TW202019436A - 硼酸衍生物 - Google Patents
硼酸衍生物 Download PDFInfo
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- TW202019436A TW202019436A TW108126286A TW108126286A TW202019436A TW 202019436 A TW202019436 A TW 202019436A TW 108126286 A TW108126286 A TW 108126286A TW 108126286 A TW108126286 A TW 108126286A TW 202019436 A TW202019436 A TW 202019436A
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
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- A61K31/69—Boron compounds
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
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Abstract
本發明係關於α-胺基硼酸衍生物。此等化合物係適用於抑制免疫蛋白酶體(LMP7)之活性及用於治療及/或預防受免疫蛋白酶體活性影響之醫學病症,諸如炎症性及自體免疫性疾病、神經退行性疾病、增生性疾病及癌症。
Description
本發明係關於α-胺基硼酸衍生物。此等化合物係適用於抑制免疫蛋白酶體(LMP7)之活性及用於治療及/或預防受免疫蛋白酶體活性影響之醫學病症,諸如炎症性及自體免疫性疾病、神經退行性疾病、增生性疾病及癌症。特定言之,本發明之化合物係選擇性免疫蛋白酶體抑制劑。
蛋白酶體係高分子量、多亞單位蛋白酶,其已在自古細菌至人類之每種經檢查之物種中經識別。該酶具有大約650,000 Da之天然分子量,且如藉由電子顯微術顯示,獨特之圓柱形形態(Rivett, (1989) Arch. Biochem. Biophys. 268:1-8;及Orlowski, (1990) Biochemistry 29:10289-10297)。蛋白酶體亞單位在自20,000至35,000之分子量之範圍內,且係彼此同源的但非與任何其他已知的蛋白酶同源。
20S蛋白酶體係700 kDa圓柱形多催化蛋白酶複合物,其包含分類為α-及β-型之佈置於4個堆疊之七聚環中之28個亞單位。在酵母及其他真核生物中,7個不同之α亞單位形成外環及7個不同之β亞單位包含內環。該等α亞單位充當用於19S (PA700)及1 IS (PR68)調節複合物之結合位點,及用於由兩個β亞單位環形成之內蛋白水解室之物理屏障。因此,活體內,據信該蛋白酶體作為26S顆粒(「26S蛋白酶體」)存在。活體內實驗已顯示該蛋白酶體之20S形式之抑制可容易與26S蛋白酶體之抑制相關。
在顆粒形成期間裂解β亞單位之胺基端前序列曝露胺基端蘇胺酸殘基,其等充當催化親核試劑。亞單位負責蛋白酶體中之催化活性之該等亞單位因此具有胺基端親核殘基,且此等亞單位屬於N端親核試劑(Ntn) ATTY REF: 26500-0023WO1水解酶之家族(其中親核N端殘基係(例如) Cys、Ser、Thr及其他親核部分)。此家族包括(例如)盤尼西林G醯基轉移酶(PGA)、盤尼西林V醯基轉移酶(PVA)、麩醯胺酸PRPP醯胺轉移酶(GAT)及細菌醣苷基天冬醯胺酸酶。除經普遍表現之β亞單位外,高等脊椎動物亦具有三種干擾素-γ-可誘導β亞單位(LMP7、LMP2及MECLl),該等干擾素-γ-可誘導β亞單位分別替代其等正常對應物β5、β1及β2。當所有三種IFN-γ-可誘導亞單位存在時,該蛋白酶體被稱為「免疫蛋白酶體」。因此,真核細胞可具有以不同比率之蛋白酶體之兩種形式。
通過使用不同之肽受質,已針對真核生物20S蛋白酶體定義三種主要之蛋白水解活性:糜蛋白酶樣活性(CT-L),其在大疏水性殘基後裂解;胰蛋白酶樣活性(T-L),其在鹼性殘基後裂解;及肽基麩胺醯基肽水解活性(PGPH),其在酸性殘基後裂解。兩種額外之經較少表徵之活性亦已歸於蛋白酶體:BrAAP活性,其在分支鏈胺基酸後裂解;及SNAAP活性,其在小中性胺基酸後裂解。儘管蛋白酶體之兩種形式均具有所有五種酶活性,但該等形式間之活性程度之差異已基於具體之受質進行描述。就蛋白酶體之兩種形式而言,主要之蛋白酶體蛋白水解活性似乎由20S核心內不同之催化位點貢獻。
在真核生物中,蛋白質降解係主要通過泛素途徑介導,其中靶向破壞之蛋白質係連接至76個胺基酸多肽泛素。一經確定標靶,則泛素化蛋白質充當用於26S蛋白酶體之受質,該26S蛋白酶體通過其三種主要之蛋白水解活性之作用將蛋白質裂解為短肽。儘管細胞內蛋白周轉中具有一般功能,但由蛋白酶體介導之降解亦在許多過程諸如主要之組織相容性複合物(MHC) I類呈遞、細胞凋亡及細胞存活率、抗原處理、NF-κΒ活化及促炎信號之轉導中發揮關鍵作用。
蛋白酶體活性在涉及蛋白分解之肌肉萎縮性疾病(諸如肌肉萎縮症、癌症及AIDS)中係高的。證據亦表明蛋白酶體在針對I類MHC分子處理抗原之過程中可能發揮之作用(Goldberg等人,(1992) Nature 357:375-379)。
蛋白酶體涉及神經退行性疾病及失調症,諸如肌肉萎縮性脊髓側索硬化症(ALS) (J Biol Chem 2003, Allen S等人、Exp Neurol 2005, Puttaparthi k等人)、休格倫氏症候群(Sjogren Syndrome) (Arthritis & Rheumatism, 2006, Egerer T等人)、全身性紅斑狼瘡及狼瘡性腎炎(SLE/LN) (Arthritis & rheuma 2011, Ichikawa等人、J Immunol, 2010, Lang VR等人、Nat Med, 2008, Neubert K等人)、腎小球性腎炎(J Am Soc nephrol 2011, Bontscho等人)、類風濕性關節炎(Clin Exp Rheumatol, 2009, Van der Heiden JW等人)、炎症性腸病(IBD)、潰瘍性結腸炎、克羅恩氏病(crohn’s diseases) (Gut 2010, Schmidt N等人、J Immunol 2010, Basler M等人、Clin Exp Immunol, 2009, Inoue S等人)、多發性硬化症(Eur J Immunol 2008, Fissolo N等人、J Mol Med 2003, Elliott PJ等人、J Neuroimmunol 2001, Hosseini等人、J Autoimmun 2000, Vanderlugt CL等人)、肌肉萎縮性脊髓側索硬化症(ALS) (Exp Neurol 2005, Puttaparthi k等人、J Biol Chem 2003, Allen S等人)、骨關節炎(Pain 2011, Ahmed s等人、Biomed Mater Eng 2008, Etienne S等人)、動脈粥樣硬化(J Cardiovasc Pharmacol 2010, Feng B等人)、牛皮癬(Genes & Immunity, 2007, Kramer U等人)、重症肌無力(J Immunol, 2011, Gomez AM等人)、皮膚纖維化(Thorax 2011, Mutlu GM等人、Inflammation 2011, Koca SS等人、Faseb J 2006, Fineschi S等人)、腎纖維化(Nephrology 2011 Sakairi T等人)、心臟纖維化(Biochem Pharmacol 2011, Ma y等人)、肝纖維化(Am J Physiol gastrointest Liver Physiol 2006, Anan A等人)、肺纖維化(Faseb J 2006, Fineschi S等人)、免疫球蛋白A腎病(IGa腎病) (Kidney Int, 2009, Coppo R等人)、血管炎(J Am Soc nephrol 2011, Bontscho等人)、移植排斥(Nephrol Dial transplant 2011, Waiser J等人)、血液系統惡性腫瘤(Br J Haematol 2011, singh AV等人、Curr Cancer Drug Target 2011, Chen D等人)及哮喘。
然而,應注意市售蛋白酶體抑制劑抑制蛋白酶體之組成性及免疫形式。即使硼替佐米(經FDA批准用於治療復發性多發性骨髓瘤病患之蛋白酶體抑制劑)亦無法在該等兩種形式之間加以區分(Altun等人,Cancer Res 65:7896, 2005)。此外,硼替佐米之用途係與治療引起之疼痛性周圍神經病變(PN)相關聯,此由硼替佐米誘導之活體外神經退行性疾病經由蛋白酶體獨立性機制發生且該硼替佐米抑制活體外及活體內數個非蛋白酶體標靶(Clin. Cancer Res, 17(9), May 1, 2011)。
除習知蛋白酶體抑制劑外,新穎途徑可特異性靶向血液特異性免疫蛋白酶體,藉此增加整體有效性並減少負脫靶效應。已顯示免疫蛋白酶體特異性抑制劑可對來自血液來源之細胞顯示增強之效用(Curr Cancer Drug Targets, 11(3), Mar, 2011)。
因此需提供對蛋白酶體之一種具體形式具有選擇性之新穎蛋白酶體抑制劑。特定言之,需提供選擇性免疫蛋白酶體抑制劑,其等在風濕性關節炎之情況下可用作用於治療(例如) SLE或其他免疫或自體免疫失調症之治療劑。選擇性免疫蛋白酶體抑制劑適用於最小化藉由組成性蛋白酶體或其他非蛋白酶體標靶之抑制介導之非所需之副作用。
WO 2013/092979 A1描述對LMP7活性之抑制顯示選擇性之硼酸衍生物。然而,用本文描述之化合物之類型可達成之選擇性之程度係有限的,特定言之關於對組成性蛋白酶體之抑制活性之分裂。
蛋白酶體及免疫蛋白酶體之非特異性抑制劑(諸如硼替佐米及卡非佐米)已證實其等在指示多發性骨髓瘤中之臨床價值。儘管此非特異性概況,但擊中免疫蛋白酶體及組成性蛋白酶體中之主要組分,就標靶抑制及臨床有效性而言被認為係有利的,此非特異性概況藉由誘導明顯之副作用(諸如血小板減少症、嗜中性球減少症及周圍神經病變)限制此等藥劑之臨床適用性。在一定程度上,此副作用概況可歸因於催化活性之廣泛抑制,尤其組成性及免疫蛋白酶體之β5亞單位之組合抑制。提出更具選擇性之免疫蛋白酶體(及尤其免疫蛋白酶體之β5i亞單位)之抑制劑以減少主要副作用之途徑已描述(例如)於關於PR-924(免疫蛋白酶體之LMP7亞單位之100倍選擇性抑制劑)之Singh等人之2011 (Br. J. Hematology 152(2): 155–163)中。作者證實多發性骨髓瘤中存在免疫蛋白酶體之高表現程度。作者亦描述LMP7亞單位之選擇性抑制劑對在MM細胞系及CD138+ MM原發性病患細胞中誘導細胞死亡而不降低健康志願者之對照PBMC之存活率之作用,其可視為概念上之證明。除針對選擇性β5i抑制劑之減小之副作用概況之概念外,其他組證實選擇性β5i抑制對硼替佐米抗細胞系之存活率之效用強調將選擇性LMP7抑制劑應用於血液系統惡性腫瘤之價值及潛在觀點(D. Niewerth等人/ Biochemical Pharmacology 89 (2014) 43–51)。
WO 2016/050356、WO 2016/050355、WO 2016/050359及WO 2016/050358描述抑制免疫蛋白酶體(LMP7)之活性並向組成性蛋白酶體之抑制活性提供有效分裂之化合物。
出人意料地,發現本發明之胺基硼酸衍生物向組成性蛋白酶體之抑制活性提供特別高之分裂。另外,鑒於血漿-蛋白質結合、CYP抑制、PK概況及口服生物利用度,本發明之胺基硼酸衍生物顯示良好之結果。
本發明提供式(I)化合物:
其中
LY 表示(CH2
)r
,其中1至5個H原子可經Hal、R3b
、OH及/或OR3b
置換,及/或其中1或2個非相鄰之CH2
基團可經O、S、SO及/或SO2
置換;
Y 表示OR3c
或Cyc1
;
X 表示X0
、X1
或X2
;
X0
表示(CH2
)l
-O-A,其中(CH2)l
中1或2個H原子可經Hal、R3a
及/或OR3a
置換;
或
(CH2
)l
-OH,其中(CH2)l
中1或2個H原子可經Hal、R3a
及/或OR3a
置換;
X1
表示(CH2
)m
-S-A,其中(CH2
)m
中1或2個H原子可經Hal、R3a
、OR3a
、Ar及/或Het置換;
或
(CH2
)m
-SH,其中(CH2
)m
中1或2個H原子可經Hal、R3a
、OR3a
、Ar及/或Het置換;
X2
表示式x2a)、x2b)、x2c)或x2d)之飽和碳環或雜環,各未經取代或經Hal、CN、R3a
、OR3a
、COR3a
、NHCOAlk及/或NR3a
COAlk單取代、二取代或三取代,其中該飽和碳環或雜環之非直接連接至T1、T2或T3之1個CH2
基團可經C=O、O、S、SO、NCOAlk或SO置換;
(未顯示x2a)、x2b)、x2c)及x2d)之可選取代基)
R1
、R2
各彼此獨立地表示H或C1
-C6
-烷基,或R1
及R2
一起形成根據式(CE)之殘基:(CE)
R3a
、R3b
、R3c
各彼此獨立地表示直鏈或分支鏈C1
-C6
-烷基,其中1至5個H原子可經Hal、OH及/或OAlk置換;
A 表示直鏈或分支鏈C1
-C6
-烷基或C3
-C6
-環烷基,各未經取代或經Hal、CN、R3a
、SR3a
、SH、OR3a
、OH、Ar、Het及/或(CH2
)q
-R6
單取代、二取代、三取代或四取代;
Alk 表示直鏈或分支鏈C1
-C6
-烷基;
Cyc1
表示2,4-、3,4-或2,3,4-經取代之苯基,其中該等取代基係選自由以下組成之群:Hal、CN、R3a
、OR3a
、CONHR3a
、CONR3b
R3a
、CONH2
、NR3a
COR3b
、SO2
R3a
、SOR3a
、NHR3a
、N(R3a
)2
、(CH2
)q
-SR3a
、(CH2
)q
-N(R3a
)2
及/或(CH2
)q
-R6
;
或
式(ya)、(yb)、(yc)、(yd)、(ye)、(yf)、(yg)、(yh)、(yi)、(yj)、(yk)、(yl)、(ym)、(yn)、(yo)或(yp)之雙環殘基,各彼此獨立地未經取代或經Hal、CN、R3a
、OR3a
、CONHR3a
、CONR3b
R3a
、CONH2
、NR3a
COR3b
、SO2
R3a
、SOR3a
、NHR3a
、N(R3a
)2
、(CH2
)q
-SR3a
、(CH2
)q
-N(R3a
)2
及/或(CH2
)q
-R6
單取代、二取代或三取代;
(未顯示(ya)至(yp)之可選取代基)
其中
Ea
表示O、S、N(Alk)或CH=CH;及
Eb
表示O、S、N(Alk)、CH2
、CH2-
CH2
、O-CH2
、S-CH2
或N(Alk)CH2
;
Cyc2
、Cyc3
各彼此獨立地表示飽和、不飽和或芳族5或6員烴環或雜環,各彼此獨立地未經取代或經Hal、CN、R3a
、OR3a
、COR3a
、NHCOR3a
及/或NR3a
COR3b
單取代、二取代、三取代;
Ar 表示苯基,其係未經取代或經Hal、CN、R3a
、OR3a
、CONHR3a
、NR3a
COR3b
、SO2
R3a
、SOR3a
、NH2
、NHR3a
、N(R3a
)2
及/或(CH2
)q
-R6
單取代或二取代;
Het 表示具有1至4個N、O及/或S原子之飽和、不飽和或芳族5或6員雜環,其係未經取代或經Hal、CN、R3a
、OR3a
、CONHR3a
、NR3a
COR3b
、SO2
R3a
、SOR3a
、NH2
、NHR3a
、N(R3a
)2
及/或(CH2
)q
-R6
單取代或二取代;
T1
、T2
、T3
各彼此獨立地表示S、O;
R6
表示OH或OR3a
;
m、l 各彼此獨立地表示1、2或3;
k、n、o、p 各彼此獨立地表示0、1或2;
q 表示1、2、3、4、5或6;
r 表示0、1、2、3或4;
Hal 表示F、Cl、Br或I;
及其前藥、溶劑合物、互變異構體、寡聚物、加合物及立體異構體及上述各者之生理上可接受之鹽,包括其以所有比率之混合物。
本發明之化合物係免疫蛋白酶體亞單位LMP7之抑制劑。本發明之化合物顯示對LMP7勝過對β5 (cP)之特別高選擇性及在溶解度、血漿-蛋白質結合、CYP抑制、PK概況及口服生物利用度方面之良好性質。
已知硼酸衍生物諸如式(I)化合物(其中R1
及R2
表示H)形成寡聚物(Boronic Acids.,由Dennis G. Hall編輯,Copyright © 2005 WILEY-VCH Verlag, GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8)。式(I)化合物之此等寡聚物(特定言之(但不限於)二聚體或三聚體)係包括於本發明中。硼酸之已知環形三聚體具有(例如)下列結構:
亦已知硼酸衍生物諸如式(I)化合物(其中R1
及R2
表示H)藉由與脂族或芳族醇、二醇、糖、糖醇、α-羥基酸或含有一、二或三個含有N-/O-之官能基(例如-NH2
、-CONH2
或C=NH、-OH、-COOH)之親核試劑反應形成加合物,其中在存在三個官能基之情況下,三個雜原子中之一者可形成配位鍵(由Dennis G. Hall編輯之「Boronic Acids」,第2版,Copyright © 2011 WILEY-VCH Verlag, GmbH & Co. KGaA, Weinheim, ISBN 978-3-527-32598-6;WO2013128419;WO2009154737)。與預組織化二醇之加合物形成係特別快的。本發明包括式(I)硼酸化合物之此等加合物(特定言之酯或雜環衍生物)。
應注意本發明之化合物在與硼酸殘基相鄰之碳原子處攜載立體異構源中心;其已在下式(I)*中用星號(*)表示:
因此,根據式(I)之化合物在此立體異構源中心顯示兩種不同構型,即(R)-構型及(S)-構型。因此,本發明之化合物可對映異構純或作為式(R)-(I)及(S)-(I)之兩種對映異構體之外消旋(1:1)混合物存在。
式(I)化合物亦可存在於混合物中,其中對映異構體(R)-(I)或(S)-(I)中之一者係相對於另一者過量存在,例如60:40、70:30、80:20、90:10、95:5或類似物。在本發明之一特定實施例中,式(Ia)化合物之式(R)-(I)之立體異構體及式(Ia)化合物之式(S)-(I)之立體異構體係以至少90份之(R)-(I)相比於不超過10份之(S)-(I),較佳至少95 (R)-(I)相比於不超過5 (S)-(I),更佳至少99 (R)-(I)相比於不超過1 (S)-(I),甚至更佳至少99.5 (R)-(I)相比於不超過0.5 (S)-(I)之(R)-(I)相比於(S)-(I)之比率存在。在本發明之另一特定實施例中,式(Ia)化合物之式(S)-(I)之立體異構體及式(Ia)化合物之式(R)-(I)之立體異構體係以至少90 (S)-(I)相比於不超過10 (R)-(I),較佳至少95 (S)-(I)相比於不超過5 (R)-(I),更佳至少99 (S)-(I)相比於不超過1 (R)-(I),甚至更佳至少99.5 (S)-(I)相比於不超過0.5 (R)-(I)之(S)-(I)相比於(R)-(I)之比率存在。
式(R)-(I)及(S)-(I)之經富集或純立體異構體可藉由此項技術中已知的常用方法及下文中描述之具體方法獲得。用於獲得該等立體異構體之特定方法係製備型管柱層析術,諸如HPLC或SFC,使用對掌性管柱材料。
本發明之特別佳之實施例包含式(R)-(I)化合物,其中在與硼酸殘基相鄰之碳原子處之立體異構源中心具有(R)-構型:
根據式(I)之化合物亦可攜載位於除與硼酸殘基相鄰之碳原子外之碳原子處之其他立體異構源中心。此等立體異構源中心均可以(R)-或(S)-構型出現。
上下文中,在其中顯示具有立體異構源中心之化學結構且未指示具體立體化學之彼等情況下,該等結構包括所有可能之立體異構體及其混合物。
給定化合物之不同立體異構體係適用於經由NMR、HPLC、SFC或任何其他合適之分析方法分析表徵具體樣品(例如出於品質控制目的)。因此,本發明之另一態樣係關於根據式(I)之化合物之立體異構體在分析表徵方法中之用途。
一般而言,出現多於一次之本文描述之化合物之所有殘基可係相同或不同的,即彼此獨立。上下文中,除非本文另有明確指示,否則殘基及參數具有針對式(I)指示之含義。因此,本發明(特定言之)係關於其中該等殘基中之至少一者具有下文指示之較佳含義中之一者之式(I)化合物。此外,下文描述之所有具體實施例應包括其衍生物、前藥、溶劑合物、互變異構體或立體異構體及上述各者之生理上可接受之鹽,包括其以所有比率之混合物。
如上文描述,式x2a)、x2c)及x2d)之飽和碳環或雜環之非直接連接至T1、T2或T3之一個CH2
基團可經C=O、O、S、SO、NCOAlk或SO置換。換而言之,若式x2a)、x2c)及x2d)之飽和碳環或雜環之CH2
基團係經C=O、O、S、SO、NCOAlk或SO置換,則T1、T2或T3及置換基團(=O、O、S、SO、NCOAlk或SO)表示非相鄰之基團。此外,式x2a)、x2b)、x2c)或x2d)之飽和碳環或雜環可係未經取代或經Hal、CN、R3a
、OR3a
、COR3a
、NHCOAlk及/或NR3a
