TWI473613B - 用作肥大細胞類胰蛋白酶抑制劑之〔4-(5-胺基甲基-2-氟-苯基)-六氫吡啶-1-基〕-〔7-氟-1-(2-甲氧基-乙基)-4-三氟甲氧基-1h-吲哚-3-基〕-甲酮 - Google Patents
用作肥大細胞類胰蛋白酶抑制劑之〔4-(5-胺基甲基-2-氟-苯基)-六氫吡啶-1-基〕-〔7-氟-1-(2-甲氧基-乙基)-4-三氟甲氧基-1h-吲哚-3-基〕-甲酮 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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Description
本發明涉及一種經取代的吲哚苯甲胺化合物及其製備、含有該化合物的醫藥組合物及其用途,以及其中間體。
肥大細胞介導的發炎症狀,尤其是哮喘,是一個日益引起關注的公共衛生問題。哮喘的特徵往往是氣管和支氣管對於免疫特異的致敏原和一般的化學或物理刺激逐漸產生高反應性,從而導致慢性炎症的發生。含IgE受體的白細胞,尤其是肥大細胞和嗜鹼細胞,存在於支氣管的上皮及下層平滑肌組織內。這些白細胞起初藉由特定的吸入抗原與IgE受體結合而被激活,然後釋放出許多化學介體。例如,肥大細胞的脫粒導致蛋白聚糖、過氧化物酶、芳基硫酸酯酶B、胃促胰酶和類胰蛋白酶的釋放,從而導致細支氣管收縮。
類胰蛋白酶貯存於肥大細胞分泌粒中,是人類肥大細胞的主要蛋白酶。類胰蛋白酶與許多生物過程有關,包括血管擴張和支氣管舒張的神經肽的降解(Caughey et al.,J. Pharmacol. Exp. Ther. 1988,244,133-137頁;Franconi et al.,J. Pharmacol. Exp.Ther.,1988,248,947-951頁;及Tam et al.,Am. J. Respir. Cell Mol. Biol.,1990,3,27-32頁)以及支氣管對組織胺的反應的調節(Sekizawa et al.,J. Clin. Invest.,1989,83,175-179頁)。
因此,類胰蛋白酶抑制劑可用作消炎劑(K Rice,P.A.Sprengler,關於藥物發現和開發的目前見解(Current Opinion in Drug Discovery and Development),1999,2(5),463-474頁),尤其是用於治療慢性哮喘(M.Q.Zhang,H.Timmerman,Mediators Inflamm.,1997,112,311-317頁),也可用於治療或預防過敏性鼻炎(S.J. Wilson et al.,Clin. Exp. Allergy,1998,28,220-227頁)、發炎性腸道疾病(S.C. Bischoff et al.,Histopathology,1996,28,1-13頁)、牛皮廯(A. Naukkarinen et al.,Arch. Dermatol. Res.,1993,285,341-346頁)、結膜炎(A.A. Irani et al.,J. Allergy Clin.Immunol.,1990,86,34-40頁)、異位性皮炎(A. Jarvikallio et al.,Br. J. Dermatol.,1997,136,871-877頁)、類風濕性關節炎(L.C Tetlow et al.,Ann. Rheum. Dis.,1998,54,549-555頁)、骨關節炎(M.G.Buckley et al.,J. Pathol.,1998,186,67-74頁)、痛風關節炎、類風濕性脊椎炎和關節軟骨破壞等疾病。
此外,已發現類胰蛋白酶是成纖維細胞的有效促細胞分裂劑,教示它參與了哮喘和間質性肺病的肺纖維化(Ruoss et al.,J. Clin.Invest.,1991,88,493-499頁)。
因此,類胰蛋白酶抑制劑可用於治療或預防纖維化症狀(J.A. Cairns和A.F. Walls,J. Clin. Invest.,1997,99,1313-1321頁),例如纖維化、硬皮症、肺纖維化、肝硬化、心肌纖維化、神經纖維瘤和肥厚性瘢痕。
另外,類胰蛋白酶抑制劑可用於治療或預防心肌梗塞、中風、心絞痛和動脈粥樣硬化斑塊破裂的其他後果(M. Jeziorska et al.,J. Pathol.,1997,182,115-122頁)。
人們還發現類胰蛋白酶可激活基質分解素前體(prostromelysin),轉而激活膠原酶,從而分別引發軟骨和牙周連接組織的破壞。
因此,類胰蛋白酶抑制劑可用於治療或預防關節炎、牙周病、糖尿病視網膜病變及腫瘤增長(W.J. Beil et al.,Exp. Hematol.,(1998)26,158-169頁)。類胰蛋白酶抑制劑還可用於治療過敏症(L.B. Schwarz et al.,J. Clin. Invest.,1995,96,2702-2710頁)、多發性硬化(M. Steinhoff et al.,Nat. Med.(N.Y.),2000,6(2),151-158頁)、消化性潰瘍及合體細胞病毒感染。
美國第6977263號專利披露了經取代的芳基甲胺,即結構式(A)所示之化合物,
此類化合物的製備,含此類化合物的醫藥組合物,及其在治療能透過抑制類胰蛋白而調節的疾病方面的醫藥用途。美國第6977263號專利特別披露的是具有如下結構式的化合物
但是,美國第6977263號專利並未披露任何其中苯基上胺基甲基的對位也被一個氟基團取代的上述[(胺基甲基苯基)-哌啶-1-基]-[吲哚基]-甲酮類化合物。而且,美國第6977263號專利,僅披露了一種[(胺基甲基苯基)-哌啶-1-基]-[吲哚基]-甲酮化合物,其中吲哚基上除了與羰基連接的芳環碳原子之外的一個芳環碳原子被取代;更具體地說,其中僅吲哚基第5位被甲氧基取代。
Bioorg. Med. Chem. Lett. 15,2734(2005)披露了三種作為類胰蛋白抑制劑的[(胺基甲基苯基)-哌啶-1-基]-[1H-吲哚-3-基]-甲酮。其中一種抑制劑涉及一種結構式為B之化合物,其中吲哚基上除了與羰基連接的芳環碳原子外所有芳環碳原子均未被取代,
其中吲哚基的氮被R1
取代,R1
是氫、甲基、乙基、異丙基、丙基、異丁基、丁基、己基、2-甲氧基乙基、環己基甲基、環丙基甲基、3-吡啶基、2-噻唑、乙醯基、噻吩-2-羰基、苯磺醯基,或甲磺醯基。第二種抑制劑涉及一種結構式為C之化合物,其中吲哚基的氮僅被氫取代,且除了與羰基連接的芳環碳原子外只有一個芳環碳原子被作為R的
甲基在第4、5、6或7位取代,或氟基在第7位取代。第三種抑制劑涉及一種結構式為D之化合物,其中吲哚基上未與羰基連接的一個芳環碳原子在第7位被甲基取代,
且吲哚基的氮原子被R1
取代,R1
是甲基、乙基、丙基、丁基,或2-甲氧基乙基。Bioorg. Med. Chem. Lett. 15,2734(2005)還披露,吲哚基上第5位或第7位芳環碳原子上的取代是可以接受的,而第4位或第6位的取代則生成活性較低的化合物。
美國第6977263號專利或Bioorg. Med. Chem. Lett. 15,2734(2005)均未披露符合下列條件的含吲哚的類胰蛋白抑制劑,其中:(1)苯基上胺基甲基的對位也被氟基團取代;(2)吲哚基的氮被2-甲氧基乙基取代;或(3)二或多個吲哚基上未與羰基連接的芳環碳原子被取代。這種化合物作為一種類胰蛋白抑制劑具有特別寶貴的醫藥性質。這種化合物應能方便地用於治療那些可用類胰蛋白酶抑制劑改善狀況的疾病,例如,以肥大細胞介導的病症、發炎以及與血管擴張和支氣管舒張的神經肽的降解相關的疾病或異常,且較不易被胺基脲敏感性胺氧化酶(SSAO)代謝。
本發明涉及式I化合物:
或上述化合物的前藥、藥學上可接受的鹽,或溶劑合物。
而且,本發明涉及一種醫藥組合物,其含有治療有效量的式I化合物以及藥學上可接受的載體。
而且,本發明還涉及將式I化合物作為類胰蛋白抑制劑使用,包括將該化合物引入一種含類胰蛋白抑制劑受體的組合物。此外,本發明還涉及將式I化合物用於治療患有或易患某種需用類胰蛋白抑制劑來改善的生理症狀的患者,包括給患者施用療效量的如申請專利範圍第1項所述之化合物。
本發明還涉及式I化合物的製備以及用於其製備的中間體。
本發明之各個方面、特點和優越性將透過以下的詳細敘述而達到更好的理解;提供該詳細敘述僅是為了說明的目的,並非旨在限制本發明。
縮寫詞表
如上文所用以及貫穿本發明之說明,下列縮寫詞應被理解為具有以下含義,除非另行說明:
n
-BuOAc 乙酸正丁酯
n
-BuLi 正丁基鋰
sec
-BuLi 仲丁基鋰
t
-Bu 叔丁基
t
-BuOH 叔丁醇
CuI 碘化亞銅
DCM 二氯甲烷,CH2
Cl2
或甲叉二氯
DMF 二甲基甲醯胺
DMSO 二甲基亞碸
dppf 1,1'-雙(二苯基膦基)二茂鐵
DSC 示差掃描量熱法
EDCI 1-乙基-3-(3-二甲基胺基丙基)碳二亞醯胺鹽酸鹽
eq 當量
Et 乙基
Et2
O 二乙醚
TEA 三乙基胺
EtOH 乙醇
EtOAc 乙酸乙酯
EtOC(O)Cl 氯甲酸乙酯
HPLC 高效液相層析
MgSO4
硫酸鎂
Me 甲基
MeOH 甲醇
MS 質譜法
MTBE 甲基叔丁基醚
NaHCO3
碳酸氫鈉
Na2
SO3
亞硫酸鈉
Na2
SO4
硫酸鈉
NMR 核磁共振
Pd(PPh3
)2
Cl2
雙三苯基膦二氯化鈀(II)
PdCl2
dppf 1,1’-雙(二苯基膦基)二茂鐵二氯化鈀(II)
Pd(dtbpf)Cl2
1,1’雙(二叔丁基膦基)二茂鐵二氯化鈀
Pd2
(dba)3
三(二亞苄基丙酮)二鈀(0)
Pd(OAc)2
乙酸鈀(II)
P(Cy)3
三環己基膦
t
-Bu3
P 三叔丁基膦
PPh3
三苯基膦
PrOH 丙醇
i
PrOH 異丙醇
i
-PrOAc 乙酸異丙酯
t
-BuOK 叔丁醇鉀
PPSE 聚磷酸三甲基甲矽烷基酯
K2
CO3
碳酸鉀
K2
SO4
硫酸鉀
LC 液相層析
Na2
SO4
硫酸鈉
rt 室溫
Rt 保留時間
TFA 三氟乙酸
TFAA 三氟乙酸酐
TGA 熱解重量分析
THF 四氫呋喃
TLC 薄層層析
TMS-乙炔 三甲基甲矽烷基-乙炔
如上文所用以及貫穿本發明之詳細說明和所附的申請專利範圍,下列術語應被理解為具有以下含義,除非另行說明:本文所用的術語「本發明之化合物」以及相當的表述,意為包括如上所述的式I化合物,該表述還包括其前藥、藥學上可接受的鹽以及溶劑合物,例如水合物。類似地,視上下文而定,當提及中間體時,無論是否就其本身提出專利權要求,均意為包括它們的鹽和溶劑合物。為了明晰起見,有時當上下文允許時會在文中舉出某些具體例子,但這些例子純粹是作為例證,並非旨在排除上下文所允許的其他例子。
本文所用的術語「治療」無論是名詞或是動詞均包括預防性治療及確診症狀的治療,例如患者症狀的改善。這類改善包括減緩疾病的發展或患者症狀的有益變化。
「患者」意為一個人或其他哺乳動物。
「有效量」旨在描述能產生預期療效的化合物之劑量。
「前藥」意為一種適宜於給患者施用而無不當毒性、刺激和過敏性反應等,且可在體內經新陳代謝(如水解)轉化為本發明之化合物的化合物。以下文獻提供了關於前驅藥物的詳盡討論:T. Higuchi and V. Stella,Pro-drugs as Novel Delivery Systems(作為新型給藥系統的前驅藥物),Vol. 14 of the A. C. S. Symposium Series,以及Edward B. Roche,ed.,Bioreversible Carriers in Drug Design(藥物設計中的生物可逆性載體),American Pharmaceutical Association and Pergamon Press,1987,兩者均作為參考文獻納入本文。
