾性及濕性)、眼色素層炎、角膜感染、糖尿病視網膜病變、視神經損害、乾眼症及青光眼；
(xii) 皮膚病，包括皮膚炎(諸如接觸性皮膚炎及異位性皮膚炎)、接觸性過敏、曬傷、皮膚病灶、化膿性汗腺炎(HS)其他囊腫引起之皮膚病及聚合性痤瘡；
(xiii) 淋巴病狀，諸如淋巴管炎及卡斯爾曼病(Castleman's disease)；
(xiv) 心理障礙，諸如抑鬱症及心理壓力；
(xv) 移植物抗宿主病；
(xvi) 觸摸痛，包括機械性觸摸痛；及
(xvii) 已確定個體攜帶NLRP3中之生殖系或體細胞非沈默突變之任何疾病。
(i) 發炎，包括由於發炎性病症(例如自體發炎性疾病)而發生之發炎、作為非發炎性病症之症狀發生之發炎、由於感染而發生之發炎或繼發於創傷、損傷或自體免疫之發炎；
(ii) 自體免疫疾病，諸如急性播散性腦炎、艾迪森氏病(Addison’s disease)、關節黏連性脊椎炎、抗磷脂抗體症候群(APS)、抗合成酶症候群、再生不良性貧血、自體免疫腎上腺炎、自體免疫肝炎、自體免疫卵巢炎、自體免疫多腺體衰竭、自體免疫甲狀腺炎、腹部疾病、克羅恩氏病、1型糖尿病(T1D)、古巴士德氏症候群(Goodpasture’s syndrome)、格雷夫氏病(Graves’ disease)、格林-巴利症候群(Guillain-Barré syndrome，GBS)、橋本氏病(Hashimoto’s disease)、特發性血小板減少紫斑症、川崎病(Kawasaki’s disease)、紅斑狼瘡(包括全身性紅斑狼瘡(SLE))、多發性硬化(MS)(包括原發進展性多發性硬化(PPMS)、繼發性進展型多發性硬化(SPMS)及復發緩解型多發性硬化(RRMS))、重症肌無力、斜視眼陣攣肌陣攣症候群(OMS)、視神經炎、沃德氏甲狀腺炎(Ord’s thyroiditis)、天疱瘡、惡性貧血、多發性關節炎、原發性膽汁性肝硬化、類風濕性關節炎(RA)、牛皮癬關節炎、幼年型特發性關節炎或斯蒂爾氏病(Still’s disease)、難治性痛風性關節炎、瑞特氏症候群(Reiter’s syndrome)、薛格連氏症候群(Sjögren’s syndrome)、全身性硬化(一種全身性結締組織病症)、高安氏動脈炎(Takayasu’s arteritis)、顳動脈炎、溫抗體型自體免疫溶血性貧血、韋格納氏肉芽腫病(Wegener’s granulomatosis)、普禿症、貝賽特氏病、恰加斯氏病(Chagas’ disease)、自主神經機能異常、子宮內膜異位症、化膿性汗腺炎(HS)、間質性膀胱炎、神經性肌強直、牛皮癬、類肉瘤病、硬皮症、潰瘍性結腸炎、施尼茨勒氏症候群、巨噬細胞活化症候群、布勞症候群(Blau syndrome)、白斑病或陰唇痛症；
(iii) 癌症，包括肺癌、胰臟癌、胃癌、骨髓發育不良症候群、白血病(包括急性淋巴球性白血病(ALL)及急性髓性白血病(AML))、腎上腺癌、肛門癌、基底及鱗狀細胞皮膚癌、膽管癌、膀胱癌、骨癌、腦及脊髓腫瘤、乳癌、子宮頸癌、慢性淋巴球性白血病(CLL)、慢性髓性白血病(CML)、慢性骨髓單核球性白血病(CMML)、結腸直腸癌、子宮內膜癌、食道癌、尤恩氏家族腫瘤(Ewing family of tumour)、眼癌、膽囊癌、胃腸類癌瘤、胃腸基質瘤(GIST)、妊娠滋養細胞病、神經膠質瘤、霍奇金氏淋巴瘤(Hodgkin lymphoma)、卡波西肉瘤(Kaposi sarcoma)、腎癌、喉及下咽癌、肝癌、肺類癌瘤、淋巴瘤(包括皮膚T細胞淋巴瘤)、惡性間皮瘤、黑色素瘤皮膚癌、默克爾細胞皮膚癌(Merkel cell skin cancer)、多發性骨髓瘤、鼻腔及鼻旁竇癌、鼻咽癌、神經胚細胞瘤、非霍奇金氏淋巴瘤、非小細胞肺癌、口腔及口咽癌、骨肉瘤、卵巢癌、陰莖癌、垂體瘤、前列腺癌、視網膜母細胞瘤、橫紋肌肉瘤、唾液腺癌、皮膚癌、小細胞肺癌、小腸癌、軟組織肉瘤、胃癌、睪丸癌、胸腺癌、甲狀腺癌(包括甲狀腺未分化癌)、子宮肉瘤、陰道癌、外陰癌、瓦登斯特隆巨球蛋白血症(Waldenstrom macroglobulinemia)及威爾姆氏瘤(Wilms tumour)；
(iv) 感染，包括病毒感染(例如來自流行性感冒病毒、人類免疫缺失病毒(HIV)、阿爾法病毒(alphavirus)(諸如屈公病病毒(Chikungunya virus)及羅氏河病毒(Ross River virus))、黃病毒(flavivirus)(諸如登革熱病毒(Dengue virus)及茲卡病毒(Zika virus))、疱疹病毒(諸如艾伯斯坦-巴爾病毒(Epstein Barr Virus)、巨細胞病毒(cytomegalovirus)、水痘帶狀疱疹病毒(Varicella-zoster virus)及KSHV)、痘病毒(諸如牛痘病毒(經改質之牛痘病毒安卡拉株(Modified vaccinia virus Ankara))及黏液瘤病毒)、腺病毒(諸如腺病毒5)或乳頭瘤病毒)、細菌感染(例如來自金黃色葡萄球菌(Staphylococcus aureus )、幽門螺旋桿菌(Helicobacter pylori )、炭疽桿菌(Bacillus anthracis )、百日咳博德特氏桿菌(Bordetella pertussis )、類鼻疽伯克氏菌(Burkholderia pseudomallei )、白喉棒狀桿菌(Corynebacterium diptheriae )、破傷風羧菌(Clostridium tetani )、肉毒桿菌(Clostridium botulinum )、肺炎鏈球菌(Streptococcus pneumoniae )、釀膿鏈球菌(Streptococcus pyogenes )、單核球增多性李氏菌(Listeria monocytogenes )、流行性感冒嗜血桿菌(Hemophilus influenzae )、多殺性巴氏桿菌(Pasteurella multicida )、痢疾志賀桿菌(Shigella dysenteriae )、結核分枝桿菌(Mycobacterium tuberculosis )、麻瘋分枝桿菌(Mycobacterium leprae )、肺炎支原體(Mycoplasma pneumoniae )、人型支原體(Mycoplasma hominis )、腦膜炎雙球菌(Neisseria meningitidis )、淋病雙球菌(Neisseria gonorrhoeae )、立氏立克次體(Rickettsia rickettsii )、嗜肺軍團菌(Legionella pneumophila )、克雷伯氏肺炎菌(Klebsiella pneumoniae )、綠膿桿菌(Pseudomonas aeruginosa )、痤瘡丙酸桿菌(Propionibacterium acnes )、梅毒密螺旋體(Treponema pallidum )、沙眼披衣菌(Chlamydia trachomatis )、霍亂弧菌(Vibrio cholerae )、鼠傷寒沙門氏菌(Salmonella typhimurium )、傷寒沙門桿菌(Salmonella typhi )、伯氏疏螺旋體(Borrelia burgdorferi )或鼠疫耶爾辛氏菌(Yersinia pestis ))、真菌感染(例如來自念珠菌屬(Candida)或麴菌屬(Aspergillus))、原生動物感染(例如來自瘧原蟲屬(Plasmodium)、巴貝蟲屬(Babesia)、梨形鞭毛蟲屬(Giardia)、阿米巴屬(Entamoeba)、利士曼原蟲屬(Leishmania)或錐體蟲屬(Trypanosomes))、蠕蟲感染(例如來自住血吸蟲屬(schistosoma)、蛔蟲、絛蟲或吸蟲)及普里昂蛋白(prion)感染；
(v) 中樞神經系統疾病，諸如帕金森氏病、阿茲海默氏病、失智症、運動神經元病、亨庭頓氏病、腦型瘧疾、肺炎球菌腦膜炎所致之腦損傷、顱內動脈瘤、創傷性腦損傷及肌肉萎縮性脊髓側索硬化症；
(vi) 代謝疾病，諸如2型糖尿病(T2D)、動脈粥樣硬化、肥胖症、痛風及假性痛風；
(vii) 心血管疾病，諸如高血壓、缺血、再灌注損傷(包括心肌梗塞後缺血性再灌注損傷)、中風(包括缺血性中風)、暫時性腦缺血發作、心肌梗塞(包括再發性心肌梗塞)、心臟衰竭(包括充血性心臟衰竭及射血分數保留性心臟衰竭)、栓塞、動脈瘤(包括腹主動脈瘤)及心包炎(包括德雷斯勒氏症候群(Dressler’s syndrome))；
(viii) 呼吸疾病，包括慢性阻塞性肺病症(COPD)、氣喘(諸如過敏性氣喘及耐受類固醇之氣喘)、石棉肺、矽肺病、奈米粒子誘發之發炎、囊性纖維化及特發性肺纖維化；