COAlk單取代、二取代或三取代。在式x2c)或x2d)之飽和碳環或雜環係經取代之情況下,一或多個取代基可結合至飽和環或稠合環Cyc2
及Cyc3
。此包括(例如)一個取代基結合至飽和環及一個取代基結合至稠合環Cyc2
或Cyc3
之化合物。在稠合環Cyc2
或Cyc3
中之一者含有一或多個CH2
基團之情況下,應瞭解此等基團係式x2c)或x2d)之飽和碳環或雜環之「環形CH2
基團」之一部分,其等可經C=O、O、S、SO、NCOAlk或SO置換。因此,若式x2c)或x2d)之飽和碳環或雜環之環形CH2
基團中之一者係經C=O、O、S、SO、NCOAlk或SO置換,則此等環形CH2
可係飽和環或稠合環Cyc2
或Cyc3
之一部分(然而,前提條件為,如上文描述,可經C=O、O、S、SO、NCOAlk或SO置換之飽和碳環或雜環之CH2
基團不應直接結合至T1、T2或T3)。
在實施例中,r表示0,LY係不存在的。
在本發明之內文中,「C1
-C6
-烷基」意謂具有1、2、3、4、5或6個碳原子且係直鏈或分支鏈之烷基部分。術語「C3
-C6
-環烷基」係指具有3、4、5或6個碳原子之飽和環形烴基。
術語「未經取代」意謂相應之原子團、基團或部分除H外無取代基;術語「經取代」當應用於自結構顯式或隱式之一或多個氫時,意謂相應之原子團、基團或部分具有除H外之一或多個取代基。在原子團具有複數個(即至少兩個)取代基,且各種取代基之選擇係經規定之情況下,該等取代基係經彼此獨立地選擇且無需相同。
術語「碳環」意謂環系統,其中所有環成員係碳原子。
術語「雜環」意謂環系統,其中環成員中之一些係雜原子,諸如N、O或S。
基團「NRR’」係胺基,其中R及R’(例如)各彼此獨立地係H或直鏈或分支鏈C1
-C6
-烷基殘基(特別甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基或第三丁基、戊基、己基)。
如(例如)包括於SOR3a
中之基團「SO」係其中S及O係經由雙鍵(S=O)連接之基團。
如(例如)包括於COR3a
中之基團「CO」係其中C及O係經由雙鍵(C=O)連接之基團。
術語「伸烷基」係指二價烷基。「伸烷基」係(聚)亞甲基(–(CH2
)x
–)。
如本文使用,術語「不飽和」意謂部分具有一或多個不飽和單元。如本文關於任何環、環系統、環部分及類似物使用,術語「部分不飽和」係指包括至少一個雙鍵或三鍵之環部分。術語「部分不飽和」意欲包含具有多於一個雙鍵或三鍵之環部分。
在本發明之內文中,諸如「O-CH3
」及「OCH3
」或「CH2
CH2
」及「-CH2
-CH2
-」之符號具有相同含義且可互換使用。
如本文使用,在結構式中,箭頭或具有垂直虛線之鍵係用以指示結合至相鄰基團之結合點。例如,x2a)中之箭頭顯示結合至相鄰之C=O基團之結合點。
本發明之特別重要之實施例包括式(I)化合物,其中:
LY 係CH2
或(CH2
)2
,其中1或2個H原子可經F、Cl或CH3
置換;
Y 表示Cyc1
;
R1
、R2
各彼此獨立地表示H或C1
-C4
-烷基,或R1
及R2
一起形成根據式(CE)之殘基;
r、m、l 各彼此獨立地表示1或2;及
A 表示直鏈或分支鏈C1
-C3
-烷基,其係未經取代或經F、Cl、CN、CH3
、C2
H5
、SCH3
、SC2
H5
、SH、OCH3
、OC2
H5
及/或OH單取代、二取代或三取代。
具體實施例包括式(I)化合物,其中:
LY 係CH2
或(CH2
)2
,其中1或2個H原子可經F、Cl或CH3
置換;
X0
表示(CH2
)l
-O-A,其中(CH2
)l
中1或2個H原子可經F、Cl、CH3
、C2
H5
、CF3
、OCH3
及/或OC2
H5
置換;
或
(CH2
)l
-OH,其中(CH2
)l
中1或2個H原子可經F、Cl、CH3
、C2
H5
、CF3
、OCH3
及/或OC2
H5
置換;
X1
表示(CH2
)m
-S-A,其中(CH2
)m
中1或2個H原子可經F、Cl、CH3
、C2
H5
、CF3
、OCH3
、OC2
H5
、Ar及/或Het置換;
或
(CH2
)m
-SH,其中(CH2
)m
中1或2個H原子可經F、Cl、CH3
、C2
H5
、CF3
、OCH3
、OC2
H5
、Ar及/或Het置換;
X2
表示式x2a)、x2b)、x2c)或x2d)之飽和碳環或雜環,各未經取代或經F、Cl、CH3
、C2
H5
、CF3
、OCH3
、OC2
H5
、OCF3
、N(CH3
)2
、CH2
N(CH3
)2
、N(C2
H5
)2
、COCH3
、COC2
H5
、NHCOCH3
及/或NHCOC2
H5
單取代、二取代或三取代;
A 表示CH3
、C2
H5
、(CH2
)2
OH、(CH2
)3
OH;
Ar 表示苯基,其係未經取代或經F、Cl、CH3
、C2
H5
、CF3
、OCH3
、OC2
H5
、COCF3
、SCH3
、SC2
H5
、CH2
OCH3
、N(CH3
)2
、CH2
N(CH3
)2
或N(C2
H5
)2
單取代或二取代;
Het 表示具有1至4個N、O及/或S原子之飽和、不飽和或芳族5或6員雜環,其係未經取代或經F、Cl、CH3
、C2
H5
、CF3
、OCH3
、OC2
H5
、COCF3
、SCH3
、SC2
H5
、CH2
OCH3
、N(CH3
)2
、CH2
N(CH3
)2
及/或N(C2
H5
)2
單取代或二取代;及
T1
、T2
、T3
各彼此獨立地表示S或O。
其他具體實施例包括式(I)化合物,其中:
X1
表示(CH2
)m
-S-A,其中(CH2
)m
中1或2個H原子可經F、Cl、CH3
、C2
H5
、CF3
、OCH3
及/或OC2
H5
置換;
或
(CH2
)m
-SH,其中(CH2
)m
中1或2個H原子可經F、Cl、CH3
、C2
H5
、CF3
、OCH3
及/或OC2
H5
置換。
在其他重要實施例中,X係選自下列基團:
其他具體實施例包含根據式(I)之化合物,其中:
Cyc1
表示2,4-、3,4-或2,3,4-經取代之苯基,其中該等取代基係選自由以下組成之群:Hal、CN、R3a
、OR3a
、CONHR3a
、CONR3b
R3a
、CONH2
、NR3a
COR3b
、SO2
R3a
、SOR3a
、NHR3a
、N(R3a
)2
、(CH2
)q
-SR3a
、(CH2
)q
-N(R3a
)2
及/或(CH2
)q
-R6
;
或
1-或2-萘基、2-或3-噻吩基、3-苯并呋喃基或2,3-二氫苯并呋喃-3-基,各彼此獨立地未經取代或經Hal、CN、R3a
、OR3a
、CONHR3a
、CONR3b
R3a
、CONH2
、NR3a
COR3b
、SO2
R3a
、SOR3a
、NHR3a
、N(R3a
)2
、(CH2
)q
-SR3a
、(CH2
)q
-N(R3a
)2
及/或(CH2
)q
-R6
單取代、二取代或三取代;
q 表示1或2;及
R3a
、R3b
各彼此獨立地表示直鏈或分支鏈C1
-C3
-烷基,其中1至5個H原子可經F、Cl、OH、OCH3
及/或OC2
H5
置換。
非常具體之實施例包含式(I)化合物,其中:
Cyc1
表示2,4-、3,4-或2,3,4-經取代之苯基或未經取代或經單取代或二取代之1-或2-萘基,其中該等取代基係各彼此獨立地選自由以下組成之群:Hal、CN、R3a
、OR3a
、CONHR3a
、CONR3b
R3a
、CONH2
、NR3a
COR3b
、SO2
R3a
、SOR3a
、NHR3a
、N(R3a
)2
、(CH2
)q
-SR3a
、(CH2
)q
-N(R3a
)2
及/或(CH2
)q
-R6
;
或
Cyc1
係根據式(Fa7)或(Fb7)之殘基:
其中,
Ga
表示H、F、Cl、Br、CN、R3a
、OR3a
、CONHR3a
、CONR3b
R3a
、CONH2
、NR3a
COR3b
、SO2
R3a
、SOR3a
、NHR3a
、N(R3a
)2
、(CH2
)q
-SR3a
、(CH2
)q
-N(R3a
)2
及/或(CH2
)q
-R6
;
Gb
表示H、F、Cl、Br、CN、R3a
、OR3a
、CONHR3a
、CONR3b
R3a
、CONH2
、NR3a
COR3b
、SO2
R3a
、SOR3a
、NHR3a
、N(R3a
)2
、(CH2
)q
-SR3a
、(CH2
)q
-N(R3a
)2
及/或(CH2
)q
-R6
;
Ka
、Kb
各彼此獨立地表示H、F、Cl、Br、CN、R3a
、OR3a
、CONHR3a
、CONR3b
R3a
、CONH2
、NR3a
COR3b
、SO2
R3a
、SOR3a
、NHR3a
、N(R3a
)2
、(CH2
)q
-SR3a
、(CH2
)q
-N(R3a
)2
及/或(CH2
)q
-R6
;
R3a
、R3b
各彼此獨立地表示直鏈或分支鏈C1
-C3
-烷基,其中1至5個H原子可經F、Cl、OH、OCH3
及/或OCH2
CH3
置換;及
q 表示1或2。
具體實施例包含根據式(I)之化合物,其中:
若Cyc1
表示2,4-、3,4-或2,3,4-經取代之苯基或未經取代或經單取代或二取代之1-或2-萘基,則可選取代基係各彼此獨立地選自由以下組成之群:F、Cl、CH3
、C2
H5
、CF3
、OCH3
、OC2
H5
、COCF3
、SCH3
、SC2
H5
、CH2
OCH3 、
N(CH3
)2
、CH2
N(CH3
)2
或N(C2
H5
)2
;
Ga
表示H、F、Cl、CH3
、C2
H5
、CF3
、OCH3
、OC2
H5
、COCF3
、SCH3
、SC2
H5
、CH2
OCH3 、
N(CH3
)2
、CH2
N(CH3
)2
或N(C2
H5
)2
;
Gb
表示H、F、Cl、CH3
、C2
H5
、CF3
、OCH3
、OC2
H5
、COCF3
、SCH3
、SC2
H5
、CH2
OCH3 、
N(CH3
)2
、CH2
N(CH3
)2
或N(C2
H5
)2
;及
Ka
、Kb
各彼此獨立地表示H、F、Cl、CH3
、C2
H5
、CF3
、OCH3
、OC2
H5
、COCF3
、SCH3
、SC2
H5
、CH2
OCH3
、N(CH3
)2
、CH2
N(CH3
)2
或N(C2
H5
)2
。
根據式(Fb7)之殘基在LY旁之碳原子處攜載立體異構源中心;其在下式(Fb7)*中已用星號(*)表示:
(Fb7)*
因此,根據式(Fb7)之殘基在此立體異構源中心處顯示兩種不同之構型,即(R)-構型及(S)-構型。因此,本發明之化合物可對映異構純或作為式(R)-(Fb7)及(S)-(Fb7)之兩種對映異構體之外消旋(1:1)混合物存在。
(S)-(Fb7)
(R)-(Fb7)
包括根據式(Fb7)之殘基之式(I)化合物亦可存在於混合物中,其中對映異構體(R)-(Fb7)或(S)-(Fb7)中之一者係相對於另一者過量存在,例如60:40、70:30、80:20、90:10、95:5或類似物。在本發明之一特定實施例中,式(I)化合物之式(R)-(Fb7)之立體異構體及式(I)化合物之式(S)-(Fb7)之立體異構體係以至少90份之(R)-(Fb7)相比於不超過10份之(S)-(Fb7),較佳至少95 (R)-(Fb7)相比於不超過5 (S)-(Fb7),更佳至少99 (R)-(Fb7)相比於不超過1 (S)-(Fb7),甚至更佳至少99.5 (R)-(Fb7)相比於不超過0.5 (S)-(Fb7)之(R)-(Fb7)相比於(S)-(Fb7)之比率存在。在本發明之另一特定實施例中,式(Fb7)化合物之式(S)-(Fb7)之立體異構體及式(I)化合物之式(R)-(Fb7)之立體異構體係以至少90 (S)-(Fb7)相比於不超過10 (R)-(Fb7),較佳至少95 (S)-(Fb7)相比於不超過5 (R)-(Fb7),更佳至少99 (S)-(Fb7b
)相比於不超過1 (R)-(Fb7),甚至更佳至少99.5 (S)-(Fb7)相比於不超過0.5 (R)-(Fb7)之(S)-(Fb7)相比於(R)-(Fb7)之比率存在。
本發明之特別佳之實施例包含式(I)化合物,其中Cyc1
係式(S)-(Fb7)之殘基(其在結合至LY之碳處具有(S)-構型)。
在此等實施例中,在二氫呋喃基殘基(Fb7)之位置3中之碳原子處之立體異構源中心顯示較佳(S)-構型,即該殘基係(視需要經取代之) (3S)-2,3-二氫苯并呋喃-3-基殘基(S)-(Fb7)*:
(S)-(Fb7)*。
其他特定實施例包含根據式(I)之化合物,其中:
LY 表示CH2
或CH2
-CH2
,其中1至4個H原子可經F或Cl置換及/或1或2個H原子可經OH、甲基、乙基、異丙基、CF3
、CF2
CF3
、OCH3
、OCH2
CH3
、OCH2
CH2
OH及/或OCH2
CH2
OCH3
置換;
Y 表示Cyc1
;
R1
、R2
各彼此獨立地表示H或C1
-C4
-烷基,或R1
及R2
一起形成如上文描述之根據式(CE)之殘基;及
R3a
、R3b
各彼此獨立地表示直鏈或分支鏈C1
-C3
-烷基,其中1至5個H原子可經F、Cl、OH及/或OCH3
、OCH2
CH3
置換;及
Cyc1
表示2,4-、3,4-或2,3,4-經取代之苯基或未經取代或經單取代或二取代之1-或2-萘基,其中該等取代基係各彼此獨立地選自由以下組成之群:Hal、CN、R3a
、OR3a
、CONHR3a
、CONR3b
R3a
、CONH2
、NR3a
COR3b
、SO2
R3a
、SOR3a
、NHR3a
、N(R3a
)2
、CH2
-R6
、CH2
-SR3a
、CH2
-N(R3a
)2
,
或
根據式(Fa7)或(S)-(Fb7)之殘基:
Ga
表示H、F、Cl、CH3
、C2
H5
、CF3
、OCH3
、OC2
H5
、COCF3
、SCH3
、SC2
H5
、CH2
OCH3 、
N(CH3
)2
、CH2
N(CH3
)2
或N(C2
H5
)2
;
Gb
表示H、F、Cl、CH3
、C2
H5
、CF3
、OCH3
、OC2
H5
、COCF3
、SCH3
、SC2
H5
、CH2
OCH3
、N(CH3
)2
、CH2
N(CH3
)2
或N(C2
H5
)2
;
Ka
、Kb
各彼此獨立地表示H、F、Cl、CH3
、C2
H5
、CF3
、OCH3
、OC2
H5
、COCF3
、SCH3
、SC2
H5
、CH2
OCH3
、N(CH3
)2
、CH2
N(CH3
)2
或N(C2
H5
)2
;及
q 表示1或2。
一般而言,包括於如上文描述之根據式(I)之化合物中之殘基可具有下列含義:
LY表示較佳-CH2
-或-CH2
-CH2
-,其中1至4個H原子可經Hal置換及/或1個H原子可經Hal、R3a
及/或OR4a
置換,及/或其中1或2個非相鄰之CH2
基團可經O、S、SO及/或SO2
置換。最佳地,LY表示-CH2
-或-CH2
-CH2
-,其中1至4個H原子可經F或Cl置換及/或1或2個H原子可經OH、甲基、乙基、異丙基、CF3
、CF2
CF3
、OCH3
、OCH2
CH3
、OCH2
CH2
OH及/或CH2
OCH3
置換及/或其中LY之1個CH2
基團可經O置換。
R1
、R2
各彼此獨立地表示較佳H或甲基、乙基、正丙基或異丙基或R1
及R2
一起形成如上文描述之根據式(CE)之殘基。最佳地,R1
、R2
表示H、甲基或乙基,及特別佳地,R1
及R2
表示H。
在其中R3a
或R3b
表示直鏈或分支鏈C1
-C6
烷基之實施例中,其等各彼此獨立地表示較佳直鏈或分支鏈甲基、乙基、正丙基或異丙基,其中1至5個H原子可經F、Cl、CN、OH及OAlk置換,其中Alk係較佳甲基或乙基。最佳地,R3a
及R3b
各彼此獨立地表示甲基、乙基、正丙基或異丙基,其中1、2或3個H原子係經F、Cl、OH、OCH3
、OC2
H5
或OCH(CH3
)2
置換。
Y之特別佳取代基係選自包含以下之群:Cl、CN、CH3
、C2
H5
、CF3
、OCH3
、OC2
H5
、COCF3
、SCH3
、SC2
H5
、CH2
OCH3
、N(CH3
)2
、CH2
N(CH3
)2
或N(C2
H5
)2
。
Ar表示較佳苯基,其係未經取代或經Hal、CN、R3a
、OR3a
、CONHR3a
、NH2
、NHR3a
及/或N(R3a
)2
單取代或二取代。因此,Ar較佳表示(例如)苯基、鄰-、間-或對-甲苯基、鄰-、間-或對-乙基苯基、鄰-、間-或對-丙基苯基、鄰-、間-或對-異丙基苯基、鄰-、間-或對-第三丁基苯基、鄰-、間-或對-羥基苯基、鄰-、間-或對-硝基苯基、鄰-、間-或對-胺基苯基、鄰-、間-或對-(N-甲基胺基)苯基、鄰-、間-或對-(N-甲基胺基羰基)苯基、鄰-、間-或對-乙醯胺基苯基、鄰-、間-或對-甲氧基苯基、鄰-、間-或對-乙氧基苯基、鄰-、間-或對-(N,N-二甲基胺基)苯基、鄰-、間-或對-(N-乙基胺基)苯基、鄰-、間-或對-(N,N-二乙基胺基)苯基、鄰-、間-或對-氟苯基、鄰-、間-或對-溴苯基、鄰-、間-或對-氯苯基、鄰-、間-或對-氰基苯基。
Het表示較佳具有1至4個N、O及/或S原子之飽和、不飽和或芳族5或6員雜環,其係未經取代或經Hal、CN、R3a
、OR3a
、CONHR3a
、NH2
、NHR3a
及/或N(R3a
)2
單取代。因此,Het可(例如)表示2-或3-呋喃基、2-或3-噻吩基、1-、2-或3-吡咯基、1-、2-、4-或5-咪唑基、1-、3-、4-或5-吡唑基、2-、4-或5-噁唑基、3-、4-或5-異噁唑基、2-、4-或5-噻唑基、3-、4-或5-異噻唑基、2-、3-或4-吡啶基、2-、4-、5-或6-嘧啶基、咪唑基、嗎啉基或哌嗪基。
Alk表示較佳甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基或第三丁基、戊基或己基,最佳甲基、乙基、丙基或異丙基,最佳甲基、乙基、正丙基或異丙基。
Hal表示較佳F、Cl或Br,最佳F或Cl。
k表示較佳0或1。
n表示較佳0或1。
o表示較佳0或1。
p表示較佳0或1。
r表示較佳0、1或2,更佳1或2及最佳1。
q表示較佳1、2、3或4及甚至更佳1或2。
術語化合物之溶劑合物意謂惰性溶劑分子加合至由於相互吸引力形成之化合物上。溶劑合物係(例如)單水合物或二水合物或烷氧化物。
應瞭解本發明亦係關於鹽之溶劑合物。
術語醫藥上可接受之衍生物意謂(例如)根據本發明之化合物之鹽及亦所謂之前藥化合物。
如本文使用及除非本文另有指示,否則術語「前藥」意謂可水解、氧化或以其他方式在生物條件下反應(活體外或活體內)以提供活性化合物,特定言之式(I)化合物之式(I)化合物之衍生物。前藥之實例包括(但不限於)包括可生物水解部分之式(I)化合物之衍生物及代謝物,諸如可生物水解醯胺、可生物水解酯、可生物水解胺基甲酸酯、可生物水解碳酸酯、可生物水解醯脲及可生物水解磷酸鹽類似物。在某些實施例中,具有羧基官能基之化合物之前藥係羧酸之低碳數烷基酯。羧酸酯係藉由酯化分子上存在之羧酸部分中之任何一者便利地形成。前藥可通常使用熟知的方法進行製備,諸如彼等由Burger's Medicinal Chemistry and Drug Discovery,第6版,(Donald J. Abraham編,2001, Wiley)及Design and Application of Prodrugs (H.Bundgaard編,1985, Harwood Academic Publishers Gmfh)描述之方法。
表達「有效量」表示在組織、系統、動物或人類中引起(例如)研究員或醫師可見或所需之生物或醫學反應之藥物或醫藥活性成分之量。
另外,表達「治療有效量」表示相較於未接受此量之相應之個體,具有下列結果之量:疾病、症候群、病症、併發症、失調症或副作用之經改善之治療、治癒、預防或消除或亦疾病、併發症或失調症之進展之減少。
表達「治療有效量」亦包含有效增加正常生理功能之量。
本發明亦係關於式(I)化合物之混合物之用途,例如兩種非對映異構體之混合物,例如以比率1:1、1:2、1:3、1:4、1:5、1:10、1:100或1:1000。
「互變異構體」係指彼此平衡之化合物之異構形式。該等異構形式之濃度將取決於發現該化合物之環境且可取決於(例如)該化合物是否為固體或於有機或水溶液中而係不同的。
此外,本發明包含用於製備如上文描述之式(I)化合物及其醫藥上可接受之鹽、互變異構體及立體異構體之方法,該方法之特徵在於使式(III)化合物
與式(VI)化合物偶合
其中式(III)及式(IV)之所有殘基係如上文定義且其中藉由用HCl、HBr、HI及/或TFA處理,在存在或缺乏過量之小分子量硼酸(諸如(但不限於) i-BuB(OH)2
)之情況下,獲得之式(Ib)化合物可接著轉化為式(Ia)化合物:。
在上文描述之方法中,式(IIII)化合物與式(IIV)化合物之間的反應係較佳在選自HATU、TBTU、由聚合物支持之1-烷基-2-氯吡啶鎓鹽(由聚合物支持之向山試劑)、1-甲基-2-氯碘化吡啶鎓(向山試劑)、碳化二亞胺之偶合劑之存在下進行。
下列縮寫係指下文使用之縮寫:
AcOH (乙酸)、ACN (乙腈)、BINAP (2,2’-雙(二苯基膦基)-1,1’-聯二萘)、dba (二苯亞甲基丙酮)、tBu (第三丁基)、tBuOK (第三丁醇鉀)、CDI (1,1’-羰基二咪唑)、DBU (1,8-二氮雜雙環[5.4.0]十一碳-7-烯)、DCC (二環己基碳二亞胺)、DCM (二氯甲烷)、DIAD (二異丁基偶氮二羧酸酯)、DIC (二異丙基碳二亞胺)、DIEA (二-異丙基乙胺)、DMA (二甲基乙醯胺)、DMAP (4-二甲基胺基吡啶)、DMSO (二甲基亞碸)、DMF (N,N-二甲基甲醯胺)、EDC·HCl (1-乙基-3-(3-二甲基胺基丙基)-碳二亞胺鹽酸鹽)、EtOAc或EE (乙酸乙酯)、EtOH (乙醇)、g (公克)、cHex (環己烷)、HATU (二甲基胺基-([1,2,3]三唑并[4,5-b]吡啶-3-基氧基)-亞甲基]-二甲基-六氟磷酸銨)、HOBt (N-羥基苯并三唑)、HPLC (高效液相層析術)、hr (小時)、MHz (百萬赫)、MeOH (甲醇)、min (分鐘)、mL (毫升)、mmol (毫莫耳)、mM (毫莫耳)、mp (熔點)、MS (質譜法)、MW (微波)、NMM (N-甲基嗎啉)、NMR (核磁共振)、NBS (N-溴琥珀醯亞胺)、PBS (磷酸鹽緩衝液)、PMB (對甲氧基苯甲基)、PyBOP (六氟磷酸苯并三唑-1-基-氧基三吡咯啶鏻)、rt (室溫)、RT (滯留時間) TBAF (四丁基氟化銨)、TBTU (N,N,N’,N’-四甲基-O-(苯并三唑1-基)四氟硼酸脲鎓)、T3P (丙烷膦酸酐)、TEA (三乙胺)、TFA (三氟乙酸)、THF (四氫呋喃)、PetEther (石油醚)、TBME (第三丁基甲醚)、TLC (薄層層析術)、TMS (三甲基矽基)、TMSI (碘化三甲基矽基)、UV (紫外線)。
一般而言,式(I)化合物(其中所有殘基係如上文定義)可獲得自如下列方案1中概述之式(III)化合物:
第一步包括式(III)化合物(其中X係如上文定義)與式(IV)化合物(其中R1
、R2
、LY及Y係如上文定義)之反應。該反應係使用熟習此項技術者熟知的用於製備醯胺之條件及方法自羧酸及標準偶合劑諸如(但不限於) HATU、TBTU、由聚合物支持之1-烷基-2-氯吡啶鎓鹽(由聚合物支持之向山試劑)、1-甲基-2-氯碘化吡啶鎓(向山試劑)、碳化二亞胺(諸如DCC、DIC、EDC)及HOBt、PyBOP®及熟習此項技術者熟知的其他此等試劑,較佳TBTU,在存在或缺乏鹼(諸如TEA、DIEA、NMM、由聚合物支持之嗎啉,較佳DIEA)之情況下,在合適之溶劑(諸如DCM、THF或DMF)中,在-10℃至50℃之溫度下,較佳在0℃下,歷時數小時,例如一小時至24 h進行。亦可使用鋰鹽(III-Li)代替游離酸(III)用於上文描述之偶合:
或者,式(III)化合物可藉由熟習此項技術者熟知的方法,諸如(但不限於)用SOCl2
、POCl3
、PCl5
、(COCl)2
處理,在存在或缺乏催化量之DMF之情況下,在存在或缺乏合適之溶劑(諸如甲苯、DCM、THF)之情況下,在自20℃上升至100℃之溫度下,較佳在50℃下,歷時數小時,例如一小時至24 h轉化為羧酸衍生物,諸如醯鹵或酸酐。羧酸衍生物至式(I)化合物之轉化可使用熟習此項技術者熟知的用於製備醯胺之條件及方法自羧酸衍生物(例如醯氯)及烷基胺,在鹼(諸如TEA、DIEA、NMM)之存在下,於合適之溶劑(諸如DCM、THF或DMF)中,在自20℃上升至100℃之溫度下,較佳在50℃下,歷時數小時,例如一小時至24 h達成。
式(Ia)化合物(其中X、LY及Y係如上文定義且其中R1
及R2
係H)可起始自式(Ib)化合物,使用熟習此項技術者熟知的用於水解硼酸酯之方法,諸如(但不限於)用HCl、HBr、HI、TFA處理,在存在或缺乏過量之小分子量硼酸,諸如(但不限於) iBuB(OH)2
之情況下進行製備(方案2)。
式(III)或(IV)化合物係市售或可藉由熟習此項技術者熟知的方法製備。
式(IV)化合物之合成係進一步描述於WO 2016/050356、WO 2016/050355、WO 2016/050359及WO 2016/050358中。
一些具體之式(III)化合物可藉由下列途徑製備:
a)
b)
c)
若上文之一組一般合成方法不適用於獲得根據式(I)之化合物及/或用於合成式(I)化合物必需之中間物,則應使用熟習此項技術者已知的合適之製備方法。
一般而言,用於任何個別式(I)化合物之合成途徑將取決於各分子之具體取代基及取決於所需中間物之隨時可用性;同樣,一般技術者知曉此等因素。就所有保護及去保護方法而言,參見Philip J. Kocienski,於「Protecting Groups」, Georg Thieme Verlag Stuttgart, New York, 1994中及Theodora W. Greene及Peter G. M. Wuts於「Protective Groups in Organic Synthesis」, Wiley Interscience,第3版,1999中。
本發明之化合物可藉由自適當之溶劑之蒸發結晶而與溶劑分子分離。含有鹼性中心之式(I)化合物之醫藥上可接受之酸加成鹽可以習知方式製備。例如,游離鹼之溶液可用純淨或在合適溶液中之合適之酸處理,且所得鹽藉由過濾或藉由在反應溶劑之真空下蒸發來進行分離。醫藥上可接受之鹼加成鹽可以類似方式藉由用合適之鹼處理含有酸中心之式(I)化合物之溶液獲得。兩種類型之鹽可使用離子交換樹脂技術來形成或相互轉化。
取決於使用之條件,反應時間係通常在幾分鐘與14天之間,及反應溫度係在約-30℃與140℃之間,通常在-10℃與90℃之間,特定言之在約0℃與約70℃之間。
此外,式(I)化合物可藉由用溶劑分解或氫解試劑處理以自式(I)化合物之官能衍生物中之一者釋放其等來獲得。
用於溶劑分解或氫解之較佳初始材料係彼等符合式(I),但含有相應之經保護之胺基及/或羥基而非一或多個游離胺基及/或羥基者,較佳彼等攜載胺基保護基團而非結合至N原子之H原子者,特定言之彼等攜載R'-N基團者,其中R'表示胺基保護基團,而非HN基團,及/或彼等攜載羥基保護基團而非羥基之H原子者,例如彼等符合式(I),但攜載-COOR”基團者,其中R”表示羥基保護基,而非-COOH基團。
複數個相同或不同之經保護之胺基及/或羥基亦可能存在於初始材料之分子中。若存在之保護基係彼此不同的,則其等可在許多情況下選擇性地裂解開來。
術語「胺基保護基團」係在一般術語中已知的且係關於適用於保護(阻斷)胺基抵抗化學反應之基團,但其等在所需化學反應已於分子別處進行後係容易移除的。此等基團之典型係(特定言之)未經取代或經取代之醯基、芳基、芳烷氧基甲基或芳烷基。由於在所需反應(或反應順序)後移除胺基保護基團,因此此外其等類型及大小並不重要;然而,優先考慮彼等具有1至20,特定言之1至8個碳原子者。術語「醯基」應在最廣泛意義上聯繫本發明方法進行瞭解。其包括衍生自脂族、芳脂族、芳族或雜環羧酸或磺酸之醯基,及特定言之,烷氧基羰基、芳氧基羰基及尤其芳烷氧基羰基。此等醯基之實例係烷醯基,諸如乙醯基、丙醯基及丁醯基;芳烷醯基,諸如苯基乙醯基;芳醯基,諸如苯甲醯基及甲苯基;芳氧基烷醯基,諸如POA;烷氧基羰基,諸如甲氧基羰基、乙氧基羰基、2,2,2-三氯乙氧基羰基、BOC (第三丁氧基羰基)及2-碘乙氧基羰基;芳烷氧基羰基,諸如CBZ (「苯甲氧羰基」)、4-甲氧基苯甲氧基羰基及FMOC;及芳基磺醯基,諸如Mtr。較佳之胺基保護基團係BOC及Mtr,此外CBZ、Fmoc、苯甲基及乙醯基。
術語「羥基保護基團」係同樣在一般術語中已知的且係關於適用於保護羥基抵抗化學反應之基團,但其等在所需化學反應已於分子別處進行後係容易移除的。此等基團之典型係上文提及之未經取代或經取代之芳基、芳烷基或醯基,此外亦烷基。由於在所需化學反應或反應順序後再次移除羥基保護基團,因此其等之性質及大小並不重要;優先考慮具有1至20,特定言之1至10個碳原子之基團。羥基保護基團之實例係尤其苯甲基、4-甲氧基苯甲基、對硝基苯甲醯基、對甲苯磺醯基、第三丁基及乙醯基,其中苯甲基及第三丁基係特別佳的。
術語「化合物之溶劑合物」意謂惰性溶劑分子加合至由於其等相互吸引力形成之化合物上。溶劑合物係(例如)單水合物或二水合物或醇化物。
式(I)化合物係釋放自其等官能衍生物–取決於使用之保護基–例如使用強酸,有利地使用TFA或過氯酸,但亦使用其他強無機酸,諸如鹽酸或硫酸,強有機羧酸,諸如三氯乙酸,或磺酸,諸如苯或對甲苯磺酸。可能存在額外之惰性溶劑,但非總必需的。合適之惰性溶劑係較佳有機的,例如羧酸,諸如乙酸,醚,諸如THF或二噁烷,醯胺,諸如DMF,鹵化烴,諸如DCM,此外亦醇,諸如甲醇、乙醇或異丙醇,及水。此外,上文提及之溶劑之混合物係合適的。TFA係較佳過量使用而不添加另一溶劑,及過氯酸係較佳以乙酸及70%過氯酸以9:1之比率之混合物之形式使用。用於裂解之反應溫度係有利地在約0與約50℃之間,較佳在15與30℃ (rt)之間。
BOC、OBut及Mtr基團可(例如)較佳使用於DCM中之TFA或使用於二噁烷中之大約3至5N HCl在15至30℃下裂解開來,及FMOC基團可使用二甲胺、二乙胺或哌啶於DMF中之大約5至50%溶液在15至30℃下裂解開來。
可氫解移除之保護基(例如CBZ、苯甲基或自其噁二唑衍生物釋放甲脒基)可(例如)藉由用氫在觸媒(例如貴金屬觸媒,諸如鈀,有利地於諸如碳之載體上)之存在下進行處理以裂解開來。本文合適之溶劑係彼等上文指示者,特定言之,例如,醇,諸如甲醇或乙醇,或醯胺,諸如DMF。氫解係通常在約0與100℃之溫度下及在在約1與200 bar之應力下,較佳在20至30℃及1至10 bar下進行。CBZ基團之氫解非常成功,例如,在於甲醇中之5至10% Pd/C上或使用於甲醇/DMF中之在Pd/C上之甲酸銨(而非氫)在20至30℃下進行。
合適之惰性溶劑之實例係烴,諸如己烷、石油醚、苯、甲苯或二甲苯;氯化烴,諸如三氯乙烯、1,2-二氯乙烷、四氯甲烷、三氟甲苯、氯仿或DCM;醇,諸如甲醇、乙醇、異丙醇、正丙醇、正丁醇或第三丁醇;醚,諸如乙醚、二異丙醚、四氫呋喃(THF)或二噁烷;二醇醚,諸如乙二醇單甲醚或單乙醚或乙二醇二甲醚(二甘醇二甲醚);酮,諸如丙酮或丁酮;醯胺,諸如乙醯胺、二甲基乙醯胺、N-甲基吡咯啶酮(NMP)或二甲基甲醯胺(DMF);腈,諸如乙腈;亞碸,諸如二甲基亞碸(DMSO);二硫化碳;羧酸,諸如甲酸或乙酸;硝基化合物,諸如硝基甲烷或硝基苯;酯,諸如EtOAc,或該等溶劑之混合物。
酯可(例如)使用於水、水/THF、水/THF/乙醇或水/二噁烷中之LiOH、NaOH或KOH,在0與100℃間之溫度下皂化。此外,酯可(例如)使用乙酸、TFA或HCl水解。
此外,游離之胺基可以習知方式使用醯氯或酸酐醯化或使用未經取代或經取代之鹵烷烷化或與CH3
-C(=NH)-OEt,有利地在惰性溶劑(諸如DCM或THF)中及/或在鹼(諸如三乙胺或吡啶)之存在下,在-60℃與+30℃之間的溫度下進行反應。
在整個說明書中,術語離去基較佳表示Cl、Br、I或經反應修飾之OH基團,諸如,例如,具有1至6個碳原子之活化酯、咪唑或烷基磺醯氧基(較佳甲基磺醯氧基或三氟甲基磺醯氧基)或具有6至10個碳原子之芳基磺醯氧基(較佳苯基-或對甲苯基磺醯氧基)。
在典型之醯化反應中用於活化羧基之此類型基團描述於文獻(例如標準著作,諸如Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart)中。
活化酯係有利地原位形成,例如通過添加HOBt或N-羥基琥珀醯亞胺。
醫藥鹽及其他形式
該等式(I)化合物可以其等最終非鹽形式使用。另一方面,本發明亦係關於此等化合物以其等醫藥上可接受之鹽之形式之用途,該等鹽可藉由此項技術中已知的程序衍生自各種有機及無機酸及鹼。式(I)化合物之醫藥上可接受之鹽形式大部分係藉由習知方法製備。若式(I)化合物含有酸性中心(諸如羧基),則其合適之鹽中之一者可藉由使該化合物與合適之鹼反應以產生相應之鹼加成鹽形成。此等鹼係(例如)鹼金屬氫氧化物,包括氫氧化鉀及氫氧化鈉;鹼土金屬氫氧化物,諸如氫氧化鎂及氫氧化鈣;及各種有機鹼,諸如哌啶、二乙醇胺及N-甲基還原葡糖胺(葡甲胺)、苄星、膽鹼、二乙醇胺、乙二胺、苯乙芐胺、二乙胺、哌嗪、離胺酸、L-精胺酸、氨、三乙醇胺、甜菜鹼、乙醇胺、嗎啉及氨丁三醇。在含有鹼性中心之某些式I化合物之情況下,酸加成鹽可藉由用醫藥上可接受之有機酸及無機酸處理此等化合物形成,例如氫鹵化物,諸如氯化氫或溴化氫,其他礦物酸及其相應之鹽,諸如硫酸鹽、硝酸鹽或磷酸鹽及類似物,及烷基-及單芳基磺酸鹽,諸如甲磺酸鹽、乙磺酸鹽、甲苯磺酸鹽及苯磺酸鹽,及其他有機酸及其相應之鹽,諸如碳酸鹽、乙酸鹽、三氟乙酸鹽、酒石酸鹽、馬來酸鹽、琥珀酸鹽、檸檬酸鹽、苯甲酸鹽、水楊酸鹽、抗壞血酸鹽及類似物。因此,式(I)化合物之醫藥上可接受之酸加成鹽包括下列:乙酸鹽、己二酸鹽、海藻酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽(苯磺酸鹽)、硫酸氫鹽、亞硫酸氫鹽、溴化物、樟腦酸鹽、樟腦磺酸鹽、癸酸鹽、辛酸鹽、氯化物、氯苯甲酸鹽、檸檬酸鹽、環己胺磺酸鹽、桂皮酸鹽、二葡萄糖酸鹽、二氫磷酸鹽、二硝基苯甲酸鹽、十二烷基硫酸鹽、乙磺酸鹽、甲酸鹽、乙醇酸鹽、延胡索酸鹽、半乳糖酸鹽(來自黏液酸)、半乳糖醛酸鹽、葡萄糖庚酸鹽、葡萄糖酸鹽、麩胺酸鹽、甘油磷酸鹽、半琥珀酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、馬尿酸鹽、鹽酸、氫溴酸、氫碘酸、2-羥基乙烷磺酸鹽、碘化物、羥乙磺酸鹽、異丁酸鹽、乳酸鹽、乳糖醛酸鹽、蘋果酸鹽、馬來酸鹽、丙二酸鹽、苦杏仁酸鹽、偏磷酸鹽、甲磺酸鹽、甲基苯甲酸鹽、磷酸一氫鹽、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、草酸鹽、油酸鹽、棕櫚酸鹽、果膠酸鹽、過硫酸鹽、苯乙酸鹽、3-苯基丙酸鹽、磷酸鹽、膦酸鹽、鄰苯二甲酸鹽,但此不表示限制。兩種類型之鹽均可較佳使用離子交換樹脂技術形成或相互轉化。
此外,式(I)化合物之鹼鹽包括鋁鹽、銨鹽、鈣鹽、銅鹽、鐵(III)鹽、鐵(II)鹽、鋰鹽、鎂鹽、錳(III)鹽、錳(II)鹽、鉀鹽、鈉鹽及鋅鹽,但此非意欲表示限制。在上文提及之鹽中,優先考慮銨鹽;鹼金屬鹽鈉及鉀,及鹼土金屬鹽鈣及鎂。衍生自醫藥上可接受之有機非毒性鹼之式(I)化合物之鹽包括以下之鹽:一級、二級及三級胺、經取代之胺,亦包括天然生成之經取代之胺、環胺,及鹼性離子交換樹脂,例如精胺酸、甜菜鹼、咖啡鹼、氯普魯卡因、膽鹼、N,N'-二苯甲基二乙胺(苄星)、二環己基胺、二乙醇胺、二乙胺、2-二乙基胺基乙醇、2-二甲基胺基乙醇、乙醇胺、乙二胺、N-乙基嗎啉、N-乙基哌啶、還原葡糖胺、葡萄胺糖、組胺酸、海巴胺、異丙胺、利多卡因、離胺酸、葡甲胺(N-甲基-D-還原葡糖胺)、嗎啉、哌嗪、哌啶、聚胺樹脂、普魯卡因、嘌呤、可哥鹼、三乙醇胺、三乙胺、三甲胺、三丙胺及參(羥甲基)甲胺(氨丁三醇),但此非意欲表示限制。
含有鹼性含氮基團之本發明之式(I)化合物可使用諸如以下之試劑季銨化:(C1
-C4
)鹵烷,例如甲基、乙基、異丙基及第三丁基氯化物、溴化物及碘化物;二(C1
-C4
)烷基硫酸鹽,例如二甲基、二乙基及二戊基硫酸鹽;(C10
-C18
)鹵烷,例如癸基、十二烷基、月桂基、肉豆蔻基及硬脂基氯化物、溴化物及碘化物;及芳基(C1
-C4
)鹵烷,例如氯甲苯及苯乙基溴化物。水溶性及油溶性式(I)化合物可使用此等鹽製備。
較佳之上文提及之醫藥鹽包括乙酸鹽、三氟乙酸鹽、苯磺酸鹽、檸檬酸鹽、延胡索酸鹽、葡糖酸鹽、半琥珀酸鹽、馬尿酸鹽、鹽酸鹽、氫溴酸鹽、羥乙基磺酸鹽、苦杏仁酸鹽、葡甲胺、硝酸鹽、油酸鹽、膦酸鹽、新戊酸鹽、磷酸鈉、硬脂酸鹽、硫酸鹽、磺基水楊酸鹽、酒石酸鹽、硫蘋果酸鹽、甲苯磺酸鹽及三甲胺,但此非意欲表示限制。
式(I)鹼性化合物之酸加成鹽係藉由使游離鹼形式與足量之所需之酸接觸,引起鹽以習知方式形成進行製備。游離鹼可藉由使該鹽形式與鹼接觸並以習知方式分離游離鹼進行再生。關於某些物理性質,游離鹼形式在某一方面不同於其相應之鹽形式,諸如於極性溶劑中之溶解性;然而,出於本發明之目的,該等鹽另外對應於其個別游離鹼形式。
如本文提及,式(I)化合物之醫藥上可接受之鹼加成鹽係與金屬或胺諸如鹼金屬及鹼土金屬或有機胺形成。較佳之金屬係鈉、鉀、鎂及鈣。較佳之有機胺係N,N’-二苯甲基乙二胺、氯普魯卡因、膽鹼、二乙醇胺、乙二胺、N-甲基-D-還原葡糖胺及普魯卡因。
式(I)酸性化合物之鹼加成鹽係藉由使游離酸形式與足量之所需之鹼接觸,引起鹽以習知方式形成進行製備。游離酸可藉由使該鹽形式與酸接觸並以習知方式分離游離酸進行再生。關於某些物理性質,游離酸形式在某一方面不同於其相應之鹽形式,諸如於極性溶劑中之溶解性;然而,出於本發明之目的,該等鹽另外對應於其個別游離酸形式。
若式(I)化合物含有多於一個可形成此類型之醫藥上可接受之鹽之基團,則式(I)亦包含多鹽。典型之多鹽形式包括(例如)酒石酸氫鹽、二乙酸鹽、二延胡索酸鹽、二葡甲胺、二磷酸鹽、二鈉及三鹽酸鹽,但此非意欲表示限制。
關於上文規定之內容,可見本發明中之術語「醫藥上可接受之鹽」意謂包含呈式(I)化合物之鹽中之一者之形式之式(I)化合物之活性成分,特定言之若相較於活性成分之游離形式或更早使用之活性成分之任何其他鹽形式,此鹽形式向活性成分賦予經改善之藥物動力學性質。活性成分之醫藥上可接受之鹽形式亦可向此活性成分首次提供早期沒有的所需之藥物動力學性質且關於其在體內之治療效用,可甚至對此活性成分之藥效動力學有積極影響。
由於式(I)化合物之分子結構,其等係對掌性的且可因此以各種對映異構體形式存在。因此,式(I)化合物可以外消旋或光學活性形式存在。
由於根據本發明之化合物之外消旋物或立體異構體之醫藥活性可不同的,因此可能需要使用對映異構體。在此等情況下,最終產物或甚至中間物可藉由熟習此項技術者已知的化學或物理措施分離為對映異構體化合物或甚至本身用於合成中。
在外消旋胺之情況下,非對映異構體係藉由與光學活性光學分割劑反應形成自混合物。合適之光學分割劑之實例係光學活性酸,諸如酒石酸、二乙醯基酒石酸、二苯甲醯基酒石酸、苦杏仁酸、蘋果酸、乳酸、合適之N經保護之胺基酸(例如N-苯甲醯基脯胺酸或N-苯磺醯基脯胺酸),或各種光學活性樟腦磺酸之(R)-及(S)-形式。藉助於光學活性光學分割劑(例如二硝基苯甲醯基苯基甘胺酸、三乙酸纖維素或醣或固定於矽膠上之對掌性衍生之甲基丙烯酸酯聚合物之其他衍生物)之層析對映異構體解析亦係有利的。適用於此目的之溶析物係含水或含醇之溶劑混合物,諸如,例如,己烷/異丙醇/乙腈,例如以比率82:15:3。
同位素
此外,式(I)化合物意欲包括其同位素標記形式。除該化合物之一或多個原子已經具有不同於通常天然存在之原子之原子質量或質量數之原子質量或質量數之原子置換之事實外,式(I)化合物之同位素標記形式係與此化合物相同的。容易購買獲得及可藉由熟知方法併入式(I)化合物內之同位素之實例包括氫、碳、氮、氧、磷、氟及氯之同位素,例如分別2
H、3
H、13
C、14
C、15
N、18
O、17
O、31
P、32
P、35
S、18
F及36
CI。含有上文提及之同位素及/或具有其他原子之其他同位素中之一或多者之式(I)化合物、其前藥或醫藥上可接受之鹽意欲為本發明之一部分。同位素標記式(I)化合物可用於許多有利之方法中。例如,已併入(例如)放射性同位素(諸如3
H或14
C)內之同位素標記式(I)化合物係適用於藥物及/或受質組織分佈分析。此等放射性同位素(即氚(3
H)及碳-14 (14
C))由於製備簡單及絕佳之可偵測性而特別佳。將較重同位素(例如氘(2
H))併入式(I)化合物內由於此同位素標記化合物之較高代謝穩定性而具有治療優勢。較高代謝穩定性直接轉譯為增加之活體內半衰期或較低劑量,在大多數情況下其將表示本發明之較佳實施例。同位素標記式(I)化合物可通常藉由進行揭示於本文中之合成方案及相關描述、實例部分及製備部分中之程序進行製備,用容易購買獲得之同位素標記反應物替代非同位素標記反應物。
出於為藉助於主要動力學同位素效應操作化合物之氧化代謝之目的,亦可將氘(2
H)併入式(I)化合物內。該主要動力學同位素效應係產生自同位素原子核之交換之化學反應之速率之變化,其進一步由在此同位素交換後共價鍵形成必需之基態能量之變化引起。較重同位素之交換通常導致化學鍵之基態能量之降低並因此引起限速鍵斷裂之速率之減小。若鍵斷裂沿多產物反應之坐標在鞍點區域中或在鞍點區域附近發生,則產物分佈比率可大體上改變。為說明:若氘於非可交換位置處結合至碳原子,則kM
/kD
= 2-7之速率差異係典型的。若將此速率差異成功施用至易氧化之式(I)化合物,則此化合物之活體內概況可經顯著修飾並導致改善之藥物動力學性質。
當探索及研發治療劑時,熟習此項技術者嘗試最佳化藥物動力學參數同時保留所需之活體外性質。假設具有較差藥物動力學概況之許多化合物易氧化代謝係合理的。當前可獲得之活體外肝微粒體分析提供有關此類型氧化代謝之過程之有價值之資訊,其進一步允許合理設計通過對此氧化代謝之抗性具有經改善之穩定性之式(I)之氘化化合物。藉此獲得式(I)化合物之藥物動力學概況之顯著改善,且可在活體內半衰期(t1/2)、最大治療效應之濃度(Cmax
)、劑量反應曲線下面積(AUC)及F之增加方面;及在減小之廓清、劑量及材料成本方面加以定量表示。
下列意欲闡述上文:具有用於氧化代謝之多個潛在攻擊位點(例如苯甲基氫原子及結合至氮原子之氫原子)之式(I)化合物係作為一系列類似物製備,其中氫原子之各種組合係經氘原子置換,使得此等氫原子中之一些、大部分或所有已經氘原子置換。半衰期測定可有利且準確地確定氧化代謝之抗性已經改善之改善之程度。以此方法,由於此類型氘-氫交換,確定親代化合物之半衰期可延長長達至100%。
式(I)化合物中之氘-氫交換亦可用以達成起始化合物之代謝物譜之有利修飾以減少或消除非所需之毒性代謝物。例如,若通過氧化碳-氫(C-H)鍵裂解產生毒性代謝物,則可合理的假設氘化類似物將極大地減少或消除非所需之代謝物之產生,即使特定之氧化非測定速率步驟。有關關於氘-氫交換之現有技術之其他資訊可參見(例如)於Hanzlik等人,J. Org. Chem. 55, 3992-3997, 1990、Reider等人,J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985、Gillette等人,Biochemistry 33(10) 2927-2937, 1994及Jarman等人,Carcinogenesis 16(4), 683-688, 1993中。