「藥學上可接受的鹽」意為這些活性成分與一種酸生成的任何鹽,它不會產生不希望有的毒性或副作用。這些酸是藥學專家們眾所周知的。適宜的鹽的非限制性例子如下:氯化物;溴化物;碘化物;天冬氨酸鹽,尤其是酸式天冬氨酸鹽;苯甲酸鹽,尤其是酸式苯甲酸鹽;檸檬酸鹽,尤其是酸式檸檬酸鹽;酒石酸鹽;磷酸鹽,尤其是酸式磷酸鹽;富馬酸鹽,尤其是酸式富馬酸鹽;甘油磷酸鹽;葡糖磷酸酯;乳酸鹽;馬來酸鹽,尤其是酸式馬來酸鹽;乳清酸鹽;草酸鹽,尤其是酸式草酸鹽;硫酸鹽,尤其是酸式硫酸鹽;三氯乙酸鹽;三氟乙酸鹽;苯磺酸鹽;甲苯磺酸鹽及甲磺酸鹽。Philip L. Gould,“Salt Selection for Basic Drugs”(基本藥物的鹽的選擇)33 Int’l J. Pharm. 201,202,214-216(1986)提供了一份經FDA批准的藥理學上可接受的鹽的一覽表;Stephen M. Berge et al.,“Pharmaceutical Salts”(藥用鹽),Journal of Pharmaceutical Sciences Vol. 66,No. 1,January 1977,pages 1-19則提供了進一步資料;Handbook of Pharmaceutical Salts(藥用鹽手冊),P. Heinrich Stahl,Camille G. Wermuth(Eds.),IUPAC Wiley-VCH,2002提供了本領域內周知的這類鹽的製備方法;這些出版物均作為參考文獻納入本文。
「溶劑合物」意指本發明之化合物與一個或數個溶劑分子的物理性締合。這種物理性締合包括氫鍵鍵合。在某些情況下,例如當結晶固體的晶格內含有一個或數個溶劑分子時,溶劑合物可以被分離。「溶劑合物」包括溶液相和可分離的溶劑合物。代表性的溶劑合物包括水合物、乙醇鹽、甲醇鹽,等等。
「鈴木偶合條件」意為使用鈴木偶合溶劑、鈴木偶合觸媒及鈴木偶合反應溫度的各種條件。
「鈴木偶合溶劑」意為一種沸點高於或等於異丙醇沸點的醇類溶劑,如正丙醇、正丁醇或類似物;極性非質子溶劑如二甲基甲醯胺、1-甲基-2-吡咯烷酮、二甲基亞碸或類似物;醚類溶劑如THF、2-甲基THF、二甲氧基乙烷或類似物;或前述溶劑和水或甲苯的任何混合物。
「鈴木偶合觸媒」意為一種Pd觸媒,如Pd(PPh3
)4
、Pd(PPh3
)2
Cl2
、Pd2
(dba)3
、Pd(dtbpf)Cl2
或類似物;或Pd觸媒如Pd(OAc)2
、Pd2
(dba)3
或類似物與一種膦配體如PPh3
、dppf、t
-Bu3
P、P(Cy)3
或類似物的結合。
「鈴木偶合反應溫度」意為從約60℃至鈴木偶聯反應混合物沸點的溫度範圍內的某溫度。
「三氟乙醯基化條件」意為使用三氟乙醯基化劑、三氟乙醯基化溶劑和三氟乙醯基化反應溫度的條件。
「三氟乙醯基化劑」意為三氟乙酸酐、1,1,1-三氯-3,3,3-三氟丙酮、三氟乙酸和聚磷酸三甲基甲矽烷基酯(PPSE)、三氟乙醯氯、三氟乙醯氟、五氟苯基三氟乙酸酯或類似物。
「三氟乙醯基化溶劑」意為一種如乙酸乙酯、乙酸異丙酯、乙酸正丁酯之類的酯類溶劑或類似物;一種芳烴溶劑如甲苯或類似物;一種氯化烴溶劑如甲叉二氯、1,2-二氯乙烷,或類似物。
「三氟乙醯基化反應溫度」意為從約-20至約30℃的溫度。
「氫化條件」意為使用氫化觸媒、氫化溶劑、氫化反應溫度以及氫化壓力的條件。
「氫化反應溶劑」意為甲醇、乙醇、異丙醇之類的醇類溶劑;或乙酸;或一種醇類溶劑或乙酸與水的混合物。
「氫化觸媒」意為PtO2
、Pd/C、Pd(OH)2
、Rh/C等等,可加或可不加無機酸如HCl之類,或有機酸如乙酸之類。
「氫化反應溫度」意為從約10至約60℃的溫度。
「氫化壓力」意為從約10至約1000psi的氫氣壓力(上限取決於設備能力)。
此外,本發明還涉及用結構式為I之化合物來治療患者,此患者之生理症狀可透過服用達療效量的結構式為I之化合物而得到改善。可用本發明之化合物治療的生理症狀的具體實例包括但當然不限於發炎性疾病,例如,關節發炎、關節炎、類風濕性關節炎、類風濕性脊椎炎、痛風關節炎、創傷性關節炎、風疹關節炎、牛皮廯關節炎及其他慢性炎性關節疾病,以及哮喘和其他發炎性呼吸道病症。可用本發明來治療的其他生理症狀的實例包括慢性阻塞性肺病(COPD)、COPD惡化、關節軟骨破壞、眼結膜炎、春季結膜炎、發炎性腸道疾病、哮喘、過敏性鼻炎、間質性肺病、纖維化、硬皮症、肺纖維化、肝硬化、心肌纖維化、神經纖維瘤、肥厚性瘢痕、諸如異位性皮炎和牛皮廯之類的各種皮膚疾病、心肌梗塞、中風、心絞痛及動脈粥樣硬化斑塊破裂的其他後果,以及牙周病、糖尿病視網膜病變、腫瘤增長、過敏症、多發性硬化、消化性潰瘍及合體細胞病毒感染。
在一較佳的實施例中,本發明涉及使用一種結構式為I之化合物來治療哮喘和其他發炎性呼吸道症狀的患者,包括對患者施用生理有效量的該化合物。
在另一較佳的實施例中,本發明涉及使用一種結構式為I之化合物來治療COPD患者,包括對患者施用生理有效量的該化合物。
在另一較佳的實施例中,本發明涉及使用一種結構式為I之化合物來治療COPD惡化患者,包括對患者施用生理有效量的該化合物。
在另一較佳的實施例中,本發明涉及使用一種結構式為I之化合物來治療過敏性鼻炎患者,包括對患者施用生理有效量的該化合物。
在另一較佳的實施例中,本發明涉及使用一種結構式為I之化合物來治療關節發炎患者,包括對患者施用生理有效量的該化合物。
在另一較佳的實施例中,本發明涉及使用一種結構式為I之化合物來治療發炎性腸道疾病患者,包括對患者施用生理有效量的該化合物。
此外,本發明還涉及一種醫藥組合物,其包括結構式為I之化合物及選自β-腎上腺素激動劑(beta andrenergic agonist)、抗膽鹼藥(anticholinergic)、消炎皮質類固醇(anti-inflammatory corticosteroid)和消炎劑(anti-inflammatory agent)之類的第二種化合物,及其在藥學上可接受的載體。在該醫藥組合物中,結構式為I之化合物和第二種化合物之含量能夠產生有效的治療活性,即相加效應或協同效應。可以用該醫藥組合物治療的具體炎症或異常包括但不限於哮喘。
此外,本發明還涉及一種治療發炎性疾病患者的方法,該方法包括對患者施用結構式為I之化合物和選自β-腎上腺素激動劑、抗膽鹼藥、消炎皮質類固醇和消炎劑的第二種化合物。在該方法中,結構式為I之化合物和第二種化合物之含量能夠產生有效的治療活性,即相加效應或協同效應。在本發明的這一方法中,本發明之化合物可在服用第二種化合物之前服用,也可在服用第二種化合物之後服用,也可兩者同時服用。按本方法所應用的腎上腺素激動劑、抗膽鹼藥、消炎皮質類固醇和消炎劑的具體實例見下文說明。欲用於本發明的抗膽鹼藥包括異丙托溴胺(ipratopium bromide)和噻托溴胺(tiotropium)。欲用於本發明的消炎皮質類固醇包括雙丙酸倍氯美松(beclomethasone dipropionate)、曲安奈德(triamcinolone acetonide)、氯尼縮松(flunisolide)、丙酸氟地松(fluticasone propionate)、糠酸莫米他松(moetasone furoate)、甲基強的松龍(methylprednisone)、強的松龍(prednisolone)和地塞米松(dexamethasone)。
本發明還涉及製備結構式為I之化合物的結構式為2-9中間體化合物
如上所述,本發明之化合物顯示了有用的藥理活性,因而可以納入一種醫藥組合物,並用於治療罹患某些疾病的患者。因此,根據本發明之另一方面,本發明提供了多種醫藥組合物,這些醫藥組合物由本發明之化合物及其藥學上可接受的載體組成。本文所用的術語「藥學上可接受的」主要是指經政府監管機構批准,尤其是指經聯邦政府或州政府批准,或被美國藥典或其他公認的藥典列為適用於動物、尤其是適用於人類。適用的藥物載體見E. W. Martin在「雷明頓製藥科學」(Remington's Pharmaceutical Sciences)中所述。
本發明之醫藥組合物可按照慣用的方法,用一種或數種藥學上可接受的佐劑或賦形劑來製備。除了其他形式之外,佐劑還包括稀釋劑、填充劑、黏合劑、崩散劑、助滑劑、潤滑劑、表面活性劑、無菌水基介質及各種無毒有機溶劑。該醫藥組合物可以採用片劑、膠囊、丸劑、持續釋放的製劑、顆粒、粉劑、水溶液或懸浮液、注射液、藥酒或糖漿等形式,可以含有甜味劑、調味劑、色素或穩定劑中的一種或數種輔劑,以製得藥學上可接受的製劑。通常,載體及載體中活性物質的含量是按照活性物質的溶解性和化學屬性、具體的給藥方式和製藥規程所遵循的規定來決定。例如,可用以下輔劑來製備片劑,如賦形劑:乳糖、微晶質纖維素、預膠化澱粉、未改性澱粉、矽化微晶質纖維素、甘露糖醇、山梨醇、木糖醇、葡聚糖、果糖、檸檬酸鈉、碳酸鈣、磷酸二鈣二水合物、無水磷酸二鈣、硫酸鈣;黏合劑:聚乙烯吡咯烷酮、羥基丙基甲基纖維素、乙基纖維素、羥乙基纖維素、甲基纖維素、羧甲基纖維素鈉、預膠化澱粉、澱粉、聚乙二醇、聚環氧乙烷、聚卡波非(polycarbophils,丙烯酸與二乙烯基乙二醇交聯共聚物)、明膠和金合歡膠;崩散劑:交聯羧甲纖維素鈉(sodium croscarmellose)、羥基乙酸澱粉鈉、交聯聚乙烯吡咯烷酮(crospovidone)、澱粉、微晶質纖維素、藻酸,某些與潤滑劑結合的複雜矽酸鹽;潤滑劑:硬脂酸鎂、硬脂酸鈣、硬脂酸、氫化植物油、礦物油、聚乙二醇、脂肪酸甘油酯、月桂基硫酸鈉;助滑劑:二氧化矽、滑石、澱粉;還有一些適用的濕潤劑,例如月桂基硫酸鈉、脫水山梨醇酯、聚氧乙烯脂肪酸酯、泊洛沙姆(poloxamer,環氧乙烷與環氧丙烷嵌段共聚物)、聚氧乙烯醚、多庫酯鈉(sodium docusate)、聚乙氧基蓖麻油和苯紮氯銨。為了製備膠囊,最好使用填充劑,例如單獨使用乳糖、微晶質纖維素、預膠化澱粉、未改性澱粉、矽化微晶質纖維素,或者使用兩種或多種填充劑的混合物,其中可使用也可不使用上述的黏合劑,再加上述適用的濕潤劑、崩散劑、助滑劑、潤滑劑等。使用水基懸浮液時,它們可含有乳化劑或有助於懸浮的輔劑。還可以使用稀釋劑,例如蔗糖、乙醇、聚乙二醇、丙二醇、甘油、氯仿或它們的混合物。藥學上可接受的載體也可以是無菌的水和油,包括從石油提煉的各種油、動物油、植物油或合成油,例如花生油、豆油、礦物油、芝麻油等等。如果醫藥組合物採用靜脈給藥的方式,則水是首選的載體。鹽水溶液、葡萄糖水溶液和甘油溶液也可用作為液體載體,尤其適用於注射液。合適的藥物賦形劑包括甘露糖醇、人血清白蛋白(HSA)、澱粉、葡萄糖、乳糖、蔗糖、明膠、麥芽、大米、麵粉、白堊、矽膠、碳酸鎂、硬脂酸鎂、硬脂酸鈉、甘油單硬脂酸酯、滑石、氯化鈉、脫脂奶粉、甘油、丙烯、乙二醇、水、乙醇等等。這些醫藥組合物可以採取溶液、懸浮液、片劑、丸劑、膠囊、粉劑、持續釋放的製劑等形式。
自然,本發明之醫藥組合物將包含療效量的活性化合物及適量載體,以形成給患者給藥的適當形式。雖然靜脈注射是一種非常有效的給藥方式,但是,也可採用其他方式,例如注射,經口腔、鼻腔或非經腸道給藥,這些內容將在下文討論。
根據文獻及下文所述的試驗,結構式為I之化合物具有類胰蛋白酶抑制活性,其試驗結果據信與人和其他哺乳動物身上的藥理活性相關。因此,在另一實施例中,本發明涉及使用結構式為I之化合物或包含該化合物的醫藥組合物來治療患有、或易患某種可用類胰蛋白酶抑制劑來改善的症狀的患者。例如,結構式為I之化合物可用於治療某種發炎性疾病,例如,關節發炎,包括關節炎、類風濕性關節炎和其他關節疾病,諸如類風濕性脊椎炎、痛風關節炎、創傷性關節炎、風疹關節炎、牛皮廯關節炎、骨關節炎或其他慢性發炎關節疾病,或關節軟骨破壞疾病,眼結膜炎、春季結膜炎、發炎性腸道疾病、哮喘、過敏性鼻炎、間質性肺病、纖維化、硬皮症、肺纖維化、肝硬化、心肌纖維化、神經纖維瘤、肥厚性瘢痕、諸如異位性皮炎和牛皮廯之類的各種皮膚疾病、心肌梗塞、中風、心絞痛或動脈粥樣硬化斑塊破裂的其他後果以及牙周病、糖尿病視網膜病變、腫瘤增長、過敏症、多發性硬化、消化性潰瘍或合體細胞病毒感染。
根據本發明的另一個特點,本發明還提供了一種方法,用於治療患有、或易患某種可用類胰蛋白酶抑制劑來改善的症狀的人或動物患者,例如以上所述的症狀;該方法包括給患者服用療效量的本發明之化合物或含本發明之化合物的醫藥組合物。