(ix) 肝病，包括非酒精性脂肪性肝病(NAFLD)及非酒精性脂肪性肝炎(NASH)(包括晚期纖維化階段F3及F4)、酒精性脂肪性肝病(AFLD)及酒精性脂肪性肝炎(ASH)；
(x) 腎病，包括慢性腎病、草酸鹽腎病變、腎鈣沈積病、腎小球性腎炎及糖尿病腎病變；
(xi) 眼部疾病，包括眼上皮之彼等疾病、年齡相關性黃斑退化(AMD) (乾性及濕性)、眼色素層炎、角膜感染、糖尿病視網膜病變、視神經損害、乾眼症及青光眼；
(xii) 皮膚病，包括皮膚炎(諸如接觸性皮膚炎及異位性皮膚炎)、接觸性過敏、曬傷、皮膚病灶、化膿性汗腺炎(HS)其他囊腫引起之皮膚病及聚合性痤瘡；
(xiii) 淋巴病狀，諸如淋巴管炎及卡斯爾曼病(Castleman's disease)；
(xiv) 心理障礙，諸如抑鬱症及心理壓力；
(xv) 移植物抗宿主病；
(xvi) 觸摸痛，包括機械性觸摸痛；及
(xvii) 已確定個體攜帶NLRP3中之生殖系或體細胞非沈默突變之任何疾病。
在一個實施例中，疾病、病症或病狀係選自：
(i) 癌症；
(ii) 感染；
(iii) 中樞神經系統疾病；
(iv) 心血管疾病；
(v) 肝病；
(vi) 眼部疾病；或
(vii) 皮膚病。
(i) 癌症；
(ii) 感染；
(iii) 中樞神經系統疾病；
(iv) 心血管疾病；
(v) 肝病；
(vi) 眼部疾病；或
(vii) 皮膚病。
更通常地，疾病、病症或病狀係選自：
(i) 癌症；
(ii) 感染；
(iii) 中樞神經系統疾病；或
(iv) 心血管疾病。
(i) 癌症；
(ii) 感染；
(iii) 中樞神經系統疾病；或
(iv) 心血管疾病。
在一個實施例中，疾病、病症或病狀係選自：
(i) 聚合性痤瘡；
(ii) 異位性皮膚炎；
(iii) 阿茲海默氏病；
(iv) 肌肉萎縮性脊髓側索硬化症；
(v) 年齡相關性黃斑退化(AMD)；
(vi) 甲狀腺未分化癌；
(vii) 隱熱蛋白相關週期性症候群(CAPS)；
(viii) 接觸性皮膚炎；
(ix) 囊性纖維化；
(x) 充血性心臟衰竭；
(xi) 慢性腎病；
(xii) 克羅恩氏病；
(xiii) 家族性寒冷自體發炎性症候群(FCAS)；
(xiv) 亨庭頓氏病；
(xv) 心臟衰竭；
(xvi) 射血分數保留性心臟衰竭；
(xvii) 缺血性再灌注損傷；
(xviii) 幼年型特發性關節炎；
(xix) 心肌梗塞；
(xx) 巨噬細胞活化症候群；
(xxi) 骨髓發育不良症候群；
(xxii) 多發性骨髓瘤；
(xxiii) 運動神經元病；
(xxiv) 多發性硬化；
(xxv) 穆-韋二氏症候群；
(xxvi) 非酒精性脂肪性肝炎(NASH)；
(xxvii) 新生兒發作型多系統發炎性疾病(NOMID)；
(xxviii) 帕金森氏病；
(xxix) 全身性幼年型特發性關節炎；
(xxx) 全身性紅斑狼瘡；
(xxxi) 創傷性腦損傷；
(xxxii) 暫時性腦缺血發作；及
(xxxiii) 潰瘍性結腸炎。
(i) 聚合性痤瘡；
(ii) 異位性皮膚炎；
(iii) 阿茲海默氏病；
(iv) 肌肉萎縮性脊髓側索硬化症；
(v) 年齡相關性黃斑退化(AMD)；
(vi) 甲狀腺未分化癌；
(vii) 隱熱蛋白相關週期性症候群(CAPS)；
(viii) 接觸性皮膚炎；
(ix) 囊性纖維化；
(x) 充血性心臟衰竭；
(xi) 慢性腎病；
(xii) 克羅恩氏病；
(xiii) 家族性寒冷自體發炎性症候群(FCAS)；
(xiv) 亨庭頓氏病；
(xv) 心臟衰竭；
(xvi) 射血分數保留性心臟衰竭；
(xvii) 缺血性再灌注損傷；
(xviii) 幼年型特發性關節炎；
(xix) 心肌梗塞；
(xx) 巨噬細胞活化症候群；
(xxi) 骨髓發育不良症候群；
(xxii) 多發性骨髓瘤；
(xxiii) 運動神經元病；
(xxiv) 多發性硬化；
(xxv) 穆-韋二氏症候群；
(xxvi) 非酒精性脂肪性肝炎(NASH)；
(xxvii) 新生兒發作型多系統發炎性疾病(NOMID)；
(xxviii) 帕金森氏病；
(xxix) 全身性幼年型特發性關節炎；
(xxx) 全身性紅斑狼瘡；
(xxxi) 創傷性腦損傷；
(xxxii) 暫時性腦缺血發作；及
(xxxiii) 潰瘍性結腸炎。
在本發明之另一典型實施例中，疾病、病症或病狀係發炎。可根據本發明之第五、第六、第七、第八、第九或第十態樣治療或預防之發炎之實例包括與以下相關或由於以下而發生之發炎性反應：
(i) 皮膚病狀，諸如接觸性過敏、大皰性類天疱瘡、曬傷、牛皮癬、異位性皮膚炎、接觸性皮膚炎、過敏性接觸性皮膚炎、脂溢性皮膚炎、扁平苔蘚、硬皮症、天疱瘡、大皰性表皮鬆解、蕁麻疹、紅斑或脫髪；
(ii) 關節病狀，諸如骨關節炎、全身性幼年型特發性關節炎、成人發作型斯蒂爾氏病、復發性多發性軟骨炎、類風濕性關節炎、幼年型慢性關節炎、痛風或血清陰性脊椎關節病變(例如關節黏連性脊椎炎、牛皮癬關節炎或瑞特氏病(Reiter's disease))；
(iii) 肌肉病狀，諸如多發性肌炎或重症肌無力；
(iv) 胃腸道病狀，諸如發炎性腸病(包括克羅恩氏病及潰瘍性結腸炎)、胃潰瘍、腹部疾病、直腸炎、胰臟炎、嗜伊紅性胃腸炎、肥大細胞增多症、抗磷脂質症候群或可具有遠離腸道之效應(例如、偏頭痛、鼻炎或濕疹)之食物相關過敏；
(v) 呼吸系統病狀，諸如慢性阻塞性肺病(COPD)、氣喘(包括枝氣管氣喘、過敏性氣喘、內因性氣喘、外因性或塵埃性氣喘及特定而言慢性或頑固性氣喘(諸如遲發性氣喘及氣道過度反應性))、枝氣管炎、鼻炎(包括急性鼻炎、過敏性鼻炎、萎縮性鼻炎、慢性鼻炎、乾酪狀鼻炎、肥厚性鼻炎、化膿性鼻炎(rhinitis pumlenta)、乾性鼻炎、藥物性鼻炎、膜性鼻炎、季節性鼻炎(例如花粉熱)及血管舒縮性鼻炎)、竇炎、特發性肺纖維化(IPF)、類肉瘤病、農夫肺、矽肺病、石棉肺、成人呼吸窘迫症候群、過敏性肺炎或特發性間質性肺炎；
(vi) 血管病狀，諸如動脈粥樣硬化、貝賽特氏病、血管炎或韋格納氏肉芽腫病；
(vii) 自體免疫病狀，諸如全身性紅斑狼瘡、薛格連氏症候群、全身性硬化、橋本氏甲狀腺炎、I型糖尿病、特發性血小板減少性紫癜或格雷夫氏病；
(viii) 眼部病狀，諸如眼色素層炎、過敏性結膜炎或春季結膜炎；
(ix) 神經病狀，諸如多發性硬化或腦脊髓炎；
(x) 感染或感染相關病狀，諸如後天性免疫缺失症候群(AIDS)、極性或慢性細菌感染、極性或慢性寄生蟲感染、極性或慢性病毒感染、極性或慢性真菌感染、腦膜炎、肝炎(A型、B型或C型或其他病毒性肝炎)、腹膜炎、肺炎、會厭炎、瘧疾、登革出血熱(dengue hemorrhagic fever)、利什曼體病、鏈球菌肌炎、結核分枝桿菌感染、鳥胞內分枝桿菌感染、卡氏肺囊蟲肺炎(pneumocystis carinii pneumonia)、睪丸炎/附睪炎(epidydimitis)、軍團菌屬(legionella)感染、萊姆病(Lyme disease)、A型流行性感冒、艾司坦-巴爾病毒感染、病毒性腦炎/無菌性腦膜炎或盆腔發炎性疾病；
(xi) 腎病狀，諸如系膜增生性腎小球性腎炎、腎病症候群、腎炎、腎小球腎炎、急性腎衰竭、尿毒症或腎炎症候群；
(xii) 淋巴病狀，諸如卡斯爾曼病；
(xiii) 免疫系統病狀或涉及免疫系統之病狀，諸如高IgE症候群、癩瘤型痲瘋病、家族性噬血球性淋巴組織球增生症或移植物抗宿主病；
(xiv) 肝病狀，諸如慢性活動性肝炎、非酒精性脂肪性肝炎(NASH)、酒精誘發之肝炎、非酒精性脂肪性肝病(NAFLD)、酒精性脂肪性肝病(AFLD)、酒精性脂肪性肝炎(ASH)或原發性膽汁性肝硬化；
(xv) 癌症，包括上文所列示之彼等癌症；
(xvi) 燒傷、傷口、創傷、出血或中風；
(xvii) 輻射曝露；及/或
(xviii) 肥胖症；及/或
(xix) 疼痛，諸如發炎性痛覺過敏。
(i) 皮膚病狀，諸如接觸性過敏、大皰性類天疱瘡、曬傷、牛皮癬、異位性皮膚炎、接觸性皮膚炎、過敏性接觸性皮膚炎、脂溢性皮膚炎、扁平苔蘚、硬皮症、天疱瘡、大皰性表皮鬆解、蕁麻疹、紅斑或脫髪；
(ii) 關節病狀，諸如骨關節炎、全身性幼年型特發性關節炎、成人發作型斯蒂爾氏病、復發性多發性軟骨炎、類風濕性關節炎、幼年型慢性關節炎、痛風或血清陰性脊椎關節病變(例如關節黏連性脊椎炎、牛皮癬關節炎或瑞特氏病(Reiter's disease))；
(iii) 肌肉病狀，諸如多發性肌炎或重症肌無力；
(iv) 胃腸道病狀，諸如發炎性腸病(包括克羅恩氏病及潰瘍性結腸炎)、胃潰瘍、腹部疾病、直腸炎、胰臟炎、嗜伊紅性胃腸炎、肥大細胞增多症、抗磷脂質症候群或可具有遠離腸道之效應(例如、偏頭痛、鼻炎或濕疹)之食物相關過敏；
