TWI385162B - 苯甲醯胺化合物 - Google Patents
苯甲醯胺化合物 Download PDFInfo
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- TWI385162B TWI385162B TW095138558A TW95138558A TWI385162B TW I385162 B TWI385162 B TW I385162B TW 095138558 A TW095138558 A TW 095138558A TW 95138558 A TW95138558 A TW 95138558A TW I385162 B TWI385162 B TW I385162B
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- Prior art keywords
- compound
- formula
- pharmaceutically acceptable
- acceptable salt
- methyl
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- 125000003831 tetrazolyl group Chemical group 0.000 description 1
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- 239000002562 thickening agent Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
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- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
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- 239000011135 tin Substances 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- 238000010361 transduction Methods 0.000 description 1
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- 229960000575 trastuzumab Drugs 0.000 description 1
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- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
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- 229960003048 vinblastine Drugs 0.000 description 1
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
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- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
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Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
Description
本發明係關於部分新穎之苯甲醯胺化合物,或其醫藥可接受之鹽,其係組蛋白脫乙醯基酶(HDAC)之強抑制劑。本發明亦係關於製備此等新穎苯甲醯胺化合物之方法,其醫藥組合物,以及其在治療方法中之用途,例如,製造藥物以在溫血動物(諸如,人類)體內抑制HDAC。
HDAC活性已被證實與諸多疾病狀態相關,諸如,癌症(Markset al.,Nature Reviews,
1,194-202,(2001))、囊性纖維變性(Li,S.et al
.,J.Biol.Chem
.,274,7803-7815,(1999))、杭丁頓氏舞蹈症(Steffan,J.S.et al
.,Nature
,413,739-743,(2001))及鐮狀細胞貧血症(Gabbianelli,M.et al
.,Blood
,95,3555-3561,(2000))。因此,本發明亦可延伸至使用本發明之苯甲醯胺化合物而治療前述任一疾病之方法,以及此等苯甲醯胺化合物於製造藥物以治療此等疾病狀態之用途。
在真核細胞中,DNA慣常係呈密集狀態,以預防轉錄因子之進入。在該細胞經活化時,此種密集之DNA會變成可由DNA-結合蛋白結合之狀態,因而容許誘發基因轉錄(Beato,M.,J.Med.Chem
.,74,711-724(1996);Wolffe,A.P.,Nature
,387,16-17(1997))。核DNA係與稱為組蛋白之核蛋白相連以形成稱為染色質之複合物。該等核組蛋白,其稱為H2A、H2B、H3及H4,係由146個DNA之鹼基對包圍,以形成染色質之基本單位,且其係稱為核小體。該等核組蛋白之N-端尾部含有離胺酸殘基,其係進行後轉錄性乙醯化作用之位點。該離胺酸側鏈末端胺基之乙醯化作用可中和該側鏈形成正電荷之潛在能力,且被認為可影響染色質之結構。
組蛋白脫乙醯基酶(HDAC)係含鋅之酶,其可催化乙醯基自群集於核小體胺端附近之離胺酸殘基之ε-胺基端之移除。HDACs可劃分為兩類,第一類(HDAC 1、2、3及8)係由酵母菌似Rpd3蛋白代表,而第二類(HDAC 4、5、6、7、9及10)則係由酵母菌似Hda1蛋白代表。該可逆之乙醯化作用已知對於轉錄作用之調控以及細胞循環之進展相當重要。此外,HDAC之失調與多種癌症相關,且HDAC抑制劑,諸如,曲古菌素A(Trichostatin A)(一種自吸水鏈黴菌(Streptomyces hygroscopicus
)分離之天然產物),已被證實具有顯著之細胞生長抑制作用及抗腫瘤作用(Meinke,P.T.,Current Medicinal Chemistry
,8,211-235(2001))。Yoshidaet al
.,(Exper.Cell Res
.,177,122-131(1988))教示,曲古菌素A可造成大鼠纖維母細胞在細胞循環G1及G2相之停滯,因而暗示HDAC於細胞循環調控中之角色。同時,曲古菌素A已被證實可在小鼠體內誘發末端分化、抑制細胞生長及預防腫瘤形成(Finninet al
.,Nature
,401,188-193(1999))。
自經公開之國際專利申請案編號WO 03/087057及WO 03/092686中已知,部分苯甲醯胺衍生物係HDAC之抑制劑。其中一種揭示於WO 03/087057中之特定化合物係N-(2-胺基苯基)-4-[1-(吡啶-2-基甲基)六氫吡啶-4-基]苯甲醯胺[1](其結構示於下)。
現已發現,某些帶有可選擇性地經取代之吡唑基(而非帶有該吡啶基)之苯甲醯胺係HDAC之強抑制劑。此外,亦已發現本發明之特定化合物具有其他有利之醫藥特性,包括較佳之細胞或體內強度、較佳之DMPK特性(例如,有利之生物可獲性內容及/或有利之血漿游離含量及/或有利之半生期及/或有利之分布體積)、以及良好或增進之可溶性。此外,本發明之苯甲醯胺衍生物一般而言可在hERG-編碼性鉀離子通道抑制分析中顯示特別低之活性,該分析係臨床上所不欲產生及嚴重之心血管副作用之指標。
根據本發明,提供式(I)之化合物:
其中R1
係C-連結之吡唑環,其可選擇性地經一或多個基團取代,該基團係選自C1 - 4
烷基、C3 - 4
環烷基、C1 - 4
烷氧基及C3 - 4
環烷氧基;或其醫藥可接受之鹽。
須明瞭,部分上文所定義之式(I)化合物可具有互變異構之現象。須明瞭,本發明在其定義中包括具有上述活性之此等互變異構形式,或其混合物,且其不僅限於任何一種用於化學式圖示中或在實例中指明之互變異構形式。
當選擇性之取代基係選自「一或多個」取代基時,須明瞭,此種定義包括所有之取代基皆係選自其中一種經指明基團或是該等取代基係選自兩種或以上之經指明基團者。
R1
之適當選擇性取代基可存在於該吡唑環中任何可用之碳或氮原子上。
R1
適當帶有自1至3個取代基。或者,R1
係未經取代者。
在本文中,辭彙「烷基」係指直鏈或支鏈。辭彙「環烷基」包括環結構,但可額外包括環烷基-烷基形式之鏈。類似者,辭彙「烷氧基」及「環烷氧基」包含經由氧原子連結之烷基、環烷基或環烷基-烷基。
R1
之適當C1 - 4
烷基或C3 - 4
環烷基取代基包括甲基、乙基、丙基、環丙基、環丁基或環丙基甲基。
R1
之適當C1 - 4
烷氧基或C3 - 4
環烷氧基取代基包括甲氧基、乙氧基、丙氧基、環丙氧基、環丁氧基或甲基環丙氧基。
在本發明之一特定具體實例中,R1
係C-連結之吡唑環,其可選擇性地經1、2或3個基團取代,該基團係選自C1 - 4
烷基或C1 - 4
烷氧基。
在本發明之另一具體實例中,R1
係碳連結性吡唑環,其可選擇性經1、2或3個基團取代,該基團係選自C1 - 2
烷基或C1 - 2
烷氧基。
R1
基團之實例包括吡唑-3-基、吡唑-4-基、1-甲基吡唑-4-基、3-乙基吡唑-4-基、1,3-二甲基吡唑-5-基、1,3-二甲基吡唑-4-基、1,3,5-三甲基吡唑-4-基、1,3-二甲基-5-甲氧基吡唑-4-基、1,5-二甲基吡唑-4-基、1-乙基-5-甲基吡唑-4-基、1-乙基吡唑-4-基及1-乙基-3-甲基吡唑-4-基(在可能處可具有互變異構情形)。
在本發明之另一具體實例中,式(I)之化合物包含式(IA)之化合物
其中R2
係氫、C1 - 4
烷基或C3 - 4
環烷基,且R3
及R5
係獨立選自氫、C1 - 4
烷基、C3 - 4
環烷基、C1 - 4
烷氧基及C3 - 4
環烷氧基。
咸可明瞭,式(IA)分子吡唑部分之環原子一般而言係如上式中所示進行編號。然而,如其中R2