如上所述,取決於所治療的疾病,其他醫藥活性製劑也可與結構式為I之化合物結合使用。例如,治療哮喘時,可以使用諸如沙丁胺醇(albuterol)、特普他林(terbutaline)、福莫特羅(formoterol)、非諾特羅(fenoterol)或普瑞那啉(prenaline)之類的β-腎上腺素激動劑,諸如異丙托溴銨(ipratropium bromide)之類的抗膽鹼藥,諸如雙丙酸倍氯美松(beclomethasone dipropionate)、曲安奈德(triamcinolone acetonide)、氟尼縮松(flunisolide)、丙酸氟地松(fluticasone propionate)、糠酸莫米他松(moetasone furoate)、甲基強的松龍(methylprednisone)、強的松龍(prednisolone),或潑尼松(predinose)之類的消炎皮質類固醇,以及諸如色甘酸鈉(sodium cromoglycate)和奈多羅米鈉(nedocromil sodium)之類的消炎劑。因此,本發明涉及一種醫藥組合物,該醫藥組合物包含結構式為I之化合物和選自β-腎上腺素激動劑、抗膽鹼藥、消炎皮質類固醇、白三烯受體拮抗劑、脂氧化酶抑制劑、磷酸二酯酶-4抑制劑以及消炎劑之類的第二種化合物,及其藥學上可接受的載體。擬用於本發明的較佳的白三烯拮抗劑是孟魯司特(montelukast)。擬用於本發明的較佳的磷酸二酯酶-4抑制劑是羅氟司特(roflumilast)和西洛司特(ciflumolast)。本文敘述了可用於此醫藥組合物的某些具體的藥物載體。
此外,本發明還涉及一種治療哮喘患者的方法,該方法包括給患者服用本發明之化合物和選自β腎上腺素激動劑、抗膽鹼藥、消炎皮質類固醇、白三烯受體拮抗劑、脂氧化酶抑制劑、磷酸二酯酶-4抑制劑,以及消炎劑之類的第二種化合物。在這一綜合方法中,本發明之化合物可在服用第二種化合物之前服用,也可在服用第二種化合物之後服用,也可兩者同時服用。
根據本發明,結構式為I之化合物或包含該化合物的醫藥組合物,可透過注射方式、經黏膜的方式(例如經口腔、鼻腔和肺)、或經直腸或經皮膚等方式對患者給藥。
擬用於本發明的有口服固體藥劑,其一般說明見「雷明頓製藥科學」(Remington's Pharmaceutical Sciences)1990年第18版(Mack Publishing Co. Easton PA 18042)第89章,該文作為參考文獻納入本文。固體劑型包括片劑、膠囊、丸劑、含片或錠劑、扁囊劑或粒劑。也可使用脂質體或類蛋白封裝方法來配製本發明之醫藥組合物(如4,925,673號美國專利所報道的類蛋白微球體)。可採用脂質體封裝方法,脂質體可衍生於各種聚合物(如5,013,556號美國專利)。Marshall,K.在Modern Pharmaceutics
(G. S. Banker和C. T. RhodesN編,1979)第10章中,敘述了治療藥物可能採用的各種固體劑型,該文作為參考文獻納入本文。一般而言,製劑將包括本發明之化合物和惰性組分,該惰性組分是為了抵抗胃內的環境,以便在腸內釋放生物活性物質,即本發明的一種化合物。
特別考慮的是本發明之化合物的口服劑型。該化合物可進行化學改性,使口服效果更佳。一般而言,涉及的化學改性是給該組分的分子本身增添至少一個附加部分,該附加部分可使該藥物(a)抑制蛋白水解;和(b)經胃或腸道吸收而進入血液。同時,還需要提高本發明之化合物的總體穩定性,延長其在體內的循環時間。此類附加部分的例子包括:聚乙二醇、乙二醇和丙二醇的共聚物、羧甲基纖維素、葡萄糖、聚乙烯醇、聚乙烯吡咯烷酮和聚脯氨酸。參閱Abuchowski和Davis,1981,「可溶性聚合物-酶加成物」(Soluble Polymer-Enzyme Adducts),Enzymes as Drugs
,Hocenberg和Roberts編輯,Wiley-Interscience,紐約,367-383頁;Newmark et al.,1982,J. Appl. Biochem. 4:185-189。可以使用的其他聚合物有聚-1,3-二氧戊環和聚-1,3,6-三氧辛環。如上所指出,用於醫藥用途的附加部分以聚乙二醇附加部分為首選。
本發明之化合物在體內的釋放部位可以是胃、小腸(十二指腸、空腸或迴腸)或大腸。本領域技術人員可提供某些在胃中不溶解、而在十二指腸或腸的其他部位釋放藥物的製劑。首選的是,為了避免胃內環境的消極作用,或者設法保護本發明之化合物,或者使化合物在胃部環境以外的部位(例如在腸內)釋放。
為了保證對胃的充分抵抗能力,必須採用一種至少能抵抗pH值5.0的膜衣。用作腸溶膜衣的較常用的惰性組分的例子包括,乙酸苯三酸纖維素(CAT)、鄰苯二甲酸羥丙基甲基纖維素(HPMCP)、HPMCP 50、HPMCP 55、聚醋酸乙烯鄰苯二甲酸酯(PVAP)、Eudragit L30D、Aquateric、乙酸鄰苯二甲酸纖維素(CAP)、Eudragit L、Eudragit S和紫膠。這些膜衣也可以混合膜的形式使用。
對於無需抵抗胃部環境的片劑也可使用某種膜衣,或聯合使用多種膜衣。這種情況可包括糖衣或者使片劑易於吞咽的膜衣。對於乾藥物(即粉末)的給藥,可使用由一層硬殼(例如明膠)構成的膠囊;對於液體劑型,可使用軟明膠膠囊。扁囊劑的外殼材料可以是稠澱粉或其他可食用紙。對於丸劑、錠劑、模製片劑或研磨製劑,則可使用潮濕塊化技術。
藥物可以製成約1毫米大小的顆粒或小粒,以多種細顆粒形式包括在製劑內。用於膠囊形式服用的製劑也可以是粉末、略經壓縮的塞片,甚至片劑。藥物可以壓縮的方式製備。
藥物中也可包含色素和調味劑。例如,可以先配製本發明之化合物(例如採用脂質體或微球體封裝),然後,再將其包括在某種可食用的產品內,例如,含色素和調味劑的冷凍飲料。
可以用某種惰性材料來稀釋或增加藥物的體積。這些稀釋劑包括碳水化合物,尤其是甘露糖醇、α-乳糖、無水乳糖、纖維素、蔗糖、改性葡萄糖和澱粉。某些無機鹽也可用作為填充劑,包括三磷酸鈣、碳酸鎂和氯化鈉。某些市售的稀釋劑有Fast-Flo、Emdex、STA-Rx 1500、Emcompress和Avicell。
可在藥物製劑中加入崩散劑,以形成一種固體劑型。用作崩散劑的材料包括但不限於澱粉,包括以澱粉為基礎的市售崩散劑Explotab。羥乙酸澱粉鈉、琥石、羧甲基纖維素鈉、支鏈澱粉(ultramylopectin)、藻酸鈉、明膠、橙皮、酸性羧甲基纖維素、天然海綿和膨潤土都可以使用。其他形式的崩散劑有不溶性陽離子交換樹脂。粉末狀樹膠可用作為崩散劑及黏合劑,此類粉末狀樹膠包括,例如瓊脂、刺梧桐樹膠或黃蓍膠。藻酸及其鈉鹽也可用作為崩散劑。
可以使用黏合劑黏住藥物,以形成硬質片劑,黏合劑包括金合歡膠、黃蓍膠、澱粉和明膠等天然產品。其他包括甲基纖維素(MC)、乙基纖維素(EC)和羧甲基纖維素(CMC)。也可將聚乙烯吡咯烷酮(PVP)和羥基丙基甲基纖維素(HPMC)加入醇溶液,以使藥物成粒狀。
可在藥物製劑中加入抗磨劑,以防在製備過程中發生黏附。可將潤滑劑塗在藥物與模具壁之間,它們包括但不限於硬脂酸及其鎂鹽和鈣鹽、聚四氟乙烯(PTFE)、液體石蠟、植物油和蠟。也可以使用可溶性潤滑劑,例如月桂基硫酸鈉、月桂基硫酸鎂、各種分子量的聚乙二醇、Carbowax 4000和6000。
也可加入助滑劑,它們在製劑製備過程中可以改善藥物的流動性,有助於在壓製過程中重新排列藥物顆粒。助滑劑可以包括澱粉、滑石、火成二氧化矽和水合矽鋁酸鹽。
為了有助於藥物在水基環境中溶解,可加入表面活性劑作為濕潤劑。表面活性劑可包括陰離子洗滌劑,例如月桂基硫酸鈉、二辛基磺基琥珀酸鈉和二辛基磺酸鈉。也可以使用陽離子洗滌劑,包括苯紮氯銨或苄索氯銨。在製劑中可用作為表面活性劑的非離子洗滌劑有聚桂醇400、硬脂酸-40-聚烴氧基酯、聚氧乙烯氫化蓖麻油10、50和60、甘油單硬脂酸酯、聚山梨醇酯40、60、65和80、蔗糖脂肪酸酯、甲基纖維素和羧甲基纖維素。這些表面活性劑可單獨加入本發明之化合物的製劑中,也可以不同比例混合後加入。
有促進本發明化合物之吸收之潛力的添加劑有,例如,脂肪酸、油酸、亞油酸和亞麻酸等。如果需要控制釋放型口服製劑,可在藥物中加入惰性基質(例如膠質),籍擴散或浸提的機理予以釋放。也可以在製劑中加入緩慢變性的基質。某些腸溶膜衣也具有延緩釋放的作用。
控制釋放這類藥物的另一種方式是以Oros給藥體系為基礎的方法(Alza公司),即將藥物封裝在半滲透膜內,此膜可讓水透過,由於滲透壓效應而經過單一小孔排出藥物。
其他膜衣也可用於藥物製劑。它們包括可在塗覆盤內塗覆的各種各樣的糖。治療劑也可採取塗膜片劑的形式,用於這種形式的材料可分為兩類。第一類是非腸溶材料,包括甲基纖維素、乙基纖維素、羥乙基纖維素、甲基羥乙基纖維素、羥丙基纖維素、羥丙基-甲基纖維素、羧基甲基纖維素鈉、聚維酮和聚乙二醇。第二類由腸溶物組成,它們一般是鄰苯二甲酸酯。
這類材料可混合使用,以產生最佳的薄膜塗覆。薄膜塗覆過程可在塗覆盤或流化床內實現,也可透過加壓塗覆的方式來實現。
擬用於本發明的給藥方式還有經肺部輸入本發明之化合物的方式,可以單獨輸入,也可加入某種醫藥組合物後再輸入。該化合物在哺乳動物呼吸時被輸入肺部,並穿過肺上皮層進入血液。有關這一方面的其他報告包括Adjei et al.,1990,Pharmaceutical Research,7:565-569;Adjei et al.,1990,International Journal of Pharmaceutics,63:135-144(柳菩林,Leuprolide acetate);Braquet et al.,1989,Journal of Cardiovascular Pharmacology,13(suppl. 5):143-146(內皮素-1);Hubbard et al.,1989,Annals of Internal Medicine,卷.III,206-212頁(a1-抗胰蛋白酶);Smith et al.,1989,J. Clin. Invest. 84:1145-1146(a-1-蛋白酶);Oswein et al.,1990,「蛋白的氣懸化」(Aerosolization of Proteins),經呼吸給藥專題會論文集II(Proceedings of Symposium on Respiratory Drug Delivery II),Keystone,Colorado,March,(重組的人體生長激素);Debs et al.,1988,J. Immunol. 140:3482-3488(干擾素-γ和腫瘤壞死因子α)和Platz等,第5,284,656號美國專利(粒細胞群刺激因子)。關於系統效應藥物經肺輸入的方法及醫藥組合物,見1995年9月19日授予Wong等人的第5,451,569號美國專利。
擬用於實施本發明的有許多設計用於經肺輸入治療藥物的機械裝置,包括但不限於噴霧器、計量吸入器和粉末吸入器,本領域的專業人士對此都非常熟悉。
適於實施本發明的市售器具的具體例子有Mallinckrodt公司(St. Louis,Missouri)製造的Ultravent噴霧器,Marquest醫療產品公司(Englewood,Colorado)製造的Acorn II噴霧器,Glaxo公司(Research Triangle Park,North Carolina)製造的Ventolin計量吸入器,以及Fisons(Bedford,Massachusetts)公司製造的Spinhaler粉末吸入器。在此僅舉數例。所有此類器具都要求採用適於本發明之化合物給藥的製劑。通常,每種製劑都需要特定類型的器具,除了治療方法中常用的稀釋劑、佐劑及/或載體外,可能還要使用適當的揮發劑。同時,也可考慮使用脂質體、微囊體或微球體、包合配合物或其他類型的載體。取決於化學改性的類型或所用器具的類型,經化學改性的本發明之化合物可以配製成不同的製劑。