(v) 呼吸系統病狀，諸如慢性阻塞性肺病(COPD)、氣喘(包括枝氣管氣喘、過敏性氣喘、內因性氣喘、外因性或塵埃性氣喘及特定而言慢性或頑固性氣喘(諸如遲發性氣喘及氣道過度反應性))、枝氣管炎、鼻炎(包括急性鼻炎、過敏性鼻炎、萎縮性鼻炎、慢性鼻炎、乾酪狀鼻炎、肥厚性鼻炎、化膿性鼻炎(rhinitis pumlenta)、乾性鼻炎、藥物性鼻炎、膜性鼻炎、季節性鼻炎(例如花粉熱)及血管舒縮性鼻炎)、竇炎、特發性肺纖維化(IPF)、類肉瘤病、農夫肺、矽肺病、石棉肺、成人呼吸窘迫症候群、過敏性肺炎或特發性間質性肺炎；
(vi) 血管病狀，諸如動脈粥樣硬化、貝賽特氏病、血管炎或韋格納氏肉芽腫病；
(vii) 自體免疫病狀，諸如全身性紅斑狼瘡、薛格連氏症候群、全身性硬化、橋本氏甲狀腺炎、I型糖尿病、特發性血小板減少性紫癜或格雷夫氏病；
(viii) 眼部病狀，諸如眼色素層炎、過敏性結膜炎或春季結膜炎；
(ix) 神經病狀，諸如多發性硬化或腦脊髓炎；
(x) 感染或感染相關病狀，諸如後天性免疫缺失症候群(AIDS)、極性或慢性細菌感染、極性或慢性寄生蟲感染、極性或慢性病毒感染、極性或慢性真菌感染、腦膜炎、肝炎(A型、B型或C型或其他病毒性肝炎)、腹膜炎、肺炎、會厭炎、瘧疾、登革出血熱(dengue hemorrhagic fever)、利什曼體病、鏈球菌肌炎、結核分枝桿菌感染、鳥胞內分枝桿菌感染、卡氏肺囊蟲肺炎(pneumocystis carinii pneumonia)、睪丸炎/附睪炎(epidydimitis)、軍團菌屬(legionella)感染、萊姆病(Lyme disease)、A型流行性感冒、艾司坦-巴爾病毒感染、病毒性腦炎/無菌性腦膜炎或盆腔發炎性疾病；
(xi) 腎病狀，諸如系膜增生性腎小球性腎炎、腎病症候群、腎炎、腎小球腎炎、急性腎衰竭、尿毒症或腎炎症候群；
(xii) 淋巴病狀，諸如卡斯爾曼病；
(xiii) 免疫系統病狀或涉及免疫系統之病狀，諸如高IgE症候群、癩瘤型痲瘋病、家族性噬血球性淋巴組織球增生症或移植物抗宿主病；
(xiv) 肝病狀，諸如慢性活動性肝炎、非酒精性脂肪性肝炎(NASH)、酒精誘發之肝炎、非酒精性脂肪性肝病(NAFLD)、酒精性脂肪性肝病(AFLD)、酒精性脂肪性肝炎(ASH)或原發性膽汁性肝硬化；
(xv) 癌症，包括上文所列示之彼等癌症；
(xvi) 燒傷、傷口、創傷、出血或中風；
(xvii) 輻射曝露；及/或
(xviii) 肥胖症；及/或
(xix) 疼痛，諸如發炎性痛覺過敏。
在本發明之第五、第六、第七、第八、第九或第十態樣之一個實施例中，疾病、病症或病狀係自體發炎性疾病，諸如隱熱蛋白相關週期性症候群(CAPS)、穆-韋二氏症候群(MWS)、家族性寒冷自體發炎性症候群(FCAS)、家族性地中海熱(FMF)、新生兒發作型多系統發炎性疾病(NOMID)、腫瘤壞死因子(TNF)受體相關週期性症候群(TRAPS)、高免疫球蛋白血症D及週期性發熱症候群(HIDS)、介白素1受體拮抗劑缺乏(DIRA)、馬吉德症候群(Majeed syndrome)、化膿性關節炎、壞疽性膿皮症及痤瘡症候群(PAPA)、成人發作型斯蒂爾氏病(AOSD)、A20之單倍劑量不足(HA20)、幼兒肉芽腫關節炎(PGA)、PLCG2相關之抗體缺乏症及免疫失調(PLAID)、PLCG2相關之自體發炎、抗體缺乏症及免疫失調(APLAID)或鐵粒幼細胞性貧血伴B細胞免疫缺失、週期性發熱及發育遲緩(SIFD)。
可對NLRP3抑制有反應且可根據本發明之第五、第六、第七、第八、第九或第十態樣治療或預防之疾病、病症或病狀之實例列示於上文中。該等疾病、病症或病狀中之一些實質上或完全上由NLRP3發炎體活性及NLRP3誘導之IL-1β及/或IL-18介導。因此，此等疾病、病症或病狀可尤其對NLRP3抑制有反應且可尤其適於根據本發明之第五、第六、第七、第八、第九或第十態樣之治療或預防。此等疾病、病症或病狀之實例包括隱熱蛋白相關週期性症候群(CAPS)、穆-韋二氏症候群(MWS)、家族性寒冷自體發炎性症候群(FCAS)、新生兒發作型多系統發炎性疾病(NOMID)、家族性地中海熱(FMF)、化膿性關節炎、壞疽性膿皮症及痤瘡症候群(PAPA)、高免疫球蛋白血症D及週期性發熱症候群(HIDS)、腫瘤壞死因子(TNF)受體相關週期性症候群(TRAPS)、全身性幼年型特發性關節炎、成人發作型斯蒂爾氏病(AOSD)、復發性多發性軟骨炎、施尼茨勒氏症候群、斯威特氏症候群、貝賽特氏病、抗合成酶症候群、介白素1受體拮抗劑缺乏(DIRA)及A20之單倍劑量不足(HA20)。
此外，上文所提及疾病、病症或病狀中之一些係由於NLRP3突變、特定而言使得NLRP3活性增加之突變而引起。因此，此等疾病、病症或病狀可尤其對NLRP3抑制有反應且可尤其適於根據本發明之第五、第六、第七、第八、第九或第十態樣之治療或預防。此等疾病、病症或病狀之實例包括隱熱蛋白相關週期性症候群(CAPS)、穆-韋二氏症候群(MWS)、家族性寒冷自體發炎性症候群(FCAS)及新生兒發作型多系統發炎性疾病(NOMID)。
本發明之第十一態樣提供抑制NLRP3之方法，該方法包括使用本發明之第一態樣之鹽、水合物或溶劑合物、本發明之第二態樣之多晶型或本發明之第四態樣之醫藥組合物來抑制NLRP3。
在本發明之第十一態樣之一個實施例中，該方法包括使用本發明之第一態樣之鹽、水合物或溶劑合物、本發明之第二態樣之多晶型或本發明之第四態樣之醫藥組合物與一或多種其他活性劑之組合。
在本發明之第十一態樣之一個實施例中，該方法離體或在活體外實施，例如以分析NLRP3抑制對細胞之效應。
在本發明之第十一態樣之另一實施例中，該方法在活體內實施。舉例而言，該方法可包括投與有效量之本發明之第一態樣之鹽、水合物或溶劑合物、本發明之第二態樣之多晶型或本發明之第四態樣之醫藥組合物之步驟，以藉此抑制NLRP3。在一個實施例中，該方法進一步包括共投與有效量之一或多種其他活性劑之步驟。通常，投與係針對有需要之個體。
或者，本發明之第十一態樣之方法可係抑制非人類動物個體中NLRP3之方法，該方法包括向該非人類動物個體投與該鹽、水合物、溶劑合物、多晶型或醫藥組合物及視情況隨後毀傷或處死該非人類動物個體之步驟。通常，此一方法進一步包括分析一或多種來自視情況經毀傷或處死之非人類動物個體之組織或流體樣品之步驟。在一個實施例中，該方法進一步包括共投與有效量之一或多種其他活性劑之步驟。
本發明之第十二態樣提供本發明之第一態樣之鹽、水合物或溶劑合物、本發明之第二態樣之多晶型或本發明之第四態樣之醫藥組合物，其用於抑制NLRP3。通常，該用途包含向個體投與該鹽、水合物、溶劑合物、多晶型或醫藥組合物。在一個實施例中，該鹽、水合物、溶劑合物、多晶型或醫藥組合物係與一或多種其他活性劑共投與。
本發明之第十三態樣提供本發明之第一態樣之鹽、水合物或溶劑合物或本發明之第二態樣之多晶型之用途，其用於製造用於抑制NLRP3之藥劑。通常，該抑制包含向個體投與該鹽、水合物、溶劑合物、多晶型或藥劑。在一個實施例中，該鹽、水合物、溶劑合物、多晶型或藥劑係與一或多種其他活性劑共投與。
在包含使用或共投與一或多種其他活性劑之本發明之第五至第十三態樣中任一態樣之任一實施例中，該一或多種其他活性劑可包含(例如)一種、兩種或三種不同其他活性劑。
該一或多種其他活性劑可在彼此及/或本發明之第一態樣之鹽、水合物或溶劑合物、本發明之第二態樣之多晶型或本發明之第四態樣之醫藥組合物之前、與其同時、依序或隨後使用或投與。在該一或多種其他活性劑與本發明之鹽、水合物、溶劑合物、多晶型或醫藥組合物同時投與之情形下，可投與本發明之第四態樣之醫藥組合物，其中該醫藥組合物另外包含該一或多種其他活性劑。
在包含使用或共投與一或多種其他活性劑之本發明之第五至第十三態樣中任一態樣之一個實施例中，該一或多種其他活性劑係選自：
(i) 化學治療劑；
(ii) 抗體；
(iii) 烷基化劑；
(iv) 抗代謝物；
(v) 抗血管生成劑；
(vi) 植物鹼及/或萜類；
(vii) 拓撲異構酶抑制劑；
(viii) mTOR抑制劑；
(ix) 二苯乙烯類；
(x) STING促效劑；
(xi) 癌症疫苗；
(xii) 免疫調節劑；
(xiii) 抗生素；
(xiv) 抗真菌劑；
(xv) 抗蠕蟲劑；及/或
(xvi) 其他活性劑。
(i) 化學治療劑；
(ii) 抗體；
(iii) 烷基化劑；
(iv) 抗代謝物；
(v) 抗血管生成劑；
(vi) 植物鹼及/或萜類；
(vii) 拓撲異構酶抑制劑；
(viii) mTOR抑制劑；