係氫,該分子會具有互變異構情形,其中該等氫基團會自該吡唑環之一個氮原子轉換置另一個上,因此意謂該等經取代之吡唑,其中R3
或R5
中之至少一者不為氫,不可避免地會係各互變異構物之混合物,且因此R3
及R5
將被視為係可互換者。
在另一具體實例中,本發明提供式(IB)之化合物
其中R2
、R3
及R5
係如上文有關式(IA)者定義。
同樣,咸可明瞭,式(IB)分子吡唑部分之環原子一般而言係如上式中所示進行編號。然而,如同上文所討論之式(IA)化合物,在R2
係氫時,該分子會具有互變異構之情形。
R2
之特定實例包括氫、甲基、乙基、丙基、環丙基、甲基環丙基或環丁基。
舉例而言,R2
係氫、甲基、乙基、丙基或環丙基。
在一特定具體實例中,R2
係氫、甲基或乙基。
在另一具體實例中,R2
係氫或甲基。
基團R3
及R5
之特定實例包括氫、甲基、乙基、丙基、環丙基、環丙基甲基、甲氧基、乙氧基、丙氧基或環丙氧基。
基團R3
或R5
之特定實例包括氫、甲基、乙基或甲氧基。
適當者,基團R3
或R5
中並無一個以上者係C1 - 4
烷氧基。
在一特定具體實例中,基團R2
、R3
及R5
中之至少一者,且較佳為至少兩者,係不為氫。
在本發明之一特定具體實例中,該等化合物具有上示之結構式(IA),其中R2
係氫或C1 - 4
烷基,且R3
及R5
係各獨立選自氫、C1 - 4
烷基或C1 - 4
烷氧基。
在另一具體實例中,該等化合物具有上示之結構式(IA),其中R2
係氫、甲基或乙基,且R3
及R5
係各獨立選自氫、甲基、乙基或甲氧基。
在另一具體實例中,該等化合物具有上示之結構式(IA),其中R2
係氫或甲基,且R3
及R5
係各獨立選自氫、甲基、乙基或甲氧基。
在另一具體實例中,該等化合物具有上示之結構式(IA),其中R2
係氫或甲基,且R3
及R5
係各獨立選自氫、甲基或甲氧基。
在另一具體實例中,該等化合物具有上示之結構式(IA),其中R2
係氫或甲基,且R3
及R5
係各獨立選自氫或甲基。
在本發明之一特定具體實例中,該等化合物具有上示之結構式(IB),其中R2
係氫或C1 - 4
烷基,且R3
及R5
係各獨立選自氫、C1 - 4
烷基或C1 - 4
烷氧基。
在另一具體實例中,該等化合物具有上示之結構式(IB),其中R2
係氫、甲基或乙基,且R3
及R5
係各獨立選自氫、甲基、乙基或甲氧基。
在另一具體實例中,該等化合物具有上示之結構式(IB),其中R2
係氫或甲基,且R3
及R5
係各獨立選自氫、甲基、乙基或甲氧基。
在另一具體實例中,該等化合物具有上示之結構式(IB),其中R2
係氫或甲基,且R3
及R5
係各獨立選自氫、甲基或甲氧基。
本發明之特定化合物包括下列之任一者:N
-(2-胺基苯基)-4-[1-(1H
-吡唑-3-基甲基)六氫吡啶-4-基]苯甲醯胺;N
-(2-胺基苯基)-4-{1-[(5-甲氧基-1,3-二甲基-1H
-吡唑-4-基甲基]六氫吡啶-4-基}苯甲醯胺;N
-(2-胺基苯基)-4-{1-[(3-乙基-1H
-吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺;N
-(2-胺基苯基)-4-{1-[(1-甲基-1H
-吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺;N
-(2-胺基苯基)-4-{1-[(1,3-二甲基-1H
-吡唑-5-基)甲基]六氫吡啶-4-基}苯甲醯胺;N
-(2-胺基苯基)-4-{1-[(1,3-二甲基-1H
-吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺;N
-(2-胺基苯基)-4-{1-[(1,3,5-三甲基-1H
-吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺;N
-(2-胺基苯基)-4-{1-[(1,5-二甲基-1H
-吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺;N
-(2-胺基苯基)-4-{1-[(1-乙基-5-甲基-1H-吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺;N
-(2-胺基苯基)-4-{1-[(1-乙基-1H
-吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺;N
-(2-胺基苯基)-4-{1-[(1-乙基-3-甲基-1H
-吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺;或其醫藥可接受之鹽。
須明瞭,部分上述之式I化合物可具有非溶劑化物之形式以及溶劑化物之形式,諸如,舉例而言,水合物形式。須明瞭,本發明涵括具有抗增殖活性之所有此等溶劑化物形式。
亦須明瞭,部分式I之化合物可具有多態性,且本發明涵括具有抗增殖活性之所有此等形式。
式I化合物之適當醫藥可接受性鹽係,舉例而言,式I化合物之酸加成鹽,例如,與無機或有機酸之酸加成鹽,諸如,鹽酸、氫溴酸、硫酸、三氟乙酸、檸檬酸或馬來酸;或是,舉例而言,具有足夠酸性之式I化合物鹽,例如,鹼金屬或鹼土金屬鹽,諸如,鈣或鎂鹽或是鋁鹽。其他式I化合物之適當醫藥可接受性鹽係,舉例而言,在投藥式I化合物後而在人體或動物體內形成之鹽。
本發明之化合物可以前藥形式投藥-此係一種化合物,其可在人體或動物體內分解以釋出本發明之化合物。前藥可用於改變本發化合物之物理特性及/或藥物動力學特性。前藥可在本發明之化合物含有其上可連附特性修飾基團之適當基團或取代基時形成。前藥之實例包括體內可切割性之醯胺衍生物,其可在式I化合物中之胺基處形成。
因此,本發明包括諸等如前文所定義之式I化合物,當其係藉由有機合成而成為可取得者,或是在人類或動物體內藉由其前藥之切割而成為可取得者。因此,本發明包括諸等由有機合成方法製備之式I化合物,亦包括在人類或動物體內藉由前體化合物之代謝而製備者,亦即,式I之化合物可係合成製備之化合物,或係代謝製備之化合物。
式I化合物之適當醫藥可接受性前藥係根據合理之醫學判斷而為適於對人體或動物體進行投藥而並無不欲產生之藥學活性且無過度之毒性者。
各種形式之前藥已述於,例如,下列之文件:a)Methods in Enzymology
[酶學方法],Vol.42,
p.309-396,K.Widder,et al
.編輯(Academic Press,1985);b)Design of Pro-drugs[前藥設計],H.Bundgaard編輯,(Elsevier,1985);c)A Textbook of Drug Design and Development[藥物設計及研發教科書],Krogsgaard-Larsen及H.Bundgaard編輯,Chapter 5"Design and Application of Pro-drugs[前藥之設計及應用]",by H.Bundgaard p.113-191(1991);d)H.Bundgaard,Advanced Drug Delivery Reviews,8,
1-38(1992);e)H.Bundgaard,et al
.,Journal of Pharmaceutical Sciences,77
,285(1988);f)N.Kakeya,et al
.,Chem.Pharm.Bull.,32,
692(1984);g)T.Higuchi and V.Stella,"Pro-Drugs as Novel Delivery Systems[以前藥作為新穎之傳遞系統]",A.C.S.Symposium Series,Volume 14;及h)E.Roche(編輯),"Bioreversible Carriers in Drug Design[藥物設計中之生物可逆性載體]",Pergamon Press,1987。
式I化合物之適當醫藥可接受性前藥係,例如,其體內可切割性之醯胺衍生物。可自胺基形成之適當醫藥可接受性醯胺包括,例如,與(1-10C)鏈烷醯基形成之醯胺,諸如,乙醯基、苯甲醯基、苯乙醯基及經取代之苯甲醯基及苯乙醯基。苯乙醯基及苯甲醯基上之環取代基實例包括胺甲基、N-烷基胺甲基、N,N-二烷基胺甲基、嗎啉基甲基、六氫吡-1-基甲基及4-(1-4C)烷基六氫吡-1-基甲基。
式I化合物之體內作用部分可由一或多種代謝物產生,其係在投藥式I化合物後於人類或動物體內形成者。如前文所述,式I化合物之體內作用亦可藉由前體化合物(前藥)之代謝而產生。
熟習技藝者將可明瞭,咸可需要/希望在部分本文所提及之方法/反應中保護該等化合物中之任何敏感性基團。就其中需要或希望進行保護之情形而言,用以提供此種保護作用之適當方法係熟習技藝者所已知者。可根據標準之實施而使用習知之保護基(就其說明,參見,T.W.Green & P.G.M.Wuts,Protective Groups in Organic Synthesis[有機合成中之保護基],3r d
版,John Wiley and Sons,1999)。因此,如反應物中包括諸如胺基、羧基或羥基之基團,其可能會希望在部分本文所述之反應中保護該基團。
可用於本文所述方法中之任何保護基一般而言係選自任何在文獻中敘述或為熟習技藝之化學家已知為適用於保護該所論基團者,且其可由習知之方法引入。保護基可由任何習知之方法移除,諸如,在文獻中敘述或為熟習技藝之化學家已知為適用於除去該所論保護基者,此等方法經選擇以有效除去保護基並對該分子中其他部分之基團產生最小之干擾。
保護基之特定實例於下為便利而提供,其中「低碳」,諸如在,例如,低碳烷基中者,指明該所應用之基團較佳具有1-4個碳原子。咸將可明瞭,此等實例並不具排外性。並未具體提及之保護基以及去保護方法之使用當然亦係在本發明之範圍之中。