本發明係關於一種醫藥調配物(較佳用於治療免疫調節異常或癌症),其包含至少一種式(I)化合物(特別治療有效量之式(I)化合物),及/或其前藥、溶劑合物、互變異構體、寡聚物、加合物或立體異構體及上述各者之醫藥上可接受之鹽,包括其以所有比率之混合物,作為活性成分,及醫藥上可接受之載劑。
出於本發明之目的,術語「醫藥調配物」係指包含一或多種活性成分,及構成載劑之一或多種惰性成分,及直接或間接產生自該等成分中之任何兩種或更多種之組合、錯合或聚集,或產生自該等成分中之一或多者之解離,或產生自自該等成分中之一或多者之反應或相互作用之其他類型之任何產物之組合物或產物。因此,本發明之醫藥調配物包含藉由混合至少一種本發明之化合物及醫藥上可接受之載劑、賦形劑或媒介物製得之任何組合物。
本發明之醫藥調配物亦包含進一步包含第二活性成分及/或其前藥或溶劑合物及上述各者之醫藥上可接受之鹽(包括其以所有比率之混合物)之任何組合物,其中該第二活性成分係除式(I)化合物外,其中所有殘基係如上文定義。
根據本發明之醫藥調配物可用作人類中之藥物及獸醫藥品。
出於本發明之目的,免疫調節異常係較佳選自由以下組成之群之自體免疫或慢性炎症性疾病:全身性紅斑性狼瘡、慢性類風濕性關節炎、炎症性腸病、多發性硬化症、肌萎縮側索硬化症(ALS)、動脈粥樣硬化、硬皮症、自體免疫性肝炎、休格倫氏症候群(Sjogren Syndrome)、狼瘡性腎炎、腎小球性腎炎、類風濕性關節炎、牛皮癬、重症肌無力、免疫球蛋白A腎病、血管炎、移植排斥、肌炎、過敏性紫癜(Henoch-Schönlein Purpura)及哮喘;癌症係較佳血液惡性腫瘤或實體瘤,其中該血液惡性腫瘤係較佳選自以下之群之疾病:惡性B-及T/NK細胞非霍奇金氏淋巴瘤(non-Hodgkin lymphoma),諸如:多發性骨髓瘤、套細胞淋巴瘤、瀰漫性大B細胞淋巴瘤、漿細胞瘤、濾泡性淋巴瘤、免疫細胞瘤、急性淋巴細胞白血病、慢性淋巴細胞白血病及骨髓性白血病;且其中該實體瘤係較佳選自以下之群之疾病:炎症性乳癌、肝癌及結腸癌、肺癌、頭頸癌、前列腺癌、胰臟癌、膀胱癌、腎癌、肝細胞癌及胃癌。
醫藥調配物可以劑量單位之形式投與,該等劑量單位包含每劑量單位既定量之活性成分。此單位可包含(例如) 0.5 mg至1 g,較佳1 mg至700 mg,特別佳5 mg至100 mg之根據本發明之化合物,取決於治療之疾病病症、投與方法及病患之年齡、體重及病症,或醫藥調配物可以包含每劑量單位既定量之活性成分之劑量單位之形式投與。較佳之劑量單位調配物係彼等如上文指示,包含每日劑量或部分劑量,或活性成分之其相應溶離份者。此外,此類型醫藥調配物可使用醫藥領域中一般已知的方法進行製備。
醫藥調配物可適用於經由任何所需之合適方法進行投與,例如藉由經口(包括經頰或舌下)、直腸、鼻、局部(包括經頰、舌下或透皮)、陰道或非經腸(包括皮下、肌內、靜脈內或皮內)方法。此等調配物可使用醫藥領域中已知的所有方法進行製備,藉由(例如)組合活性成分與賦形劑或佐劑。
適用於經口投與之醫藥調配物可作為獨立單元進行投與,諸如,例如,膠囊或錠劑;粉末或顆粒;於水性或非水性液體中之溶液或懸浮液;可食用泡沫或泡沫食品;或水包油液體乳液或油包水液體乳液。
因此,例如,在以錠劑或膠囊之形式經口投與之情況下,活性成分組分可與經口、無毒且醫藥上可接受之惰性賦形劑(諸如,例如,乙醇、甘油、水及類似物)組合。粉末係藉由將化合物粉碎至合適之精細尺寸並使其與以類似方式粉碎之醫藥賦形劑(諸如,例如,可食用醣類,諸如,例如,澱粉或甘露醇)混合進行製備。調味劑、防腐劑、分散劑及染料可同樣存在。
膠囊係藉由製備如上文描述之粉末混合物並用其填充成形之明膠外殼產生。可在填充操作前將助滑劑及潤滑劑(諸如,例如,呈固體形式之高度分散之矽酸、滑石、硬脂酸鎂、硬脂酸鈣或聚乙二醇)添加至該粉末混合物。可同樣添加崩解劑或增溶劑(諸如,例如,瓊脂-瓊脂、碳酸鈣或碳酸鈉)以改善已服用膠囊後之藥物之可用性。
另外,視需要或有必要,合適之黏合劑、潤滑劑及崩解劑及染料可同樣併入混合物內。合適之黏合劑包括澱粉、明膠、天然糖(諸如,例如,葡萄糖或β-乳糖)、由玉米製成之甜味劑、天然及合成橡膠(諸如,例如,阿拉伯樹膠)、黃蓍膠或海藻酸鈉、羧甲基纖維素、聚乙二醇、蠟及類似物。用於此等劑型中之潤滑劑包括油酸鈉、硬脂酸鈉、硬脂酸鎂、苯甲酸鈉、乙酸鈉、氯化鈉及類似物。該等崩解劑包括(但不限於)澱粉、甲基纖維素、瓊脂、膨潤土、三仙膠及類似物。該等錠劑係藉由(例如)製備粉末混合物,粒化或乾壓該混合物,添加潤滑劑及崩解劑並壓制整個混合物以產生錠劑進行調配。如上文描述,粉末混合物係藉由混合以合適方式粉碎之化合物及稀釋液或鹼,及視需要黏合劑(諸如,例如,羧甲基纖維素、海藻酸鹽、明膠或聚乙烯吡咯啶酮)、溶解阻滯劑(諸如,例如,石蠟)、吸收促進劑(諸如,例如,季鹽)及/或吸收劑(諸如,例如,膨潤土、高嶺土或磷酸二鈣)進行製備。該粉末混合物可藉由用黏合劑(諸如,例如,糖漿、澱粉糊劑、阿拉伯膠漿或纖維素之溶液或聚合物材料)將其潤濕並通過篩子壓制該混合物進行粒化。作為粒化之替代,該粉末混合物可運行通過壓錠機,產生非均勻形狀之塊狀物,該等塊狀物破碎以形成顆粒。該等顆粒可藉由添加硬脂酸、硬脂酸鹽、滑石或礦物油潤滑以防止黏附至錠劑鑄模。然後壓制經潤滑之混合物以產生錠劑。活性成分亦可與自由流動之惰性賦形劑組合且然後直接壓制以產生錠劑而不進行粒化或乾壓步驟。可存在由蟲膠密封層、糖或聚合物材料之層及蠟之光澤層組成之透明或不透明保護層。可向此等塗層添加染料以可在不同之劑量單位中加以區分。
經口液體(諸如,例如,溶液、糖漿及酏劑)可以劑量單位之形式製備使得使給定量包含預先規定量之化合物。儘管酏劑係使用無毒酒精媒介物製備,但糖漿可藉由將該等化合物溶解於具有合適風味之水溶液中進行製備。懸浮液可藉由將化合物分散於無毒媒介物中進行調配。增溶劑及乳化劑(諸如,例如,乙氧基化異硬脂醇及聚氧乙烯山梨醇醚)、防腐劑、香味添加劑(諸如,例如,薄荷油)或天然調味劑或糖精,或其他人造甜味劑及類似物可同樣添加。
用於經口投與之劑量單位調配物可(視需要)囊封於微膠囊中。調配物亦可以將釋放延長或減緩之方式進行製備,諸如,例如,藉由將顆粒材料塗覆或包埋於聚合物、蠟及類似物中。
式(I)化合物及其鹽、溶劑合物及生理功能衍生物及其他活性成分亦可以脂質體遞送系統(諸如,例如,小單層囊泡、大單層囊泡及多層囊泡)之形式進行投與。脂質體可形成自各種磷脂,諸如,例如,膽固醇、硬脂醯胺或磷脂醯膽鹼。
式(I)化合物及其鹽、溶劑合物及生理功能衍生物及其他活性成分亦可使用單株抗體作為與化合物分子偶合之個別載劑進行遞送。該等化合物亦可作為靶向藥物載劑偶合至可溶性聚合物。此等聚合物可包含聚乙烯吡咯啶酮、哌喃共聚物、聚羥丙基甲基丙烯醯胺苯酚、聚羥乙基天冬醯胺-苯酚或經棕櫚醯基取代之聚環氧乙烷聚離胺酸。此外,該等化合物可偶合至可生物降解之聚合物之類別,其等適用於達成藥物之控釋,例如聚乳酸、聚-ε-己內酯、聚羥基丁酸、聚原酸酯、聚縮醛、聚二羥基哌喃、聚氰基丙烯酸酯及水凝膠之交聯或兩親性嵌段共聚物。
適用於透皮投與之醫藥調配物可作為獨立膏藥投與用於與接受者之表皮延長、密切接觸。因此,如於Pharmaceutical Research, 3(6), 318 (1986)中以一般術語描述,例如,活性成分可藉由離子電滲法遞送自該膏藥。
適用於局部投與之醫藥化合物可調配為軟膏、乳膏、懸浮液、洗劑、粉末、溶液、糊劑、凝膠、噴霧、氣溶膠或油。
為治療眼或其他外部組織(例如嘴及皮膚),調配物係較佳作為局部軟膏或乳膏施用。在調配以產生軟膏之情況下,活性成分可與石蠟或水溶性乳膏基底一起採用。或者,可調配活性成分以產生具有水包油乳膏基底或油包水基底之乳膏。
適用於向眼局部施用之醫藥調配物包括滴眼液,其中將活性成分溶解或懸浮於合適之載劑(特定言之水溶劑)中。
適用於在嘴中局部施用之醫藥調配物包含口含錠、含片及漱口水。
適用於直腸投與之醫藥調配物可以栓劑或灌腸劑之形式進行投與。
其中載劑物質係固體之適用於經鼻投與之醫藥調配物包含具有(例如)在20至500微米之範圍內之粒度之粗糙粉末,其係以鼻吸之方式進行投與,即藉由經由鼻通路自靠近鼻之含有該粉末之容器快速吸入。適用於作為鼻噴霧或滴鼻劑以液體作為載劑物質投與之調配物包含於水或油中之活性成分溶液。
適用於藉由吸入投與之醫藥調配物包含細顆粒粉塵或粉霧,其等可藉由具有氣溶膠、霧化器或吹入器之各種類型之加壓分配器產生。
適用於陰道投與之醫藥調配物可作為陰道栓、衛生棉條、乳膏、凝膠、糊劑、泡沫或噴霧調配物投與。
適用於非經腸投與之醫藥調配物包括無菌注射水溶液或無菌注射非水溶液,該等溶液包含抗氧化劑、緩衝液、抑菌劑及溶質,藉助於其等使該調配物與待治療之接受者之血液等滲;及無菌水懸浮液及無菌非水懸浮液,其等可包含懸浮液介質及增稠劑。該等調配物可以單劑量或多劑量容器(例如密封之安瓿及小瓶)投與,並以冷凍乾燥(凍乾)狀態保存,使得在使用前僅需立即添加無菌載劑液體(例如用於注射目的之水)。
根據處方製備之注射溶液及懸浮液可製備自無菌粉末、顆粒及錠劑。
不言而喻,除上文特別提及之構成外,調配物亦可包含在此領域中關於調配物之特定類型通常使用之其他藥劑;因此,例如,適用於經口投與之調配物可包含調味劑。
根據本發明之組合物/調配物可用作人類中之藥物及獸醫醫藥。
式(I)化合物及其他活性成分之治療有效量取決於許多因素,包括(例如)動物之年齡及體重、需要治療之精確疾病病症及其嚴重性、調配物之性質及投與方法,且最終由治療醫生或獸醫確定。然而,化合物之有效量係一般自0.1至100 mg/kg接受者(哺乳動物)體重/天之範圍內及特別通常在自1至10 mg/kg體重/天之範圍內。因此,用於重70 kg之成年哺乳動物之每天實際量係通常在70與700 mg之間,其中此量可作為每天個別劑量或通常以每天一系列部分劑量(諸如,例如,二、三、四、五或六個)進行投與,使得總每日劑量相同。其鹽或溶劑合物或生理功能衍生物之有效量可確定為該化合物本身之有效量之分數。
本發明進一步係關於根據式(I)之化合物或上文描述之任何具體實施例及/或其前藥、溶劑合物、互變異構體、寡聚物、加合物或立體異構體及上述各者之醫藥上可接受之鹽,包括其以所有比率之混合物,用於預防及/或治療受抑制LMP7影響之醫學病症。
本發明係關於根據式(I)之化合物或上文描述之任何具體實施例及/或其前藥、溶劑合物、互變異構體、寡聚物、加合物或立體異構體及上述各者之醫藥上可接受之鹽,包括其以所有比率之混合物,用於治療及/或預防(防止)免疫調節異常或癌症(包括特定言之血液系統惡性腫瘤及實體瘤)。
此外,本發明係關於治療罹患免疫調節異常或癌症之個體之方法,其包括以有效治療該免疫調節異常或癌症之量向該個體投與式(I)化合物。本發明較佳係關於治療罹患自體免疫或慢性炎症性疾病、血液惡性腫瘤或實體瘤之個體之方法。
本文揭示之式(I)化合物可與其他已知治療劑(活性成分),包括抗癌劑組合投與及/或使用。如本文使用,術語「抗癌劑」係關於出於治療癌症之目的,向患有癌症之病患投與之任何藥劑。
上文定義之抗癌治療可作為單一治療或除本文揭示之式(I)化合物外,亦可涉及習知外科手術或放射治療或醫學治療進行施用。此等醫學治療(例如化學治療或靶向治療)可包括下列抗腫瘤藥劑中之一或多者,但較佳一者:烷化劑
諸如六甲蜜胺(altretamine)、苯達莫司汀(bendamustine)、白消安(busulfan)、卡莫司汀(carmustine)、苯丁酸氮芥(chlorambucil)、氮芥(chlormethine)、環磷醯胺(cyclophosphamide)、達卡巴嗪(dacarbazine)、異環磷醯胺(ifosfamide)、英丙舒凡(improsulfan)、托西酸鹽(tosilate)、洛莫司汀(lomustine)、美法崙(melphalan)、二溴甘露醇(mitobronitol)、二溴衛矛醇(mitolactol)、尼莫司汀(nimustine)、雷莫司汀(ranimustine)、替莫唑胺(temozolomide)、噻替派(thiotepa)、蘇消安(treosulfan)、氮芥(mechloretamine)、卡波醌(carboquone);
阿哌喹酮(apaziquone)、福莫司汀(fotemustine)、葡磷醯胺(glufosfamide)、帕利伐米(palifosfamide)、脈血生(pipobroman)、曲洛磷胺(trofosfamide)、烏拉莫司汀(uramustine)、TH-3024
、VAL-0834
;鉑化合物
諸如卡鉑(carboplatin)、順鉑(cisplatin)、依鉑(eptaplatin)、米鉑水合物(miriplatine hydrate)、奧沙利鉑(oxaliplatin)、樂鉑(lobaplatin)、奈達鉑(nedaplatin)、吡鉑(picoplatin)、賽特鉑(satraplatin);DNA 改變劑
諸如胺柔比星(amrubicin)、比生群(bisantrene)、地西他濱(decitabine)、米托蒽醌(mitoxantrone)、甲基苄肼(procarbazine)、曲貝替定(trabectedin)、氯法拉濱(clofarabine);
安吖啶(amsacrine)、肉芽腫桿菌素(brostallicin)、匹克生瓊(pixantrone)、拉羅莫司汀1,3
(laromustine1,3
); 拓撲異構酶抑制劑
諸如依託泊苷(etoposide)、伊立替康(irinotecan)、雷佐生(razoxane)、索布佐生(sobuzoxane)、替尼泊苷(teniposide)、拓撲替康(topotecan);
胺萘非特(amonafide)、貝洛替康(belotecan)、乙酸龍膽(elliptinium acetate)、伏洛辛(voreloxin);微管修飾劑
諸如卡巴他賽(cabazitaxel)、多西他賽(docetaxel)、艾瑞布林(eribulin)、伊沙匹隆(ixabepilone)、紫杉醇(paclitaxel)、長春花鹼(vinblastine)、長春新鹼(vincristine)、長春瑞濱(vinorelbine)、長春地辛(vindesine)、長春氟寧(vinflunine);
福他布林(fosbretabulin)、替司他賽(tesetaxel);抗代謝物
諸如門冬醯胺酶3
(asparaginase3
)、阿紮胞苷(azacitidine)、左旋葉酸鈣(calcium levofolinate)、卡培他濱(capecitabine)、克拉屈濱(cladribine)、阿糖胞苷(cytarabine)、依諾他濱(enocitabine)、氟尿苷(floxuridine)、氟達拉濱(fludarabine)、氟尿嘧啶(fluorouracil)、吉西他濱(gemcitabine)、巰嘌呤(mercaptopurine)、甲胺蝶呤(methotrexate)、奈拉濱(nelarabine)、培美曲塞(pemetrexed)、服瘤停(pralatrexate)、咪唑硫嘌呤(azathioprine)、硫鳥嘌呤(thioguanine)、卡莫氟(carmofur)、去氧氟尿苷(doxifluridine)、艾西拉濱(elacytarabine)、雷替曲塞(raltitrexed)、沙帕西汀(sapacitabine)、喃氟啶2,3
(tegafur2,3
)、三甲曲沙(trimetrexate);抗癌抗生素
諸如博來黴素(bleomycin)、更生黴素(dactinomycin)、阿黴素(doxorubicin)、表柔比星(epirubicin)、伊達比星(idarubicin)、左旋咪唑(levamisole)、米替福新(miltefosine)、絲裂黴素C(mitomycin C)、羅米地辛(romidepsin)、鏈脲菌素(streptozocin)、戊柔比星(valrubicin)、淨司他丁(zinostatin)、佐柔比星(zorubicin)、柔紅黴素(daunurobicin)、普卡黴素(plicamycin)、阿柔比星(aclarubicin)、培洛黴素(peplomycin)、吡柔比星(pirarubicin);激素 / 拮抗劑
諸如阿巴瑞克(abarelix)、阿比特龍(abiraterone)、比卡魯胺(bicalutamide)、布捨瑞林(buserelin)、卡普睪酮(calusterone)、氯烯雌酚醚(chlorotrianisene)、地加瑞克(degarelix)、地塞米松(dexamethasone)、雌二醇(estradiol)、氟可龍(fluocortolone)、氟甲睪酮(fluoxymesterone)、氟他米特(flutamide)、氟維司群(fulvestrant)、戈捨瑞林(goserelin)、組胺瑞林(histrelin)、亮丙瑞林(leuprorelin)、甲地孕酮(megestrol)、米托坦(mitotane)、那法瑞林(nafarelin)、諾龍(nandrolone)、尼魯米特(nilutamide)、奧曲肽(octreotide)、潑尼松龍(prednisolone)、雷洛昔芬(raloxifene)、他莫昔芬(tamoxifen)、促甲狀腺素α(thyrotropin alfa)、托瑞米芬(toremifene)、曲洛司坦(trilostane)、曲普瑞林(triptorelin)、二乙基己烯雌酚(diethylstilbestrol);
阿考比芬(acolbifene)、達那唑(danazol)、地洛瑞琳(deslorelin)、環硫雄醇(epitiostanol)、奧特羅內爾(orteronel)、恩雜魯胺1,3
(enzalutamide1,3
);芳香酶抑制劑
諸如胺基導眠能(aminoglutethimide)、阿那曲唑(anastrozole)、依西美坦(exemestane)、法倔唑(fadrozole)、來曲唑(letrozole)、睪內酯(testolactone);
福美司坦(formestane);小分子激酶抑制劑
諸如克裡唑替尼(crizotinib)、達沙替尼(dasatinib)、埃羅替尼(erlotinib)、伊馬替尼(imatinib)、拉帕替尼(lapatinib)、尼羅替尼(nilotinib)、帕唑帕尼(pazopanib)、瑞戈非尼(regorafenib)、魯索替尼(ruxolitinib)、索拉菲尼(sorafenib)、舒尼替尼(sunitinib)、凡德他尼(vandetanib)、威羅菲尼(vemurafenib)、博舒替尼(bosutinib)、吉非替尼(gefitinib)、阿西替尼(axitinib);
阿法替尼(afatinib)、阿立塞替(alisertib)、達拉菲尼(dabrafenib)、達克替尼(dacomitinib)、迪納西利布(dinaciclib)、多韋替尼(dovitinib)、恩紮他林(enzastaurin)、尼達尼布(nintedanib)、來伐替尼(lenvatinib)、利尼法尼(linifanib)、林西替尼(linsitinib)、馬賽替尼(masitinib)、米哚妥林(midostaurin)、莫特塞尼(motesanib)、來那替尼(neratinib)、奧蘭替尼(orantinib)、哌立福新(perifosine)、帕納替尼(ponatinib)、拉多替尼(radotinib)、裡格塞蒂(rigosertib)、替吡法尼(tipifarnib)、替伐替尼(tivantinib)、替伐紮尼(tivozanib)、曲美替尼(trametinib)、匹馬司替布(pimasertib)、丙胺酸布裡瓦尼(brivanib alaninate)、西地尼布(cediranib)、阿帕替尼4
(apatinib4
)、S-蘋果酸卡波紮坦尼1,3
(cabozantinib S-malate1,3
)、依魯替尼1,3
(ibrutinib1,3
)、埃克替尼4
(icotinib4
)、布帕利西布2
(buparlisib2
)、西帕替尼4
(cipatinib4
)、考比替尼1,3
(cobimetinib1,3
)、依達拉西布1,3
(idelalisib1,3
)、非德替尼1
(fedratinib1
)、XL-6474
;光敏劑
諸如甲氧沙林3
(methoxsalen3
);
卟吩姆鈉(porfimer sodium)、他拉泊芬(talaporfin)、替莫泊芬(temoporfin);抗體
諸如阿崙單抗(alemtuzumab)、貝索單抗(besilesomab)、布魯昔單抗(brentuximab vedotin)、西妥昔單抗(cetuximab)、地諾單抗(denosumab)、易普利姆瑪單抗(ipilimumab)、奧法木單抗(ofatumumab)、帕尼單抗(panitumumab)、利妥昔單抗(rituximab)、托西莫單抗(tositumomab)、曲妥珠單抗(trastuzumab)、貝伐珠單抗(bevacizumab)、帕妥珠單抗2,3
(pertuzumab2,3