(ix) 二苯乙烯類；
(x) STING促效劑；
(xi) 癌症疫苗；
(xii) 免疫調節劑；
(xiii) 抗生素；
(xiv) 抗真菌劑；
(xv) 抗蠕蟲劑；及/或
(xvi) 其他活性劑。
應瞭解，根據活性劑之寬類別定義之該等一般實施例不相互排斥。就此而言，可根據上述一般實施例中之一者以上對任何特定活性劑進行分類。非限制性實例係烏瑞魯單抗(urelumab)，其係用於治療癌症之免疫調節劑抗體。
在一些實施例中，一或多種化學治療劑係選自乙酸阿比特龍(abiraterone acetate)、六甲蜜胺(altretamine)、安吖啶(amsacrine)、脫水長春鹼(anhydrovinblastine)、奧里斯他汀(auristatin)、硫唑嘌呤、阿德力黴素(adriamycin)、貝沙羅汀(bexarotene)、比卡魯胺(bicalutamide)、BMS 184476、博來黴素(bleomycin)、N,N-二甲基-L-纈胺醯基-L-纈胺醯基-N-甲基-L-纈胺醯基-L-脯胺醯基-L-脯胺酸-第三丁基醯胺、順鉑(cisplatin)、卡鉑(carboplatin)、卡鉑環磷醯胺、氮芥苯丁酸(chlorambucil)、惡病質素(cachectin)、西馬多丁(cemadotin)、環磷醯胺、卡莫司汀(carmustine)、念珠藻素(cryptophycin)、阿糖胞苷(cytarabine)、多西他賽(docetaxel)、多西紫杉醇(doxetaxel)、多柔比星(doxorubicin)、達卡巴嗪(dacarbazine)(DTIC)、放線菌素D (dactinomycin)、道諾黴素(daunorubicin)、地西他濱(decitabine)、尾海兔素(dolastatin)、依託泊苷(etoposide)、磷酸依託泊苷、恩雜魯胺(enzalutamide)(MDV3100)、5-氟尿嘧啶、氟達拉濱(fludarabine)、氟他胺(flutamide)、吉西他濱(gemcitabine)、羥基脲及羥基脲紫杉烷、伊達比星(idarubicin)、異環磷醯胺(ifosfamide)、伊立替康(irinotecan)、甲醯四氫葉酸、氯尼達明(lonidamine)、洛莫司汀(lomustine)(CCNU)、拉洛他賽(larotaxel)(RPR109881)、甲基二氯乙基胺、巰嘌呤、胺甲喋呤(methotrexate)、絲裂黴素C (mitomycin C)、米托蒽醌(mitoxantrone)、美法侖(melphalan)、米伏布爾(mivobulin)、3',4'-二去氫-4'-去氧-8'-去甲長春鹼、尼魯米特(nilutamide)、奧沙利鉑(oxaliplatin)、奧那司酮(onapristone)、潑尼莫司汀(prednimustine)、丙卡巴肼(procarbazine)、太平洋紫杉醇(paclitaxel)、含鉑抗癌劑、2,3,4,5,6-五氟-N-(3-氟-4-甲氧基苯基)苯磺醯胺、潑尼莫司汀(prednimustine)、丙卡巴肼、利索新(rhizoxin)、色特奈福(sertenef)、鏈脲黴素(streptozocin)、磷酸司曲莫司汀(stramustine phosphate)、維A酸(tretinoin)、他索那敏(tasonermin)、紫杉醇、托泊替康(topotecan)、他莫昔芬(tamoxifen)、替尼泊苷(teniposide)、紫杉烷、替加氟(tegafur)/尿嘧啶、長春新鹼(vincristine)、長春鹼(vinblastine)、長春瑞濱(vinorelbine)、長春地辛(vindesine)、硫酸長春地辛及/或長春氟寧(vinflunine)。
或者或另外，一或多種化學治療劑可選自CD59補體片段、纖連蛋白片段、gro-β (CXCL2)、肝素酶、肝素六醣片段、人類絨毛膜促性腺激素(hCG)、干擾素α、干擾素β、干擾素γ、干擾素誘導型蛋白(IP-10)、介白素-12、環狀結構區5 (纖維蛋白溶酶原片段)、金屬蛋白酶抑制劑(TIMP)、2-甲氧基雌二醇、胎盤核糖核酸酶抑制劑、纖維蛋白溶酶原活化劑抑制劑、血小板因子-4 (PF4)、泌乳素16 kD片段、增殖蛋白相關蛋白(PRP)、各種類視色素、四氫皮質醇-S、凝血酶敏感蛋白-1 (TSP-1)、轉化生長因子-β (TGF-β)、血管抑制素、血管形成抑制素(鈣網蛋白片段)及/或細胞介素(包括介白素，諸如介白素-2 (IL-2)或IL-10)。
在一些實施例中，一或多種抗體可包含一或多種單株抗體。在一些實施例中，該一或多種抗體係選自阿昔單抗(abciximab)、阿達木單抗(adalimumab)、阿倫單抗(alemtuzumab)、阿塔珠單抗(atlizumab)、巴利昔單抗(basiliximab)、貝利木單抗(belimumab)、貝伐珠單抗(bevacizumab)、貝倫妥單抗維多汀(bretuximab vedotin)、卡那單抗、西妥昔單抗(cetuximab)、賽妥珠單抗注射液(ceertolizumab pegol)、達克珠單抗(daclizumab)、地諾單抗(denosumab)、依庫珠單抗(eculizumab)、依法利珠單抗(efalizumab)、吉妥珠單抗(gemtuzumab)、戈利木單抗(golimumab)、替伊莫單抗(ibritumomab tiuxetan)、英利昔單抗(infliximab)、伊匹單抗(ipilimumab)、莫羅單抗-CD3 (muromonab-CD3)、那他珠單抗(natalizumab)、奧法木單抗(ofatumumab)、奧馬珠單抗(omalizumab)、帕利珠單抗(palivizumab)、帕尼單抗(panitumuab)、蘭尼單抗(ranibizumab)、利妥昔單抗(rituximab)、托珠單抗(tocilizumab)、托西莫單抗(tositumomab)及/或曲妥珠單抗(trastuzumab)。
在一些實施例中，一或多種烷基化劑可包含能夠在存在於細胞(包括(例如)癌細胞)中之條件下使親核官能基烷基化之劑。在一些實施例中，該一或多種烷基化劑係選自順鉑、卡鉑、甲基二氯乙基胺、環磷醯胺、氮芥苯丁酸、異環磷醯胺及/或奧沙利鉑。在一些實施例中，烷基化劑可藉由與生物學上重要分子中之胺基、羧基、硫氫基及/或磷酸酯基形成共價鍵損害細胞功能來起作用。在一些實施例中，烷基化劑可藉由修改細胞之DNA來起作用。
在一些實施例中，一或多種抗代謝物可包含能夠影響或防止RNA或DNA合成之劑。在一些實施例中，該一或多種抗代謝物係選自硫唑嘌呤及/或巰嘌呤。
在一些實施例中，一或多種抗血管生成劑係選自內皮抑素、血管生成素抑制劑、血管抑素、血管抑制蛋白(angioarrestin)、血管抑素(纖維蛋白溶酶原片段)、基底膜膠原源抗血管生成因子(腫瘤抑素、血管能抑素或抑制蛋白)、抗血管生成抗凝血酶III及/或軟骨源抑制劑(CDI)。
在一些實施例中，一或多種植物鹼及/或萜類可阻止微管功能。在一些實施例中，該一或多種植物鹼及/或萜類係選自長春花生物鹼、鬼臼毒素(podophyllotoxin)及/或紫杉烷。在一些實施例中，一或多種長春花生物鹼可源自長春花(Madagascar periwinkle)、日日春(Catharanthus roseus)(舊稱四時花(Vinca rosea))，且可選自長春新鹼、長春鹼、長春瑞濱及/或長春地辛。在一些實施例中，一或多種紫杉烷係選自紫杉醇、太平洋紫杉醇、多西他賽及/或奧他賽(ortataxel)。在一些實施例中，一或多種鬼臼毒素係選自依託泊苷及/或替尼泊苷。
在一些實施例中，一或多種拓撲異構酶抑制劑係選自I型拓撲異構酶抑制劑及/或II型拓撲異構酶抑制劑，且可藉由干擾DNA成為超螺旋而干擾DNA之轉錄及/或複製。在一些實施例中，一或多種I型拓撲異構酶抑制劑可包含喜樹鹼(camptothecin)，其可選自依沙替康(exatecan)、伊立替康、勒托替康(lurtotecan)、托泊替康、BNP 1350、CKD 602、DB 67 (AR67)及/或ST 1481。在一些實施例中，一或多種II型拓撲異構酶抑制劑可包含表鬼臼毒素(epipodophyllotoxin)，其可選自安吖啶、依託泊苷、磷酸依託泊苷及/或替尼泊苷。
在一些實施例中，一或多種mTOR (雷帕黴素(rapamycin)之哺乳動物靶標，亦稱為雷帕黴素之機械靶標)抑制劑係選自雷帕黴素、依維莫司(everolimus)、替西羅莫司(temsirolimus)及/或地伏莫司(deforolimus)。