適用於噴射型或超聲波型噴霧器的製劑通常含有溶於水的本發明之化合物,其濃度為每毫升溶液含約0.1mg至25mg該化合物。製劑中還可包括緩衝劑和單糖(例如,用於穩定和調節滲透壓)。適用於噴霧器的製劑還可含有表面活性劑,以減少或防止在形成噴霧時因溶液霧化而引起化合物的聚集。
適用於計量吸入器的製劑,一般包括含本發明之化合物的微細粉末,它們在表面活性劑的作用下懸浮在揮發劑中。揮發劑可以是通常用於這一目的的任何材料,例如含氯氟烴、氫氯氟烴、氫氟烴或烴,包括三氯氟甲烷、二氯二氟甲烷、二氯四氟乙醇和1,1,2-四氟乙烷,或它們的組合。適用的表面活性劑包括失水山梨醇三油酸酯和大豆卵磷脂。油酸也可用作表面活性劑。
適用於粉末吸入器給藥的製劑將包括含本發明之化合物的微細粉末,還可包括增量劑,例如乳糖、山梨醇、蔗糖或甘露糖醇,增量劑的加入量應有利於該器具分配粉末,例如,佔製劑重量的50-90%。本發明之化合物最好製成平均粒徑小於10毫米(或微米)的微粒狀,為了有效地輸送到肺部末端,最好是0.5-5毫米。
還考慮了經鼻腔輸入本發明之化合物的方式。藥物輸入鼻腔後使該化合物直接進入血液,而不必沉積到肺部。適於鼻腔給藥的製劑包括那些採用葡聚糖或環狀糊精的製劑。
本領域內有許多各種各樣已知的經皮給藥方法可用於本發明,例如經皮貼片。有許多專利介紹了經皮貼片,例如,美國專利5,407,713、5,352,456、5,332,213、5,336,168、5,290,561、5,254,346、5,164,189、5,163,899、5,088,977、5,087,240、5,008,110、以及4,921,475,上述每一項專利披露都以其整體作為參考文獻納入本文。
可以很容易理解的是,可透過使用皮膚滲透增強劑以增強經皮給藥途徑的功效,例如,美國專利5,164,189、5,008,110和4,879,119中所述的增強劑,上述每一項專利披露都以其整體作為參考文獻納入本文。
對於局部給藥,可使用含有本發明之化合物的凝膠(水基或醇基)、乳脂或軟膏。本發明之化合物還可與凝膠或基體材料結合,作為貼劑使用,以控制釋放的方式使該化合物穿越皮膚障礙。
直腸給藥的固體醫藥組合物包括按照已知方法配製、含有本發明之化合物的栓劑。
本發明之醫藥組合物中的活性組分,其百分比是可以變化的,其構成比例應達到適用的劑量。顯然,幾種單位劑型可幾乎同時使用。採用的劑量將由醫生決定,並取決於所需的治療效果、給藥途徑、治療延續時間和患者的狀況。成人劑量,若為吸入給藥,則按每公斤體重計算,一般每天約為0.001-50mg,最好約為0.001-5mg;若為口服,則按每公斤體重計算,每天約為0.01-100mg,最好為0.1-70mg,0.5-10mg則更佳;若為靜脈給藥,按每公斤體重計算,每天約為0.001-10,最好為0.01到1mg。在每種具體情況下,劑量應根據治療對象的具體因素而確定,例如年齡、體重、總的健康狀況以及可影響醫藥產品功效的其他特點。
此外,為了達到所需的療效,可根據需要而頻繁地使用本發明之化合物。有些患者對劑量高低的反應非常迅速,也許採用低得多的維持劑量即可。對於其他患者,按照每個具體患者的生理要求,則可能需要長期治療,每天1至4劑。通常,該活性產品可以每天口服1至4次。當然,對於某些患者而言,處方量應不超過每天1劑或2劑。
自然,本發明之化合物作為一種有效的治療藥物,最好是用於人類,但也可用於動物。因此,本領域內一般的專業人士可以很容易地理解,本發明之方法和醫藥組合物可用於獸醫用途,特別適合於任何動物,尤其是哺乳動物,其中包括但決不限於諸如貓科或犬科之類的家畜,諸如(但不限於)牛、馬、山羊、綿羊和豬之類的農畜,野生動物(不管是處於野生環境還是動物園環境),諸如小鼠、大鼠、兔、山羊、綿羊、豬、狗、貓之類的研究動物,諸如雞、火雞、鳴禽之類的禽類。
結構式為I之化合物可透過應用或改進已知的方法來製備,這些方法是指迄今為止所使用的或文獻中所述的方法,例如R. C. Larock在「綜合有機轉化」(Comprehensive Organic Transformations,VCH publishers,1989)中所述的,或如本文所述的那些方法。
在下述反應中,可能有必要保護某些反應官能團,例如胺基,以避免其不希望地參與反應。可以按照標準的規程使用某些常規的保護基,例如可參閱T. W. Greene和P. G. M Wuts的「有機化學中的保護基」(Protective Grooupsin Organic Chemistry,John Wiley and Sons,1991)。
尤其是,結構式為I之化合物可按照方案1與2所示的方法製備。
例如,本發明之化合物是非手性的化合物,其製備方法包括匯集合成。採取苯甲酸鹽形式的本發明之化合物,是按照如下所示方案製備的。
(i)氯甲酸乙酯、吡啶、THF,0℃,100%;(ii)a:sec
-BuLi、THF,-78℃,b:I2
、THF,-78℃,52-68%;(iii)TMS-乙炔、TEA、CuI、Pd(PPh3
)2
Cl2
、脫氣THF,60℃,93%;(iv)KOH、t
-BuOH,70℃,91%;(v)粉末KOH、2-甲氧基乙基溴、DMSO,室溫,95%;(vi)TFAA、DMF,40℃,89%;(vii)5M NaOH、MeOH,85℃,96%;(viii)2,2,2-三氟-N
-(氟-3-哌啶-4-基苄基)-乙醯胺鹽酸鹽、EDCI、TEA、CH2
Cl2
(DCM),室溫,99%;(ix)a:K2
CO3
、MeOH/H2
O,b:1M HCl的Et2
O溶液,90%。
在一種適宜的鹼如吡啶存在條件下,用一種胺基保護劑如氯甲酸乙酯保護胺基,將化合物1
轉化為化合物2
,即得受保護的化合物2
。
在一個三步驟過程中,將化合物2
轉化為化合物5
。使化合物2
與一種強鹼如仲丁基鋰反應,化合物2
在胺基甲酸酯的鄰位碘化而形成陰離子,後者再與一種碘化物源如分子碘反應,即得化合物3
。然後使用催化條件如碘化亞銅(I)和雙三苯基膦二氯化鈀(II),在三甲基甲矽烷基乙炔和鹼如三乙基胺存在條件下,將化合物3
轉化為炔屬化合物4
。使用一種強鹼如氫氧化鉀並加熱以將化合物4
環化,即得吲哚化合物5
。
用一種烷基鹵在一種強鹼如氫氧化鉀存在條件下,在一種偶極性非質子溶劑如二甲基亞碸中,於室溫使化合物5
的吲哚氮發生烷基化而將其轉化為化合物6
,即得化合物6
。
在一個兩步驟過程中,將化合物6
轉化為化合物8
。首先,在一種溶劑如N,N
-二甲基甲醯胺存在條件下,用三氟乙酸酐處理化合物6
並加熱以將化合物6
轉化為化合物7
。再用一種強鹼如氫氧化鈉處理化合物7
,即得化合物8
,後者在3-位上有一個酸官能團。
在一種酸性偶合劑如EDCI和一種有機鹼如三乙基胺存在條件下,在一種惰性溶劑如二氯甲烷中,使酸8
與2,2,2-三氟-N
-(氟-3-哌啶-4-基苄基)-乙醯胺鹽酸鹽(化合物14
)反應,將化合物8
轉化為醯胺9
。
在一種混合溶劑如甲醇/水中,用弱鹼如碳酸鉀處理N
-苄基三氟乙醯胺使其脫保護,從而將化合物9
轉化為化合物10
。在一種極性有機溶劑如醚存在條件下可形成鹽酸鹽,即得化合物10
,後者是結構式為I的([4-(5-胺基甲基-2-氟苯基)-哌啶-1-基]-[7-氟-1-(2-甲氧基乙基)-4-甲基-1H-吲哚-3-基]-甲酮)的鹽酸鹽。
此方案的諸反應如下。
在一段30分鐘的時間內,於0℃下向化合物1
(50.72g,0.26mol)和吡啶(27.3mL,0.34mol)的THF(500mL)溶液滴加氯甲酸乙酯(32.2mL,0.39mol)。1小時之後,LC/MS和TLC均顯示反應已完全。將反應混合物在H2
O和EtOAc之間分配。將兩層分離,將有機層用1MHCl、H2
O和鹽水洗滌,用MgSO4
乾燥,過濾,並在真空中濃縮。以庚烷/EtOAc(95/5 to 70/30)為洗脫劑,在矽膠上純化該粗製物,即得69.23g(99%)產物2
,為透明無色液體。1
H NMR(CDCl3
)8.11(br s,1H),7.07(dd,J
=9.1,9.3Hz,1H),7.00-6.80(m,2H),4.27(q,J
=7.1Hz,2H),1.33(t,J
=7.1Hz,3H);19
F NMR(CDCl3
)-57.84(s,3F),-134.01(br s,1F);MS309(M+CH3CN+1,100%),268(M+1)。
在一段1小時的時間內,於-78℃下向化合物2
(31.34g,117.2mmol)的THF(180mL)溶液滴加sec
-BuLi(1.4M的環己烷溶液,200mL,280mmol)。於20分鐘之後,在一段30分鐘的時間內,滴加I2
(44.6g,175.8mmol)的THF(150mL)溶液。然後於-78℃將該混合物攪拌30分鐘。加入飽和NH4
Cl並移去冷浴。將反應混合物在H2
O和EtOAc之間分配。將兩層分離,將有機層用10% Na2
SO3
、H2
O和鹽水洗滌,用MgSO4
乾燥,過濾,並在真空中濃縮。將殘餘物懸浮於DCM(50mL)中,並加入庚烷(300mL)。以吸濾法從生成的懸浮液收集白色粉末3
(18.1g,39%)並用空氣乾燥。將濾液在真空中濃縮,並將殘餘物懸浮於庚烷(200mL)中。以吸濾法收集另一批化合物3
(3.8g,8%)並用空氣乾燥。經矽膠層析純化濾液可獲得進一步產物。1
H NMR(CDCl3
)7.30-17.10(m,2H),6.16(br s,1H),4.26(q,J
=7.1Hz,2H),1.32(t,J
=7.1Hz,3H);19
F NMR(CDCl3
)-56.90(s,3F),-114.35(d,J
=8.5Hz,1F);MS 394(M+1,100%),374,364,321,267。
將化合物3
(18.1g,45.9mmol)、Et3
N(12.8mL,91.9mmol)、Pd(PPh)2
Cl2
(1.6g,5% mol)、CuI(0.7g,8% mol)和TMS-乙炔(19.6mL,137.8mmol)在脫氣THF(180mL)中的混合物於60℃加熱過夜。將該混合物冷卻至室溫,然後在H2
O和EtOAc之間分配。將此混合物通過矽藻土過濾以除去不溶物。將兩層濾液分離,將有機層用H2
O和鹽水洗滌,用MgSO4
乾燥,過濾,並在真空中濃縮。以庚烷/EtOAc為洗脫劑,在矽膠上純化該粗製物,即得15.6g(93%)產物4
,為米黃色固體。1
H NMR(CDCl3
)7.15-7.00(m,2H),6.41(br s,1H),4.26(q,J
=7.1Hz,2H),1.31(t,J
=7.1Hz,3H),0.27(s,9H);19
F NMR(CDCl3
)-57.59(s,3F),-118.15(s,1F);MS 364(M+1,100%)。
將化合物4
(28.9g,79.6mmol)和KOH(35.7g,636.7mmol)在脫氣t
-BuOH(300mL)中的混合物於70℃加熱過夜。LC/MS顯示反應已完全。將該混合物冷卻至室溫,然後在H2
O和Et2
O之間分配。將兩層分離,並用Et2
O抽提水層(2X)。將合併後有機層用H2
O和鹽水洗滌,用MgSO4
乾燥,過濾,並在真空中濃縮。以庚烷/EtOAc(100/0至60/40)為洗脫劑,在矽膠上純化該粗製物,即得16g(91%)化合物5
,為黃色液體。1
H NMR(CDCl3
)δ8.47(br s,1H),7.35-7.20(m,1H),6.95-6.80(m,2H),6.68(d,J
=2.5Hz,1H);19
F NMR(CDCl3
)δ-57.63(s,3F),-136.10(d,J
=8.5Hz,1F);MS 220(M+1,100%),200。
將化合物5
(16g,72.8mmol)和粉末KOH(20.4g,364.2mmol)在DMSO(150mL)中的混合物於室溫攪拌10分鐘。加入2-甲氧基乙基溴(10.3mL,109.2mmol)。將此混合物於室溫攪拌過夜。LC/MS顯示反應已完全。將該混合物在H2
O和Et2
O之間分配。將兩層分離,並用Et2