胺基或烷胺基之適當保護基係,舉例而言,醯基(例如,鏈烷醯基,諸如,乙醯基)、烷氧羰基(例如,甲氧羰基、乙氧羰基或第三丁氧羰基)、芳基甲氧羰基(例如,苄氧羰基)或芳醯基(例如,苯甲醯基)。上述保護基之去保護條件必然會隨保護基之選擇而各異。因此,舉例而言,醯基(諸如,鏈烷醯基)或烷氧羰基或芳醯基可,例如,藉著以適當之鹼進行水解而移除,諸如,鹼金屬氫氧化物,例如,氫氧化鋰或鈉。或者,醯基(諸如,第三丁氧羰基)可,例如,藉著以適當之酸進行處理而移除,諸如,鹽酸、硫或磷酸或三氟乙酸,且芳基甲氧羰基(諸如,苄氧羰基)可,例如,藉著以催化劑進行氫化作用(諸如,鈀被碳)或是藉著以路易斯酸進行處理(例如,硼三(三氟乙酸化物))而移除。一級胺基之其他適當保護基係,例如,苯二甲醯基,其可藉由烷基胺(例如,二甲胺基丙胺)或肼之處理而移除。
羥基之適當保護基係,舉例而言,醯基(例如,鏈烷醯基,諸如,乙醯基)、芳醯基(例如,苯甲醯基)或芳甲基(例如,苄基)。上述保護基之去保護條件必然會隨保護基之選擇而各異。因此,舉例而言,醯基(諸如,鏈烷醯基)或烷氧羰基或芳醯基可,例如,藉著以適當之鹼進行水解而移除,諸如,鹼金屬氫氧化物,例如,氫氧化鋰或鈉。或者,芳甲基(諸如,苄基)可,例如,藉著以催化劑進行氫化作用(諸如,鈀被碳)而移除。
羧基之適當保護基係,舉例而言,酯化性基團,例如甲基或乙基(其可,例如,藉著以鹼進行水解而移除,諸如,氫氧化鈉),或是例如第三丁基(其可,例如,藉著以酸進行處理而移除,例如,有機酸,諸如,三氟乙酸),或是例如苄基(其可,例如,藉著以催化劑進行氫化作用而移除,諸如,鈀被碳)。
該等保護基可在任何便利之合成階段,使用化學技藝中所熟知之習知技術而移除。
在另一部份,本發明提供製備式(I)化合物或其醫藥可接受性鹽之方法,該方法包含:(a)使式(II)化合物
其中該苯胺分子部分可經適當保護;與式(III)化合物R1
CHO(III)
其中R1
係如本文所定義,在還原劑之存在下反應,並在其後,如需要,除去可能存在之任何殘餘保護基。
方法(a)之適當還原劑包括,例如,無機之硼氫化物鹽(諸如,硼氫化鈉、三乙醯氧基硼氫化鈉或氰基硼氫化鈉)以及氫氣。使用氫氣所進行之還原性胺化反應選擇性可在適當催化劑之存在下(諸如,舉例而言,Pd/C、Pd(OH)2
/C、Pt/C、PtO2
或Rh被氧化鋁),且其亦可在壓力下,(例如,1-10巴),於,例如,0-150℃之溫度範圍進行。
方法(a)可在適當酸之存在下進行。方法(a)之適當酸包括,布朗斯台德酸(Bronsted acid),諸如,舉例而言,甲酸、醋酸、三氟乙酸、鹽酸、硫酸、對甲苯磺酸或樟腦磺酸;或是式MQz
之路易斯酸(Lewis acids),其中M係金屬,Q係反應基,諸如,舉例而言,鹵代基或磺醯氧基,例如,氯、溴、碘、甲磺醯氧基、三氟甲磺醯氧基或甲苯-4-磺醯氧基,且z係在1-6之範圍中,而z值將取決於金屬M。適當路易斯酸之典型實例包括三氟化硼、三氟甲磺酸鈧(III)、氯化錫(VI)、異丙醇化鈦(IV)或氯化鋅(II)。
或者,式(I)化合物可由下述者製備:(b)使式(II)化合物
其中該苯胺分子部分可經適當保護;與式(IV)化合物R1
CH2
X(IV)在適當之鹼存在下反應;其中X係一反應基;並在其後,如需要,除去可能存在之任何殘餘保護基。
適當之反應基X係,舉例而言,鹵代基或磺醯氧基,例如,氯、溴、碘、甲磺醯氧基、三氟甲磺醯氧基或甲苯-4-磺醯氧基。
可用於上述方法(b)之適當鹼係,例如,有機胺鹼(諸如,舉例而言,吡啶、2,6-二甲基吡啶、柯林鹼(collidine)、4-二甲胺基吡啶、三乙胺、嗎啉、二異丙基乙胺(DIPEA)、N
-甲基嗎啉或二吖雙環[5.4.0]十一碳-7-烯),或是例如,鹼金屬或鹼土金屬碳酸鹽或氫氧化物(例如,碳酸鈉、碳酸鉀、碳酸鈣、氫氧化鈉或氫氧化鉀),或是例如,鹼金屬氫化物(例如,氫化鈉)、鹼土金屬碳酸氫鹽(諸如,碳酸氫鈉)或金屬醇化物(諸如,乙醇化鈉)。
苯胺分子部分或是六氫吡啶環之適當保護基可為胺基甲酸酯,諸如,第三丁氧羰基或苄氧羰基。
基團R1
之特定實例係如上所述。
方法(a)及(b)中所定義之反應可在適當鈍性溶劑或稀釋劑之存在下便利進行,例如,鏈烷醇或酯(諸如,甲醇、乙醇、異丙醇或乙酸乙酯)、鹵化溶劑(諸如,二氯甲烷、氯仿或四氯化碳)、醚(諸如,四氫呋喃、1,2-二甲氧基乙烷或1,4-二烷)、芳族溶劑(諸如,甲苯)或偶極性質子惰性溶劑(諸如,N
,N
-二甲基甲醯胺、N
,N
-二甲基乙醯胺、N
-甲基吡咯啶-2-酮或二甲亞碸)。
上述之式II化合物可由下列方法之一製備:(c)使式(V)化合物,其中該苯胺可經適當保護,
其中X係一反應基,如前文所定義,在一適當鹼之存在下與式(VI)化合物反應
其中M係金屬,L係配位體,整數z係0至3,且該四氫吡啶環可經保護;或是使式(VII)化合物,其中該苯胺及該四氫吡啶環可經適當保護,且M、L及z係如上所定義,
與式(VIII)化合物反應:
在一適當鹼之存在下進行;其中X係一反應基,如前文所定義,並在其後,如需要,且可以任何適當之順序或組合進行:自該四氫吡啶環除去任何保護基,及/或將該四氫吡啶環還原成為六氫吡啶,及/或除去存在之任何殘餘保護基。
該四氫吡啶環之適當保護基係諸如丁氧羰基(亦在本文中稱為「BOC」或苄氧羰基之基團。該苯胺分子部分之適當保護基亦可為一胺基甲酸酯,諸如,BOC或苄氧羰基。
可用於方法(c)之適當鹼係,例如,有機胺鹼(諸如,舉例而言,吡啶、2,6-二甲基吡啶、柯林鹼、4-二甲胺基吡啶、三乙胺、嗎啉、N
-甲基嗎啉或二吖雙環[5.4.0]十一碳-7-烯),或是例如,鹼金屬或鹼土金屬碳酸鹽或氫氧化物(例如,碳酸鈉、碳酸鉀、碳酸鈣、碳酸銫、氫氧化鈉或氫氧化鉀),或是例如,鹼金屬氫化物(例如,氫化鈉)、鹼土金屬碳酸氫鹽(諸如,碳酸氫鈉)或金屬醇化物(諸如,乙醇化鈉)。
上述方法(c)中所定義之反應可在適當鈍性溶劑或稀釋劑之存在下便利進行,例如,鏈烷醇或酯(諸如,甲醇、乙醇、異丙醇或乙酸乙酯)、鹵化溶劑(諸如,二氯甲烷、氯仿或四氯化碳)、醚(諸如,四氫呋喃、1,2-二甲氧基乙烷或1,4-二烷)、芳族溶劑(諸如,甲苯)或偶極性質子惰性溶劑(諸如,N
,N
-二甲基甲醯胺、N
,N
-二甲基乙醯胺、N
-甲基吡咯啶-2-酮或二甲亞碸)。該反應可在,例如,10至250℃範圍之溫度下便利進行,較佳係在40至80℃之範圍。
金屬M可為任何在文獻中已知可形成有機金屬化合物而可進行催化性交叉偶合反應之金屬。適當金屬之實例包括硼、錫、鋅及鎂。
整數z之適當值取決於金屬M,但其通常係在0-3之範圍。
配位體L之適當值,在存在時,包括,例如,羥基、鹵代、(1-4C)烷氧基或(1-6C)烷基配位體,例如,羥基、溴、氯、氟、碘、甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、甲基、乙基、丙基、異丙基或丁基配位體,或者,當整數z係2且金屬M係硼時,該兩個存在之配位體可連結並與其所連附之硼原子共同形成環。適當者,基團MLz
係式-BL1
L2
之基團,其中B係硼,且L1
及L2
係如上述配位體L所定義。特定言之,配位體L1
及L2
可連結並與其所連附之硼原子共同形成環。舉例而言,L1
及L2
可共同定義一氧基-(2-4C)醯基-氧基,例如,氧基乙烯氧基、頗那醇基(pinacolato)(-O-C(CH3
)2
C(CH3
)2
-O-)或氧基丙烯氧基,其與其所連附之硼原子共同形成一環狀硼酸酯基團。
可用於方法(c)之適當催化劑包括,舉例而言,金屬催化劑,諸如,鈀(0)、鈀(II)、鎳(0)或鎳(II)催化劑,例如,四(三苯膦)鈀(0)、氯化鈀(II)、溴化鈀(II)、雙(三苯膦)氯化鈀(II)、四(三苯膦)鎳(0)、氯化鎳(II)、溴化鎳(II)、雙(三苯膦)氯化鎳(II)或二氯[1-1’-雙(二苯膦基)二茂鐵]鈀(II)。此外,可便利加入一自由基起始物,例如,疊氮化合物,諸如,疊氮(雙異丁腈)。
適當者,上述方法(c)中之四氫吡啶環係藉由氫化反應而還原成為六氫吡啶環。氫化反應一般而言係在適當催化劑之存在下進行(諸如,舉例而言,Pd/C、Pd(OH)2
/C、Pt/C、PtO2
或Rh被氧化鋁),且其亦可在壓力下進行(例如,1-10巴)。氫化作用亦可適當在一適當酸之存在下(例如,氫溴酸、鹽酸、檸檬酸、醋酸及甲磺酸),並於適當之溶劑或溶劑混合物中(諸如,例如,水、乙醇、四氫呋喃(THF)、甲醇、乙腈或丙-2-醇)進行。
(d)使式(IX)化合物,其中Q1
係-OH、-Cl或-O-
Q2 +
(其中Q2 +
係一陽離子)
在適當溶劑之存在下與式(X)化合物反應,且其中式(X)化合物中諸等胺基中之一者可經保護;
以形成式(XI)化合物
其中該苯胺可經保護;並在其後:藉由使用適當之還原劑及/或適當之還原條件,使該吡啶-4-基環還原成為六氫吡啶-4-基環,因而將該式(XI)化合物轉化成為式(II)化合物;並選擇性地除去存在之任何殘餘保護基。
Q1
之適當值係-O-
Na+
(亦即,-O-
Q2 +
,其中Q2 +
係Na+
)。
適當者,式(X)化合物中諸等胺基中之一者可經如前文所定義之適當胺基保護基保護,諸如,BOC基團。
適當者,在式(XI)化合物中,該苯胺可經如前文所定義之胺基保護基保護,諸如,BOC基團。
任何適當之溶劑,諸如本文先前所提及者,皆可用於進行化合物IX及X之反應。
式(XI)化合物係使用適當之還原劑及/或適當之還原條件而轉化成為式(II)化合物。其中一種適當之反應係氫化作用。氫化作用選擇性可在適當催化劑之存在下進行(諸如,舉例而言,Pd/C、Pd(OH)2
/C、Pt/C、PtO2
或Rh被氧化鋁),且其亦可在壓力下進行(例如,1-10巴)。氫化作用亦可適當在一適當酸之存在下(例如,氫溴酸、鹽酸、檸檬酸、醋酸及甲磺酸),並於適當之溶劑或溶劑混合物中(諸如,例如,水、乙醇、四氫呋喃(THF)、甲醇、乙腈或丙-2-醇)進行。
其中一種用以製備式(XI)化合物之適當方法包含將式(IX)化合物轉化成為反應性羧酸衍生物(其可在原位產生,且並不一定需要分離),再與式(X)化合物進行一後續之反應。
適當之反應性羧酸衍生物係,舉例而言,醯基鹵化物,例如,由該酸與無機酸氯化物反應形成之醯基氯化物,例如,亞硫醯氯;混合性之酐,例如,由該酸與氯仿反應形成之酐,例如,異丁基氯甲酸酯;活性酯;該酸與碳化二醯亞胺之反應產物,諸如,二環己基碳化二醯亞胺;或是酸與4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基嗎啉鎓氯化物(DMTMM)之反應產物,或是酸與1,1’-羰基二咪唑(CDI)之反應產物。