在一些實施例中，一或多種二苯乙烯類係選自白藜蘆醇(resveratrol)、白皮杉醇(piceatannol)、銀松素(pinosylvin)、紫檀芪(pterostilbene)、α-維尼非林(alpha-viniferin)、蛇葡萄素A (ampelopsin A)、蛇葡萄素E、地妥因萘素C (diptoindonesin C)、地妥因萘素F、ε-維尼非林、福續索A (flexuosol A)、吉奈汀H (gnetin H)、海樂亞諾爾D (hemsleyanol D)、希臘苯酚(hopeaphenol)、反式-地妥因萘素B、阿斯曲吉(astringin)、雲杉新甙(piceid)及/或地妥因萘素A。
在一些實施例中，一或多種STING (干擾素基因刺激物，亦稱為跨膜蛋白(TMEM) 173)促效劑可包含環狀二核苷酸，諸如cAMP、cGMP及cGAMP，及/或經修飾之環狀二核苷酸，其可包括以下修飾特徵中之一或多者：2'-O/3'-O鍵聯、硫代磷酸酯鍵聯、腺嘌呤及/或鳥嘌呤類似物及/或2'-OH修飾(例如利用甲基保護2'-OH或由-F或-N3
置換2'-OH)。
在一些實施例中，一或多種癌症疫苗係選自HPV 疫苗、B型肝炎疫苗、Oncophage及/或Provenge。
在一些實施例中，一或多種免疫調節劑可包含免疫檢查點抑制劑。免疫檢查點抑制劑可靶向免疫檢查點受體或受體之組合，該等受體包含(例如) CTLA-4、PD-1、PD-L1、PD-L2、T細胞免疫球蛋白及黏蛋白3 (TIM3或HAVCR2)、半乳糖凝集素9、磷酯醯絲胺酸、淋巴球活化基因3蛋白(LAG3)、I類MHC、II類MHC、4-1BB、4-1BBL、OX40、OX40L、GITR、GITRL、CD27、CD70、TNFRSF25、TL1A、CD40、CD40L、HVEM、LIGHT、BTLA、CD160、CD80、CD244、CD48、ICOS、ICOSL、B7-H3、B7-H4、VISTA、TMIGD2、HHLA2、TMIGD2、嗜乳脂蛋白(包括BTNL2)、Siglec家族成員、TIGIT、PVR、殺手細胞免疫球蛋白樣受體、ILT、白血球免疫球蛋白樣受體、NKG2D、NKG2A、MICA、MICB、CD28、CD86、SIRPA、CD47、VEGF、神經纖毛蛋白、CD30、CD39、CD73、CXCR4及/或CXCL12。
在一些實施例中，免疫檢查點抑制劑係選自烏瑞魯單抗、PF-05082566、MEDI6469、TRX518、瓦利單抗(varlilumab)、CP-870893、派姆單抗(pembrolizumab)(PD1)、尼沃魯單抗(nivolumab)(PD1)、阿替珠單抗(atezolizumab)(舊稱MPDL3280A) (PD-L1)、MEDI4736 (PD-L1)、阿維魯單抗(avelumab)(PD-L1)、PDR001 (PD1)、BMS-986016、MGA271、利麗單抗(lirilumab)、IPH2201、依妥珠單抗(emactuzumab)、INCB024360、加魯色替(galunisertib)、烏樂庫魯單抗(ulocuplumab)、BKT140、巴維昔單抗(bavituximab)、CC-90002、貝伐珠單抗及/或MNRP1685A。
在一些實施例中，一或多種抗生素係選自阿米卡星(amikacin)、慶大黴素(gentamicin)、康黴素(kanamycin)、新黴素(neomycin)、奈替米星(netilmicin)、妥布黴素(tobramycin)、巴龍黴素(paromomycin)、鏈黴素(streptomycin)、大觀黴素(spectinomycin)、格爾德黴素(geldanamycin)、除莠黴素(herbimycin)、利福昔明(rifaximin)、氯碳頭孢(loracarbef)、厄他培南(ertapenem)、多尼培南(doripenem)、亞胺培南(imipenem)、西司他汀(cilastatin)、美羅培南(meropenem)、頭孢羥胺苄(cefadroxil)、頭孢若林(cefazolin)、頭孢婁新(cefalotin)、頭孢噻吩(cefalothin)、頭孢胺苄(cefalexin)、頭孢可若(cefaclor)、頭孢孟多(cefamandole)、頭孢西丁(cefoxitin)、頭孢丙烯(cefprozil)、頭孢呋辛(cefuroxime)、希復欣敏(cefixime)、頭孢地尼(cefdinir)、頭孢托侖(cefditoren)、頭孢哌酮(cefoperazone)、頭孢噻肟(cefotaxime)、頭孢泊肟(cefpodoxime)、頭孢他啶(ceftazidime)、頭孢布烯(ceftibuten)、頭孢唑肟(ceftizoxime)、頭孢曲松(ceftriaxone)、頭孢吡肟(cefepime)、頭孢洛林酯(ceftaroline fosamil)、頭孢吡普(ceftobiprole)、替考拉寧(teicoplanin)、萬古黴素(vancomycin)、特拉萬星(telavancin)、達巴萬星(dalbavancin)、奧利萬星(oritavancin)、克林達黴素(clindamycin)、林可黴素(lincomycin)、達托黴素(daptomycin)、阿奇黴素(azithromycin)、克拉黴素(clarithromycin)、地紅黴素(dirithromycin)、紅黴素(erythromycin)、羅紅黴素(roxithromycin)、醋竹桃黴素(troleandomycin)、泰利黴素(telithromycin)、螺旋黴素(spiramycin)、胺曲南(aztreonam)、呋喃唑酮(furazolidone)、呋喃妥因(nitrofurantoin)、利奈唑胺(linezolid)、泊斯挫胺(posizolid)、雷得唑來(radezolid)、特地佐利(torezolid)、阿莫西林(amoxicillin)、胺苄青黴素(ampicillin)、阿洛西林(azlocillin)、卡本西林(carbenicillin)、氯噻青黴素(cloxacillin)、二氯噻青黴素(dicloxacillin)、氟氯西林(flucloxacillin)、美洛西林(mezlocillin)、甲氧西林(methicillin)、萘夫西林(nafcillin)、扼煞西林(oxacillin)、青黴素G、青黴素V、必倍西林(piperacillin)、替莫西林(temocillin)、替卡西林(ticarcillin)、克拉維酸鹽(clavulanate)、胺苄青黴素、舒巴坦(subbactam)、三唑巴坦(tazobactam)、替卡西林、克拉維酸鹽、桿菌肽、黏菌素、多黏菌素B、環丙沙星(ciprofloxacin)、依諾沙星(enoxacin)、加替沙星(gatifloxacin)、吉米沙星(gemifloxacin)、左氧氟沙星(levofloxacin)、洛美沙星(lomefloxacin)、莫西沙星(moxifloxacin)、萘啶酮酸(nalidixic acid)、諾氟沙星(norfloxacin)、氧氟沙星(ofloxacin)、曲伐沙星(trovafloxacin)、格帕沙星(grepafloxacin)、司帕沙星(sparfloxacin)、替馬沙星(temafloxacin)、磺胺米隆(mafenide)、磺乙醯胺、磺胺嘧啶(sulfadiazine)、磺胺嘧啶銀、磺胺地托辛(sulfadimethoxine)、磺胺甲噁唑、磺胺劑(sulfanamide)、磺胺塞拉金(sulfasalazine)、磺胺異噁唑(sulfisoxazole)、甲氧苄啶-磺胺甲噁唑(trimethoprim-sulfamethoxazole)、磺醯胺柯衣定(sulfonamideochrysoidine)、地美環素(demeclocycline)、米諾四環素(minocycline)、羥四環素(oytetracycline)、四環素(tetracycline)、氯法齊明(clofazimine)、胺苯碸(dapsone)、捲曲黴素(dapreomycin)、環絲胺酸、乙胺丁醇(ethambutol)、乙硫異菸胺(ethionamide)、異菸酸肼(isoniazid)、吡嗪醯胺、利福平(rifampicin)、利福布汀(rifabutin)、利福噴丁(rifapentine)、鏈黴素、胂凡納明(arsphenamine)、氯黴素(chloramphenicol)、磷黴素(fosfomycin)、夫西地酸(fusidic acid)、甲硝唑(metronidazole)、莫匹羅星(mupirocin)、平板黴素(platensimycin)、奎奴普汀(quinupristin)、達福普汀(dalopristin)、甲碸黴素(thiamphenicol)、老虎黴素(tigecycyline)、替硝唑(tinidazole)、甲氧苄啶(trimethoprim)及/或泰斯巴汀(teixobactin)。