O抽提水層(2X)。將合併後有機層用H2
O和鹽水洗滌,用MgSO4
乾燥,過濾,並在真空中濃縮。以庚烷/EtOAc(100/0至50/50)為洗脫劑,在矽膠上純化該粗製物,即得19.3g(95%)的化合物6
,為黃色液體。1
H NMR(CDCl3
)δ7.15(d,J
=2.1Hz,1H),6.90-6.75(m,2H),6.56(t,J
=2.5Hz,1H),3.72(t,J
=5.2Hz,2H),3.72(t,J
=5.2Hz,2H),3.31(s,3H);19
F NMR(CDCl3
)δ-57.54(s,3F),-137.00(d,J
=11.3Hz,1F);MS 278(M+1,100%)。
向化合物6
(19.3g,69.7mmol)在DMF(135mL)中的混合物加入TFAA(26.2mL,188.2mmol)。將此混合物於40℃加熱過夜。TLC顯示反應已完全。將該混合物冷卻至室溫,然後在H2
O和Et2
O之間分配。將兩層分離,將有機層用飽和NaHCO3
(2X)、H2
O和鹽水洗滌,用MgSO4
乾燥,過濾,並在真空中濃縮。以庚烷/EtOAc(100/0至50/50)為洗脫劑,在矽膠上純化該粗製物,即得23.4g(89%)化合物7,為微綠色固體。1
H NMR(CDCl3
)δ8.03(d,J=1.4Hz,1H),7.20-6.95(m,2H),4.54(t,J
=4.9Hz,2H),3.76(t,J
=4.8Hz,2H),3.33(s,3H);19
F NMR(CDCl3
)δ-57.74(s,3F),-71.10(s,3F),-134.95(d,J
=11.5Hz,1F);MS 374(M+1,100%)。
將化合物7
(23.4g,62.6mmol)在MeOH(100mL)和5M NaOH(100mL)中的混合物於80℃加熱過夜。LC/MS顯示反應已完全。將反應混合物冷卻至室溫,然後在真空中濃縮以除去大部分MeOH。將殘餘物溶解於H2
O中,然後用Et2
O洗滌一遍。用濃HCl將水層緩慢地酸化至pH~2。用Et2
O抽提酸化的懸浮液,並用H2
O和鹽水洗滌有機抽提液,用MgSO4
乾燥,過濾,並在真空中濃縮。將殘餘物懸浮於DCM/庚烷(10/90)中。以吸濾法收集懸浮液中的白色粉末8
(19.4g,96%)並用空氣乾燥。1
H NMR(CDCl3
)δ8.02(s,1H),7.15-7.05(m,1H),7.00-6.90(m,1H),4.49(t,J
=5.0Hz,2H),3.75(t,J
=4.9Hz,2H),3.33(s,3H);19
F NMR(CDCl3
)δ-57.74(s,3F),-135.65(d,J=11.3Hz,1F);MS 363(M+CH3
CN+1),322(M+1,100%)。
將化合物8
(19.1g,59.6mmol)、Et3
N(24.8mL,177.9mmol)、2,2,2-三氟-N
-(4-氟-3-哌啶-4-基苄基)-乙醯胺鹽酸鹽(11,26.4g,77.5mmol)(14
)和EDCI(17.1g,89.3mmol)在CH2
Cl2
中的混合物於室溫攪拌過夜。TLC和LC/MS均顯示反應已完全。將該混合物在H2
O和CH2
Cl2
之間分配。將兩層分離,將有機層用鹽水洗滌,用MgSO4
乾燥,過濾,並在真空中濃縮。以庚烷/EtOAc(40/60 to 0/100)為洗脫劑,在矽膠上純化該粗製物,即得化合物9
(36g,99%),為白色泡沫。1
H NMR(CDCl3
)δ7.37(s,1H),7.20-7.10(m,2H),7.10-6.85(m,4H),4.95(br s,1H),4.60-4.35(m,4H),3.90(br s,1H),3.73(t,J
=5.0Hz,2H),3.32(s,3H),3.25-2.70(m,3H),2.05-1.50(m,4H);19
F NMR(CDCl3
)δ-57.54(s,3F),-75.39(s,3F),-119.31(s,1F),-134.96(d,J
=11.3Hz,1F);MS 608(M+1,100%)。
向化合物9
(36g,59.3mmol)與MeOH(400mL)的混合物加入K2
CO3
水溶液(65.5g,474mmol,溶於120mL H2
O)。將此混合物於室溫攪拌過夜。LC/MS顯示反應已完全。將反應混合物在真空中濃縮以除去大部分甲醇。將殘餘物在H2
O和EtOAc之間分配。將兩層分離,將有機層用H2
O和鹽水洗滌,用MgSO4
乾燥,過濾,並在真空中濃縮,即得27.5g(90%)的化合物10
,為透明無色黏膠。1
H NMR(CDCl3
)7.42(s,1H),7.25-7.10(m,2H),7.05-6.85(m,3H),4.92(br s,1H),4.46(t,J
=5.2Hz,2H),3.86(br s,3H),3.74(t,J
=5.1Hz,2H),3.32(s,3H),3.30-2.75(m,3H),2.24(br s,2H),2.05-1.55(m,4H);19
F NMR(CDCl3
)-57.52(s,3F),-121.64(s,1F),-136.03(d,J
=11.3Hz,1F);MS 512(M+1,100%)。
向上述物質(2.856g,5.59mmol)的Et2
O(30mL)溶液滴加2N HCl/Et2
O(3mL,6mmol)。形成固體沉澱,除去乙醚溶液。再用部分Et2
O洗滌該固體然後潷去乙醚溶液。將剩餘淺黃色固體溶於溫熱MeOH(10mL),然後加入Et2O(50mL)直至該溶液略呈混濁。約2小時後出現固體沉澱。再加入部分Et2
O(5-10mL),然後將懸浮液置入冰箱過夜。收集白色結晶狀產物(2.475g,4.52mmol)並在高真空中乾燥4小時。
1
H NMR(DMSO-d6
)δ8.32(br s,2H),7.71(s,1H),7.43(d,1H,J=7.2Hz),7.36(m,1H),7.26-7.20(m,1H),7.12-7.08(m,2H),4.49(t,J=5.1Hz,2H),4.00(s,2H),3.71(t,J=5.1Hz,2H),3.32(s,3H),3.21-3.07(m,3H),2.99(brs,2H),1.80-1.62(m,4H);19
F NMR(DMSO-d6
)δ-56.79(s,3F),-119.34(s,1F),-134.53(d,J=9.6Hz,1F);MS 512(M+1,100%)。CHN:理論值:C53.06%,H5.16%,N7.42%(計算為1.0H2
O)。實際值:C53.03%,H4.82%,N7.22,C16.64%。
將20-L玻璃夾套反應器內含[4-(5-胺基甲基-2-氟苯基)哌啶-1-基][7-氟-1-(2-甲氧基乙基)-4-三氟甲氧基-1H
-吲哚-3-基]甲酮(1320g,2.58mol)的甲苯溶液攪拌並加熱至61℃。加入苯甲酸(316g,2.58mol),在所有苯甲酸溶解後,加入環己烷(6.04L)。將反應物加熱至77℃,用前一批[4-(5-胺基甲基-2-氟苯基)哌啶-1-基][7-氟-1-(2-甲氧基乙基)-4-三氟甲氧基-1H
-吲哚-3-基]甲酮苯甲酸鹽(0.100g)作為晶種。於77℃結晶,15分鐘之後,以-10℃/小時的梯度冷卻該反應物。當反應物溫度達到61℃時,停止攪拌和冷卻,任反應物冷卻至室溫。靜止過夜之後,恢復攪拌並以過濾收集產物。用從甲苯(3L)和環己烷(1.5L)製備的混合溶劑洗滌濾餅。以抽吸法部分乾燥後,將產物轉移至乾燥烘箱內於40℃乾燥,即得[4-(5-胺基甲基-2-氟苯基)哌啶-1-基][7-氟-1-(2-甲氧基乙基)-4-三氟甲氧基-1H
-吲哚-3-基]甲酮苯甲酸鹽,為無色固體:1408.8g(86%),熔點=156-159℃。元素分析:C25
H26
F5
N3
O3
.C7
H6
O2
計算值:C,60.66;H,5.09;N,6.63。實際值:C,60.44;H,5.01;N,6.87。紅外光譜特徵(cm-1):1612,1526,1511,1501,1394,1362,1256,1232,1211,1158,1117,999,826。
在一種沸點至少與異丙醇相同的醇溶劑如正丙醇、正丁醇中;在極性非質子溶劑如二甲基甲醯胺、1-甲基-2-吡咯烷酮、二甲基亞碸中,在醚類溶劑如2-甲基四氫呋喃、二甲氧基乙烷中,使3-溴-4-氟甲苯胺鹽酸鹽(Wychem)與吡啶-4-硼酸(Clariant或Boron Molecular)反應。在上述任何溶劑和水的混合物中,在一種適宜的觸媒如1,1’-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷複合物(PdCl2
dppf-CH2
Cl2
)、Pd(PPh3
)4
、PdCl2
(PPh3
)2
、Pd(dtbpf)Cl2
等存在條件下,將化合物12和化合物13從約70℃充分加熱至鈴木偶合反應混合物的沸點溫度,即得吡啶。
在三氟乙醯基化條件下,用一種適宜的三氟乙醯基化劑如三氟乙酸酐、三氟乙醯基氟化物、三氟乙酸五氟苯酯,在一種三氟乙醯基化溶劑如乙酸乙酯、乙酸異丙酯等酯類溶劑中,或一種芳烴溶劑如甲苯或類似物中,或一種氯化烴溶劑如甲叉二氯、1,2-二氯乙烷或類似物中,於約-20至約30℃的三氟乙醯基化反應溫度下,將此吡啶轉化為三氟乙醯胺化合物2,2,2-三氟-N
-(4-氟-3-吡啶-4-基苄基)-乙醯胺。再用鹽酸處理使其轉化為鹽酸鹽。
在氫化條件下,在一種氫化觸媒PtO2
、Pd/C、Pd(OH)2
,Rh/C和類似物存在條件下,可加或可不加無機酸如HCl和類似物,或有機酸如乙酸和類似物,在一種氫化反應溶劑如乙醇、異丙醇之類的醇溶劑中,或乙酸中,或一種醇溶劑或乙酸和水的混合物中,於約10至約60℃的氫化反應溫度以及約20至1000psi的氫化壓力下,用氫氣處理將2,2,2-三氟-N
-(4-氟-3-吡啶-4-基苄基)-乙醯胺鹽酸鹽還原為化合物14。
本發明之化合物是鹼性的。此類化合物可以游離鹼的形式或其藥學上可接受的酸加成鹽形式使用。
酸式加成鹽也許是更便於使用的形式;實際上,以該鹽的形式使用在本質上相當於以游離鹼的形式使用。可用於製備酸加成鹽的較佳的酸是當與游離鹼結合時能生成藥學上可接受的鹽的那些酸,即在藥用劑量條件下其陰離子對患者無毒性的那些鹽,使得該游離鹼內在的有益抑制作用不會因陰離子的副作用而失效。雖然上述鹼性化合物之藥學上可接受的鹽是首選的,但所有酸式加成鹽均可作為游離鹼形式的來源,即使某種特定的鹽本身只是作為中間產品,例如,當僅僅是出於純化和鑒別的目的而製備該鹽時,或當使用該鹽作為中間體以離子交換步驟製備一種藥學上可接受的鹽時。本發明範圍內的藥學上可接受的鹽包括那些從無機酸和有機酸衍生的鹽,並包括鹵化氫如氯化氫和溴化氫、硫酸鹽、磷酸鹽、硝酸鹽、胺基磺酸鹽、乙酸鹽、檸檬酸鹽、乳酸鹽、酒石酸鹽、丙二酸鹽、草酸鹽、水楊酸鹽、丙酸鹽、琥珀酸鹽、富馬酸鹽、馬來酸鹽、亞甲基-雙-β-羥基萘甲酸鹽、苯甲酸鹽、甲苯磺酸鹽、龍膽酸鹽、羥乙基磺酸鹽、二對甲苯醯基酒石酸鹽、甲磺酸鹽、乙磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽、環己基胺基磺酸鹽和奎尼酸鹽。一種較佳的結構式為I之化合物的鹽是鹽酸鹽。本發明另一種較佳的鹽是結構式為I之化合物的富馬酸鹽。本發明的一種首選的藥學上可接受的鹽是結構式為I之化合物的苯甲酸鹽。
本發明之化合物的鹽不但其本身作為活性化合物是很有用的,從純化該化合物的目的而言,它們也是很有用的,例如,以本領域專業人士眾所周知的技術,利用該鹽、副產物和/或初始材料與母體化合物之間在溶解性上的差別可純化該化合物。
依照本發明的另一個特點,本發明之化合物的酸式加成鹽可透過應用或改進已知的方法透過游離鹼與適當的酸進行反應來製備。例如,本發明之化合物的酸式加成鹽可透過以下任一步驟製備:或者是將該游離鹼溶於水或醇的水溶液,或其他含有適當酸的適當溶劑,並透過蒸發該溶液而分離出該鹽;或者是讓該游離鹼在一種有機溶劑中與酸反應,在此情況下可直接分離出該鹽或可透過濃縮該溶液的方式而獲得該鹽。