式(III)及(IV)之化合物可自商業來源取得,例如,Flurochem Ltd,Old Glossop,Derbyshire SK13 7RY,UK,或者,其可使用熟習技藝者已知及/或報告於文獻中(例如,Makino,K.;Kim,H.S and Kurasawa Y;J.Heterocyclic Chem.1998,35,489-497及其中之參考文獻)之方法合成。
下列之分析(a)至(c)可用於測量一或多種本發明化合物作為HDAC抑制劑、作為Hi5昆蟲細胞中所製備人類HDAC1之體外抑制劑、以及在全細胞及腫瘤中作為組蛋白H3之體外及體內誘發劑之作用。其亦可評估此等化合物抑制人類腫瘤細胞增殖之能力。
(a)重組HDAC1之體外酶分析
針對Hi5昆蟲細胞中所製備之重組人類HDAC1篩選HDAC抑制劑。將該酶與FLAG標記共同選殖至該基因之C-端,再使用取自SIGMA之抗-FLAG M2瓊脂糖(A2220)進行親和純化。
該脫乙醯基酶分析係在50微升之反應中進行。將以15微升反應緩衝液(25 mM TrisHCl(pH 8)、137 mM NaCl、2.7 mM KCl、1 mM MgCl2
)稀釋之HDAC1(75奈克之酶),與單獨之緩衝液(10微升)或含化合物之緩衝液(10微升),在室溫下混合30分鐘。接著在該反應中加入以25微升緩衝液稀釋之25 μM乙醯化組蛋白H4肽(KI 174 Biomol),並在室溫下進行恆溫共置1小時。加入等體積(50微升)含2 μM曲古菌素A之Fluor de Lys顯色劑(Biomol)而中止反應。使該反應在室溫下進行30顯色分鐘,接著在360 nM之激發波長及465 nM之發射波長下測量螢光。藉著對個別化合物進行劑量反應曲線,並測定可造成最大信號(稀釋劑控制組)50%減少之抑制劑濃度而測定HDAC酶抑制劑之IC5 0
值。
(b)全細胞增殖抑制之體外分析
使用Promega細胞效價96孔水性增殖分析(Promega #G5421)而分析全細胞中之增殖抑制。將HCT116細胞以1x103
個細胞/孔之濃度接種於96孔試驗盤中,再使其隔夜進行黏附。以抑制劑對其進行處理72小時。在各孔中加入20微升之四唑鎓染劑MTS,再使該等試驗盤再次進行恆溫共置3小時。接著在96孔盤視讀器上,測量490 nM之吸收值。藉著對個別化合物進行劑量反應曲線,並測定可造成最大信號(稀釋劑控制組)50%減少之抑制劑濃度而測定HDAC抑制劑之IC5 0
值。
(c)全細胞中組蛋白脫乙醯基酶活性之體外酶分析
使用免疫組織化學測量全細胞中組蛋白H3之乙醯化作用,並使用Cellomics陣列掃描進行分析。將A549或HCT116細胞以1x104
個細胞/孔之濃度接種於96孔試驗盤中,再使其隔夜進行黏附。以抑制劑對其進行處理24小時,接著以tris緩衝鹽水(TBS)中之1.8%甲醛對其進行固定1小時。以冰冷之甲醇對該等細胞進行透化處理5分鐘,以TBS沖洗,接著再在TBS中以3%之低脂奶粉進行阻斷90分鐘。接著使該等細胞與對於乙醯化組蛋白H3具有專一性之多株抗體(Upstate #06-599)(以TBS 3%牛奶進行1對500之稀釋)進行恆溫共置1小時。以TBS沖洗該等細胞三次,接著再使其與螢光綴合性次級抗體(Molecular Probes #A11008)以及Hoechst 333542(1微克/毫升)(Molecular Probes #H3570),在添加1%牛血清白蛋白(Sigma #B6917)之TBS中進行恆溫共置1小時。以TBS沖洗三次以除去未連結之抗體,再在最後一次之沖洗後,在該等細胞中加入100微升之TBS,再密封該等試驗盤,並使用Cellomics陣列掃描進行分析。
藉著對個別化合物進行劑量反應曲線,接著測定可產生50%最大信號(參考化合物控制組-曲古菌素A(Sigma))之抑制劑濃度而測定HDAC抑制劑之EC5 0
值。
亦可使用下述之分析(d)至(f)評估本發明化合物之hERG活性及溶解度:(d)hERG-編碼性鉀離子通道抑制分析細胞培養物
在37℃,於溼化環境下(5% CO2
),在含麩胺醯胺、10%胎牛血清(FCS)及0.6毫克/毫升潮黴素之F-12 Ham培養基中(皆為Sigma),使表現hERG-編碼性通道之中國倉鼠卵巢(CHO)細胞生長至半鋪滿。在使用前,使用預熱(37℃)之3毫升小份Versene 1:5,000(Invitrogen)清洗該單層細胞。在抽出此溶液後,在37℃下,於恆溫培養箱中,使此燒瓶與與另外2毫升之versene 1:5,000進行恆溫共置6分鐘。接著藉由輕敲而使該等細胞自該燒瓶之底部分離,再在該燒瓶中加入10毫升含鈣(0.9 mM)及鎂(0.5 mM)(PBS)之Dulbecco's-PBS(Invitrogen),再在進行離心前(50 g,4分鐘),將其抽吸置入15毫升之離心管中。
丟棄所得之上清液,再使該沈澱物溫和重新懸浮於3毫升小份之PBS中。取出0.5毫升小份之細胞懸浮液以進行自動細胞計數(Innovatis Cedex),再以PBS調整該終細胞懸浮液之體積,以取得所欲之終細胞濃度。
電生理學
此種裝置之原則及操作已於先前獲得敘述(Schroeder et al.,Journal of Biomolecular Screening(2003)8(1),50-64)。簡言之,該技術係根據一384-孔之試驗盤(PatchPlateT M
),其中係藉由抽吸以試著將一細胞定位並維持在分隔兩個分離液室之小孔中而在各孔中嘗試進行記錄。一旦進行密封後,其即將PatchPlateT M
下部之溶液換成含有兩性黴素B(Sigma)之溶液。如此可使蓋住各孔中該小洞之細胞膜片產生透化,並因此容許在各孔中嘗試進行穿孔性全細胞膜片鉗之記錄。
就各次之IonWorksT M
HT而言,其係在室溫下(~21℃)以下列方式進行操作。其在「緩衝液」位置之「船」中加入4毫升之PBS,並在「細胞」位置之「船」中加入上述之CHO-hERG細胞懸浮液。將含有欲試驗化合物(其濃度為3X其終試驗濃度)之96-孔試驗盤(V-形底,Greiner Bio-one)置於「試驗盤1」之位置,並將PatchPlateT M
置於該裝置中,並使用PatchPlateT M
蓋定位。
對各化合物試驗盤進行輸出,以容許建立十組8-點濃度作用曲線;該試驗盤上之剩餘兩個管柱則係載劑(0.33% DMSO)(以定義該分析基線)以及超最大阻斷濃度之西沙必利(cisapride)(10 μM)(以定義100%抑制量)。Ion WorksT M
HT之流控頭(F-頭)接著會在該PatchPlateT M
之各孔中加入3.5微升之PBS,而其下部則灌注「內部」溶液,其具有下列之組成(mM單位):K-葡糖酸鹽100、KCl 40、MgCl2
3.2、EGTA 3及HEPES 5(皆為Sigma)(使用10 M KOH而使其成為pH 7.25-7.30)。在進行起動及去泡之後,電子頭(E-頭)接著即會在PatchPlateT M
上四處移動而進行孔洞試驗(亦即’應用一電壓脈衝以測定各孔中之該洞是否開啟)。接著,F-頭會在PatchPlateT M
之各孔中分配3.5微升之上述細胞懸浮液,並給予該等細胞200秒以到達並密封各孔中之該洞。接著,E-頭會在PatchPlateT M
上四處移動以測定各孔中所取得之密封電阻。
接著將PatchPlateT M
下部之溶液置換成為「通路」溶液,其具有下列之組成(mM單位):KCl 140、EGTA 1、MgCl2
1及HEPES 20(皆為Sigma)(使用10 M KOH而使其成為pH 7.25-7.30),添加100微克/毫升之兩性黴素B。在容許該膜片進行穿孔9分鐘後,接著使該E-頭在該膜片盤之全部384個孔處移動,以取得前-化合物hERG電流測量值。接著,F-頭會在PatchPlateT M
之4孔中加入3.5微升取自化合物試驗盤各孔之溶液。其經程式設定而會自該化合物試驗盤上濃度最低之孔起始並順序進行至該濃度最高之孔,以將任何轉移問題之影響降至最低。
在約三分半鐘之共置後,接著使該E-頭在該PatchPlateT M
之全部384個孔處移動,以取得後-化合物hERG電流測量值。如此,可產生非累積性之濃度作用曲線,其中,如在足夠百分比之孔中達成接受範圍(參見下文),各濃度試驗化合物之作用即係根據取自介於1及4孔間之記錄。
各孔之接受範圍係:掃描前密封電阻>60 MΩ,掃描前hERG尾電流幅度>0.15 nA;掃描後密封電阻>60 MΩ。該前-及後-化合物hERG電流係由一電壓脈衝激發,其係由維持在-70 mV之20 s間期、至-60 mV之160 ms步驟、回到-70 mV之100 ms步驟、至+40 mV之1 s步驟、至-30 mV之2 s步驟以及至-70 mV之500 ms最終步驟構成。在該前-及後-化合物電壓脈衝之間,並無膜電位之箝制。
e)水溶解度之評估
將試驗化合物(自1至1.6毫克)秤重置入小瓶中,並加入1毫升之0.1 M磷酸緩衝液(pH 7.4)。同時在一小瓶中將1.0及1.6毫克間之試驗化合物溶於1.8毫升之DMSO中,以作為校正溶液。在25℃下攪拌該兩種溶液24小時。接著將該飽和之水溶液及DMSO校正溶液移置至96孔深孔試驗盤中。在4310 g之相對離心力下對該飽和緩衝溶液試驗盤進行離心,接著將該水性上清液移置至第二深孔試驗盤中,並進行離心。在再次移置該水性上清液並以緩衝液進行50%稀釋後,使用HPLC-UV-MS分析該終樣本試驗盤及該DMSO校正試驗盤。樣本溶解度之定量係藉由比較250 nm處之樣本及校正UK峰區域(可選擇其他波長,如250 nm並不適當),並以MS確認該化合物之身分。
f)緩衝液及模擬腸液中水溶解度之評估
在指定之溫度下,於下列之基質中試驗溶解度:模擬腸液(絕食性)FaSSIF(Galia and Dressman et al.,Pharms Res,15(5),1998,p698)
。
牛磺膽酸鈉(3 mM);蛋卵磷脂(0.75 mM);KH2
PO4
(0.03 M);KCl(0.1 M);NaOH(調整至pH 6.5)。在37℃下測量。