在一些實施例中，一或多種抗生素可包含一或多種細胞毒性抗生素。在一些實施例中，一或多種細胞毒性抗生素係選自放線菌素、蒽二酮、蒽環、沙利竇邁(thalidomide)、二氯乙酸、菸鹼酸、2-去氧葡萄糖及/或克風敏(chlofazimine)。在一些實施例中，一或多種放線菌素係選自放線菌素D、桿菌肽、黏菌素(多黏菌素E)及/或多黏菌素B。在一些實施例中，一或多種蒽二酮係選自米托蒽醌及/或匹杉瓊(pixantrone)。在一些實施例中，一或多種蒽環係選自博來黴素、多柔比星(阿德力黴素)、道諾黴素(daunorubicin、daunomycin)、泛艾黴素(epirubicin)、伊達比星、絲裂黴素、普卡黴素(plicamycin)及/或戊柔比星(valrubicin)。
在一些實施例中，一或多種抗真菌劑係選自聯苯苄唑(bifonazole)、布康唑(butoconazole)、克黴唑(clotrimazole)、益康唑(econazole)、酮康唑(ketoconazole)、魯利康唑(luliconazole)、咪康唑(miconazole)、奧莫康唑(omoconazole)、奧昔康唑(oxiconazole)、舍他康唑(sertaconazole)、硫康唑(sulconazole)、噻康唑(tioconazole)、阿巴康唑(albaconazole)、艾氟康唑(efinaconazole)、氟環唑(epoziconazole)、氟康唑(fluconazole)、艾沙康唑(isavuconazole)、伊曲康唑(itraconazole)、泊沙康唑(posaconazole)、丙環唑(propiconazole)、雷夫康唑(ravusconazole)、特康唑(terconazole)、伏立康唑(voriconazole)、阿巴芬淨(abafungin)、阿莫羅芬(amorolfin)、布替萘芬(butenafine)、萘替芬(naftifine)、特比萘芬(terbinafine)、阿尼芬淨(anidulafungin)、卡泊芬淨(caspofungin)、米卡芬淨(micafungin)、苯甲酸、環吡酮(ciclopirox)、氟胞嘧啶、5-氟胞嘧啶、灰黃黴素(griseofulvin)、鹵普羅近(haloprogin)、托奈福特(tolnaflate)、十一烷烯酸及/或秘魯香膠)。
在一些實施例中，一或多種抗蠕蟲劑係選自苯并咪唑類(包括阿苯達唑(albendazole)、甲苯達唑(mebendazole)、噻苯咪唑(thiabendazole)、芬苯達唑(fenbendazole)、三氯苯達唑(triclabendazole)及氟苯達唑(flubendazole))、阿巴汀(abamectin)、二乙基乙胺嗪、伊維菌素(ivermectin)、舒拉明(suramin)、雙羥萘酸噻嘧啶、左旋咪唑(levamisole)、柳基苯胺類(salicylanilide)(包括氯硝柳胺(niclosamide)及羥氯紮胺(oxyclozanide))及/或硝唑尼特(nitazoxanide)。
在一些實施例中，其他活性劑係選自生長抑制劑、抗發炎劑(包括非類固醇抗發炎劑)、抗牛皮癬劑(包括蒽酚及其衍生物)、維生素及維生素衍生物(包括類視色素及VDR受體配位體)、皮質類固醇、離子通道阻斷劑(包括鉀通道阻斷劑)、免疫系統調節劑(包括環孢素、FK 506及糖皮質激素)、黃體化激素釋放激素促效劑(諸如亮丙瑞林(leuprolidine)、戈舍瑞林(goserelin)、曲普瑞林(triptorelin)、組胺瑞林(histrelin)、比卡魯胺、氟他胺及/或尼魯米特)及/或激素(包括雌激素)。
除非另有說明，否則在本發明之第五至第十三態樣中之任一態樣中，個體可係任何人類或其他動物。通常，個體係哺乳動物，更通常為人類或家養哺乳動物，諸如牛、豬、羔羊、綿羊、山羊、馬、貓、狗、兔、小鼠等。最通常地，個體係人類。
本發明中所採用之任一藥劑可藉由以下來投與：經口、非經腸(包括靜脈內、皮下、肌內、真皮內、氣管內、腹膜內、關節內、顱內及硬膜外)、氣道(氣溶膠)、經直腸、經陰道、經眼或經局部(包括經皮、經頰、經黏膜、舌下及局部經眼)投與。
通常，所選投與模式最適合於欲治療或預防之病症、疾病或病狀。倘若投與一或多種其他活性劑，則投與模式可與本發明之鹽、水合物、溶劑合物、多晶型或醫藥組合物之投與模式相同或不同。
對於經口投與而言，本發明之鹽、水合物、溶劑合物、多晶型或醫藥組合物通常將以以下形式提供：錠劑、膠囊、硬質或軟質明膠膠囊、膠囊型錠劑、糖錠劑或菱形錠劑、粉末或顆粒或水溶液、懸浮液或分散液。
口服用錠劑可包括與醫藥學上可接受之賦形劑混合之活性成分，該等醫藥學上可接受之賦形劑諸如惰性稀釋劑、崩解劑、黏合劑、潤滑劑、甜味劑、矯味劑、著色劑及防腐劑。適宜惰性稀釋劑包括碳酸鈉及碳酸鈣、磷酸鈉及磷酸鈣以及乳糖。玉米澱粉及海藻酸係適宜崩解劑。黏合劑可包括澱粉及明膠。潤滑劑(若存在)可係硬脂酸鎂、硬脂酸或滑石粉。若期望，錠劑可經諸如單硬脂酸甘油基酯或二硬脂酸甘油基酯之材料包衣，以延遲在胃腸道中之吸收。錠劑亦可係泡騰劑及/或溶解錠劑。
口服用膠囊包括其中活性成分與固體稀釋劑混合之硬質明膠膠囊，及其中活性成分與水或油(諸如花生油、液體石蠟或橄欖油)混合之軟質明膠膠囊。
口服用粉末或顆粒可以小藥囊或小藥盒(tub)提供。水溶液、懸浮液或分散液可藉由將水添加至粉末、顆粒或錠劑來製備。
適於經口投與之任一形式可視情況包括甜味劑(諸如糖)、矯味劑、著色劑及/或防腐劑。
用於經直腸投與之調配物可作為具有適宜基質之栓劑呈遞，該適宜基質包含(例如)可可脂或柳酸酯。
適於經陰道投與之調配物可作為陰道栓、陰道塞、乳霜、凝膠、膏糊、泡沫或噴霧調配物呈遞，其除活性成分以外亦含有此項技術中已知適當之此等載劑。
對於非經腸使用而言，本發明之鹽、水合物、溶劑合物或多晶型通常將以緩衝至適當pH及等滲性之無菌水溶液或懸浮液提供。適宜水性媒劑包括林格氏溶液(Ringer’s solution)及等滲氯化鈉或葡萄糖。本發明之水性懸浮液可包括懸浮劑(諸如纖維素衍生物、海藻酸鈉、聚乙烯基吡咯啶酮及黃蓍膠)及潤濕劑(諸如卵磷脂)。用於水性懸浮液之適宜防腐劑包括對羥基苯甲酸乙酯及對羥基苯甲酸正丙酯。本發明之鹽、水合物、溶劑合物、多晶型或醫藥組合物亦可作為脂質體調配物呈遞。
對於經眼投與而言，本發明之鹽、水合物、溶劑合物或多晶型通常將以適於局部投與之形式提供，例如作為滴眼液。適宜形式可包括眼用溶液、凝膠形成溶液、復溶用無菌粉末、眼用懸浮液、眼用軟膏劑、眼用乳液、眼用凝膠及眼用嵌入劑。或者，本發明之鹽、水合物、溶劑合物或多晶型可以適於其他類型之經眼投與之形式來提供，例如作為眼內製劑(包括作為灌洗溶液、作為眼內、玻璃體內或近鞏膜注射調配物或作為玻璃體內植入物)、作為封裝或角膜護罩、作為前房內、結膜下或眼球後注射調配物或作為離子電滲調配物。
對於經皮及其他局部投與而言，本發明之鹽、水合物、溶劑合物、多晶型或醫藥組合物通常將以以下形式提供：軟膏劑、泥罨劑(糊藥)、膏糊、粉末、敷料、乳霜、硬膏劑或貼片。
適宜懸浮液及溶液可用於吸入器中以供氣道(氣溶膠)投與。
本發明之鹽、水合物、溶劑合物或多晶型之劑量當然將隨欲治療或預防之疾病、病症或病狀而變。一般而言，適宜劑量將在0.01 mg/公斤接受者體重/天至500 mg/公斤接受者體重/天範圍內。期望劑量可以適當間隔呈遞，諸如每隔一天一次、一天一次、一天兩次、一天三次或一天四次。期望劑量可以單位劑型投與，例如每單位劑型含有1 mg至50 g活性成分。
為避免疑問，在可行之範圍內，本發明之給定態樣之任一實施例可與本發明之同一態樣之任何其他實施例組合發生。另外，在可行之範圍內，應理解，本發明之任一態樣之任何一較佳、典型或視情況選用之實施例亦應視為本發明之任何其他態樣之較佳、典型或視情況選用之實施例。
實例
實例
除非另有說明，否則所有溶劑、試劑及化合物均為購買的且不經進一步純化即使用。
實例中所提及之X射線粉末繞射(XRPD)、離子層析(IC)、卡爾費希爾滴定(Karl Fischer titration，KF)、熱重分析(TGA)、差示掃描量熱法(DSC)及高效液相層析(HPLC)技術係在以下條件下實施：