本發明之化合物的酸式加成鹽可透過應用或改進已知的方法從鹽再生。例如,透過用一種鹼例如碳酸氫鈉水溶液或氨水溶液處理,本發明的母體化合物可從它們的酸式加成鹽再生。
原料和中間體可藉由應用或改進已知的方法來製備,例如對照實例中所述的方法或顯然與它們相當的化學方法。
本發明還涉及方案1中的某些中間體,因此,本文所述的它們的製備過程也構成了本發明的進一步特點。
透過參考以下作為本發明示範性例子的非限制性實例,對本發明將會有更透徹的理解。提供以下實例是為了更充分地闡明本發明之較佳的實施例。然而,不應以任何方式將它們解釋為是對本發明廣闊範圍的限制。提供以下對照實例是為了披露如何製備用於製備結構式為I之化合物的中間體。
在下文列出的核磁共振光譜(NMR)中,化學位移以ppm表示,以四甲基甲矽烷為內標。各縮寫詞分別具有以下含意:br=寬峰,dd=雙峰,s=單峰;m=多重峰。
於室溫在一燒瓶中加入NaHCO3
(126g,1.5mol)、3-溴-4-氟甲苯胺鹽酸鹽(11
,120g,0.5mole)、吡啶-4-硼酸(13,67.6g,0.55mmol)、i
PrOH(750mL)和水(375mL)。於10℃用N2
使懸浮液脫氣1小時。向該混合物加入1,1’-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷複合物(PdCl2
dppf-CH2
Cl2
,16.4g,20mmol)。將反應混合物加熱至80℃同時蒸餾出一部分直至內部溫度達到80℃,攪拌10小時。待反應完全後(經HPLC分析),將該混合物冷卻至室溫,並加入2N HCl水溶液(750mL),攪拌0.5小時。用DCM(750mL和500mL)洗滌該溶液。在水相中加入50% NaOH水溶液(100mL)以調節pH>13。加入n
-BuOAc(2L)之後,向有機層加入活性碳(50g)。讓此混合物通過矽藻土層(50g)過濾。進行共沸蒸餾。進一步加入n
-BuOAc(1L)後,將反應物冷卻至5℃。於5℃向該溶液緩慢地加入TFAA(157g,0.6mol)。待反應完全後(經HPLC分析),用10% Na2
CO3
水溶液(1L)洗滌反應混合物。於10℃向粗制有機層加入5-6N HCl的i
PrOH溶液(120mL)。然後再加入部分n
-BuOAc(1L),於室溫靜置懸浮液過夜。於10℃過濾所得固體,並於50℃在烘箱中乾燥,即得124g(75%)化合物15
為白色固體:熔點=220℃。
C14
H10
F4
N2
O-HCl分析計算值:C,50.24;H,3.31;N,8.37。實際值:C,50.16;H,3.08;N,8.38。MS(ESI)m/z 299(M+H)。1
H NMR(300MHz,D2
O)δ8.70(d,J=6.9Hz,2H),8.14(d,J=6.9Hz,2H),7.56-7.20(m,3H),4.51(s,2H)。
於室溫在一帕爾燒瓶中加入化合物13
(123g,0.37mol)和MeOH(740mL),然後加入5% Pt/C(36.9g,30w/w%)。將此反應燒瓶置入一帕爾氫化系統並於50-60psi通入H2
。將該混合物振搖48小時以上,同時通入H2
直至壓力達到穩態(於白天期間每2-3小時通入H2
至50-60psi,若不繼續通入氫氣則在過夜之後觀察到壓力為10-20psi)。當HPLC分析顯示反應完全時,將反應混合物通過矽藻土層過濾。在加入n
-BuOAc(1.25L)的同時,於40-50℃蒸出濾液。待MeOH完全蒸出後,再加入部分n
-BuOAc(1L)。任所得懸浮液冷卻至室溫過夜。將該懸浮液冷卻至10℃,過濾,並於50℃在烘箱內乾燥,即得112g(89%)化合物14
為白色固體:熔點=134℃。C14
H10
F4
N2
O-HCl分析計算值:C,50.24;H,3.31;N,8.37。實際值:C,50.16;H,3.08;N,8.38。MS(ESI)m/z 305.4(M+H)。1
H NMR(300MHz,D2
O)。7.16-6.98(m,3H),4.34(s,2H),3.42(d,J=12.9Hz,2H),3.14-2.99(m,3H),1.98-1.81(m,4H)。
於0℃在一段30分鐘時間內向化合物1
(50.72g,0.26mol)和吡啶(27.3mL,0.34mol)的THF(500mL)溶液滴加氯甲酸乙酯(32.2mL,0.39mol)。在1小時後,LC/MS和TLC均顯示反應已完全。將該反應混合物在H2
O和EtOAc之間分配。將兩層分離,將有機層用1M HCl、H2
O和鹽水洗滌,用MgSO4
乾燥,過濾,並在真空中濃縮。以庚烷/EtOAc(95/5至70/30)為洗脫劑,在矽膠上純化該粗製物,即得69.23g(99%)產物2
為透明無色液體。1
H NMR(CDCl3
)8.11(br s,1H),7.07(dd,J
=9.1,9.3Hz,1H),7.00-6.80(m,2H),4.27(q,J
=7.1Hz,2H),1.33(t,J
=7.1Hz,3H);19
F NMR(CDCl3
)-57.84(s,3F),-134.01(br s,1F);MS 309(M+CH3CN+1,100%),268(M+1)。
在一段1小時的時間內,於-78℃向化合物2
(31.34g,117.2mmol)的THF溶液(180mL)滴加sec
-BuLi(1.4M的環己烷溶液,200mL,280mmol)。於20分鐘後,在一段30分鐘的時間內,滴加I2
(44.6g,175.8mmol)的THF溶液(150mL)。然後於-78℃將該混合物攪拌30分鐘。加入飽和NH4
Cl並移去冷浴。將反應混合物在H2
O和EtOAc之間分配。將兩層分離,將有機層用10% Na2
SO3
、H2
O和鹽水洗滌,用MgSO4
乾燥,過濾,並在真空中濃縮。將殘餘物懸浮於DCM(50mL),並加入庚烷(300mL)。以吸濾法從生成的懸浮液收集白色粉末3
(18.1g,39%)並用空氣乾燥。將濾液在真空中濃縮,並將殘餘物懸浮於庚烷(200mL)中。以吸濾法收集另一批化合物3
(3.8g,8%)並用空氣乾燥。經矽膠層析純化濾液可獲得更多產物。1
H NMR(CDCl3
)7.30-17.10(m,2H),6.16(br s,1H),4.26(q,J
=7.1Hz,2H),1.32(t,J
=7.1Hz,3H);19
F NMR(CDCl3
)-56.90(s,3F),-114.35(d,J
=8.5Hz,1F);MS 394(M+1,100%),374,364,321,267。
將化合物3
(18.1g,45.9mmol)、Et3
N(12.8mL,91.9mmol)、Pd(PPh)2
Cl2
(1.6g,5% mol)、CuI(0.7g,8% mol)和TMS-乙炔(19.6mL,137.8mmol)在脫氣THF(180mL)中的混合物於60℃加熱過夜。將該混合物冷卻至室溫,然後在H2
O和EtOAc之間分配。將此混合物通過矽藻土過濾以除去不溶物。將兩層濾液分離,將有機層用H2
O和鹽水洗滌,用MgSO4
乾燥,過濾,並在真空中濃縮。以庚烷/EtOAc為洗脫劑,在矽膠上純化該粗製物,即得15.6g(93%)產物4
,為米黃色固體。1
H NMR(CDCl3
)7.15-7.00(m,2H),6.41(br s,1H),4.26(q,J
=7.1Hz,2H),1.31(t,J
=7.1Hz,3H),0.27(s,9H);19
F NMR(CDCl3
)-57.59(s,3F),-118.15(s,1F);MS 364(M+1,100%)。
將化合物4
(28.9g,79.6mmol)和KOH(35.7g,636.7mmol)在脫氣t
-BuOH(300mL)中的混合物於70℃加熱過夜。LC/MS顯示反應已完全。將該混合物冷卻至室溫,然後在H2
O和Et2
O之間分配。將兩層分離,並用Et2
O抽提水層(2X)。將合併後有機層用H2
O和鹽水洗滌,用MgSO4
乾燥,過濾,並在真空中濃縮。以庚烷/EtOAc(100/0至60/40)為洗脫劑,在矽膠上純化該粗製物,即得16g(91%)的化合物5
,為黃色液體。1
H NMR(CDCl3
)8.47(br s,1H),7.35-7.20(m,1H),6.95-6.80(m,2H),6.68(d,J
=2.5Hz,1H);19
F NMR(CDCl3)-57.63(s,3F),-136.10(d,J
=8.5Hz,1F);MS 220(M+1,100%),200。
將化合物5
(16g,72.8mmol)和粉末KOH(20.4g,364.2mmol)在DMSO(150mL)中的混合物於室溫攪拌10分鐘。加入2-甲氧基乙基溴(10.3mL,109.2mmol)。將此混合物於室溫攪拌過夜。LC/MS顯示反應已完全。將該混合物在H2
O和Et2
O之間分配。將兩層分離,並用Et2
O抽提水層(2X)。將合併後有機層用H2
O和鹽水洗滌,用MgSO4
乾燥,過濾,並在真空中濃縮。以庚烷/EtOAc(100/0至50/50)為洗脫劑,在矽膠上純化該粗製物,即得19.3g(95%)的化合物6
,為黃色液體。1
H NMR(CDCl3
)7.15(d,J
=2.1Hz,1H),6.90-6.75(m,2H),6.56(t,J
=2.5Hz,1H),3.72(t,J
=5.2Hz,2H),3.72(t,J
=5.2Hz,2H),3.31(s,3H);19
F NMR(CDCl3
)-57.54(s,3F),-137.00(d,J
=11.3Hz,1F);MS 278(M+1,100%)。
向化合物6
(19.3g,69.7mmol)在DMF(135mL)中的混合物加入TFAA(26.2mL,188.2mmol)。將此混合物於40℃加熱過夜。TLC顯示反應已完全。將該混合物冷卻至室溫,然後在H2
O和Et2
O之間分配。將兩層分離,將有機層用飽和NaHCO3
(2X)、H2
O和鹽水洗滌,用MgSO4
乾燥,過濾,並在真空中濃縮。以庚烷/EtOAc(100/0至50/50)為洗脫劑,在矽膠上純化該粗製物,即得23.4g(89%)的化合物7
,為微綠色固體。1
H NMR(CDCl3
)8.03(d,J=1.4Hz,1H),7.20-6.95(m,2H),4.54(t,J
=4.9Hz,2H),3.76(t,J
=4.8Hz,2H),3.33(s,3H);19
F NMR(CDCl3
)-57.74(s,3F),-71.10(s,3F),-134.95(d,J
=11.5Hz,1F);MS 374(M+1,100%)。
將化合物7
(23.4g,62.6mmol)在MeOH(100mL)和5M NaOH(100mL)中的混合物於80℃加熱過夜。LC/MS顯示反應已完全。將反應混合物冷卻至室溫,然後在真空中濃縮以除去大部分MeOH。將殘餘物溶解於H2
O中,然後用Et2
O洗滌一遍。用濃HCl將水層緩慢地酸化至pH~2。用Et2
O抽提酸化的懸浮液,並用H2
O和鹽水洗滌有機抽提液,用MgSO4
乾燥,過濾,並在真空中濃縮。將殘餘物懸浮於DCM/庚烷(10/90)中。以吸濾法收集懸浮液中的白色粉末8
(19.4g,96%)並用空氣乾燥。1
H NMR(CDCl3
)8.02(s,1H),7.15-7.05(m,1H),7.00-6.90(m,1H),4.49(t,J
=5.0Hz,2H),3.75(t,J
=4.9Hz,2H),3.33(s,3H);19
F NMR(CDCl3
)-57.74(s,3F),-135.65(d,J=11.3Hz,1F);MS 363(M+CH3
CN+1),322(M+1,100%)。
於室溫將化合物8
(19.1g,59.6mmol)、Et3
N(24.8mL,177.9mmol)、2,2,2-三氟-N
-(4-氟-3-哌啶-4-基苄基)-乙醯胺鹽酸鹽(11,26.4g,77.5mmol)(14