Srensen氏磷酸緩衝液(Handbook of Biochemistry,pg 234-237)。
溶液A 0.067 M之磷酸一鉀溶液B 0.067 M之磷酸二鈉在25℃及37℃下測量。
將適當量(自上述之溶解度試驗(f)及/或預測性pH溶解度曲線測定)之試驗化合物以二重試驗之方式精確秤重置入2-英錢之玻璃小瓶中。
在各組之重複小瓶中,加入最小1.50毫升之適當基質,其係pH 6.8 Srensen氏磷酸緩衝液或FaSSIF。在各情形下,所有之秤重物皆必須足以使該基質飽和。
各小瓶中,加入PTFE塗覆性磁性隨動件,接著再密封並置於Variomag磁性反應攪拌塊上(CamLab)。將該攪拌塊至於適當之溫度下(參見上文),以鋁箔遮蓋以降低曝光,再以800 r.p.m以交替方向進行攪拌。針對試驗基質,在預定之時間點對各小瓶進行取樣。以下列方式在各時間點首先測定pH值接著測定活性含量。
pH
使用適當之pH計(Hydrus 400-Fisher)、電極及標準pH緩衝液,在室溫下於pH 4.01及7.00校正該儀器。
藉著將該電極置於各重複樣本中,在室溫下測定其pH,並報導該結果至小數點後一位。在每次測定之間,以去離子水沖洗該電極並擦乾。
以HPLC測定活性含量自各個樣本中,將0.4毫升之小份移置聚碳酸酯超離心管中(Beckman)。在該試驗基質之適當溫度下,使用TL最適超離心機(Beckman),以40000 r.p.m.對該等樣本進行離心15分鐘。將取自各個超離心管之上清液移置第二超離心管中,再在相同之條件下再次進行離心。
在針對該試驗化合物而經最適化之HPLC方法下,分析取自各樣本之上清液,再相對外部標準物而測定活性含量。可能須以適當之溶劑稀釋該上清液,以使該濃度成為該HPLC方法之線性範圍中者。此種稀釋一般而言可自其預測性pH水溶解度曲線估計,且就共溶劑之情形而言,可自已加入之化合物量估計。
儘管式I化合物之藥學特性預期會隨結構變化而各異,一般而言,式I化合物所具有之活性可在上述試驗(a)、(b)、(c)或(d)之一或多者中,以下列之濃度或劑量顯示:試驗(a):-例如,100 nM或以下範圍中之IC5 0
;試驗(b):-例如,1 μM或以下範圍中之IC5 0
;試驗(c):-例如,1 μM或以下範圍中之IC5 0
;試驗(d):-例如,大於30 μM之IC5 0
。
舉例而言,在使用試驗(a)分析HDAC1之抑制並使用試驗(b)分析全細胞之增殖抑制時,本文實例4中所述之化合物可產生示於下表A中之IC5 0
結果。該表亦包括N-(2-胺基苯基)-4-[1-(吡啶-2-基甲基)六氫吡啶-4-基]苯甲醯胺(上文化合物[1])之對應結果:
在試驗(d)中,於該等試驗化合物之有效劑量下,並未觀察到生理不可接受之毒性。因此,在以後文所定義之劑量範圍投藥式I化合物或其醫藥可接受性鹽時,並不會預期產生任何非所欲之毒性作用。
此外,儘管式I化合物之溶解度無可避免會如預期而隨結構變化改變,一般而言,式I化合物具有在上述試驗(e)中所測得之,例如,大於100 μM之溶解度。
根據本發明之另一部份,其提供一種醫藥組合物,其包含式(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義,結合醫藥可接受之稀釋劑或載體。
本發明之組合物可為適合進行口服使用(例如,如錠劑、錠片、硬或軟膠囊、水性或油性懸浮液、乳液、可分散性粉末或顆粒、糖漿或酊劑)、局部使用(例如,如,乳霜、油膏、凝膠或是水性或油性之溶液或懸浮液)、吸入投藥(例如,如,細割粉末或液體氣溶膠)、吹入投藥(例如,如,細割粉末)或腸外投藥(例如,如,用以進行靜脈內、皮下、肌內或肌內投劑之無菌水性或油性溶液,或用以進行直腸投劑之栓劑)之形式。
本發明之組合物可如技藝中所熟知者,藉由習知之方法,使用習知之醫藥賦形劑而取得。因此,欲用於口服使用之組合物可含有,例如,一或多種著色劑甜味劑、調味劑及/或防腐劑。
錠劑調配物之適當醫藥可接受性賦形劑包括,例如,鈍性稀釋劑(諸如,乳糖、碳酸鈉、磷酸鈣或碳酸鈣);粒化及崩解劑(諸如,玉米澱粉或藻酸);結合劑(諸如,澱粉);潤滑劑(諸如,硬脂酸鎂、硬脂酸或滑石);防腐劑(諸如,乙基或丙基對羥基苯甲酸酯),及抗氧化劑(諸如,抗壞血酸)。錠劑調配物可為無塗層或塗層形式,以修飾其崩解以及其活性成分在胃腸道中之後續吸收,或是改良其安定性及/或外觀,在任一情形下,此皆可使用習知之塗層劑及技藝中所熟知之方法進行。
用於口服使用之組合物可為硬明膠膠囊之形式,其中該活性成分係與鈍性固態稀釋劑混合,例如,碳酸該、磷酸鈣或高嶺土,或是可為軟明膠膠囊之形式,其中該活性成分係與水或油混合,諸如,花生油、液態石蠟、大豆油、椰子油,或較佳者為橄欖油,或是任何其他可接受之載體。
水性懸浮液一般而言含有細粉形式之活性成分,以及一或多種懸浮劑,諸如,羧甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、藻酸鈉、聚乙烯基-吡咯啶酮、黃蓍膠及阿拉伯膠;分散或溼潤劑,諸如,卵磷脂,或是烯化氧與脂肪酸之縮合產物(例如,聚氧乙烯硬脂酸酯),或是環氧乙烷與長鏈脂族醇之縮合產物(例如,十七碳乙烯氧基十六烷醇),或是環氧乙烷與衍生自脂肪酸與己醣醇之部分酯之縮合產物(諸如,聚氧乙烯山梨糖醇單油酸酯),或是或是環氧乙烷與長鏈脂族醇之縮合產物(例如,十七碳乙烯氧基十六烷醇),或是環氧乙烷與衍生自脂肪酸與己醣醇之部分酯之縮合產物(諸如,聚氧乙烯山梨糖醇單油酸酯),或是環氧乙烷與衍生自脂肪酸與己醣醇無水物之部分酯之縮合產物(諸如,聚氧乙烯山梨糖醇單油酸酯)。水性懸浮液亦可含有一或多種防腐劑(諸如,乙基或丙基對羥基苯甲酸酯)、抗氧化劑(諸如,抗壞血酸)、著色劑、調味劑及/或甜味劑(諸如,蔗糖、糖精或阿斯巴甜)。
油性懸浮液可藉著使活性成分懸浮於蔬菜油(諸如,花生油、橄欖油、芝麻油或椰子油)或礦物油(諸如,液體石蠟)中而調配。油性懸浮液亦可含有增稠劑,諸如,蜂蠟、硬石蠟或鯨蠟醇。可加入甜味劑(諸如上述者)及調味劑,以提供美味之口服製劑。此等組合物可藉由添加抗氧化劑(諸如,抗壞血酸)而保存。
適合藉由加入水而製備水性懸浮液或溶液之可分散性或凍乾性粉末及顆粒一般而言含有該活性成粉以及分散或溼潤劑、懸浮劑以及一或多種防腐劑。適當分散或溼潤劑及懸浮劑之實例係已於上文所提及者。亦可存在其他賦形劑,諸如,甜味劑、調味劑及著色劑。
本發明之醫藥組合物亦可為水包油乳液之形式。該油相可為蔬菜油,諸如,橄欖油或花生油,或為礦物油,諸如,舉例而言,液體石蠟,或是任何此等之混合物。適當之乳化劑可為,舉例而言,天然存在之膠體(諸如,阿拉伯膠或黃蓍膠),天然存在之磷脂(諸如,大豆卵磷脂),或是衍生自脂肪酸及己糖醇酐之酯或部分酯(例如,山梨糖醇單油酸酯),以及該部分酯與環氧乙烷之縮合產物(諸如,聚氧乙烯山梨糖醇單油酸酯)。此等乳液亦可含有甜味劑、調味劑及防腐劑。
糖漿及酊劑可與甜味劑共同調配,諸如,甘油、丙二醇、山梨糖醇、阿斯巴甜或蔗糖,且其亦可含有緩和劑防腐劑、調味劑及/或著色劑。
該等醫藥組合物亦可為無菌可注射性水或油懸浮液、溶液、乳液或特別系統之形式,其可根據已知之流程,使用一或多種已於上文提及之適當分散劑或溼潤劑以及懸浮劑而調配。無菌可注射性製備物亦可為無毒性腸外可接受性稀釋劑或溶劑中之無菌可注射性溶液或懸浮液,例如,於聚乙二醇中之溶液。
栓劑調配物可藉著使該活性成分混合適當之無刺激性賦形劑而製備,該賦形劑在一般室溫下為固體,但在直腸溫度下為液體,並因而將會在直腸中融化而釋出該藥物。適當之賦形劑包括,例如,可可脂及聚乙二醇。
局部調配物,諸如,乳霜、油膏、凝膠及水或油溶液或懸浮液,一般而言可藉由使用技藝中已為熟知之習知流程,調配該活性成份與習知之局部可接受性載劑或稀釋劑而取得。
用以藉由吹入投藥之組合物可為細割粉末之形式,其含有平均直徑為,例如,30 μm或以下之顆粒,較佳者係5 μm或以下,更佳者係介於5 μm及1 μm間,該粉末本身僅含有活性成分或是含有經一或多種生理可接受性載體(諸如,乳糖)稀釋之活性成分。接著,該用以進行吹入之粉末可便利保存於一膠囊中(其含有,例如,1至50毫克之活性成分)而以渦輪吸入器裝置使用,諸如用於吹入已知試劑色甘酸鈉者。
用以藉由吸入投藥之組合物可為習知之加壓性氣溶膠形式,其係安排以含有細割固體或液體小滴之形式分配該活性成分。可使用習知之氣溶膠推進劑,諸如,揮發性氟化烴或烴,而該氣溶膠裝置可便利安排而分配定量之活性成分。
就其他有關調配物之資訊,讀者可參見Comprehensive Medicinal Chemistry(Corwin Hansch;Chairman of Editorial Board),Pergamon Press 1990第5冊之章節25.2。
一般而言,上述之組合物可以習知之方式,使用習知之賦形劑製備。
式(I)化合物一般而言將係以5-5000毫克/平方公尺該動物體面積範圍內之單元劑量而對溫血動物投藥,亦即,約0.1-100毫克/公斤,且此一般而言可提供治療有效性之劑量。單元劑形(諸如,錠劑或膠囊)通常可含有,例如,1-250毫克之活性成分。較佳者,其係使用1-50毫克/公斤範圍內之每日劑量。然而,該每日劑量將必定會隨該經治療之宿主、特定之投藥途徑以及欲治療疾病之嚴重性而變化。因此,最佳之劑量將可由治療任何特定病患之醫師判定。
咸已發現,本發明所定義之化合物,或其醫藥可接受之鹽,係有效之細胞循環抑制劑(抗細胞增殖劑),且咸信此種特性係由其HDAC抑制活性產生。咸亦相信,本發明之化合物可涉及血管新生作用之抑制、脫噬作用及分化作用之活化。因此,本發明之化合物預期可用於治療單獨或部分係由HDAC酶中介之疾病或醫學病況,亦即,該等化合物可用於在需要此種治療之溫血動物體內產生HDAC抑制作用。因此,本發明之化合物可提供一種治療惡性細胞增殖之方法,其特徵在於HDAC酶之抑制,亦即,該等化合物可用於產生單獨或部分係由HDAC之抑制中介之抗增殖作用。
根據本發明之另一部份,其提供式(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義,以用於由治療進行之人類或動物體之治療方法中。
因此,根據本發明之另一部份,其提供式(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義,以作為藥物。