);卡妥索單抗(catumaxomab)、埃羅妥珠單抗(elotuzumab)、依帕珠單抗(epratuzumab)、法魯珠單抗(farletuzumab)、莫加利單抗(mogamulizumab)、奈米單抗(necitumumab)、尼妥珠單抗(nimotuzumab)、奧匹妥珠單抗(obinutuzumab)、奧卡曲單抗(ocaratuzumab)、奧戈伏單抗(oregovomab)、雷莫蘆單抗(ramucirumab)、利妥珠單抗(rilotumumab)、沙妥昔單抗(siltuximab)、塔西單抗(tocilizumab)、紮魯單抗(zalutumumab)、紮諾米單抗(zanolimumab)、馬妥珠單抗(matuzumab)、達魯珠單抗(dalotuzumab1,2,3
)、阿那妥單抗1,3
(onartuzumab1,3
)、拉托單抗1
(racotumomab1
)、他巴單抗1,3
(tabalumab1,3
)、EMD-5257974
、納武單抗1,3
(nivolumab1,3
);細胞介素
諸如阿地白介素(aldesleukin)、干擾素α2
、干擾素α2a3
、干擾素α2b2,3
;西莫白介素(celmoleukin)、他索納明(tasonermin)、替西白介素(teceleukin)、奧普瑞白介素1,3
(oprelvekin1,3
)、重組干擾素β-1a4
;藥物結合物
諸如地尼白介素-毒素連接物(denileukin diftitox)、替伊莫單抗噻嗪坦(ibritumomab tiuxetan)、碘苄胍I123 (iobenguane I123)、潑尼莫司汀(prednimustine)、曲妥珠單抗肌酐(trastuzumab emtansine)、雌氮芥(estramustine)、吉妥珠單抗(gemtuzumab)、奧佐米星(ozogamicin)、阿柏西普(aflibercept);苦參鹼(cintredekin besudotox)、雷公藤內酯(edotreotide)、伊妥珠單抗奧佐米星(inotuzumab ozogamicin)、納普圖莫單抗(naptumomab estafenatox)、阿曲單抗(oportuzumab monatox)、鍀(99mTc)阿西莫單抗1,3
(technetium (99mTc) arcitumomab1,3
)、長春花酯1,3
(vintafolide1,3
);疫苗
諸如西普盧塞3
(sipuleucel3
);維特斯朋3
(vitespen3
)、艾美佩特-S3
(emepepimut-S3
)、oncoVAX4
、綠膿桿菌3
(rindopepimut3
)、troVax4
、MGN-16014
、MGN-17034
;雜項
阿利維A酸(alitretinoin)、蓓薩羅丁(bexarotene)、硼替佐米(bortezomib)、依維莫司(everolimus)、伊班膦酸(ibandronic acid)、咪喹莫特(imiquimod)、來那度胺(lenalidomide)、香菇多糖(lentinan)、甲酪胺酸(metirosine)、米伐木肽(mifamurtide)、帕米膦酸(pamidronic acid)、培門冬酶(pegaspargase)、噴司他丁(pentostatin)、西布盧賽爾3
(sipuleucel3
)、西咗喃(sizofiran)、他米巴羅汀(tamibarotene)、替西羅莫司(temsirolimus)、沙利度胺(thalidomide)、維A酸(tretinoin)、維莫德吉(vismodegib)、唑來膦酸(zoledronic acid)、伏立諾他(vorinostat);塞來昔布(celecoxib)、西崙吉肽(cilengitide)、恩替諾特(entinostat)、依他硝唑(etanidazole)、熱休克蛋白90抑制劑(ganetespib)、依屈諾昔(idronoxil)、伊尼帕利布(iniparib)、伊沙佐米(ixazomib)、氯尼達明(lonidamine)、尼莫拉唑(nimorazole)、帕比司他(panobinostat)、培维A酸(peretinoin)、普利提環肽(plitidepsin)、泊馬度胺(pomalidomide)、泊可達佐(procodazol)、地磷莫司(ridaforolimus)、他喹莫德(tasquinimod)、特羅司他(telotristat)、胸腺法新(thymalfasin)、替拉紮明(tirapazamine)、托捨多特(tosedostat)、挫本德生(trabedersen)、烏苯美司(ubenimex)、伐司樸達(valspodar)、今堤森4
(gendicine4
)、畢西巴尼4
(picibanil4
)、溶瘤病毒4
(reolysin4
)、鹽酸瑞巴黴素1,3
(retaspimycin hydrochloride1,3
)、特伯納尼(trebananib)2,3
、維如利金4
(virulizin4
)、卡非佐米1,3
(carfilzomib1,3
)、內皮抑素4
(endostatin4
)、依木可特(immucothel)4
、貝利司他3
(belinostat3
)、MGN-17034
;1
Prop. INN (經提議之國際非專利名稱)2
Rec. INN (經推薦之國際非專利名稱)3
USAN (美國採用之名稱)4
無INN。
此外,本發明係關於式(I)及相關式之化合物與至少一種其他藥物活性成分組合之之用途,較佳用於治療多發性硬化症之藥物,諸如克拉屈濱或另一共藥物,諸如干擾素、例如聚乙二醇化或非聚乙二醇化干擾素,較佳干擾素β及/或與改善血管功能之化合物組合或與免疫調節劑組合,例如芬戈莫德(Fingolimod);環孢菌素類(cyclosporins)、雷帕黴素類(rapamycins)或子囊黴素類(ascomycins),或其等免疫抑制類似物例如環孢菌素A、環孢菌素g,FK-506、ABT-281、ASM981、雷帕黴素、40-O-(2-羥基)乙基-雷帕黴素等;皮質類固醇(corticosteroids);環磷醯胺(cyclophosphamide);咪唑硫嘌呤(azathioprene);甲胺蝶呤(methotrexate);來氟米特(leflunomide);咪唑立賓(mizoribine);黴酚酸(mycophenolic add);黴酚酸酯(mycophenolate mofetil);15-脫氧精胍菌素;戊酸雙氟可龍(diflucortolone valerate);二氟潑尼酯(difluprednate);二丙阿氯米松(Alclometasone dipropionate);安西奈德(amcinonide);安吖啶(amsacrine);門冬醯胺酶(asparaginase);咪唑硫嘌呤(azathioprine);巴厘昔單抗(basiliximab);二丙酸倍氯米松(beclometasone dipropionate);倍他米松(betamethasone);鹽酸倍他米松(betamethasone acetate);二丙酸倍他米松(betamethasone dipropionate);倍他米松磷酸鈉(betamethasone phosphate sodique);戊酸倍他米松(betamethasone valerate);布地奈德(budesonide);卡托普利(captopril);鹽酸氯甲胺(chlormethine chlorhydrate);克拉屈濱(cladribine);丙酸氯倍他索(clobetasol propionate);乙酸可的松(cortisone acetate);可的伐唑(cortivazol);環磷醯胺(cyclophosphamide);阿糖胞苷(cytarabine);達克珠單抗(daclizumab);更生黴素(dactinomycine);地索奈德(desonide);去羥米松(desoximetasone);地塞米松(dexamethasone);乙酸地塞米松(dexamethasone acetate);異菸鹼酸地塞米松(dexamethasone isonicotinate);地塞米松間磺基苯甲鈉(dexamethasone metasulfobenzoate sodique);磷酸地塞米松(dexamethasone phosphate);第三丁乙酸地塞米松(dexamethasone tebutate);乙酸二氯異丙酯(dichlorisone acetate);鹽酸多柔比星(doxorubicine chlorhydrate);鹽酸表柔比星(epirubicine chlorhydrate);氟氯奈德(fluclorolone acetonide);乙酸氟氫可的松(fludrocortisone acetate);氟氫縮松(fludroxycortide);特戊酸氟米松(flumetasone pivalate);氟尼縮松(flunisolide);氟輕松安奈德(fluocinolone acetonide);乙酸氟輕松(fluocinonide);氟可龍(fluocortolone);己酸氟可龍(fluocortolone hexanoate);特戊酸氟可龍(fluocortolone pivalate);氟米龍(fluorometholone);乙酸氟強的松(fluprednidene acetate);丙酸氟替卡松(fluticasone propionate);鹽酸吉西他濱(gemcitabine chlorhydrate);哈西奈德(halcinonide);氫化可的松(hydrocortisone)、乙酸氫化可的松(hydrocortisone acetate)、丁酸氫化可的松(hydrocortisone butyrate)、半琥珀酸氫化可的松(hydrocortisone hemisuccinate);美法崙(melphalan);甲基潑尼松(meprednisone);巰嘌呤;甲基潑尼松龍;乙酸甲基潑尼松龍;半琥珀酸甲基潑尼松龍;米索前列腺(misoprostol);莫羅單抗-cd3(muromonab-cd3);黴酚酸酯;乙酸帕拉米松(paramethasone acetate);潑那唑啉(prednazoline)、潑尼松龍;乙酸潑尼松龍;己酸潑尼松龍(prednisolone caproate);潑尼松龍間磺基苯甲酸鈉(prednisolone metasulfobenzoate sodique);潑尼松龍磷酸鈉(prednisolone phosphate sodique);強的松(prednisone);潑尼立定(prednylidene);利福平(rifampicine);利福平鈉(rifampicine sodique);他克莫司(tacrolimus);特立氟胺(teriflunomide);薩利多胺(thalidomide);噻替派(thiotepa);特戊酸替可的松(tixocortol pivalate);去炎松(triamcinolone);半琥珀酸去炎松曲安奈德(triamcinolone acetonide hemisuccinate);去炎松曲安奈德(triamcinolone benetonide);二乙酸曲安奈德(triamcinolone diacetate);己曲安奈德(triamcinolone hexacetonide);免疫抑制單株抗體,例如,對白細胞受體之單株抗體,例如,MHC、CD2、CD3、CD4、CD7、CD25、CD28、B7、CD40、CD45或CD58或其等配體;或其他免疫調節化合物,例如CTLA41g,或其他黏附分子抑制劑,例如mAbs或低分子量抑制劑,其等包括選擇素拮抗劑及VLA-4拮抗劑。較佳之組合物係具有環孢菌素A、FK506、雷帕黴素或40-(2-羥基)乙基-雷帕黴素及芬戈莫德。此等其他藥物諸如干擾素β可(例如藉由皮下、肌內或經口途徑)伴隨或順序投與。
此外,本發明係關於式(I)及相關式之化合物與至少一種其他藥物活性成分組合之之用途,較佳用於治療癌症之藥物(諸如特定言之,上文描述之抗癌及/或抗腫瘤劑)。
本發明進一步係關於由以下之獨立包裝組成之裝置(套組):
(a) 有效量之式(I)化合物及/或其前藥、溶劑合物、互變異構體、寡聚物、加合物或立體異構體及上述各者之醫藥上可接受之鹽,包括其以所有比率之混合物,
及
(b) 有效量之另一藥物活性成分。
本發明之化合物可根據下列方案及實例之程序,使用適當之材料進行製備,並由下列具體實例進一步例示。
此外,藉由利用本文描述之程序,結合此項技術中之一般技術,可容易製備本文主張之額外之本發明化合物。然而,實例中闡述之化合物不應視為形成被視為本發明之唯一屬。該等實例進一步闡述用於製備本發明之化合物之細節。熟習此項技術者將容易瞭解下列製備型程序之條件及方法之已知變更可用以製備此等化合物。
用於製備本發明之化合物之初始材料可藉由如實例中描述之方法或藉由本身已知的方法進行製備,如描述於合成有機化學及熟習技工已知的文獻中,或可購買獲得。
式(IV)化合物之合成係描述於WO 2016/050356、WO 2016/050355、WO 2016/050359及WO 2016/050358中。
實例 HPLC :
方法A:
2 mL/min;215 nm;緩衝液A:0.05% TFA/H2
O;緩衝液B:0.04% TFA/ACN;0.0-0.2 min 5%緩衝液B;0.2-8.1 min 5%-100%緩衝液B;8.1-10.0 min 100%-5%緩衝液B。管柱:XBridge C8 (50 x 4.6 mm, 3.5 µm)。
本發明將由參考下列實例中描述之具體實施例進行闡述但不限於此。除非方案中另有指示,否則變量具有如上文描述之相同含義。
除非另有規定,否則所有起始材料係獲得自商業供應商且無需進一步純化即可使用。除非另有規定,否則所有溫度係以℃表示且所有反應係在室溫下進行。化合物係藉由二氧化矽層析術或製備型HPLC進行純化。
除非另有規定,否則其中未指示具體之立體化學之下文指示之所有結構係指立體異構體之混合物。
步驟 1 :苯并呋喃 -3- 基甲醇
1-苯并呋喃-3-甲醛(5 g,34.2 mmol)於甲醇(50 mL)中之溶液用冰冷卻並滴加硼氫化鈉(1.9 g,51.3 mmol)。在室溫下將該反應混合物攪拌1 h。濃縮該反應混合物並將殘餘物分配至飽和氯化銨與乙酸乙酯之間。將有機層分離,於硫酸鈉上乾燥並濃縮(5.0 g,無色液體,98%,粗產物)。該粗產物無需純化即可用於下一步驟中。1
H NMR (400 MHz, CDCl3
): δ 7.70-7.68 (m, 1H), 7.62 (s, 1H), 7.52-7.50 (m, 1H), 7.36-7.26 (m, 2H), 4.86 (s, 2H)。
步驟 2 : 3-( 溴甲基 ) 苯并呋喃
苯并呋喃-3-基甲醇(5.0 g,33.7 mmol)於乙醚(50 mL)中之冷(0℃)溶液用三溴化磷(1.1 mL,11.2 mmol)處理並在0℃下將該反應混合物攪拌30 min。然後將該反應混合物倒入冰中並用醚萃取。有機層係於硫酸鈉上乾燥並濃縮(7.1 g,黃色液體,100%,粗產物)。該粗產物無需純化即可用於下一步驟中。1
H NMR (400MHz, CDCl3
): δ 7.74-7.71 (m, 2H), 7.53 (s, 1H), 7.39-7.31 (m, 2H), 4.65 (s, 2H)。
步驟 3 : 2-( 苯并呋喃 -3- 基甲基 )-4,4,5,5- 四甲基 -1,3,2- 二氧雜硼烷
3-(溴甲基)苯并呋喃(7.1 g,33.8 mmol)於經脫氣之1,4-二噁烷(70 mL)中之溶液係用雙(頻哪醇基)二硼(10.3 g,40.5mmol)、碳酸鉀(13.9 g,101.0mmol)、肆(三苯基膦)鈀(0) (1.9 g,1.7 mmol)處理並在100℃下將該混合物加熱12 h。將燒瓶之內容物冷卻至室溫並通過矽藻土床過濾。濃縮濾液及粗產物係藉由快速管柱層析術於矽膠上,用於石油醚中之2至5%乙酸乙酯溶析進行純化以獲得2-(苯并呋喃-3-基甲基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷(6.1 g,69%,黃色油)。1
H NMR (400 MHz, CDCl3
) δ 7.57-7.52 (m, 2H), 7.46-7.44 (m, 1H), 7.30-7.21 (m, 2H), 2.23 (s, 2H), 1.29 (s, 12H)。
步驟 4 : 2-( 苯并呋喃 -3- 基甲基 ) 硼酸 (+)- 蒎烷二醇酯
2-(苯并呋喃-3-基甲基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷(6.1 g,23.6 mmol)於乙醚(60 mL)中之溶液係用(1S,2S,3R,5S)-(+)-蒎烷二醇(6.0 g,35.4 mmol)處理。在室溫下將該反應混合物攪拌12 h,然後該混合物用水清洗(兩次),然後用鹽水清洗,及所得溶液係於無水硫酸鈉上乾燥並濃縮。粗產物係藉由快速管柱層析術於矽膠上,用於石油醚中之5%乙酸乙酯溶析進行純化以獲得2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯(6.3 g,82%)。1
H NMR (400 MHz, CDCl3
): δ 7.58-7.56 (m, 1H), 7.55-7.53 (m, 1H), 7.46-7.44 (m, 1H), 7.28-7.23 (m, 2H), 4.33 (dd, J = 1.88, 8.76 Hz, 1H), 2.34-2.32 (m, 1H), 2.28 (s, 2H), 2.22-2.21 (m, 1H), 2.08 (t, J = 5.88 Hz, 1H), 1.42 (s, 3H), 1.29 (s, 3H), 1.13 (d, J = 10.92 Hz, 1H), 0.85 (s, 3H)。GCMS: m/z: 310。
步驟 5 : [(1S)-1- 氯 - 2-( 苯并呋喃 -3- 基甲基 ) 硼酸 (+)- 蒎烷二醇酯
向二氯甲烷(6.3 mL,60.9 mmol)及無水四氫呋喃(36 mL)之經冷卻(-100℃)之混合物添加正丁基鋰(1.6 M於己烷中,14.0 mL,(22.3 mmol),歷時20 min。攪拌20 min後,在-100℃下,添加2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯(6.3 g,20.3 mmol)於無水THF (22 mL)中之溶液,歷時20 min。然後在-100℃下添加氯化鋅(0.5 M於THF中,36.5 mL,18.2 mmol)之溶液,歷時30 min。容許該混合物達成室溫,攪拌18 h並濃縮。向所得油添加乙醚及飽和氯化銨。有機層係於無水硫酸鈉上乾燥並在真空中濃縮(7.3 g,99%,粗產物)。該粗產物係用於下一步驟中。1
H NMR (400 MHz, DMSO-d6): δ 7.60-7.57 (m, 2H), 7.49-7.47 (m, 1H), 7.31-7.25 (m, 2H), 4.36-4.34 (m, 1H), 3.31-3.29 (m, 1H), 3.24-3.22 (m, 1H), 2.35-2.31 (m, 1H), 2.14-2.12 (m, 1H), 2.06 (t, J = 5.84 Hz, 1H), 1.90-1.86 (m, 2H), 1.42 (s, 3H), 1.04 (d, J = 11.04 Hz, 1H), 0.85 (s, 3H)。GCMS: m/z: 358.2。
步驟 6 : [(1R)-1-[ 雙 ( 三甲基矽基 ) 胺基 ]- 2-( 苯并呋喃 -3- 基甲基 ) 硼酸 (+)- 蒎烷二醇酯
向[(1S)-1-氯-2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯(7.3 g,20.3 mmol)於40 mL無水四氫呋喃中之經冷卻(-78℃)之溶液添加雙(三甲基矽基)醯胺鋰(1M於THF中,25.5 mL,25.5 mmol)。在室溫下將該混合物攪拌18 h。濃縮至乾燥後,添加所得殘餘物己烷,並濾除經沈澱之固體。濃縮濾液以產生所需之粗產物(6.7 g,68%),其無需純化即可原樣用於下一步驟中。1
H NMR (400 MHz, CDCl3
): δ 7.60-7.59 (m, 1H), 7.50-7.45 (m, 2H), 7.28-7.24 (m, 2H), 4.31 (dd, J = 1.56, 8.70 Hz, 1H), 3.18-3.14 (m, 1H), 2.92-2.90 (m, 1H), 2.75-2.72 (m, 1H), 2.34-2.30 (m, 1H), 2.15-2.14 (m, 1H), 2.03 (t, J = 5.68 Hz, 1H), 1.88-1.80 (m, 2H), 1.39 (s, 3H), 1.30 (s, 3H), 1.01 (d, J = 10.88 Hz, 1H), 0.84 (s, 3H), 0.09 (s, 18H)。
步驟 7 : [(1R)-1- 胺基 - 2-( 苯并呋喃 -3- 基甲基 ) 硼酸 (+)- 蒎烷二醇酯三氟乙酸鹽
[(1R)-1-[雙(三甲基矽基)胺基]-2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯(6.7 g,13.9 mmol)於乙醚(30 mL)中之經冷卻(0℃)之溶液係用三氟乙酸(3.2 mL,41.7 mmol)逐滴處理。然後在室溫下將該反應混合物攪拌3 h (可見沈澱)。將該反應混合物冷卻至0℃並過濾。經過濾之固體用冷醚清洗並在真空下乾燥以提供[(1R)-1-胺基-2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯三氟乙酸鹽(2.3 g,白色固體,36%)。1