)以及EDCI(17.1g,89.3mmol)在CH2
Cl2
中的混合物攪拌過夜。TLC和LC/MS均顯示反應已完全。將該混合物在H2
O和CH2
Cl2
之間分配。將兩層分離,將有機層用鹽水洗滌,用MgSO4
乾燥,過濾,並在真空中濃縮。以庚烷/EtOAc(40/60至0/100)為洗脫劑,在矽膠上純化該粗製物,即得化合物9
(36g,99%)為白色泡沫。1
H NMR(CDCl3
)7.37(s,1H),7.20-7.10(m,2H),7.10-6.85(m,4H),4.95(br s,1H),4.60-4.35(m,4H),3.90(br s,1H),3.73(t,J
=5.0Hz,2H),3.32(s,3H),3.25-2.70(m,3H),2.05-1.50(m,4H);19
F NMR(CDCl3
)-57.54(s,3F),-75.39(s,3F),-119.31(s,1F),-134.96(d,J
=11.3Hz,1F);MS 608(M+1,100%)。
向化合物9
(36g,59.3mmol)與MeOH(400mL)的混合物加入K2
CO3
水溶液(65.5g,474mmol,溶於120mL H2
O)。將此混合物於室溫攪拌過夜。LC/MS顯示反應已完全。將反應混合物在真空中濃縮以除去大部分甲醇。將殘餘物在H2
O和EtOAc之間分配。將兩層分離,將有機層用H2
O和鹽水洗滌,用MgSO4
乾燥,過濾,並在真空中濃縮,即得27.5g(90%)的化合物10
,為透明無色黏膠。1
H NMR(CDCl3
)7.42(s,1H),7.25-7.10(m,2H),7.05-6.85(m,3H),4.92(br s,1H),4.46(t,J
=5.2Hz,2H),3.86(br s,3H),3.74(t,J
=5.1Hz,2H),3.32(s,3H),3.30-2.75(m,3H),2.24(br s,2H),2.05-1.55(m,4H);19
F NMR(CDCl3
)-57.52(s,3F),-121.64(s,1F),-136.03(d,J
=11.3Hz,1F);MS 512(M+1,100%)。
向上述物質(2.856g,5.59mmol)的Et2
O(30mL)溶液滴加2N HCl/Et2
O(3mL,6mmol)。形成固體沉澱,除去乙醚溶液。再用部分Et2
O洗滌該固體然後除去乙醚溶液。將剩餘淺黃色固體溶於溫熱MeOH(10mL),然後加入Et2
O(50mL)直至該溶液略呈混濁。約2小時後出現固體沉澱。再加入部分Et2
O(5-10mL),然後將懸浮液置入冰箱過夜。收集白色結晶狀產物(2.475g,4.52mmol)並在高真空中乾燥4小時。
1
H NMR(DMSO-d6
)69 8.32(br s,2H),7.71(s,1H),7.43(d,1H,J=7.2Hz),7.36(m,1H),7.26-7.20(m,1H),7.12-7.08(m,2H),4.49(t,J=5.1Hz,2H),4.00(s,2H),3.71(t,J=5.1Hz,2H),3.32(s,3H),3.21-3.07(m,3H),2.99(br s,2H),1.80-1.62(m,4H);19
F NMR(DMSO-d6
)δ-56.79(s,3F),-119.34(s,1F),-134.53(d,J=9.6Hz,1F);MS 512(M+1,100%)。CHN:理論值:C 53.06%,H 5.16%,N 7.42%(計算為1.0 H2
O)。實際值:C 53.03%,H 4.82%,N 7.22,Cl 6.64%。
將20-L玻璃夾套反應器內含[4-(5-胺基甲基-2-氟苯基)哌啶-1-基][7-氟-1-(2-甲氧基乙基)-4-三氟甲氧基-1H
-吲哚-3-基]甲酮(1320g,2.58mol)的甲苯溶液攪拌並加熱至61℃。加入苯甲酸(316g,2.58mol),在所有苯甲酸溶解後,加入環己烷(6.04L)。將反應物加熱至77℃,用前一批的[4-(5-胺基甲基-2-氟苯基)哌啶-1-基][7-氟-1-(2-甲氧基乙基)-4-三氟甲氧基-1H
-吲哚-3-基]甲酮苯甲酸鹽(0.100g)作為晶種。於77℃結晶,15分鐘之後,以-10℃/小時的梯度冷卻該反應物。當反應物溫度達到61℃時,停止攪拌和冷卻,任反應物冷卻至室溫。靜置過夜之後,恢復攪拌並以過濾收集產物。用從甲苯(3L)和環己烷(1.5L)製備的混合溶劑洗滌濾餅。以抽吸法部分乾燥後,將產物轉移至乾燥烘箱內於40℃乾燥,即得[4-(5-胺基甲基-2-氟苯基)哌啶-1-基][7-氟-1-(2-甲氧基乙基)-4-三氟甲氧基-1H
-吲哚-3-基]甲酮苯甲酸鹽,為無色固體:1408.8g(86%),熔點=156-159℃。
將苯磺酸一水合物(698mg,3.84mmol)的乙腈溶液(12mL)滴加至攪拌中的[4-(5-胺基甲基-2-氟苯基)哌啶-1-基][7-氟-1-(2-甲氧基乙基)-4-三氟甲氧基-1H-吲哚-3-基]甲酮(2.0g,3.91mmol)在乙腈(5mL)中的懸浮液。當最終的游離鹼溶解時,開始從該混合物結晶出苯磺酸鹽。2小時之後,以過濾收集產物並用乙腈洗滌。任濾餅乾燥過夜。粉碎固體並在真空烘箱中於43-44℃和6.8-7.3”Hg柱用氮氣乾燥7.5小時,即得[4-(5-胺基甲基-2-氟苯基)哌啶-1-基][7-氟-1-(2-甲氧基乙基)-4-三氟甲氧基-1H-吲哚-3-基]甲酮苯磺酸鹽,為無色固體:2.27g 1(86.7%),熔點=215-218℃。C25
H26
F5
N3
O3
‧C6
H6
O3
S分析計算值:C,55.60;H,4.82;N,6.27。實際值:C,55.65;H,4.65;N,6.27。卡爾費歇爾法(Karl Fischer):<0.10。紅外光譜特徵(cm-1):1587,1545,1445,1210,1167,1125,1036,1018。
在一圓底燒瓶中加入[4-(5-胺基甲基-2-氟苯基)-哌啶-1-基][7-氟-1-(2-甲氧基乙基)-4-三氟甲氧基-1H-吲哚-3-基]甲酮(10.4g,20.4mmol)和富馬酸(4.74g,40.7mmol)。加入異丙醇(IPA,62mL),並在一蒸汽浴上加熱生成的混合物。大部分物質在出現鹽的結晶前溶解。當在蒸汽浴上加熱時,再分批每次加入30mL的IPA。在總共加入152mL的IPA後,得到完全的溶液。將生成的溶液過濾並任濾液冷卻至室溫。在一冰浴中進一步冷卻濾液1.5小時,再以過濾收集產物。用冷IPA(50mL)洗滌所收集的產物,以抽吸法進行部分乾燥並轉移至一乾燥烘箱內於45℃乾燥。乾燥過夜後,分離所需產物為無色固體:11.8g(84%)。IR(cm-1
):3122-2700,2920,2824,1698,1584,1512,1443,1397-1368,1293-1217,822,794,639。1
H NMR(300MHz,DMSO-d6):69 10.07(br,3H),7.71(s,1H),7.43(dd,J
=2.4,7.1,1H),7.36(ddd,J
=2.4,4.9,8.4,1H),7.19(d,J
=8.4,10.7,1H),7.10(d,J
=8.7,11.7,1H),7.05(ddd,J
=1.4,3.3,8.7,1H),6.50(s,3H),4.69(br,1H),4.48(t,J
=5.3,2H),3.97(s,2H),3.69(t,J
=5.4,2H),3.24(s,3H),3.08(dddd,J
=3.5,3.5,12.1,12.1,1H),2.91(br,2H),1.75(br,2H),1.63(br,2H)。C25
H26
F5
N3
O3
-1.5C4
H4
O4
分析計算值:C,54.31;H,4.70;N,6.13。實際值:C,54.30;H,4.62;N,6.04。MS(ESI)m/z 512.2(M+H)。
向[4-(5-胺基甲基-2-氟苯基)-哌啶-1-基]-[7-氟-1-(2-甲氧基乙基)-4-三氟甲氧基-1H
-吲哚-3-基]-甲酮(488mg,0.95mmol)與乙腈(3mL)的混合物加入對甲苯磺酸一水合物(181mg,0.95mmol)的乙腈溶液(3mL)。將此混合物在一冰箱內儲存過夜。以吸濾法收集生成的米黃色晶體,用甲苯洗滌,並於50℃在真空中乾燥過夜。產率為453mg(69%)。1
H NMR(DMSO-d6
)δ8.08(bs,3H),7.70(s,1H),7.80-6.95(m,9H),5.00-4.30(m,3H),4.20-3.90(m,2H),3.80-3.60(m,3H),3.23(s,3H),3.25-2.80(m,3H),2.28(s,3H),1.95-1.45(m,4H);19
F NMR(DMSO-d6
)δ-55.61(s,3F),-118.98(s,1F),-134.33(d,J
=9.3Hz,1F);LC 2.627min;MS 512(M+1,100%)。熔點219℃。紅外光譜特徵(cm-1):1583,1548,1511,1501,1250,1200,1169,1123,1115。
在一20ml玻璃小瓶中稱出[4-(5-胺基甲基-2-氟苯基)-哌啶-1-基]-[7-氟-1-(2-甲氧基乙基)-4-三氟甲氧基-1H
-吲哚-3-基]-甲酮(423mg,0.827mmol)。在此固體中加入硫酸溶液(1.0N試劑,1.5當量,1.30mmol,2.60ml)和1.7ml水。於室溫攪拌2小時後,析出結晶產物。過濾和乾燥之後,發現此固體為無定形。用幾滴水處理後,此無定形固體還原為結晶形式。熔點62℃。紅外光譜特徵(cm-1):1574,1545,1511,1483,1362,1267,1219,1212,1162,1096,1051。
在一20ml玻璃小瓶中稱出[4-(5-胺基甲基-2-氟苯基)-哌啶-1-基]-[7-氟-1-(2-甲氧基乙基)-4-三氟甲氧基-1H
-吲哚-3-基]-甲酮(265mg,0.52mmol)。再加入檸檬酸在2:1(v/v)乙腈/水中的溶液(3.30ml的0.158mmol/ml檸檬酸)。所有固體均迅速溶解生成一透明溶液,後者於室溫靜置1小時。在氮氣流中蒸發該溶液,然後於室溫在真空中乾燥。加入最低量的水,將此固體在熱乙腈中重結晶,即得一透明溶液。冷卻時,該溶液析出產物,為很長的纖維狀顆粒,於室溫靜止後又轉化為板狀。熔點112℃。紅外光譜特徵(cm-1):1721,1590,1553,1369,1245,1174,1155,1119。
在一20ml玻璃小瓶中稱出[4-(5-胺基甲基-2-氟苯基)-哌啶-1-基]-[7-氟-1-(2-甲氧基乙基)-4-三氟甲氧基-1H
-吲哚-3-基]-甲酮(0.250g,0.489mmol)。加入甲磺酸水溶液(0.98ml的0.50mmol/ml溶液)並將此混合物邊攪拌邊加熱至~60℃。並非所有固體都溶解,再加入25ul甲磺酸溶液,即得一透明溶液。於室溫攪拌1小時,在旋轉蒸發器中真空蒸發此溶液,即得一非常黏的油。此油在乙腈中重結晶形成正方形板。紅外光譜特徵(cm-1):1596,1540,1214,1159,1112,1040,1020。
在一20ml玻璃小瓶中稱出[4-(5-胺基甲基-2-氟苯基)-哌啶-1-基]-[7-氟-1-(2-甲氧基乙基)-4-三氟甲氧基-1H
-吲哚-3-基]-甲酮(0.250g,0.554mmol)。在5:1(v/v)乙腈/水中製備2.66mmol/ml L-(+)-酒石酸溶液,並將0.2084ml此溶液加入已稱重的固體,邊攪拌邊加熱至~60℃,即得一透明溶液。在旋轉蒸發器中真空蒸發此溶液,將剩餘的玻璃狀固體在熱的乙酸異丙酯中重結晶,加入最低量異丙醇,即得一透明溶液。冷卻時,以過濾分離結晶產物並於室溫在真空中乾燥。
加入[4-(5-胺基甲基-2-氟苯基)-哌啶-1-基]-[7-氟-1-(2-甲氧基乙基)-4-三氟甲氧基-1H