根據本發明之另一部份,其提供式(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義,以用於製造藥物而用於在溫血動物(諸如,人類)體內產生HDAC抑制作用。
根據本發明此一部份之另一特徵,其提供一種在需要此種治療之溫血動物(諸如,人類)體內產生HDAC抑制作用之方法,其包含對該動物投藥有效量之式(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義。
根據本發明之另一部份,其提供式(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義,於製造藥物而用於在溫血動物(諸如,人類)體內產生細胞循環抑制(抗細胞增殖)作用之用途。
根據本發明此一部份之另一特徵,其提供一種在需要此種治療之溫血動物(諸如,人類)體內產生細胞循環抑制(抗細胞增殖)作用之方法,其包含對該動物投藥有效量之式(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義。
根據本發明此一部份之另一特徵,其提供一種在需要此種治療之溫血動物(諸如,人類)體內治療癌症之方法,其包含對該動物投藥有效量之式(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義。
根據本發明之另一特徵,其提供式(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義,以用於製造藥物而用於治療癌症。
根據本發明此一部份之另一特徵,其提供(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義,以用於治療癌症。
根據本發明此一部份之另一特徵,其提供(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義,於製造藥物而用於治療癌症之用途。
在本發明之另一部份,其提供(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義,於製造藥物而用於治療肺癌、結腸直腸癌、乳癌、列腺癌、淋巴瘤及/或白血病之用途。
在本發明之另一部份,其提供一種在需要此種治療之溫血動物(諸如,人類)體內治療肺癌、結腸直腸癌、乳癌、列腺癌、淋巴瘤或白血病之方法,其包含對該動物投藥有效量之式(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義。
可以本發明治療之癌症包括食道癌、骨髓瘤、肝細胞、胰臟及頸癌、Ewings氏腫瘤、神經母細胞瘤、卡波希肉瘤、卵巢癌、乳癌、結腸直腸癌、前列腺癌、膀胱癌、黑素瘤、肺癌[包括非小細胞肺癌(NSCLC)及小細胞肺癌(SCLC)]、胃癌、淋巴瘤及白血病。
前文所定義之HDAC抑制活性可以單一治療之方式應用,或者可在本發明之化合物外尚涉及一或多種其他物質及/或治療。此等結合治療可由同時、順序或分別投藥個別治療組成份而達成。在醫學癌學之領域中,使用不同形式之治療組合治療個別癌症病患係其正常實施。在醫學癌學中,除前文所定義之細胞循環抑制治療之外,此種結合治療之其他組成份可為:手術、放射治療或化療。此種化療可包括一或多種下列類型之抗腫瘤劑:(i)抗增殖劑/抗腫瘤藥物及其結合,如用於醫學癌學中者,諸如,烷化劑(例如,順鉑(cisplatin)、卡鉑(carboplatin)、環磷醯胺、氮芥、美法崙(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulphan)及硝脲);抗代謝物(例如,抗葉酸,諸如,氟嘧啶,如,5-氟尿嘧啶及替加氟(tegafur)、雷替曲塞(raltitrexed)、胺甲喋呤、阿糖胞苷及羥基脲);抗腫瘤抗生素(例如,蒽環黴素,如,阿黴素(adriamycin)、博來黴素(bleomycin)、多柔比星(doxorubicin)、道諾黴素(daunomycin)、表阿黴素(epirubicin)、伊達比星(idarubicin)、絲裂黴素C(mitomycin-C)、放線菌素D(dactinomycin)及光神黴素(mithramycin));抗有絲分裂劑(例如,長春花生物鹼,如,長春新鹼、長春花鹼、長春地辛(vindesine)及長春瑞賓(vinorelbine),以及紫杉醇,如,紫杉醇及紫杉德(taxotere));以及拓撲異構酶抑制劑(例如,鬼臼毒素,如,依托泊苷(etoposide)及替尼泊苷(teniposide)、安吖啶(amsacrine)、拓撲替康(topotecan)及喜樹鹼(camptothecin));(ii)細胞抑制劑,諸如,抗雌激素(例如,他莫昔芬(tamoxifen)、托瑞米芬(toremifene)、雷洛西芬(raloxifene)、屈洛昔芬(droloxifene)及iodoxyfene),雌激素受體負調節劑(例如,fulvestrant)、抗雄激素(例如,必卡他胺(bicalutamide)、氟他胺(flutamide)、尼魯米特(nilutamide)及醋酸環丙孕酮(cyproterone acetate)),LHRH拮抗劑或LHRH激動劑(例如,戈舍瑞林(goserelin)、亮丙瑞林(leuprolide)及布舍瑞林(buserelin)),孕酮(例如,醋酸甲地孕酮(megestrol acetate),芳環轉化酶抑制劑(例如,阿那曲唑(anastrozole)、來曲唑(letrazole)、伏氯唑(vorazole)及依西美坦(exemestane))以及5α-還原酶抑制劑(例如,非那雄胺(finasteride));(iii)可抑制癌症侵染之試劑(例如,金屬蛋白酶抑制劑,如,馬立馬司他(marimastat),以及尿激酶血纖蛋白溶酶原激活物受體功能之抑制劑);(iv)生長因子功能之抑制劑,例如,諸等抑制劑,包括生長因子抗體、生長因子受體抗體(例如,抗-erbb2抗體曲妥珠單抗(trastuzumab)[HerceptinT M
]以及抗-erbb1抗體西妥昔單抗(cetuximab)[C225])、法尼基轉移酶抑制劑、MEK抑制劑、酪胺酸激酶抑制劑及絲胺酸/羥丁胺酸激酶抑制劑,例如,表皮生長因子家族之抑制劑(例如,EGFR家族酪胺酸激酶抑制劑,諸如,N
-(3-氯-4-氟苯基)-7-甲氧基-6-(3-嗎啉基丙氧基)喹唑啉-4-胺(吉非替尼(gefitinib))、N
-(3-乙炔基苯基)-6,7-雙(2-甲氧基乙氧基)喹唑啉-4-胺(埃羅替尼(erlotinib),OSI-774)及6-丙烯醯胺基-N
-(3-氯-4-氟苯基)-7-(3-嗎啉基丙氧基)喹唑啉-4-胺(CI 1033)),例如血小板衍生性生長因子家族之抑制劑,以及例如肝細胞生長因子家族之抑制劑;(v)抗血管生成劑,諸如,可抑制血管內皮生長因子作用者(例如,抗血管內皮生長因子抗體貝伐單抗(bevacizumab)[AvastinT M
],諸如述於國際專利申請案WO 97/22596、WO 97/30035、WO 97/32856及WO 98/13354中之諸等化合物)以及可以其他機制作用之化合物(例如,linomide、整合素αvβ3功能之抑制劑以及血管抑制素);(vi)血管損傷劑,諸如,Combretastatin A4,以及揭示於國際專利申請案WO 99/02166、WO 00/40529、WO 00/41669、WO 01/92224、WO 02/04434及WO 02/08213中之化合物;(vii)反義物(antisense)治療,例如,可導向上列目標者,諸如,ISIS 2503,一種抗ras之反義物;(viii)基因治療方法,包括,可取代異常基因(諸如,異常之p53或是異常之BRCA1或BRCA2)之方法、GDEPT(基因導向性酶前藥治療)方法(諸如,使用胞嘧啶脫胺酶、胸苷激酶或細菌性硝基還原酶者)以及可增加病患對於化療或放射治療之耐受度之方法(諸如,多重藥物抗性基因治療);(ix)免疫治療方法,包括,例如,可增加病患腫瘤細胞免疫原性之體外及體內方法(諸如,以細胞因子進行之轉導,諸如,間白素2、間白素4或粒細胞-巨噬細胞集落刺激因子)、可降低T細胞無反應性之方法、使用轉染性免疫細胞之方法(諸如,細胞因子轉染性樹狀細胞)、使用細胞因子轉染性腫瘤細胞系之方法以及使用抗獨特型抗體之方法;(x)細胞循環抑制劑,例如,CDK抑制劑(如,flavopiridol)及其他細胞循環關卡之抑制劑(如,關卡激酶);極光(aurora)激酶以及其他涉及有絲分裂及胞質分裂調控之激酶(如,有絲分裂驅動蛋白)之抑制劑;以及其他組蛋白脫乙醯基酶抑制劑;以及(xi)分化劑(例如,視黃酸以及維生素D)。
根據本發明之此一部份,其提供一種醫藥組合物,其包含式(I)化合物,如前文所定義,以及其他抗腫瘤物質,如前文所定義,以進行癌症之結合治療。
其尚提供式(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義,以用於治療炎性疾病、自體免疫疾病以及過敏/特應性疾病之方法。
特定言之,其提供式(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義,以用於治療關節發炎(特別係類風濕性關節炎、骨關節炎及痛風)、胃腸道發炎(特別係炎性腸疾、潰瘍性腸炎及胃炎)、皮膚發炎(特別係牛皮癬、溼疹、皮膚炎)、多重硬化、動脈硬化、脊柱關節病(僵直性脊髓炎、乾癬性關節炎、與潰瘍性腸炎相關之關節炎)、AIDS-相關性神經疾病、全身性紅斑狼瘡、氣喘、慢性阻塞性肺病、支氣管炎、肋膜炎、成人呼吸窘迫症候群、敗血病以及急性及慢性肝炎(病毒性、細菌性或毒性)。
咸尚提供式(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義,以作為藥物而用於在溫血動物(諸如,人類)體內治療炎性疾病、自體免疫疾病以及過敏/特應性疾病。