H NMR (400 MHz, DMSO-d6
): δ 7.66 (s, 1H), 7.61-7.60 (m, 1H), 7.47-7.45 (m, 1H), 7.29-7.20 (m, 2H), 4.30-4.28 (m, 1H), 3.27-3.16 (m, 3H), 2.25-2.13 (m, 3H), 1.94 (t, J = 5.56 Hz, 1H), 1.86-1.81 (m, 2H), 1.25 (s, 6H), 1.01 (d, J = 8.00 Hz, 1H), 0.75 (s, 3H)。
步驟 1 : 2-(2,4- 二甲基 - 苯甲基 )-4,4,5,5- 四甲基 -[1,3,2] 二氧雜硼烷
向1-溴甲基-2,4-二甲基-苯(25.00 g;114.40 mmol;1.00當量)於經脫氣之二噁烷(250.00 mL)中之溶液添加雙(頻哪醇基)二硼(35.21 g;137.28 mmol;1.20當量)、無水K2
CO3
(47.91 g;343.19 mmol;3.00當量)及肆(三苯基膦)鈀(0) (6623 mg;5.72 mmol;0.05當量)。然後在100℃下在氮氛圍下將該反應混合物加熱16 h。該反應混合物用二氯甲烷稀釋並濾過矽藻土。濃縮濾液及將殘餘物溶解於乙酸乙酯中並用鹽水清洗。有機層係於無水Na2
SO4
上乾燥,過濾並濃縮。粗產物係藉由管柱層析術使用於石油醚中之1%乙酸乙酯純化以獲得呈無色液體之2-(2,4-二甲基-苯甲基)-4,4,5,5-四甲基-[1,3,2]二氧雜硼烷(11.50 g;37.84 mmol;33.1%)。1
H NMR (400 MHz, CDCl3
) δ 7.04-7.02 (m, 1H), 6.95-6.93 (m, 1H), 6.92-6.90 (m, 1H), 2.28 (s, 3H), 2.25 (s, 3H), 2.23 (s, 2H), 1.24 (s, 12H)。
步驟 2 : (1S,2S,6R,8S)-4-(2,4- 二甲基 - 苯甲基 )-2,9,9- 三甲基 -3,5- 二氧雜 -4- 硼 - 三環 [6.1.1.02,6] 癸烷
在氮氛圍下向2-(2,4-二甲基-苯甲基)-4,4,5,5-四甲基-[1,3,2]二氧雜硼烷(24.00 g;79.3 mmol;1.0當量)於乙醚(240.00 mL)中之經冰冷卻之溶液添加(1S,2S,3R,5S)-2,6,6-三甲基-雙環[3.1.1]庚烷-2,3-二醇(20.68 g;119.07 mmol;1.50當量)並在室溫下將該反應混合物攪拌14 h。TLC分析顯示反應之完成。該反應混合物用鹽水清洗。有機層係於無水Na2
SO4
上乾燥並濃縮。粗產物係藉由快速管柱層析術使用於石油醚中之2%乙酸乙酯純化以獲得呈無色油之(1S,2S,6R,8S)-4-(2,4-二甲基-苯甲基)-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(28.00 g;82.96 mmol;90.0%)。1
H NMR (400 MHz, CDCl3
): δ 7.05-7.03 (m, 1H), 6.95-6.94 (m, 1H), 6.92-6.90 (m, 1H), 4.27-4.25 (m, 1H), 2.33-2.30 (m, 9H), 2.27-2.17 (m, 1H), 2.05 (t, J = 5.76 Hz, 1H), 1.90-1.89 (m, 1H), 1.84-1.80 (m, 1H), 1.38 (s, 3H), 1.28 (s, 3H), 1.11-1.09 (m, 1H), 0.91 (s, 3H)。GCMS: m/z: 298.3。
步驟 3 : (1S,2S,6R,8S)-4-[(S)-1- 氯 -2-(2,4- 二甲基 - 苯基 )- 乙基 ] -2,9,9- 三甲基 -3,5- 二氧雜 -4- 硼 - 三環 [6.1.1.02,6] 癸烷
在氮之正壓下將於四氫呋喃(140.00 mL)中之二氯甲烷(37.33 mL;583.45 mmol;3.00當量)放置於RB燒瓶中並使用液氮-乙醇混合物冷卻至 -99℃。通過該RB燒瓶之側面向此溶液滴加正丁基鋰(1.6 M於THF中) (133.71 mL;213.93 mmol;1.10當量) (以中等速率,添加耗時約35 min)使得內部溫度維持在-92℃與-102℃之間。添加後,將該反應混合物攪拌25分鐘。在反應之過程期間,形成白色沈澱(將內部溫度維持在-90℃與-96℃之間)。然後通過該RB燒瓶之側面在-94℃與-100℃之間的溫度下滴加(1S,2S,6R,8S)-4-(2,4-二甲基-苯甲基)-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(28.00 g;93.89 mmol;0.48當量)及(1S,2S,6R,8S)-4-(2,4-二甲基-苯甲基)-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(30.00 g;100.59 mmol;0.52當量)一起於四氫呋喃(300.00 mL)中之溶液(約40 min)。然後,將該反應混合物攪拌10 min。然後通過該RB燒瓶之側面在-94℃與-99℃之間的溫度下滴加氯化鋅(0.5 M於THF中) (388.97 mL;194.48 mmol;1.00當量) (以中等速率,添加耗時約35 min)。然後緩慢容許該反應混合物達成20℃並在20℃下攪拌2.5 h。濃縮該反應混合物(浴溫30℃)。將殘餘物分配至乙醚與飽和NH4
Cl溶液之間。有機層係於無水Na2
SO4
上乾燥並濃縮(浴溫30℃)以提供呈白色固體之(1S,2S,6R,8S)-4-[(S)-1-氯-2-(2,4-二甲基-苯基)-乙基]-2,9,9-三甲基 -3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(75.70 g;154.83 mmol;79.6%)。1
H NMR (400 MHz, CDCl3
): δ 7.12 (d, J = 7.64 Hz, 1H), 6.98 (s, 1H), 6.96 (d, J = 7.68 Hz, 1H), 4.38-4.36 (m, 1H), 3.67-3.62 (m, 1H), 3.18-3.11 (m, 2H), 2.40-2.36 (m, 2H), 2.32 (s, 3H), 2.30 (s, 3H), 2.23-2.20 (m, 1H), 2.08 (t, J = 5.96 Hz, 1H), 1.93-1.87 (m, 2H), 1.36 (s, 3H), 1.30 (s, 3H), 1.14-1.11 (m, 1H), 0.84 (s, 3H)。 7.18-7.08 (m, 5H), 4.37 (dd, J = 1.32, 8.74 Hz, 1H), 3.77-3.75 (m, 1H), 3.67-3.63 (m, 1H), 3.19-3.17 (m, 1H), 3.10-3.08 (m, 1H), 2.36-2.31 (m, 5H), 2.09 (t, J = 5.84 Hz, 1H), 1.93-1.86 (m, 4H), 1.39 (s, 3H), 1.30 (s, 3H), 1.13-1.10 (m, 1H), 0.84 (s, 3H)。GCMS: m/z: 346.3。
步驟 4 : (1S,2S,6R,8S)-4-[(R)-2-(2,4- 二甲基 - 苯基 )-1-(1,1,1,3,3,3- 六甲基 - 二矽氮 -2- 基 )- 乙基 ]-2,9,9- 三甲基 -3,5- 二氧雜 -4- 硼 - 三環 [6.1.1.02,6] 癸烷
在氮氛圍之正壓下將(1S,2S,6R,8S)-4-[(S)-1-氯-2-(2,4-二甲基-苯基)-乙基]-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(75.70 g;218.35 mmol;1.00當量)於THF (400.00 mL)中之溶液冷卻至-78℃。向此溶液滴加(雙三甲基矽基)醯胺鋰(1.0 M於THF中) (262 mL;262 mmol;1.20當量)之溶液,歷時30分鐘之週期。容許該反應混合物達到室溫並在室溫下攪拌18 h。在溫度30℃下蒸發該反應混合物。用己烷研磨殘餘物並過濾形成之固體。在溫度30℃下濃縮濾液以獲得(1S,2S,6R,8S)-4-[(R)-2-(2,4-二甲基-苯基)-1-(1,1,1,3,3,3-六甲基-二矽氮-2-基)-乙基] -2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(80.10 g;169.84 mmol;77.8%;棕色油)。粗產物無需純化即可用於下一步驟中。1
H NMR (400 MHz, CDCl3
): δ: 7.06 (d, J = 7.64 Hz, 1H), 6.94 (s, 1H), 6.90 (d, J = 7.80 Hz, 1H), 4.29-4.27 (m, 1H), 3.15-3.10 (m, 1H), 2.87-2.83 (m, 1H), 2.58-2.53 (m, 1H), 2.34-2.32 (m, 2H), 2.30 (s, 3H), 2.28 (s, 3H), 2.15-2.13 (m, 1H), 2.03 (t, J = 5.88 Hz, 1H), 1.90-1.88 (m, 1H), 1.81-1.77 (m, 1H), 1.39 (s, 3H), 1.32 (s, 3H), 1.01-0.98 (m, 1H), 0.93 (s, 3H), 0.85 (s, 3H), 0.09 (s, 18H)。
步驟 5 : (R)-2-(2,4- 二甲基 - 苯基 )-1-((1S,2S,6R,8S)-2,9,9- 三甲基 -3,5- 二氧雜 -4- 硼 - 三環 [6.1.1.02,6] 癸 -4- 基 )- 乙胺鹽酸鹽
在氮氛圍下將(1S,2S,6R,8S)-4-[(R)-2-(2,4-二甲基-苯基)-1-(1,1,1,3,3,3-六甲基-二矽氮-2-基)-乙基]-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(80.10 g;169.84 mmol;1.00當量)於乙醚(400.00 mL)中之攪拌溶液冷卻至-10℃。向此溶液滴加鹽酸於乙醚(212.30 mL;424.59 mmol;2.50當量)中之2M溶液。在室溫下將該反應混合物攪拌2 h。在減壓下蒸發該反應混合物以獲得(R)-2-(2,4-二甲基-苯基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸-4-基)-乙胺鹽酸鹽(63.00 g;72.61 mmol;42.8%;棕色吸濕性固體)。1
H NMR (400 MHz, DMSO-d6): δ 8.19 (s, 3H), 7.05 (d, J = 7.68 Hz, 1H), 6.95 (s, 1H), 6.90 (d, J = 8.16 Hz, 1H), 4.31 (dd, J = 1.80, 8.76 Hz, 1H), 3.02-3.00 (m, 1H), 2.99-2.92 (m, 1H), 2.87-2.84 (m, 1H), 2.26-2.24 (m, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 2.03-2.00 (m, 1H), 1.91 (t, J = 5.68 Hz, 1H), 1.82-1.80 (m, 1H), 1.71-1.66 (m, 1H), 1.31 (s, 3H), 1.21 (s, 3H), 0.98-0.96 (m, 1H), 0.77 (s, 3H)。
中間物
3
:
2-(7-
甲基
-
苯并呋喃
-3-
基
)-1-((1S,2S,6R,8S)-2,9,9-
三甲基
-3,5-
二氧雜
-4-
硼
-
三環
[6.1.1.02,6]
癸
-4-
基
)-
乙胺鹽酸鹽
步驟 1 : 7- 甲基 - 苯并呋喃 -3- 羧酸乙酯
向2-羥基-3-甲基-苯甲醛(20.00 g;139.55 mmol;1.00當量)於二氯甲烷(120 mL)中之溶液添加四氟硼酸乙醚錯合物(1.88 mL;13.96 mmol;0.10當量)。在25至30℃ (內部溫度)下向所得深紅色混合物緩慢滴加於二氯甲烷(80 mL)中之重氮乙酸乙酯(31.70 mL;300.04 mmol;2.15當量),歷時約50 min。16 h後,添加濃H2
SO4
。將該反應混合物攪拌30 min。然後該反應混合物用固體NaHCO3
中和,濾過矽藻土並濃縮濾液以獲得粗殘餘物。該殘餘物係藉由管柱層析術使用於石油醚中之2%乙酸乙酯純化以提供7-甲基-苯并呋喃-3-羧酸乙酯(19.00 g;86.83 mmol;62.2%;黃色油;經純化之產物)。
HPLC (方法A):RT 4.98 min (HPLC純度93%)1
H NMR, 400 MHz, CDCl3
: 8.27 (s, 1H), 7.88-7.90 (m, 1H), 7.25-7.29 (m, 1H), 7.17 (d, J = 7.32 Hz, 1H), 4.39-4.45 (m, 2H), 2.55 (s, 3H), 1.44 (t, J = 7.16 Hz, 3H)。
步驟 2 : (7- 甲基 - 苯并呋喃 -3- 基 )- 甲醇
在氮下在-78℃下向7-甲基-苯并呋喃-3-羧酸乙酯(19.00 g;86.83 mmol;1.00當量)於二氯甲烷(190.00 mL)中之溶液滴加二異丁基氫化鋁(1.0 M於甲苯中) (191.03 mL;191.03 mmol;2.20當量)。容許該反應混合物達到室溫並攪拌1 h。該反應混合物用冰浴冷卻並用1.5N HCl水溶液淬滅。所得混合物(其使黏性固體物質懸浮於溶劑中)用乙酸乙酯稀釋並濾過矽藻土。矽藻土床用乙酸乙酯及二氯甲烷徹底清洗。蒸發濾液以獲得粗殘餘物。取出留在矽藻土中之固體及用乙酸乙酯研磨並過濾。將濾液與粗殘餘物混合在一起並蒸發。將因此獲得之殘餘物溶解於乙酸乙酯中並用1.5 N HCl之水溶液及鹽水清洗。有機層係於無水Na2
SO4
上乾燥並濃縮。獲得之殘餘物係藉由快速管柱層析術使用於石油醚中之40至50%乙酸乙酯作為溶析液純化以獲得(7-甲基-苯并呋喃-3-基)-甲醇(8.20 g;48.40 mmol;55.7%;淡黃色油)。
HPLC (方法A):RT 3.33 min,(HPLC純度95.7%)。1
H NMR, 400 MHz, CDCl3
: 7.64 (s, 1H), 7.50-7.52 (m, 1H), 7.17-7.21 (m, 1H), 7.14 (d, J = 7.20 Hz, 1H), 4.86-4.86 (m, 2H), 2.54 (s, 3H)。
步驟 3 : 3-( 溴甲基 )-7- 甲基 - 苯并呋喃
在氮氛圍下向(7-甲基-苯并呋喃-3-基)-甲醇(8.20 g;48.40 mmol;1.00當量)於乙醚(82.00 mL)中之經冰冷卻之溶液滴加三溴化磷(1.53 mL;16.12 mmol;0.33當量)並在冰冷條件下將該反應混合物攪拌30分鐘。將該反應混合物倒入冰中並用乙醚萃取。有機層係於無水Na2
SO4
上乾燥並濃縮以提供3-溴甲基-7-甲基-苯并呋喃(10.00 g;44.43 mmol;91.8%;無色油)。該粗產物無需純化即可用於下一步驟中。1
H NMR, 400 MHz, CDCl3
: 7.71 (s, 1H), 7.53-7.55 (m, 1H), 7.21-7.25 (m, 1H), 7.16 (d, J = 7.32 Hz, 1H), 4.65 (s, 2H), 2.48 (s, 3H)。
步驟 4 : 7- 甲基 -3-(4,4,5,5- 四甲基 -[1,3,2] 二氧雜環戊硼 -2- 基甲基 )- 苯并呋喃
向3-溴甲基-7-甲基-苯并呋喃(10.00 g;44.43 mmol;1.00當量)於經脫氣之二噁烷-1,4 (100.00 mL)中之溶液添加雙(頻哪醇基)二硼(13.68 g;53.31 mmol;1.20當量)、無水K2
CO3
(18.61 g;133.28 mmol;3.00當量)及肆(三苯基膦)鈀(0) (2.57 g;2.22 mmol;0.05當量)。然後在100℃下在氮氛圍下將該反應混合物加熱16 h。該反應混合物用二氯甲烷稀釋並濾過矽藻土。濃縮濾液。將殘餘物溶解於乙酸乙酯中並用鹽水清洗。有機層係於無水Na2
SO4
上乾燥並濃縮。粗產物係藉由管柱層析術使用於石油醚中之2%乙酸乙酯純化以獲得7-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧雜環戊硼-2-基甲基)-苯并呋喃(5.00 g;18.37 mmol;41.4%;無色液體)。1
H NMR, 400 MHz, DMSO-d6: 7.65 (s, 1H), 7.33-7.35 (m, 1H), 7.07-7.13 (m, 2H), 2.43 (s, 3H), 2.13 (s, 2H), 1.16 (s, 12H)。
步驟 5 : 三甲基 -4-(7- 甲基 - 苯并呋喃 -3- 基甲基 )-3,5- 二氧雜 -4- 硼 - 三環 [6.1.1.02,6] 癸烷
在氮氛圍下向7-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧雜環戊硼-2-基甲基)-苯并呋喃(5.00 g;18.37 mmol;1.00當量)於Et2
O (50.00 mL)中之經冰冷卻之溶液添加1S,2S,3R,5S-(+)-2,3-蒎烷二醇(4.69 g;27.56 mmol;1.50當量)並在室溫下將該反應混合物攪拌14 h。TLC分析顯示反應之完成。該反應混合物用鹽水清洗。有機層係於無水Na2
SO4
上乾燥並濃縮。粗產物係藉由快速管柱層析術使用於石油醚中之2%乙酸乙酯純化以獲得(1S,2S,6R,8S)-2,9,9-三甲基-4-(7-甲基-苯并呋喃-3-基甲基)-3,5-二氧雜 -4-硼-三環[6.1.1.02,6]癸烷(5.00 g;13.00 mmol;70.7%;無色液體)。
GCMS: m/z: 324.2。1
H NMR, 400 MHz, CDCl3
: 7.53-7.55 (m, 1H), 7.39-7.40 (m, 1H), 7.12-7.27 (m, 1H), 7.06-7.08 (m, 1H), 4.31-4.34 (m, 1H), 2.53 (s, 3H), 2.30-2.37 (m, 1H), 2.26 (s, 2H), 2.18-2.23 (m, 1H), 2.07 (t, J = 5.76 Hz, 1H), 1.84-1.93 (m, 2H), 1.42 (s, 3H), 1.29 (s, 3H), 1.12-1.15 (m, 1H), 0.85 (s, 3H)。
步驟 6 : (1S,2S,6R,8S)-4-[1- 氯 -2-(7- 甲基 - 苯并呋喃 -3- 基 )- 乙基 ] -2,9,9- 三甲基 -3,5- 二氧雜 -4- 硼 - 三環 [6.1.1.02,6] 癸烷
在氮之正壓下將於THF (40mL)中之二氯甲烷(2.96 mL;46.26 mmol;3.00當量)放置於RB燒瓶中並使用液氮-乙醇混合物冷卻至-95℃。通過該RB燒瓶之側面向此溶液滴加正丁基鋰(1.6 M於己烷中) (10.60 mL;16.96 mmol;1.10當量) (以中等速率,添加耗時約30 min)使得內部溫度維持在-95℃與-100℃之間。添加後,將該反應混合物攪拌20分鐘。在反應之過程期間,形成白色沈澱(將內部溫度維持在-95℃與-100℃之間)。然後通過該RB燒瓶之側面滴加(1S,2S,6R,8S)-2,9,9-三甲基-4-(7-甲基-苯并呋喃-3-基甲基)-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(5.00 g;15.42 mmol;1.00當量)於THF (20 mL)中之溶液(約25 min)使得內部溫度維持在-95℃與-100℃之間。添加後,立即通過該RB燒瓶之側面滴加氯化鋅(0.5 M於THF中) (27.76 mL;13.88 mmol;0.90當量) (以中等速率,添加耗時約45 min)使得內部溫度維持在-95℃與-100℃之間。然後緩慢容許該反應混合物達到室溫並在室溫下攪拌16 h。濃縮該反應混合物(浴溫30℃)。將殘餘物分配至乙醚與飽和NH4
Cl溶液之間。將有機層分離,於無水Na2
SO4
上乾燥並濃縮(浴溫30℃)以提供(1S,2S,6R,8S)-4-[1-氯-2-(7-甲基-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(5.90 g;15.83 mmol;102.7%;棕色液體)。1
H NMR, 400 MHz, CDCl3
: 7.57 (s, 1H), 7.42-7.44 (m, 1H), 7.27 (s, 1H), 7.09-7.18 (m, 1H), 4.34-4.36 (m, 1H), 3.74-3.76 (m, 1H), 3.28-3.30 (m, 1H), 3.20-3.22 (m, 1H), 2.52 (s, 3H), 2.32-2.34 (m, 1H), 2.07 (t, J = 5.88 Hz, 1H), 1.85-1.91 (m, 2H), 1.42 (s, 3H), 1.29 (s, 3H), 1.06-1.09 (m, 1H), 0.85 (s, 3H)。