-吲哚-3-基]-甲酮(133.9mg,0.262mmol)和磷酸溶液(1mmole/mL磷酸異丙醇溶液,1.1當量)。用一磁性攪拌器攪拌於室溫將此混合物溶於500μL異丙醇。於室溫將此物質蒸發至乾,無結晶物析出。再將此物質溶於500μL丙酮、500μL乙酸乙酯和1mL庚烷。分離出油狀產物。將此混合物在氮氣流中蒸發至乾。一旦蒸乾,即加入乙酸乙酯(500μL)和甲苯(500μL),分離出油狀產物。將此混合物於室溫蒸發過夜至乾。加入甲基異丁基酮(1mL)和甲苯(500μL)以溶解此物質。將此混合物於室溫蒸發過夜。於室溫以真空過濾分離並收集結晶。於室溫將此物質在真空烘箱中(~300mbar)乾燥過夜。
加入[4-(5-胺基甲基-2-氟苯基)-哌啶-1-基]-[7-氟-1-(2-甲氧基乙基)-4-三氟甲氧基-1H
-吲哚-3-基]-甲酮(138.8mg,0.271mmol)、谷氨酸溶液(162.4mg/20mL水溶液,1.1當量)。加入甲醇(2mL)以溶解此物質。於室溫將此混合物蒸發過夜,析出白色無定形物質。在此物質中加入異丙醇(600μL)。出現結晶,於室溫以真空過濾收集結晶。於室溫在真空烘箱中(~300mbar)乾燥此物質過夜。
製備苯甲酸鹽懸浮液,相當於50mg游離鹼/mL超純水,即1mL水含63.6mg鹽。以500rpm轉速攪拌試樣過夜,並靜止4小時後再離心(處於懸浮液狀態總計29小時)。以13000rpm轉速離心8分鐘,以XRPD(X射線粉末衍射)分析收集的濕固體試樣,並以顯微鏡評估。然後於室溫用空氣乾燥該濕固體試樣過夜,作為XRPD分析和熱分析的乾試樣。將此原樣藥物作為初始物質比較。同時以游離鹼藥物的XRPD分析作為比較。該苯甲酸鹽似乎是一種含水量可變的水合物,不同水含量的XRPD顯示相同的峰值。
XRPD法
帶Cu反陰極的Siemens Model D5000
程式:1.0 Sec. dql
範圍:2°至40°。2-θ座標
步幅:0.02°
氣氛:環境溫度和濕度條件。
採用標準的頂部載樣和小容積腔載樣
DSC-TGA:TA Instrument製造Q-600 Simultaneous DSC-TGA型分析儀
吹掃氣體:氦氣,100mL/分鐘
溫度程式:線性加熱率10℃/分鐘
試樣準備:將約3-5mg粉末移入一個敞口鋁盤並載入TGA。使用一個空鋁盤作為對照。
在濕的和乾的試樣上進行了XRPD和熱分析。濕試樣的XRPD顯示基線有所漂移和升高。但是,在乾燥(過夜)後,XRPD顯示峰的解析度比初始物質有所改善。乾試樣的熱分析顯示了與初始物質相同的TGA曲線。根據XRPD和熱分析,未觀察到游離鹼或向水合物形式的轉化。提供了游離鹼的XRPD結果。
圖1顯示了結構式為I之化合物的苯甲酸鹽之結晶形式A的XRPD結果。此圖顯示了試樣的相對強度(%)與角度(2θ)的關係。以下列角度顯示了各峰:7.75、10.13、17.03、17.16、17.99、18.39、20.51、21.33、21.88、23.19、23.43以及27.59。
圖2顯示了結構式為I之化合物的苯甲酸鹽之結晶形式A的DSC結果。此圖顯示於160.29℃開始熔化並於162℃全部熔化。
本發明之化合物顯示了以下特性:1)其抑制β類胰蛋白的能力(IC50
和Ki
值)。
如「本發明之背景」一節所述,鑒於類胰蛋白的所有活動都依賴於其觸媒活性,任何能抑制其觸媒活性的化合物都有可能抑制類胰蛋白的作用。這種對觸媒活性的抑制作用可透過體外酶活性分析和細胞分析來測量。
對於類胰蛋白活性的抑制作用既可以用分離出的人肺類胰蛋白來驗證,也可以用表達在酶細胞上的重組人β類胰蛋白來驗證。無論是使用分離出的原生酶、還是表達酶,均獲得了基本相同的測試結果。該分析過程使用一個96孔的微量盤(Costar 3590),以L-焦穀氨醯基-L-脯氨醯基-L-精氨醯對硝基苯胺(L-pyroglutamyl-L-prolyl-L-arginine-para
-nitroanilide,S2366:Quadratech)為受質(與McEuen等人在Biochem Pharm 1996年第52期第331-340頁上所介紹的基本相同)。分析在室溫下進行,受質為0.5mM(2 x Km
)溶於50mM Tris(pH 8.2)、100mM NaCl、0.05% Tween 20、50μg/mL肝素的溶液,用微量盤閱讀器(Bckman Biomek平板閱讀器)在405nm波長下閱讀微量盤。
本測試步驟與上述測試步驟基本相同,只是一式兩份加入的被測化合物之最終濃度分別為:0.01、0.03、0.1、0.3、1、3、10μM(全部以手工操作方式稀釋)。每次分析時,無論是單點或IC50
測量,都使用一種標準化合物,以比較IC50
測量值。根據IC50
測量值,可用以下公式Ki
=IC50
/(1+[受質]/Km
)計算出Ki
值。
結構式為I之化合物對β類胰蛋白活性的抑制作用以Ki值表示為26±5nM。
抗原致敏和激發:於第1天(2008年8月25日)用卵白蛋白(0.5ml 1%溶液,腹腔內和皮下)使雄性Hartley天竺鼠(225-250g)致敏。於第4天(2008年8月28日),給動物增強注射(腹腔內)0.5ml 1%卵白蛋白。於第21天(2008年9月16日),給動物口服(2ml/kg)賦形劑(0.5%甲基纖維素/0.2% Tween 80)或於抗原激發前24小時口服化合物。於抗原激發前30分鐘給動物注射美吡拉敏(mepyramine)(10mg/kg,腹腔內)以防過敏性休克。然後,用DeVildis Ultraneb噴霧器給動物噴以霧狀1%卵白蛋白20分鐘。不激發負對照動物。致敏溶液:將1克(1g)取自雞蛋清的白蛋白(Sigma A55031G;批號087K7004)加入100ml生理鹽水,待其形成溶液。
氣道阻力測量:激發後18至24小時,將動物麻醉(肌肉注射0.5ml劑含氯胺酮(ketamine,62mg/kg)、甲苯噻嗪(xylazine,30mg/kg)和乙醯丙嗪(promace,1.5mg/kg)的混合藥劑),手術準備,然後置入全身體積描記器。將動物與Ugo-Basile通氣器連接,該通氣器經過一根氣管插管以50次呼吸/分鐘的速率輸入1ml/100g氣量。在頸靜脈上也插管用於組胺激發。安置一根充水的食管插管以便記錄跨肺壓。用差壓轉換器測量作為氣管和食管插管之間差別的跨肺壓。使用一個肺部分析系統(Buxco XA軟體)監測體積、氣流量及跨肺壓信號,並用結果計算肺的阻力(cmH2O/ml/s)和動態順應性(ml/cmH2O)。計算每次呼吸的氣道阻力和動態順應性。靜脈注射組胺並評估對濃度(1-20μg/kg)增加的反應。
對於結構式為I之化合物的富馬酸鹽的分析結果如下表所示。此分析與用該化合物治療哮喘的潛在有效性相關。對於抗原誘導的氣道過度反應性,當於抗原激發之前24小時用藥時,結構式為I之化合物的富馬酸鹽顯示了與劑量相關的抑制作用,如以下表格所示。
本發明之範圍將不受此處所述之特定具體實施例的限制。確實,對於熟悉本領域的人士而言,透過以上的說明及所附的數據,除了此處所述的以外,對於本發明可做的各種各樣的修改將是明顯的。這類修改將包括在所附的專利申請範圍內。
本文引用了各種各樣的出版物,所披露的內容均作為參考文獻以其整體而納入本文。
圖1顯示了結構式為I之化合物的苯甲酸鹽之結晶形式A的XRPD結果。此圖顯示了試樣的相對強度(%)與角度(2θ)的關係。以下列角度顯示了各峰:7.75、10.13、17.03、17.16、17.99、18.39、20.51、21.33、21.88、23.19、23.43以及27.59。
圖2顯示了結構式為I之化合物的苯甲酸鹽之結晶形式A的DSC結果。此圖顯示於160.29℃開始熔化並於162℃全部熔化。
Claims (32)
- 一種式I化合物:
- 如專利申請範圍第1項之化合物,其為藥學上可接受的鹽。
- 如專利申請範圍第2項之化合物,其中所述的藥學上可接受的鹽係選自:鹽酸鹽、富馬酸鹽、苯磺酸鹽、甲苯磺酸鹽、硫酸鹽、檸檬酸鹽、甲磺酸鹽、酒石酸鹽、磷酸鹽、谷氨酸鹽以及苯甲酸鹽。
- 如專利申請範圍第3項之化合物,其中所述的鹽是鹽酸鹽。
- 如專利申請範圍第3項之化合物,其中所述的鹽是富馬酸鹽。
- 如專利申請範圍第3項之化合物,其中所述的鹽是苯磺酸鹽。
- 如專利申請範圍第3項之化合物,其中所述的鹽是甲苯磺酸鹽。
- 如專利申請範圍第3項之化合物,其中所述的鹽是硫酸鹽。
- 如專利申請範圍第3項之化合物,其中所述的鹽是檸檬酸鹽。
- 如專利申請範圍第3項之化合物,其中所述的鹽是甲磺酸鹽。
- 如專利申請範圍第3項之化合物,其中所述的鹽是酒石酸鹽。
- 如專利申請範圍第3項之化合物,其中所述的鹽是磷酸鹽。
- 如專利申請範圍第3項之化合物,其中所述的鹽是谷氨酸鹽。
- 如專利申請範圍第3項之化合物,其中所述的鹽是苯甲酸鹽。
- 一種如專利申請範圍第14項之化合物的結晶形式A,其中所述的結晶形式在至少五個角具有XRPD峰:7.75、10.13、17.03、17.16、18.39、21.33,以及21.88。
- 一種如專利申請範圍第15項之化合物的結晶形式,其中所述的結晶形式於攝氏162度熔化。
- 一種治療有效量之如專利申請範圍第1項之化合物的用途,係用於製備治療或需藉由類胰蛋白酶之抑制作用來改善生理症狀的藥物。
- 如專利申請範圍第17項之用途,其中所述的生理症狀選自下列群組:發炎性疾病、關節軟骨破壞疾病、眼結膜炎、春季結膜炎、過敏性鼻炎、間質性肺病、纖維化、慢性阻塞性肺病、硬皮症、肺纖維化、肝硬化、心肌纖維化、神 經纖維瘤、肥厚性瘢痕、皮膚病症狀、與動脈粥樣硬化斑塊破裂有關的症狀、牙周病、糖尿病視網膜病變、腫瘤增長、過敏症、多發性硬化症、消化性潰瘍,以及合體細胞病毒感染。
- 如專利申請範圍第18項之用途,其中所述的生理症狀是發炎性疾病。
- 如專利申請範圍第19項之用途,其中所述的其中所述的發炎性疾病是關節發炎、發炎性腸道疾病、關節炎、類風濕性關節炎、類風濕性脊椎炎、痛風關節炎、創傷性關節炎、風疹關節炎、牛皮癬關節炎、哮喘或骨關節炎。
- 如專利申請範圍第18項之用途,其中所述的發炎性疾病是發炎性腸道疾病。
- 如專利申請範圍第18項之用途,其中所述的生理症狀是COPD。
- 如專利申請範圍第20項之用途,其中所述的生理症狀是哮喘。
- 如專利申請範圍第18項之用途,其中所述的生理症狀是一種皮膚病症狀。
- 如專利申請範圍第24項之用途,其中所述的皮膚病症狀是遺傳過敏性皮炎、牛皮癬和濕疹。
- 如專利申請範圍第25項之用途,其中所述的皮膚病症狀是遺傳過敏性皮炎。
- 如專利申請範圍第25項之用途,其中所述的皮膚病症狀是牛皮癬。
- 一種醫藥組合物,其含有治療有效量的如專利申請範圍第1項之化合物及其藥學上可接受的載體。
- 一種具有下式之化合物:
- 一種製備如專利申請範圍第2項之2,2,2-三氟-N-(4-氟-3-吡啶-4-基苄基)-乙醯胺鹽酸鹽的方法,包括在鈴木偶合條件下使3-溴-4-氟甲苯胺鹽酸鹽和吡啶-4-硼酸偶合,以產生2,2,2-三氟-N-(4-氟-3-吡啶-4-基苄基)-乙醯胺鹽酸鹽。
- 如專利申請範圍第4項之方法,其中所述的鈴木偶合條件使用一種選自如下溶劑的鈴木偶合溶劑:其沸點至少與異丙醇相同的醇類溶劑、極性非質子溶劑,或醚類溶劑,或任何前述溶劑和水或甲苯的混合物。
- 如專利申請範圍第5項之方法,其中所述的鈴木偶合溶劑是一種其沸點至少與異丙醇相同的醇類溶劑。
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Patent Citations (1)
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WO2001090101A1 (en) * | 2000-05-22 | 2001-11-29 | Aventis Pharmaceuticals Inc. | Arylmethylamine derivatives for use as tryptase inhibitors |
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