使用CuKα輻射(40 kV, 40 mA)及裝配有Ge單色器之θ-2θ測角器在Bruker D8繞射儀上收集XRPD繞射圖。入射束穿過2.0 mm發散狹縫，之後穿過0.2 mm防散射狹縫及刀口。繞射束穿過具有2.5°索勒狹縫(Soller slit)之8.0 mm接收狹縫，之後為Lynxeye偵測器。用於數據收集及分析之軟體分別係Diffrac Plus XRD Commander及Diffrac Plus EVA。使用呈接收原樣之粉末，在環境條件下以平板試樣形式對樣品進行操作。在拋光零背景(510)矽晶圓上藉由輕輕地壓至平坦表面上或封裝至切割腔中來製備樣品。使樣品在其自身平面中旋轉。所用s數據收集方法之細節為：
• 角度範圍：2° 2θ至42° 2θ
• 步長：0.05° 2θ
• 收集時間：0.5 s/步(總收集時間：6.40 min)
使用CuKα輻射(40 kV, 40 mA)及裝配有Ge單色器之θ-2θ測角器在Bruker D8繞射儀上收集XRPD繞射圖。入射束穿過2.0 mm發散狹縫，之後穿過0.2 mm防散射狹縫及刀口。繞射束穿過具有2.5°索勒狹縫(Soller slit)之8.0 mm接收狹縫，之後為Lynxeye偵測器。用於數據收集及分析之軟體分別係Diffrac Plus XRD Commander及Diffrac Plus EVA。使用呈接收原樣之粉末，在環境條件下以平板試樣形式對樣品進行操作。在拋光零背景(510)矽晶圓上藉由輕輕地壓至平坦表面上或封裝至切割腔中來製備樣品。使樣品在其自身平面中旋轉。所用s數據收集方法之細節為：
• 角度範圍：2° 2θ至42° 2θ
• 步長：0.05° 2θ
• 收集時間：0.5 s/步(總收集時間：6.40 min)
使用IC MagicNet軟體，在具有858專業自動進樣器及800 Dosino劑量單位監測器之Metrohm 930 Compact IC Flex上收集IC數據。將準確稱重之樣品於適宜溶劑中製備為原液。藉由與已知濃度之所分析離子之標準溶液進行比較來達成量化。除非另有說明，否則以一式兩份來實施分析且給出值之平均值。
用於陽離子層析之 IC 方法
用於陰離子層析之 IC 方法
用於陽離子層析之 IC 方法
使用Hydranal Coulomat AG烘箱試劑及氮氣吹掃，利用851 Titrano庫侖計在150℃下在Metrohm 874烘箱樣品處理器上實施KF分析。將稱重之固體樣品引入至密封之樣品小瓶中。每次滴定使用大約10 mg樣品，且進行一式兩份測定。除非另有說明，否則呈現該等結果之平均值。使用Tiamo軟體實施數據收集及分析。
在配備有25位自動進樣器之TA Instruments Discovery TGA上收集TGA數據。通常，將5-10 mg每一樣品加載至預先配衡之鋁DSC盤上，且以10℃/min自環境溫度加熱至350℃。在樣品上方維持25 ml/min之氮氣吹掃。儀器控制軟體係TRIOS，且使用TRIOS或Universal分析來分析數據。
在配備有50位自動進樣器之TA Instruments Q2000上收集DSC數據。通常，將於具針孔鋁盤中之0.5-3 mg每一樣品以10℃/min自25℃加熱至300℃。在樣品上方維持50 ml/min之乾燥氮氣吹掃。使用2℃/min之基礎加熱速率及每60秒(週期) ±0.636℃ (幅度)之溫度調製參數實施調製式溫度DSC。儀器控制軟體係Advantage for Q Series及Thermal Advantage，且使用Universal分析或TRIOS來分析數據。
在配備有二極體陣列偵測器之Agilent HP1100系列系統上且使用ChemStation軟體來實施反相HPLC純度分析。
用於化學純度測定之 HPLC 方法
實例1：N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺單鈉一水合物(形式1)
用於化學純度測定之 HPLC 方法
將N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺游離酸稱重至四個小瓶中(每小瓶50 mg)。將NaOH (1 M於水中) (參見表3之添加當量/體積)及水(4 ml)添加至該等樣品小瓶中之每一者。該等樣品經受之條件彙總於表3中。樣品在溶液中保持攪拌3小時。接著試圖藉由旋轉蒸發器去除水，但3小時後所去除之水量極小。接著使溶液展開在載玻片上以在室溫下蒸發。收集所形成之固體，且藉由XRPD、1
H-NMR、HPLC、IC及KF進行分析。IC及KF分析確認形成單鈉鹽一水合物。XRPD分析確認形成形式1多晶型物。
表 3
實例2：N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺單鈉一水合物(形式1)
表 3
將N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺游離酸(50 mg)用丙酮及水之9:1 (v:v)溶劑混合物(0.5 ml)處理。在25℃下攪拌所得懸浮液，之後添加NaOEt (1.1當量，1 M EtOH溶液)。再添加NaOEt溶液直至完全溶解為止(總計1.3當量NaOEt)。將第三丁基甲醚反溶劑(0.25 ml)添加至每一樣品，之後添加N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺單鈉一水合物形式1多晶型物之晶種(約2%-4%)。再添加第三丁基甲醚反溶劑以產生1:3 (實例2A)及1:5 (實例2B)之最終溶劑:反溶劑比。接著將樣品在25℃下攪拌2小時，之後經由PE玻料分離固體。接著將樣品在真空下在室溫下儲存18小時，之後藉由XRPD、1
H-NMR、HPLC、IC、KF、TGA及DSC進行分析。
表 4
表 4
IC及KF分析確認形成單鈉鹽一水合物。XRPD分析確認形成形式1多晶型物。XRPD光譜示於圖1中。TGA及DSC光譜示於圖2中。
圖1中所示之XRPD光譜係直接在產物製備後、在40℃及75%相對濕度下儲存1週及5週後以及在25℃及97%相對濕度下儲存1週及5週後獲得的。圖1中所示之XRPD光譜指示，實例2中所獲得之產物在升高之溫度及濕度下儲存後顯示關於轉化成其他多晶型之穩定性。
實例3：N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺單鈉無水物(形式2)
實例3：N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺單鈉無水物(形式2)
將N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺單鈉鹽(500 mg)用異丙醇及H2
O之10:1 (v:v)溶劑混合物(30 ml)處理，且將反應混合物在25℃下攪拌30分鐘。接著使所得澄清溶液蒸發以產生結晶固體，藉由XRPD、1
H-NMR、HPLC、IC、KF、TGA及DSC分析該結晶固體。
IC及KF分析確認形成單鈉鹽無水物。HPLC純度係96.5%。XRPD分析確認形成形式2多晶型物。XRPD光譜示於圖3中。TGA及DSC光譜示於圖4中。
圖3中所示之XRPD光譜係直接在產物製備後、在40℃及75%相對濕度下儲存1週後及在25℃及97%相對濕度下儲存1週後獲得的。圖3亦顯示形式1多晶型物之XRPD光譜以供參照。圖3中所示之XRPD光譜指示，實例3中所獲得之單鈉無水物(形式2)在升高之溫度(40℃)下係穩定的，且在升高之濕度(97% RH)下轉化成單鈉一水合物(形式1)。
比較實例1：N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺游離酸
比較實例1：N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺游離酸
N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺游離酸係如WO 2016/131098 A1中所闡述來製備。
比較實例2：N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺鉀鹽
比較實例2：N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺鉀鹽
稱出N
-((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H