步驟 7 : ((1S,2S,6R,8S)-4-[1-(1,1,1,3,3,3- 六甲基 - 二矽氮 -2- 基 )-2-(7- 甲基 - 苯并呋喃 -3- 基 )- 乙基 ]-2,9,9- 三甲基 -3,5- 二氧雜 -4- 硼 - 三環 [6.1.1.02,6] 癸烷
在氮氛圍之正壓下將(1S,2S,6R,8S)-4-[1-氯-2-(7-甲基-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(5.90 g;15.83 mmol;1.00當量)於THF (40.00 mL)中之溶液冷卻至-78℃。向此溶液滴加(雙三甲基矽基)醯胺鋰(1.0 M於THF中) (17.41 mL;17.41 mmol;1.10當量)之溶液,歷時30分鐘之週期。容許該反應混合物達到室溫並在室溫下攪拌18 h。在30℃下蒸發該反應混合物。用正己烷研磨殘餘物並過濾形成之固體。在30℃下濃縮濾液以獲得(1S,2S,6R,8S)-4-[1-(1,1,1,3,3,3-六甲基-二矽氮-2-基)-2-(7-甲基-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(6.00 g;12.06 mmol;76.2%;棕黑色油)。1
H NMR, 400 MHz, CDCl3
: 7.50 (s, 1H), 7.41-7.43 (m, 1H), 7.12-7.16 (m, 1H), 7.06-7.08 (m, 1H), 4.29-4.32 (m, 1H), 3.17-3.09 (m, 1H), 2.70-2.89 (m, 1H), 2.52-2.70 (m, 1H), 2.52 (s, 3H), 2.28-2.31 (m, 1H), 2.14-2.14 (m, 1H), 2.03 (t, J = 5.68 Hz, 1H), 1.78-1.89 (m, 2H), 1.39 (s, 3H), 1.31 (s, 3H), 1.01-1.04 (m, 1H), 0.90-0.92 (m, 2H), 0.88 (s, 3H), 0.12 (s, 18H)。
步驟 8 : 2-(7- 甲基 - 苯并呋喃 -3- 基 )-1-((1S,2S,6R,8S)-2,9,9- 三甲基 -3,5- 二氧雜 -4- 硼 - 三環 [6.1.1.02,6] 癸 -4- 基 )- 乙胺鹽酸鹽
在氮氛圍下將(1S,2S,6R,8S)-4-[1-(1,1,1,3,3,3-六甲基-二矽氮-2-基) -2-(7-甲基-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(6.00 g;12.06 mmol;1.00當量)於乙醚(60.00 mL)中之攪拌溶液冷卻至-10℃。向此溶液滴加鹽酸於乙醚(15.07 mL;30.14 mmol;2.50當量)中之2M溶液。在室溫下將該反應混合物攪拌2 h。在30℃下蒸發該反應混合物。向殘餘物添加乙醚(20 mL)並濾除形成之固體,用冷乙醚清洗並在真空下乾燥以獲得2-(7-甲基-苯并呋喃-3-基)-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸-4-基)-乙胺鹽酸鹽(3.50 g;8.98 mmol;74.5%;棕橙色固體)。1
H NMR, 400 MHz, DMSO-d6: 8.09 (s, 3H), 7.83 (s, 1H), 7.52-7.53 (m, 1H), 7.12-7.19 (m, 2H), 4.39 (dd, J = 1.84, 8.62 Hz, 1H), 3.07-3.13 (m, 1H), 3.03-3.07 (m, 2H), 2.43 (s, 4H), 2.28-2.30 (m, 1H), 2.07-2.08 (m, 1H), 1.92 (t, J = 5.68 Hz, 1H), 1.82-1.84 (m, 1H), 1.71-1.75 (m, 1H), 1.19-1.25 (m, 8H), 1.00-1.08 (m, 1H), 0.78 (s, 3H)。
中間物
4
:
(R)-2-(2,3-
二氫
-
苯并呋喃
-3-
基
)-1-((1S,2S,6R,8S)-2,9,9-
三甲基
-3,5-
二氧雜
-4-
硼
-
三環
[6.1.1.02,6]
癸
-4-
基
)-
乙胺鹽酸鹽
步驟 1 : (1S,2S,6R,8S)-4-(2,3- 二氫 - 苯并呋喃 -3- 基甲基 )-2,9,9- 三甲基 -3,5- 二氧雜 -4- 硼 - 三環 [6.1.1.02,6] 癸烷
在小高壓釜中向(1S,2S,6R,8S)-4-苯并呋喃-3-基甲基-2,9,9-三甲基 -3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(5.00 g;10.72 mmol;1.00當量)於甲醇(100.00 mL)中之溶液添加碳載鈀(10重量%) (2.28 g;2.14 mmol;0.20當量)。在5 Kg/cm2
之H2
應力下將內容物氫化3 h。使該反應混合物濾過矽藻土並蒸發濾液。粗產物係藉由Biotage-isolera管柱層析術(C18管柱;流動相:ACN/H2
O;50:50等梯度)純化以獲得(1S,2S,6R,8S) -4-(2,3-二氫-苯并呋喃-3-基甲基)-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(4.10 g;13.13 mmol;122.5%;淺黃色液體)。
GCMS: m/z : 312.3。
步驟 2 : (1S,2S,6R,8S)-4-[1- 氯 -2-(7- 甲基 - 苯并呋喃 -3- 基 )- 乙基 ] -2,9,9- 三甲基 -3,5- 二氧雜 -4- 硼 - 三環 [6.1.1.02,6] 癸烷
在氮之正壓下將於THF (40.00 mL)中之二氯甲烷(2.46 mL;38.44 mmol;3.00當量)放置於RB燒瓶中並使用液氮-乙醇混合物冷卻至-95℃。通過該RB燒瓶之側面向此溶液滴加正丁基鋰(1.6 M於THF中) (8.81 mL;14.09 mmol;1.10當量) (以中等速率,添加耗時約20 min)使得內部溫度維持在-95℃與-100℃之間。添加後,將該反應混合物攪拌25分鐘。在反應之過程期間,形成白色沈澱(將內部溫度維持在-95℃與-100℃之間)。然後通過該RB燒瓶之側面滴加(1S,2S,6R,8S)-4-(2,3-二氫-苯并呋喃-3-基甲基)-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(4.00 g;12.81 mmol;1.00當量)於THF (15.00 mL)中之溶液(約25 min)使得內部溫度維持在-95℃與-100℃之間。添加後,立即通過該RB燒瓶之側面滴加氯化鋅(0.5 M於THF中) (25.62 mL;12.81 mmol;1.00當量) (以中等速率,添加耗時約25 min)使得內部溫度維持在-95℃與-100℃之間。然後緩慢容許該反應混合物達到室溫並在室溫下攪拌18 h。濃縮該反應混合物(浴溫30℃)。將殘餘物分配至乙醚與飽和NH4
Cl溶液之間。有機層係於無水Na2
SO4
上乾燥並濃縮(浴溫30℃)以提供(1S,2S,6R,8S)-4-[(S)-1-氯-2-(2,3-二氫-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(4.60 g;12.75 mmol;99.5%;黃色油)。
1H NMR, 400 MHz, CDCl3
: 7.29 (d, J = 6.72 Hz, 1H), 7.21-7.10 (m, 1H), 6.90-6.77 (m, 2H), 4.68-4.65 (m, 1H), 4.32-4.29 (m, 2H), 3.65-3.60 (m, 1H), 2.40-2.08 (m, 4H), 1.94-1.85 (m, 2H), 1.42 (s, 3H), 1.33 (s, 3H), 1.22 (s, 3H), 1.17-1.15 (m, 1H), 0.86 (s, 3H)。
步驟 3 : (1S,2S,6R,8S)-4-[(R)-2-(2,3- 二氫 - 苯并呋喃 -3- 基 )-1-(1,1,1,3,3,3- 六甲基 - 二矽氮 -2- 基 )- 乙基 ]-2,9,9- 三甲基 -3,5- 二氧雜 -4- 硼 - 三環 [6.1.1.02,6] 癸烷
在氮氛圍之正壓下將(1S,2S,6R,8S)-4-[(S)-1-氯-2-(2,3-二氫-苯并呋喃-3-基)-乙基]-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(4.60 g;12.75 mmol;1.00當量)於THF (45.00 mL)中之溶液冷卻至-78℃。向此溶液滴加(雙三甲基矽基)醯胺鋰(1.0 M於THF中) (16.58 mL;16.58 mmol;1.30當量)之溶液,歷時30分鐘之週期。容許該反應混合物達到室溫並在室溫下攪拌18 h。在30℃下蒸發該反應混合物。用己烷研磨殘餘物並過濾形成之固體。容許將濾液在真空下靜置一段時間且若形成任何固體,則將其再次過濾。在30℃下濃縮濾液以獲得(1S,2S,6R,8S)-4-[(R)-2-(2,3-二氫-苯并呋喃-3-基)-1-(1,1,1,3,3,3-六甲基-二矽氮-2-基)-乙基] -2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(3.77 g;7.76 mmol;60.9%;黃色油)。
1H NMR, 400 MHz, CDCl3
: 7.22-7.10 (m, 2H), 6.90-6.79 (m, 2H), 4.62-4.59 (m, 1H), 4.33-4.27 (m, 1H), 2.34-2.20 (m, 2H), 2.07-2.05 (m, 1H), 1.94-1.84 (m, 2H), 1.40 (s, 3H), 1.30 (s, 3H), 1.15-1.13 (m, 1H), 0.86 (s, 3H), 0.10 (s, 18H)。
步驟 4 : (R)-2-(2,3- 二氫 - 苯并呋喃 -3- 基 )-1-((1S,2S,6R,8S)-2,9,9- 三甲基 -3,5- 二氧雜 -4- 硼 - 三環 [6.1.1.02,6] 癸 -4- 基 )- 乙胺鹽酸鹽
在氮氛圍下將(1S,2S,6R,8S)-4-[(R)-2-(2,3-二氫-苯并呋喃-3-基)-1-(1,1,1,3,3,3-六甲基-二矽氮-2-基)-乙基]-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸烷(3.77 g;7.76 mmol;1.00當量)於Et2
O (35.00 mL)中之攪拌溶液冷卻至-10℃。向此溶液滴加鹽酸於乙醚(9.70 mL;19.41 mmol;2.50當量)中之2M溶液。在室溫下將該反應混合物攪拌2 h。在減壓下將該反應混合物蒸發至乾燥以獲得固體。形成之固體用乙醚研磨,過濾,用乙醚清洗並在真空下乾燥以獲得(R)-2-(2,3-二氫-苯并呋喃-3-基) -1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸-4-基)-乙胺鹽酸鹽(2.30 g;5.25 mmol;67.7%;淺棕色固體)。
分析顯示在指示(*)之位置存在異構體(~ 65.50% + 20.75%)。
LCMS: 4.73 min, 86.25% (ma x ), 80.47% (220 nm), 342.20 (M+1)。
1H NMR, 400 MHz, DMSO-d6: 8.11 (s, 3H), 7.23-7.19 (m, 1H), 7.13-7.10 (m, 1H), 6.85 (t, J = 7.40 Hz, 1H), 6.77 (d, J = 8.04 Hz, 1H), 4.61-4.57 (m, 1H), 4.48-4.45 (m, 1H), 4.25-4.22 (m, 1H), 3.68-3.62 (m, 1H), 2.90-2.85 (m, 1H), 2.34-2.32 (m, 1H), 2.19-2.17 (m, 1H), 2.02-1.99 (m, 2H), 1.89-1.77 (m, 3H), 1.39 (s, 3H), 1.25 (s, 3H), 1.17-1.14 (m, 1H), 0.82 (s, 3H)。
步驟 1 : (3- 羥基 - 丙基氫硫基 )- 乙酸甲酯
在室溫下在攪拌下將三乙胺(4.77 mL;34.38 mmol)滴加至溴乙酸甲酯(2.90 mL;31.25 mmol)及3-巰基-丙-1-醇(2.80 mL;31.25 mmol)於10.5 mL無水甲醇中之溶液,歷時30 min。將該反應混合物再攪拌一小時。移除溶劑後,將殘餘物溶解於乙酸乙酯中並藉由過濾移除不溶性三乙基溴化銨。濃縮乙酸乙酯濾液並藉由快速層析術(矽膠;正庚烷/乙酸乙酯梯度;0至50%乙酸乙酯)純化以產生4.78 g (93%)呈無色油之標題化合物。
LCMS (Agilent 70108359 - Chromolith Speed Rod RP18e 50-4.6 mm;極性.m;2.4 mL/min;220 nm;緩衝液A:0.05% HCOOH/H2
O,緩衝液B:0.04% HCOOH/ACN;0.0-2.8 min 4%-100%緩衝液B;2.8-3.3 min 100%緩衝液B;3.3-3.4 min 100%-4%緩衝液B):(M+H) 165.0;Rt 1.18 min。
步驟 2 : 2-(3- 羥丙基氫硫基 ) 乙酸鋰
在250 mL圓底燒瓶中,將(3-羥基-丙基氫硫基)-乙酸甲酯(4.78 g;29.11 mmol)溶解於24 mL THF及24 mL去離子水中。使用冰水浴將溶液冷卻至0℃並添加LiOH (697 mg)。1.5 h後,蒸發THF並凍乾殘餘物以產生4.46g呈白色固體之標題化合物,其無需進一步純化即可用於下一步驟中。
步驟 3 : N-[(R)-2- 苯并呋喃 -3- 基 -1-((1S,2S,6R,8S)-2,9,9- 三甲基 -3,5- 二氧雜 -4- 硼 - 三環 [6.1.1.02,6] 癸 -4- 基 )- 乙基 ]-2-(3- 羥基 - 丙基氫硫基 )- 乙醯胺
在-10℃下在氬氛圍下向(R)-2-苯并呋喃-3-基-1-((1S,2S,6R,8S) -2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸-4-基)-乙胺鹽酸鹽(0.300 g;0.799 mmol;含有~15% (S)-2-苯并呋喃-3-基-1-((1S,2S,6R,8S)-2,9,9-三甲基-3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸-4-基)-乙胺鹽酸鹽之混合物)於10 mL無水N,N-二甲基甲醯胺中之溶液添加2-(3-羥丙基氫硫基)乙酸鋰(0.129 g;0.799 mmol)。然後添加N-乙基二異丙胺(0.407 mL;2.396 mmol)及[(苯并三唑1-基氧基)-二甲基胺基-亞甲基]-二甲基-四氟硼酸銨(TBTU) (0.308 g;0.958 mmol)並在-10℃下將黃色溶液攪拌整夜。DMF溶液用EE稀釋並用NaHCO3
水溶液,水及鹽水清洗。將有機層乾燥,濃縮並吸附於二氧化矽上以藉由快速層析術(矽膠;正庚烷/EE梯度;0至90% EE)純化。獲得之非對映異構體之混合物係使用對掌性製備型HPLC (對掌性Pak AD-H;正庚烷/2-丙醇90:10;220 nm)分離以產生90 mg呈無色非晶型固體之標題化合物。
LCMS (Agilent 70108359 - Chromolith Speed Rod RP18e 50-4.6 mm;極性.m;2.4 mL/min;220 nm;緩衝液A:0.05% HCOOH/H2
O,緩衝液B:0.04% HCOOH/ACN;0.0-2.8 min 4%-100%緩衝液B;2.8-3.3 min 100%緩衝液B;3.3-3.4 min 100%-4%緩衝液B):(M+H) 472.0;Rt 2.45 min。
步驟 4 : [(1R)-2-( 苯并呋喃 -3- 基 )-1-[[2-(3- 羥丙基氫硫基 ) 乙醯基 ] 胺基 ] 乙基 ] 硼酸
在0℃下向N-[(R)-2-苯并呋喃-3-基-1-((1S,2S,6R,8S)-2,9,9-三甲基 -3,5-二氧雜-4-硼-三環[6.1.1.02,6]癸-4-基)-乙基]-2-(3-羥基-丙基氫硫基)-乙醯胺(0.090 g;0.191 mmol)於7 mL正戊烷及3.5 mL甲醇異丁基硼酸(0.078 g;0.764 mmol)及0.9 mL鹽酸中之兩相系統添加1 mol/L (4.5當量)。在0℃下將無色混合物攪拌整夜。該反應混合物用戊烷清洗(4 x )。蒸發甲醇水層(浴溫30℃),殘餘物用1N NaOH鹼化並用DCM萃取(3 x )。水相用1 N HCl酸化並用DCM再次萃取(5 x )。濃縮水層並使用RP層析術(RP矽膠C18;水/ACN梯度;0至50% CAN;220 nm)純化殘餘物。將含有產物之溶離份減少至乾燥並凍乾以產生29 mg呈灰白色粉末之標題化合物(產率45%)。
1H NMR (500 MHz, DMSO-d6/D2
O) d 7.61 (s, 1H), 7.61 – 7.58 (m, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.29 – 7.25 (m, 1H), 7.23 – 7.19 (m, 1H), 3.35 (t, J = 6.3 Hz, 2H), 3.27 (dd, J = 8.4, 5.6 Hz, 1H), 3.10 – 3.02 (m, 2H), 2.92 – 2.86 (m, 1H), 2.78 (dd, J = 15.0, 8.4 Hz, 1H), 2.39 (t, J = 7.3 Hz, 2H), 1.55 (p, J = 6.5 Hz, 2H)。
Waters XBridge C8 3.5 µm 4.6 x 50 mm (A19/533 - La Chrom Elite;70173815);8.1 min;2 mL/min;215 nm;緩衝液A:0.05% TFA/H2
O;緩衝液B:0.04% TFA/ACN;0.0-0.2min 5%緩衝液B;0.2-8.1 min 5%-100%緩衝液B;8.1-10.0 min 100%-5%緩衝液B:(面積百分比) 98,8%;Rt 3.65 min。
HPLC MS (Agilent 70108359 - Chromolith Speed Rod RP18e 50-4.6 mm;極性.m;2.4 mL/min;220 nm;緩衝液A:0.05% HCOOH/H2
O,緩衝液B:0.04% HCOOH/ACN;0.0-2.8 min 4%-100%緩衝液B;2.8-3.3 min 100%緩衝液B;3.3-3.4 min 100%-4%緩衝液B):381.2 [M+H-H2
O];Rt 1.60 min。
其他例示性化合物係描述於下表1中。此等化合物可起始自市售酸(或藉由市售酯之皂化合成之酸)或文獻中根據實例1步驟3及4描述之酸進行合成。在一些實例中,此等實例含有未經分離之立體異構體之混合物:表 1 :例示性化合物之列表 表 2 :分析資料
生物活性 LMP7 活性之測定:
LMP7抑制之量測係以基於螢光強度分析之384孔形式進行。
在25℃下於含有50 mM Tris pH 7.4、0.03% SDS、1 mM EDTA及1% DMSO之分析緩衝液中將經純化之人類免疫蛋白酶體(0.25 nM)及於DMSO中之連續稀釋化合物(濃度範圍自30 µM至15 pM)或對照培養20分鐘或120分鐘(長培養)。該反應係藉由以40 µM之濃度,添加螢光肽受質Suc-LLVY-AMC (Bachem I-1395)啟始。在37℃下培養60分鐘後,螢光強度係在λex
= 350 nm及λem
= 450 nm下使用螢光讀數器(Perkin Elmer Envision讀數器或等同物)進行量測。
化合物之LMP7活性係總結於表3中。除非另有說明,否則結果係在培養20分鐘後獲得。
Beta5 活性之測定:
Beta5抑制之量測係以基於螢光強度分析之384孔形式進行。
在25℃下於含有50 mM Tris pH 7.4、0.03% SDS、1 mM EDTA及1% DMSO之分析緩衝液中將經純化之人類組成性蛋白酶體(1.25 nM)及於DMSO中之連續稀釋化合物(濃度範圍自30 µM至15 pM)或對照培養20分鐘或120分鐘(長培養)。該反應係藉由以40µM之濃度,添加螢光肽受質Suc-LLVY-AMC (Bachem I-1395)啟始。在37℃下培養60分鐘後,螢光強度係在λex
= 350 nm及λem
= 450 nm下使用螢光讀數器(Perkin Elmer Envision讀數器或等同物)進行量測。
表3顯示根據本發明之化合物之Beta5活性及其等對LMP7相對於Beta5之選擇性。除非另有說明,否則結果係在培養20分鐘後獲得。
表3:
*:5 μM < IC50
≤ 3.0*10-5
M,**:0.5 μM < IC50
≤ 5 μM,***:0.05 μM < IC50