特定言之,其提供式(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義,以作為藥物而用於治療關節發炎(特別係類風濕性關節炎、骨關節炎及痛風)、胃腸道發炎(特別係炎性腸疾、潰瘍性腸炎及胃炎)、皮膚發炎(特別係牛皮癬、溼疹、皮膚炎)、多重硬化、動脈硬化、脊柱關節病(僵直性脊髓炎、乾癬性關節炎、與潰瘍性腸炎相關之關節炎)、AIDS-相關性神經疾病、全身性紅斑狼瘡、氣喘、慢性阻塞性肺病、支氣管炎、肋膜炎、成人呼吸窘迫症候群、敗血病以及急性及慢性肝炎(病毒性、細菌性或毒性)。
咸尚提供式(I)化合物,或其醫藥可接受之鹽或前藥,如前文所定義,於製造藥物而用於在溫血動物(諸如,人類)體內治療炎性疾病、自體免疫疾病以及過敏/特應性疾病之用途。
如上文所言,特定細胞增殖疾病之治療性或預防性治療所需之劑量大小將必然會隨所治療之宿主、投藥之途徑、以及該欲治療疾病之嚴重性而各異。可預期1-100毫克/公斤範圍內之單元劑量,較佳為1-50毫克/公斤。
除其在於治療醫學上之用途外,式(I)化合物及其醫藥可接受之鹽亦可作為藥學工具而用於進行體外及體內試驗系統之研發及標準化,以在實驗動物(諸如,貓、狗、兔、猴、大鼠及小鼠)體內評估細胞循環活性抑制劑之作用,因而尋找新穎之治療劑。
本發明現將以下列之實例說明,其中,一般而言:(i)操作係在室溫下(意即,在17至25℃之範圍中)且係在鈍性氣體大氣下(諸如,氬氣)進行,除非另外指明;(ii)蒸發係在真空下以旋轉蒸發進行,且其製成流程係在以過濾除去殘餘固體之後進行;(iii)管柱層析(以閃蒸流程進行)以及中壓液相層析(MPLC)係在取自E.Merck,Darmstadt,Germany之Merck Kieselgel矽膠(Art.9385)或Merck Lichroprep RP-18(Art.9303)反相矽膠上進行,或是使用專利預裝填性正相矽膠柱,例如,取自Presearch Ltd.,Hitchin,UK之Redisep(TM)可拋棄式層析柱而進行,或者,高壓液相層析(HPLC)係在C18反相矽膠上進行,例如,Dynamax C-18 60製備性反相管柱;(iv)產率,在其提出時,並不一定為最大可取得值;(v)一般而言,式(I)終產物之結構係經核磁共振(NMR)及/或質譜技術確認;快速原子轟擊(FAB)質譜數據係使用Platform分光計而取得,且在適當時,其可收集陽離子數據或陰離子數據;NMR化學位移數據係使用以400 MHz場強度操作之Jeol JNM EX 400分光計、以300 MHz場強度操作之Varian Gemini 2000分光計、以400 MHz操作之Bruker DPX-400或是以300 MHz場強度操作之Bruker AM300分光計測定,以δ級度質子磁共振光譜進行測量-測量係在室溫下進行,除非另外指明;(vi)中間化合物一般而言並不會完全進行定性,且其純度係由薄層層析、HPLC、紅外線(IR)及/或NMR分析評估;(vii)熔點係未經校正者,且係使用Mettler SP62自動熔點裝置或是油浴裝置測定;式(I)終產物之熔點係在自習知有機溶劑中結晶之後測定,諸如,單獨或混合之乙醇、甲醇、丙酮、乙醚或己烷;(viii)使用下列之縮寫:DMSO 二甲亞碸THF 四氫呋喃DIPEAN,N
-二異丙基乙胺IPA 異丙醇Boc/BOC 第三丁氧羰基HCl 鹽酸Cbz/CBZ 苄氧羰基Tf 三氟甲基磺醯基LiHMDS 六甲基乙矽烷疊氮化鋰PhNTf2 N
-苯基-雙(三氟甲磺醯亞胺)DME 1,2-二甲氧基乙烷CDMT 2-氯-4,6-二甲氧基-1,3,5-三嗪
N
-(2-胺基苯基)-4-{1-[(1-甲基-1H
-吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺
在裝有1-甲基-1H
-吡唑-4-甲醛(84.5毫克,0.77毫莫耳)之反應瓶中,加入第三丁基2-[(4-六氫吡啶-4-基苯甲醯基)胺基]苯基胺基甲酸酯(如述於下文方法1中者製備;300毫克,0.76毫莫耳)於二氯甲烷(7毫升)及N,N
-二甲基甲醯胺(0.5毫升)中之溶液。第三丁基2-[(4-六氫吡啶-4-基苯甲醯基)胺基]苯基胺基甲酸酯亦可根據述於下文方法4中之方法製備。加入醋酸(50微升,0.87毫莫耳),再使該反應混合物在室溫下攪拌45分鐘。接著加入三乙醯氧基硼氫化鈉(250毫克,1.18毫莫耳),再使該反應物再攪拌76小時,然後再以甲醇稀釋,並直接倒至一SCX-2柱(10克)上。以甲醇(80毫升)清洗該柱,然後再以氨於甲醇中之2 M溶液(50毫升)溶析該產物。將相關之級份蒸發至乾,再將所得之殘餘物溶於二氯甲烷(3毫升)中,並以三氟乙酸(1毫升)處理。在室溫下攪拌此混合物2小時,然後再以二氯甲烷稀釋,並倒至一SCX-2柱(5克)上。以甲醇(20毫升)清洗該柱,接著再以氨於甲醇中之2 M溶液(20毫升)溶析產物。將該氨級份蒸發至乾,再在矽膠上,以閃蒸層析純化所得之殘餘物,以二氯甲烷中之10%甲醇溶析,以產生標題化合物(117毫克,40%);NMR光譜
:(DMSO d6
)δ 1.70(m,4H),2.01(t,2H),2.57(m,1H),2.95(m,2H),3.38(s,2H),3.81(s,3H),4.86(s,2H),6.60(m,1H),6.78(m,1H),6.97(m,1H),7.18(m,1H),7.31(s,1H),7.37(d,2H),7.57(s,1H),7.91(d,2H),9.56(s,1H);質譜
:M+H+
390。
使用類似述於實例1者之流程,使第三丁基2-[(4-六氫吡啶-4-基苯甲醯基)胺基]苯基胺基甲酸酯與適當之吡唑甲醛起始物質(SM)反應,以產生述於表1之化合物。
N
-(2-胺基苯基)-4-[1-(1H
-吡唑-3-基甲基)六氫吡啶-4-基]苯甲醯胺
在室溫下,於二氯甲烷(5毫升)中,使第三丁基2-[(4-六氫吡啶-4-基苯甲醯基)胺基]苯基胺基甲酸酯(如述於下文方法1中者製備;200毫克,0.51毫莫耳)及1H
-吡唑-3-甲醛(50.7毫克,0.53毫莫耳)攪拌1小時。加入三乙醯氧基硼氫化鈉(150毫克,0.71毫莫耳),再在室溫下攪拌該混合物48小時。使該所得之溶液吸收至一SCX-2管柱上(該管柱已經甲醇(2倍管柱體積)清洗),接著再以氨於甲醇中之2 M溶液(2倍管柱體積)溶析該產物,以產生一泡沫體。將此物質溶於1,4-二烷(2毫升)中,加入鹽酸於1,4-二烷中之4 M溶液(2毫升),再在室溫下攪拌該溶液48小時。濾出該產物,並以乙醚清洗,再進行風乾。將該所得之固體溶於水中,以2 N氫氧化鈉鹼化,再濾出所得之固體,以水清洗,並在真空下進行乾燥,以產生標題化合物(61毫克,44%)。NMR光譜
:1
H NMR(DMSO d6
)δ 1.71(m,4H),2.07(m,2H),2.56(m,1H),2.95(m,2H),3.53(s,2H),4.86(s,2H),6.16(s,1H),6.60(m,1H),6.78(d,1H),6.97(t,1H),7.18(d,1H),7.37(d,2H),7.64(m,1H),7.91(d,2H),9.55(s,1H),12.59(m,1H);質譜
:M+H+
376。
N
-(2-胺基苯基)-4-{1-[(5-甲氧基-1,3-二甲基-1H
-吡唑-4-基甲基]六氫吡啶-4-基}苯甲醯胺
使用類似述於實例3者之流程,使第三丁基2-[(4-六氫吡啶-4-基苯甲醯基)胺基]苯基胺基甲酸酯(如述於下文方法1中者製備;200毫克,0.51毫莫耳)與5-甲氧基-1,3-二甲基-1H
-吡唑-4-甲醛反應(92.6毫克,0.60毫莫耳),以產生標題化合物(68毫克,36%);NMR光譜
:(DMSO d6
)δ 1.63(m,2H),1.78(m,2H),2.00(m,2H),2.06(s,3H),2.57(m,1H),2.94(m,2H),3.25(s,2H),3.50(s,3H),3.99(s,3H),4.86(br s,2H),6.60(m,1H),6.78(d,1H),6.97(m,1H),7.17(d,1H),7.37(d,2H),7.91(d,2H),9.55(s,1H);質譜
:M+H+
434。
N
-(2-胺基苯基)-4-{1-[(3-乙基-1H
-吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺
在室溫下,於二氯甲烷(10毫升)中,使第三丁基2-[(4-六氫吡啶-4-基苯甲醯基)胺基]苯基胺基甲酸酯(如述於下文方法1中者製備;395毫克,1.0毫莫耳)及3-乙基-1H
-吡唑-4-甲醛(149毫克,1.2毫莫耳)攪拌1小時。加入三乙醯氧基硼氫化鈉(297毫克,1.4毫莫耳),再在室溫下攪拌該混合物24小時。使該所得之溶液吸收至一SCX-2管柱上(該管柱已經甲醇(2倍管柱體積)清洗),接著再以氨於甲醇中之2 M溶液(2倍管柱體積)溶析該產物,以產生呈白色泡沫體之產物。在矽膠上,以層析純化此物質,以二氯甲烷中之10%甲醇溶析。將該殘餘物溶於二氯甲烷(4毫升)中,加入三氟乙酸(1毫升),再在室溫下攪拌該混合物3小時。使該所得之溶液吸收至一SCX-2管柱上(該管柱已經甲醇(2倍管柱體積)清洗),接著再以氨於甲醇中之2 M溶液(2倍管柱體積)溶析該產物,以產生標題化合物(232毫克,75%)。NMR光譜
:(DMSO d6
)δ 1.18(t,3H),1.65(m,2H),1.77(m,2H),2.00(m,2H),2.57(m,3H),2.95(m,2H),3.34(s,2H),4.86(br s,2H),6.60(m,1H),6.78(d,1H),6.97(m,1H),7.17(d,1H),7.29(br s,1H),7.37(d,2H),7.91(d,2H),9.55(s,1H),12.39(s,1H);質譜
:M+H+
404。
N
-(2-胺基苯基)-4-{1-[(1,3,5-三甲基-1H
-吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺;
使用類似述於實例5者之流程,使第三丁基2-[(4-六氫吡啶-4-基苯甲醯基)胺基]苯基胺基甲酸酯(如述於下文方法1中者製備;200毫克,0.51毫莫耳)與1,3,5-三甲基-1H