-吡唑-3-磺醯胺游離酸(100 mg)，且添加KOH (1.1當量，1 M水溶液，283 μl)。添加水，且在室溫下攪拌反應混合物直至獲得澄清溶液為止。將反應混合物攪拌2小時，且接著藉由旋轉蒸發隔夜來去除水以產生固體，藉由XRPD、1
H-NMR、HPLC及IC分析該固體。
IC分析確認形成鉀鹽。HPLC純度係96.3%。XRPD分析揭示無明顯繞射峰之完全非晶形材料。
藉由自乙腈或異丙醇蒸發來試圖使鉀鹽轉化成結晶物質係不成功的，在每一情形下均產生膠狀物。
評估實例1
評估實例1
評估實例2之鈉鹽及比較實例1之游離酸於水中之溶解度、於水性介質中之穩定性及固有溶解速率。結果列於表5中。
表5
表5
於水中量測熱力學水溶解度。發現鈉鹽可溶於水(81 mg/ml)中，所得pH為9.7。發現游離酸於水中之溶解度極差(＜0.5 mg/ml)。
為量測於水性介質中之穩定性，將鈉鹽以0.2 mg/ml之濃度溶解於水中。由於游離酸之水溶解度極差，因此將游離酸以0.2 mg/ml之相同濃度溶解於水及乙腈之1:1混合物中。將樣品在50℃下保持在琥珀色小瓶中且在室溫下保持在琥珀色小瓶以及透明小瓶中。發現鈉鹽在水性介質中穩定，而發現游離酸不穩定。
藉由美國藥典(US Pharmacopoeia)第1087章中所陳述之程序來量測固有溶解速率。發現鈉鹽之固有溶解速率至少為游離酸之兩倍。
與比較實例1及2之游離酸及鉀鹽相比，實例1、2及3之鈉鹽具有改良之性質。該等改良之性質包括結晶度、水溶解度、固有溶解速率、在升高之溫度及/或相對濕度下儲存之穩定性及於水性介質中之穩定性。
將理解，上文僅以舉例方式闡述本發明。該等實例不意欲限制本發明之範圍。在不背離僅由以下申請專利範圍界定之本發明之範圍及精神之情形下，可作出各種修改及實施例。
圖1顯示實例2之鹽的XRPD分析。
圖2顯示實例2之鹽的TGA及DSC分析。
圖3顯示實例3之鹽的XRPD分析。
圖4顯示實例3之鹽的TGA及DSC分析。
Claims (21)
- 一種N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺之鈉鹽，或其水合物或溶劑合物。
- 如申請專利範圍第1項之鹽，其中該鹽係單鈉鹽。
- 如申請專利範圍第1項或第2項之鹽，其中該鹽係一水合物。
- 如申請專利範圍第1項至第3項中任一項之鹽，其中該鹽係結晶的。
- 如申請專利範圍第1項至第4項中任一項之鹽，其中該鹽係結晶的N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺單鈉鹽一水合物。
- 一種如申請專利範圍第5項之鹽之多晶型，其具有包含在大約以下各處之峰的XRPD光譜：4.3 °2θ、8.7 °2θ及20.6 °2θ。
- 一種如申請專利範圍第5項或第6項之鹽之多晶型，其具有如下XRPD光譜：其中10個最強峰包括5個或更多個具有選自以下之近似2θ值之峰：4.3 °2θ、6.2 °2θ、6.7 °2θ、7.3 °2θ、8.7 °2θ、9.0 °2θ、12.1 °2θ、15.8 °2θ、16.5 °2θ、18.0 °2θ、18.1 °2θ、20.6 °2θ、21.6 °2θ及24.5 °2θ。
- 一種用於製備N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺之鈉鹽之方法，其包括： (a) 使N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺游離酸與鈉離子源在一或多種極性溶劑存在下接觸以形成混合物；及 (b) 自該混合物獲得N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺之固體鈉鹽。
- 如申請專利範圍第8項之方法，其中步驟(a)中所用之該一或多種極性溶劑包含水及極性非質子有機溶劑。
- 一種用於製備呈如申請專利範圍第6項或第7項之多晶型之結晶的N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺單鈉鹽一水合物之方法，其包括： (a) 使N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺游離酸與鈉離子源在水及視情況極性非質子有機溶劑存在下接觸以形成溶液；或將N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺單鈉鹽溶解於包含水及視情況極性非質子有機溶劑之溶劑混合物中以形成溶液；及 (b) 自該溶液獲得呈如申請專利範圍第6項或第7項之多晶型之結晶的N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺單鈉鹽一水合物。
- 如申請專利範圍第9項或第10項之方法，其中步驟(a)中所用之該極性非質子有機溶劑係丙酮。
- 如申請專利範圍第8項至第11項中任一項之方法，其中N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺之該鈉鹽係在步驟(b)中藉由添加反溶劑來獲得。
- 如申請專利範圍第12項之方法，其中該反溶劑係第三丁基甲醚。
- 一種N -((1,2,3,5,6,7-六氫-s-二環戊二烯并苯-4-基)胺甲醯基)-1-異丙基-1H -吡唑-3-磺醯胺之鈉鹽，其可藉由如申請專利範圍第8項至第13項中任一項之方法獲得或藉由其獲得。
- 如申請專利範圍第14項之鹽，其中該鹽係如申請專利範圍第1項至第5項中任一項之鹽或如申請專利範圍第6項或第7項之多晶型。
- 一種醫藥組合物，其包含如申請專利範圍第1項至第5項、第14項或第15項中任一項之鹽或如申請專利範圍第6項或第7項之多晶型以及醫藥學上可接受之賦形劑。
- 如申請專利範圍第1項至第5項、第14項或第15項中任一項之鹽或如申請專利範圍第6項或第7項之多晶型或如申請專利範圍第16項之醫藥組合物，其用於醫藥中。
- 如申請專利範圍第1項至第5項、第14項或第15項中任一項之鹽或如申請專利範圍第6項或第7項之多晶型或如申請專利範圍第16項之醫藥組合物，其用於治療或預防疾病、病症或病狀，其中該疾病、病症或病狀對NLRP3抑制有反應。
- 如申請專利範圍第1項至第5項、第14項或第15項中任一項之鹽或如申請專利範圍第6項或第7項之多晶型或如申請專利範圍第16項之醫藥組合物，其用於治療或預防疾病、病症或病狀，其中該疾病、病症或病狀係選自： (i) 發炎； (ii) 自體免疫疾病； (iii) 癌症； (iv) 感染； (v) 中樞神經系統疾病； (vi) 代謝疾病； (vii) 心血管疾病； (viii) 呼吸疾病； (ix) 肝病； (x) 腎病； (xi) 眼部疾病； (xii) 皮膚病； (xiii) 淋巴病狀； (xiv) 心理障礙； (xv) 移植物抗宿主病； (xvi) 觸摸痛；及 (xvii)已確定個體攜帶NLRP3中之生殖系或體細胞非沈默突變之任何疾病。
- 如申請專利範圍第1項至第5項、第14項或第15項中任一項之鹽或如申請專利範圍第6項或第7項之多晶型或如申請專利範圍第16項之醫藥組合物，其用於治療或預防疾病、病症或病狀，其中該疾病、病症或病狀係選自： (i) 隱熱蛋白相關週期性症候群(CAPS)； (ii) 穆-韋二氏症候群(Muckle-Wells syndrome，MWS)； (iii) 家族性寒冷自體發炎性症候群(FCAS)； (iv) 新生兒發作型多系統發炎性疾病(NOMID)； (v) 家族性地中海熱(FMF)； (vi) 化膿性關節炎、壞疽性膿皮症及痤瘡症候群(PAPA)； (vii) 高免疫球蛋白血症D及週期性發熱症候群(HIDS)； (viii) 腫瘤壞死因子(TNF)受體相關週期性症候群(TRAPS)； (ix) 全身性幼年型特發性關節炎； (x) 成人發作型斯蒂爾氏病(adult-onset Still’s disease，AOSD)； (xi) 復發性多發性軟骨炎； (xii) 施尼茨勒氏症候群(Schnitzler’s syndrome)； (xiii) 斯威特氏症候群(Sweet’s syndrome)； (xiv) 貝賽特氏病(Behcet’s disease)； (xv) 抗合成酶症候群； (xvi) 介白素1受體拮抗劑缺乏(DIRA)；及 (xvii) A20之單倍劑量不足(HA20)。
- 一種抑制NLRP3之方法，該方法包括使用如申請專利範圍第1項至第5項、第14項或第15項中任一項之鹽或如申請專利範圍第6項或第7項之多晶型或如申請專利範圍第16項之醫藥組合物來抑制NLRP3。
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