≤ 0.5 μM,****:IC50
≤ 0.05 μM,+:選擇性< 100,++:100 ≤選擇性< 300,+++:300 ≤選擇性< 500,++++:選擇性≥ 500;根據上文描述之方法,「長培養」意謂將樣品培養120 min。
下列實例係關於藥物:
實例A:注射小瓶
使用2 N鹽酸將100 g式(I)活性成分及5 g磷酸氫二鈉於3 l重蒸餾水中之溶液調整至pH 6.5,經無菌過濾,轉移至注射小瓶中,在無菌條件下凍乾並在無菌條件下密封。各注射小瓶含有5 mg活性成分。
實例B:栓劑
將20 g式(I)活性成分與100 g大豆卵磷脂及1400 g可可脂之混合物融化,倒入模具中並容許冷卻。各栓劑含有20 mg活性成分。
實例C:溶液
溶液係製備自於940 mL重蒸餾水中之1 g式I活性成分、9.38 g NaH2
PO4
2 H2
O、28.48 g Na2
HPO4
∙ 12 H2
O及0.1 g苯紮氯銨。將pH調整至6.8,將該溶液製成1 l並藉由輻射滅菌。此溶液可以滴眼液之形式使用。
實例D:軟膏
將500 mg式(I)活性成分與99.5 g凡士林在無菌條件下混合。
實例E:錠劑
以習知方式壓制1 kg式I活性成分、4 kg乳糖、1.2 kg馬鈴薯澱粉、0.2 kg滑石及0.1 kg硬脂酸鎂之混合物以使各錠劑含有10 mg活性成分之方式產生錠劑。
實例F:糖衣錠
錠劑係類似於實例E壓制並接著以習知方式用蔗糖、馬鈴薯澱粉、滑石、黃蓍膠及染料之包衣進行包覆。
實例G:膠囊
以習知方式以使各膠囊含有20 mg活性成分之方法將2 kg式(I)活性成分引入硬質明膠膠囊內。
實例H:安瓿
將1 kg式(I)活性成分於60 l重蒸餾水中之溶液無菌過濾,轉移至安瓿中,在無菌條件下凍乾並在無菌條件下密封。各安瓿含有10 mg活性成分。
Claims (19)
- 一種式(I)化合物, 其中: LY 表示(CH2 )r ,其中1至5個H原子可經Hal、R3b 、OH及/或OR3b 置換,及/或其中1或2個非相鄰之CH2 基團可經O、S、SO及/或SO2 置換; Y 表示OR3c 或Cyc1 ; X 表示X0 、X1 或X2 ; X0 表示(CH2 )l -O-A,其中(CH2 )l 中1或2個H原子可經Hal、R3a 及/或OR3a 置換; 或 (CH2 )l -OH,其中(CH2 )l 中1或2個H原子可經Hal、R3a 及/或OR3a 置換; X1 表示(CH2 )m -S-A,其中(CH2 )m 中1或2個H原子可經Hal、R3a 、OR3a 、Ar及/或Het置換; 或 (CH2 )m -SH,其中(CH2 )m 中1或2個H原子可經Hal、R3a 、OR3a 、Ar及/或Het置換; X2 表示式x2a)、x2b)、x2c)或x2d)之飽和碳環或雜環,其各自未經取代或經Hal、CN、R3a 、OR3a 、COR3a 、NHCOAlk及/或NR3a COAlk單取代、二取代或三取代,其中該飽和碳環或雜環之非直接連接至T1、T2或T3之1個CH2 基團可經C=O、O、S、SO、NCOAlk或SO置換; R1 、R2 各彼此獨立地表示H或C1 -C6 -烷基,或R1 及R2 一起形成根據式(CE)之殘基:(CE) R3a 、R3b 、R3c 各彼此獨立地表示直鏈或分支鏈C1 -C6 -烷基,其中1至5個H原子可經Hal、OH及/或OAlk置換; A 表示直鏈或分支鏈C1 -C6 -烷基或C3 -C6 -環烷基,其各自未經取代或經Hal、CN、R3a 、SR3a 、SH、OR3a 、OH、Ar、Het及/或(CH2 )q -R6 單取代、二取代、三取代或四取代; Alk 表示直鏈或分支鏈C1 -C6 -烷基; Cyc1 表示2,4-、3,4-或2,3,4-經取代之苯基,其中該等取代基係選自由以下組成之群:Hal、CN、R3a 、OR3a 、CONHR3a 、CONR3b R3a 、CONH2 、NR3a COR3b 、SO2 R3a 、SOR3a 、NHR3a 、N(R3a )2 、(CH2 )q -SR3a 、(CH2 )q -N(R3a )2 及/或(CH2 )q -R6 ; 或 式(ya)、(yb)、(yc)、(yd)、(ye)、(yf)、(yg)、(yh)、(yi)、(yj)、(yk)、(yl)、(ym)、(yn)、(yo)或(yp)之雙環殘基,其各自彼此獨立地未經取代或經Hal、CN、R3a 、OR3a 、CONHR3a 、CONR3b R3a 、CONH2 、NR3a COR3b 、SO2 R3a 、SOR3a 、NHR3a 、N(R3a )2 、(CH2 )q -SR3a 、(CH2 )q -N(R3a )2 及/或(CH2 )q -R6 單取代、二取代或三取代; 其中 Ea 表示O、S、N(Alk)或CH=CH; Eb 表示O、S、N(Alk)、CH2 、CH2- CH2 、O-CH2 、S-CH2 或N(Alk)CH2 ; Cyc2 、Cyc3 各彼此獨立地表示飽和、不飽和或芳族5或6員烴環或雜環,其各自彼此獨立地未經取代或經Hal、CN、R3a 、OR3a 、COR3a 、NHCOR3a 及/或NR3a COR3b 單取代、二取代、三取代; Ar 表示苯基,其係未經取代或經Hal、CN、R3a 、OR3a 、CONHR3a 、NR3a COR3b 、SO2 R3a 、SOR3a 、NH2 、NHR3a 、N(R3a )2 及/或(CH2 )q -R6 單取代或二取代; Het 表示具有1至4個N、O及/或S原子之飽和、不飽和或芳族5或6員雜環,其係未經取代或經Hal、CN、R3a 、OR3a 、CONHR3a 、NR3a COR3b 、SO2 R3a 、SOR3a 、NH2 、NHR3a 、N(R3a )2 及/或(CH2 )q -R6 單取代或二取代; T1 、T2 、T3 各彼此獨立地表示S、O; R6 表示OH或OR3a ; m、l 表示1、2或3; k、n、o、p 各彼此獨立地表示0、1或2; q 表示1、2、3、4、5或6; r 表示0、1、2、3或4; Hal 表示F、Cl、Br或I; 及其前藥、溶劑合物、互變異構體、寡聚物、加合物及立體異構體及上述各者之生理上可接受之鹽,包括其以所有比率之混合物。
- 如請求項1或2之化合物,其中: LY 係CH2 或(CH2 )2 ,其中1或2個H原子可經F、Cl或CH3 置換; X0 表示(CH2 )l -O-A,其中(CH2 )l 中1或2個H原子可經F、Cl、CH3 、C2 H5 、CF3 、OCH3 及/或OC2 H5 置換; 或 (CH2 )l -OH,其中(CH2 )l 中1或2個H原子可經F、Cl、CH3 、C2 H5 、CF3 、OCH3 及/或OC2 H5 置換; X1 表示(CH2 )m -S-A,其中(CH2 )m 中1或2個H原子可經F、Cl、CH3 、C2 H5 、CF3 、OCH3 、OC2 H5 、Ar及/或Het置換; 或 (CH2 )m -SH,其中(CH2 )m 中1或2個H原子可經F、Cl、CH3 、C2 H5 、CF3 、OCH3 、OC2 H5 、Ar及/或Het置換; X2 表示式x2a)、x2b)、x2c)或x2d)之飽和碳環或雜環,其各自未經取代或經F、Cl、CH3 、C2 H5 、CF3 、OCH3 、OC2 H5 、OCF3 、N(CH3 )2 、CH2 N(CH3 )2 、N(C2 H5 )2 、COCH3 、COC2 H5 、NHCOCH3 及/或NHCOC2 H5 單取代、二取代或三取代; A 表示CH3 、C2 H5 、(CH2 )2 OH、(CH2 )3 OH; Ar 表示苯基,其係未經取代或經F、Cl、CH3 、C2 H5 、CF3 、OCH3 、OC2 H5 、COCF3 、SCH3 、SC2 H5 、CH2 OCH3 、N(CH3 )2 、CH2 N(CH3 )2 或N(C2 H5 )2 單取代或二取代; Het 表示具有1至4個N、O及/或S原子之飽和、不飽和或芳族5或6員雜環,其係未經取代或經F、Cl、CH3 、C2 H5 、CF3 、OCH3 、OC2 H5 、COCF3 、SCH3 、SC2 H5 、CH2 OCH3 、 N(CH3 )2 、CH2 N(CH3 )2 及/或N(C2 H5 )2 單取代或二取代; T1 、T2 、T3 各彼此獨立地表示S或O; 及其前藥、溶劑合物、互變異構體、寡聚物、加合物及立體異構體及上述各者之生理上可接受之鹽,包括其以所有比率之混合物。
- 如請求項1或2之化合物,其中: X1 表示(CH2 )m -S-A,其中(CH2 )m 中1或2個H原子可經F、Cl、CH3 、C2 H5 、CF3 、OCH3 及/或OC2 H5 置換; 或 (CH2 )m -SH,其中(CH2 )m 中1或2個H原子可經F、Cl、CH3 、C2 H5 、CF3 、OCH3 及/或OC2 H5 置換; 及其前藥、溶劑合物、互變異構體、寡聚物、加合物及立體異構體及上述各者之生理上可接受之鹽,包括其以所有比率之混合物。
- 如請求項1之化合物,其中: Cyc1 表示2,4-、3,4-或2,3,4-經取代之苯基,其中該等取代基係選自由以下組成之群:Hal、CN、R3a 、OR3a 、CONHR3a 、CONR3b R3a 、CONH2 、NR3a COR3b 、SO2 R3a 、SOR3a 、NHR3a 、N(R3a )2 、(CH2 )q -SR3a 、(CH2 )q -N(R3a )2 及/或(CH2 )q -R6 ; 或 1-或2-萘基、2-或3-噻吩基、3-苯并呋喃基或2,3-二氫苯并呋喃-3-基,其各自彼此獨立地未經取代或經Hal、CN、R3a 、OR3a 、CONHR3a 、CONR3b R3a 、CONH2 、NR3a COR3b 、SO2 R3a 、SOR3a 、NHR3a 、N(R3a )2 、(CH2 )q -SR3a 、(CH2 )q -N(R3a )2 及/或(CH2 )q -R6 單取代、二取代或三取代; q 表示1或2; R3a 、R3b 各彼此獨立地表示直鏈或分支鏈C1 -C3 -烷基,其中1至5個H原子可經F、Cl、OH、OCH3 及/或OC2 H5 置換; 及其前藥、溶劑合物、互變異構體、寡聚物、加合物及立體異構體及上述各者之生理上可接受之鹽,包括其以所有比率之混合物。
- 如請求項6之化合物,其中: Cyc1 表示2,4-、3,4-或2,3,4-經取代之苯基或未經取代或經單取代或二取代之1-或2-萘基,其中該等取代基係各自彼此獨立地選自由以下組成之群:Hal、CN、R3a 、OR3a 、CONHR3a 、CONR3b R3a 、CONH2 、NR3a COR3b 、SO2 R3a 、SOR3a 、NHR3a 、N(R3a )2 、(CH2 )q -SR3a 、(CH2 )q -N(R3a )2 及/或(CH2 )q -R6 ; 或 Cyc1 係根據式(Fa7)或(Fb7)之殘基: 其中: Ga 表示H、F、Cl、Br、CN、R3a 、OR3a 、CONHR3a 、CONR3b R3a 、CONH2 、NR3a COR3b 、SO2 R3a 、SOR3a 、NHR3a 、N(R3a )2 、(CH2 )q -SR3a 、(CH2 )q -N(R3a )2 及/或(CH2 )q -R6 ; Gb 表示H、F、Cl、Br、CN、R3a 、OR3a 、CONHR3a 、CONR3b R3a 、CONH2 、NR3a COR3b 、SO2 R3a 、SOR3a 、NHR3a 、N(R3a )2 、(CH2 )q -SR3a 、(CH2 )q -N(R3a )2 及/或(CH2 )q -R6 ; Ka 、Kb 各彼此獨立地表示H、F、Cl、Br、CN、R3a 、OR3a 、CONHR3a 、CONR3b R3a 、CONH2 、NR3a COR3b 、SO2 R3a 、SOR3a 、NHR3a 、N(R3a )2 、(CH2 )q -SR3a 、(CH2 )q -N(R3a )2 及/或(CH2 )q -R6 ; R3a 、R3b 各彼此獨立地表示直鏈或分支鏈C1 -C3 -烷基,其中1至5個H原子可經F、Cl、OH、OCH3 及/或OCH2 CH3 置換; q 表示1或2; 及其前藥、溶劑合物、互變異構體、寡聚物、加合物及立體異構體及上述各者之生理上可接受之鹽,包括其以所有比率之混合物。
- 如請求項7之化合物,其中: Cyc1 表示2,4-、3,4-或2,3,4-經取代之苯基或未經取代或經單取代或二取代之1-或2-萘基,其中該等取代基係各彼此獨立地選自由以下組成之群:Hal、CN、R3a 、OR3a 、CONHR3a 、CONR3b R3a 、CONH2 、NR3a COR3b 、SO2 R3a 、SOR3a 、NHR3a 、N(R3a )2 、(CH2 )q -SR3a 、(CH2 )q -N(R3a )2 及/或(CH2 )q -R6 ; 或 Cyc1 係根據式(Fa7)或(S)-(Fb7)之殘基: 其中: Ga 表示H、F、Cl、Br、CN、R3a 、OR3a 、CONHR3a 、CONR3b R3a 、CONH2 、NR3a COR3b 、SO2 R3a 、SOR3a 、NHR3a 、N(R3a )2 、(CH2 )q -SR3a 、(CH2 )q -N(R3a )2 及/或(CH2 )q -R6 ; Gb 表示H、F、Cl、Br、CN、R3a 、OR3a 、CONHR3a 、CONR3b R3a 、CONH2 、NR3a COR3b 、SO2 R3a 、SOR3a 、NHR3a 、N(R3a )2 、(CH2 )q -SR3a 、(CH2 )q -N(R3a )2 及/或(CH2 )q -R6 ; Ka 、Kb 各彼此獨立地表示H、F、Cl、Br、CN、R3a 、OR3a 、CONHR3a 、CONR3b R3a 、CONH2 、NR3a COR3b 、SO2 R3a 、SOR3a 、NHR3a 、N(R3a )2 、(CH2 )q -SR3a 、(CH2 )q -N(R3a )2 及/或(CH2 )q -R6 ; R3a 、R3b 及R3c 各彼此獨立地表示直鏈或分支鏈C1 -C3 -烷基,其中1至5個H原子可經F、Cl、OH及/或OCH3 、OC2 H5 置換; q 表示1或2; 及其前藥、溶劑合物、互變異構體、寡聚物、加合物及立體異構體及上述各者之生理上可接受之鹽,包括其以所有比率之混合物。
- 如請求項7或8之化合物,其中: 若Cyc1 表示2,4-、3,4-或2,3,4-經取代之苯基或未經取代或經單取代或二取代之1-或2-萘基,則該等可選取代基係各自彼此獨立地選自由以下組成之群:F、Cl、CH3 、C2 H5 、CF3 、OCH3 、OC2 H5 、COCF3 、SCH3 、SC2 H5 、CH2 OCH3 、N(CH3 )2 、CH2 N(CH3 )2 或N(C2 H5 )2 ; Ga 表示H、F、Cl、CH3 、C2 H5 、CF3 、OCH3 、OC2 H5 、COCF3 、SCH3 、SC2 H5 、CH2 OCH3 、 N(CH3 )2 、CH2 N(CH3 )2 或N(C2 H5 )2 ; Gb 表示H、F、Cl、CH3 、C2 H5 、CF3 、OCH3 、OC2 H5 、COCF3 、SCH3 、SC2 H5 、CH2 OCH3 、N(CH3 )2 、CH2 N(CH3 )2 或N(C2 H5 )2 ; Ka 、Kb 各彼此獨立地表示H、F、Cl、CH3 、C2 H5 、CF3 、OCH3 、OC2 H5 、COCF3 、SCH3 、SC2 H5 、CH2 OCH3 、N(CH3 )2 、CH2 N(CH3 )2 或N(C2 H5 )2 ; 及其前藥、溶劑合物、互變異構體、寡聚物、加合物及立體異構體及上述各者之生理上可接受之鹽,包括其以所有比率之混合物。
- 如請求項1或2之化合物,其中: LY 表示CH2 或CH2 -CH2 ,其中1至4個H原子可經F或Cl置換及/或1或2個H原子可經OH、甲基、乙基、異丙基、CF3 、CF2 CF3 、OCH3 、OCH2 CH3 、OCH2 CH2 OH及/或OCH2 CH2 OCH3 置換; Y 表示Cyc1 ; R1 、R2 各彼此獨立地表示H或C1 -C4 -烷基,或R1 及R2 一起形成如上文描述之根據式(CE)之殘基;及 R3a 、R3b 各彼此獨立地表示直鏈或分支鏈C1 -C3 -烷基,其中1至5個H原子可經F、Cl、OH及/或OCH3 、OCH2 CH3 置換;及 Cyc1 表示2,4-、3,4-或2,3,4-經取代之苯基或未經取代或經單取代或二取代之1-或2-萘基,其中該等取代基係各自彼此獨立地選自由以下組成之群:Hal、CN、R3a 、OR3a 、CONHR3a 、CONR3b R3a 、CONH2 、NR3a COR3b 、SO2 R3a 、SOR3a 、NHR3a 、N(R3a )2 、CH2 -R6 、CH2 -SR3a 、CH2 -N(R3a )2 , 或 根據式(Fa7)或(S)-(Fb7)之殘基: Ga 表示H、F、Cl、CH3 、C2 H5 、CF3 、OCH3 、OC2 H5 、COCF3 、SCH3 、SC2 H5 、CH2 OCH3 、N(CH3 )2 、CH2 N(CH3 )2 或N(C2 H5 )2 ; Gb 表示H、F、Cl、CH3 、C2 H5 、CF3 、OCH3 、OC2 H5 、COCF3 、SCH3 、SC2 H5 、CH2 OCH3 、N(CH3 )2 、CH2 N(CH3 )2 或N(C2 H5 )2 ; Ka 、Kb 各彼此獨立地表示H、F、Cl、CH3 、C2 H5 、CF3 、OCH3 、OC2 H5 、COCF3 、SCH3 、SC2 H5 、CH2 OCH3 、N(CH3 )2 、CH2 N(CH3 )2 或N(C2 H5 )2 ; q 表示1或2; 及其前藥、溶劑合物、互變異構體、寡聚物、加合物及立體異構體及上述各者之生理上可接受之鹽,包括其以所有比率之混合物。
- 如請求項1或2之化合物,其中在與硼酸殘基相鄰之碳原子處之立體異構源中心顯示(R)-構型,及其前藥、溶劑合物、互變異構體、寡聚物、加合物及立體異構體及上述各者之生理上可接受之鹽,包括其以所有比率之混合物。
- 一種醫藥組合物,其包含作為活性成分的至少一種式(I)化合物,其中所有殘基係如請求項1至12中任一項定義,及/或其前藥、溶劑合物、互變異構體、寡聚物、加合物或立體異構體及上述各者之生理上可接受之鹽,包括其以所有比率之混合物,及醫藥上可接受之載劑。
- 如請求項14之醫藥組合物,其進一步包含第二活性成分,其中該第二活性成分係除式(I)化合物外,其中所有殘基係如請求項1至12中任一項定義。
- 如請求項1至12中任一項之式(I)化合物及/或其前藥、溶劑合物、互變異構體、寡聚物、加合物及立體異構體及上述各者之生理上可接受之鹽,包括其以所有比率之混合物,其用於預防及/或治療受抑制LMP7影響之醫學病症。
- 如請求項16之化合物,其用於治療及/或預防免疫調節異常或癌症,諸如特定言之血液惡性腫瘤或實體瘤。
- 如請求項17之化合物,其中該免疫調節異常係選自由以下組成之群之自體免疫性或慢性炎症性疾病:全身性紅斑性狼瘡、慢性類風濕性關節炎、炎症性腸病、多發性硬化症、肌萎縮側索硬化症(ALS)、動脈粥樣硬化、硬皮症、自體免疫性肝炎、休格倫氏症候群(Sjogren Syndrome)、狼瘡性腎炎、腎小球性腎炎、類風濕性關節炎、牛皮癬、重症肌無力、免疫球蛋白A腎病、血管炎、移植排斥、肌炎、過敏性紫癜(Henoch-Schönlein purpura)及哮喘;及其中該血液惡性腫瘤係選自由以下組成之群之疾病:多發性骨髓瘤、套細胞淋巴瘤、瀰漫性大B細胞淋巴瘤、漿細胞瘤、濾泡性淋巴瘤、免疫細胞瘤、急性淋巴細胞白血病、慢性淋巴細胞白血病及骨髓性白血病;及其中該實體瘤係選自由以下組成之群:炎症性乳癌及結腸癌、肺癌、頭頸癌、前列腺癌、胰臟癌、膀胱癌、腎癌、肝細胞癌及胃癌。
- 一種裝置(套組),其由以下之獨立包裝組成: (a) 有效量之式(I)化合物及/或其醫藥上可接受之鹽、互變異構體及立體異構體,包括其以所有比率之混合物; 及 (b) 有效量之另一活性成分。
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TW202237143A (zh) * | 2020-12-10 | 2022-10-01 | 南韓商Lg化學股份有限公司 | 酸(Boronic Acid)化合物 |
WO2023061445A1 (zh) * | 2021-10-14 | 2023-04-20 | 首药控股(北京)股份有限公司 | 硼酸衍生物 |
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CN110540547A (zh) * | 2018-05-28 | 2019-12-06 | 秦艳茹 | 一种肽硼酸酯类化合物的合成与用途 |
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CN112469480A (zh) | 2021-03-09 |
AU2019310779A1 (en) | 2021-03-18 |
KR20210038590A (ko) | 2021-04-07 |
EP3826723A1 (en) | 2021-06-02 |
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WO2020020858A1 (en) | 2020-01-30 |
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