-吡唑-4-甲醛反應(83.5毫克,0.60毫莫耳),以產生標題化合物(70毫克,56%);NMR光譜
:(DMSO d6)δ 1.65(m,2H),1.77(m,2H),1.98(m,2H),2.09(s,3H),2.18(s,3H),2.57(m,1H),2.92(m,2H),3.24(s,2H),3.63(s,3H),4.86(br s,2H),6.60(m,1H),6.78(d,1H),6.97(m,1H),7.17(d,1H),7.37(d,2H),7.91(d,2H),9.55(s,1H);質譜
:M+H+
418。
N
-(2-胺基苯基)-4-{1-[(1,3-二甲基-1H
-吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺
使用冰-水浴,將第三丁基(2-{[4-(1-{1,3-二甲基-1H
-吡唑-4-基甲基}六氫吡啶-4-基)苯甲醯基]胺基}苯基)胺基甲酸酯(如述於下文方法6中者製備;7.61克,15.11毫莫耳)溶於1,4-二烷(70毫升)中,並冷卻至0℃。接著緩慢加入鹽酸於1,4-二烷中之4 M溶液(150毫升,600毫莫耳)。使該所得之懸浮液回溫至室溫,再以玻璃棒攪拌以分散塊狀物。在室溫下攪拌該反應混合物18小時。在抽氣之下過濾該混合物。將該取得之固體溶於水(200毫升)中,再藉由緩慢加入2 M氫氧化鈉水溶液而將該溶液調整至pH 12。以二氯甲烷(300毫升)萃取該所得之混合物,再分離有機物。以二氯甲烷(200毫升)再次萃取該水相,再以鹽水清洗該結合之萃取物,以硫酸鎂去水,過濾,再進行蒸發,以產生一澄清膠體。將該膠體溶於乙醚中,並再次蒸發至乾,以產生標題化合物(5.69克,93%);NMR光譜
(CDCl3
)δ 1.81(m,4H),2.07(m,2H),2.25(s,3H),2.56(m,1H),3.04(m,2H),3.39(s,2H),3.81(s,3H),3.85(s,2H),6.84(m,2H),7.08(m,1H),7.24(s,1H),7.33(m,3H),7.82(m,3H)。質譜:M+H+
404。
N
-(2-胺基苯基)-4-{1-[(1,3-二甲基-1H
-吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺
使第三丁基(2-{[4-(1-{1,3-二甲基-1H
-吡唑-4-基甲基}六氫吡啶-4-基)苯甲醯基]胺基}苯基)胺基甲酸酯(下文方法6;92.3克,183.3毫莫耳)於甲醇(754毫升)及水(141毫升)中形成漿液,並冷卻至0-5℃。加入濃鹽酸,同時使該溫度維持在低於20℃。在室溫下攪拌該反應混合物20小時。將該反應物冷卻至0-5℃,再加入氫氧化鈉水溶液,同時使該溫度維持在低於20℃,直到取得12-14之pH值為止。將該反應混合物加熱至回流溫度30分鐘,然後再以4小時之時間冷卻至20℃。過濾收集該產物,再以甲醇水溶液清洗,然後再在45℃於真空下乾燥至恆定重量,以產生標題化合物(63.3克,86%)。
NMR光譜
(DMSO d6
),1.65(m,2H),1.73(m,2H),1.96(t,2H),2.08(s,3H),2.55(m,1H),2.92(d,2H),3.28(s,2H),3.75(s,3H),4.87(s,2H),6.59(m,1H),6.77(m,1H),6.96(m,1H),7.2(d,1H),7.35(d,2H),7.44(s,1H),7.90(d,2H),9.56(s,1H)。
質譜:M+H+
404。
N
-(2-胺基苯基)-4-{1-[(1,5-二甲基-1H
-吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺
將第三丁基{2-[(4-{1-[(1,5-二甲基-1H
-吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯基)胺基]苯基}胺基甲酸酯(如述於下文方法7中者製備;308毫克,0.61毫莫耳)溶於二氯甲烷(2毫升)中,再加入三氟乙酸(1毫升)。在室溫下攪拌該反應混合物1小時,然後再將其倒至一SCX-3柱(5克)上。以二氯甲烷(50毫升)及甲醇(50毫升)清洗該柱,然後再以氨於甲醇中之2 M溶液(50毫升)溶析該產物。蒸發該氨級份,以產生一白色固體(182毫克),其以反相製備性HPLC純化,產生標題化合物(134毫克,55%);NMR光譜
:(DMSO d6
)δ 1.70(m,4H),2.01(m,2H),2.22(s,3H),2.57(m,1H),2.95(m,2H),3.28(s,2H),3.71(s,3H),4.86(s,2H),6.60(m,1H),6.78(m,1H),6.97(m,1H),7.17(m,1H),7.23(s,1H),7.37(d,2H),7.90(d,2H),9.55(s,1H);質譜
:M+H+
404。
N
-(2-胺基苯基)-4-{1-[(1-乙基-5-甲基-1H
-吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺
在1-乙基-5-甲基-1H
-吡唑-4-甲醛(141毫克,1.02毫莫耳)於二氯甲烷(1毫升)中之溶液中,加入第三丁基2-[(4-六氫吡啶-4-基苯甲醯基)胺基]苯基胺基甲酸酯(如述於下文方法1中者製備;300毫克,0.76毫莫耳)於二氯甲烷(6.5毫升)中之溶液。加入醋酸(45微升,0.79毫莫耳),再使該反應混合物攪拌4小時。接著加入N,N
二甲基甲醯胺(1毫升),再繼續攪拌30分鐘,然後加入固體形式之三乙醯氧基硼氫化鈉(245毫克,1.16毫莫耳)。接著在室溫下攪拌該反應混合物18小時(隔夜)。藉由加入甲醇而將該反應混合物稀釋至雙倍體積,再將其直接倒至一經預洗(以甲醇)之SCX-2柱(10克)上。以甲醇(60毫升)清洗該柱,然後再以氨於甲醇中之2 M溶液(50毫升)溶析產物。蒸發該氨溶析液,以產生一無色膠體(420毫克),將其溶於二氯甲烷(5毫升)中,再以三氟乙酸(2毫升)處理。使該混合物在室溫下攪拌2小時,然後再以二氯甲烷(10毫升)稀釋,並倒至一經預洗(以甲醇)之SCX-2柱(10克)上。以二氯甲烷(40毫升)、甲醇(50毫升)清洗該柱,接著再以氨於甲醇中之2 M溶液(50毫升)溶析產物。蒸發該氨級份,以產生一淺黃色之膠體(300毫克),其以反相製備性HPLC純化,產生標題化合物(172毫克,54%);NMR光譜
:(DMSO d6
)δ 1.27(t,3H),1.66(m,4H),1.98(m,2H),2.21(s,3H),2.56(m,1H),2.92(m,2H),3.29(s,2H),4.02(q,2H),4.85(s,2H),6.59(m,1H),6.77(m,1H),6.95(m,1H),7.16(m,1H),7.23(s,1H),7.35(d,2H),7.89(d,2H),9.54(s,1H);質譜
:M+H+
418。
使用類似述於實例9者之流程,使第三丁基2-[(4-六氫吡啶-4-基苯甲醯基)胺基]苯基胺基甲酸酯(如述於下文方法1中者製備)與適當之吡唑甲醛起始物質反應,以產生述於表2之化合物。
{2-[(4-六氫吡啶-4-基苯甲醯基}胺基]苯基}胺基甲酸第三丁酯
在苄基4-{4-[({2-[(第三丁氧羰基)胺基]苯基}胺基)羰基]苯基}-3,6-二氫吡啶-1(2H
)-羧酸酯(269克,524毫莫耳;如述於下文方法2中者製備)於甲醇(3000毫升)中之溶液中,加入10%鈀被碳(10克)。將該反應混合物置於5巴壓力之氫氣下,並加熱至50℃ 1小時。使該反應混合物冷卻至室溫,通過矽藻土墊過濾,再在減壓條件下蒸發溶劑。在乙醚中研製該所得之泡沫體,並進行過濾,以產生一白色固體。細磨此一產物,並使其與95:5之乙醚/乙酸乙酯攪拌,接著再以抽氣過濾進行收集。以乙醚、異己烷清洗此固體,再在真空下進行乾燥,以產生標題化合物(167克,81%);NMR光譜
:(DMSO-d6
)1.45(s,9H),1.57(m,2H),1.72(m,2H),2.61(t,2H),2.69(m,1H),3.07(m,2H),7.18(m,2H),7.40(d,2H),7.53(d,2H),7.91(d,2H),8.70(br s,1H),9.82(br s,1H);質譜
:M+H+
396。
4-{4-[({2-[(第三丁氧羰基)胺基]苯基}胺基)羰基]苯基}-3,6-二氫吡啶-1(2H
)-羧酸苄酯
將四(三苯膦)鈀(0)(8.0克,6.92毫莫耳)加入N
-(2-t-丁氧羰胺基苯基)-4-(4,4,5,5-四甲基-1,3,2,-二硼戊環2-基)苯甲醯胺(288克,657毫莫耳;如國際專利申請案WO 03/087057號,方法13,第60頁所述製備)及4-{[(三氟甲基)磺醯基]氧基}-3,6-二氫吡啶-1(2H
)-羧酸苄酯(240克,657毫莫耳;如述於下文方法3中者製備)於1,2-二甲氧基乙烷(3000毫升)及飽和碳酸氫鈉水溶液(3000毫升)中之攪拌懸浮液中。將該反應混合物加熱至80℃ 7小時,然後再使其冷卻至室溫,同時予以攪拌。接著將該反應混合物倒至水(2000毫升)上,並以乙酸乙酯進行萃取。接著以硫酸鎂對該有機萃取物進行去水,過濾,並蒸發至乾,以產生呈灰色固體之粗製產物。在矽膠上,以閃蒸層析純此物質,以乙酸乙酯/己烷(30:70 v/v)溶析,以產生標題化合物(279克,82%);NMR光譜
:(DMSO-d6
)δ 1.44(s,9H),2.56(m,2H),3.66(m,2H),4.14(m,2H),5.13(s,2H),6.34(m,1H),7.18(m,2H),7.33(m,1H),7.40(m,4H),7.54(m,2H),7.62(d,2H),7.94(d,2H),8.64(br s,1H),9.81(br s,1H);質譜
:MNa+
550。
4-{[(三氟甲基)磺醯基]氧基}-3,6-二氫吡啶-1(2H
)-羧酸苄酯
在氮氣大氣下,將苄基4-氧六氫吡啶-1-羧酸酯(147克,630毫莫耳)溶於四氫呋喃(500毫升)中。在氮氣下,以2小時之時間將此溶液逐滴加入六甲基乙矽烷疊氮化鋰(於四氫呋喃中之20%溶液,556毫升,662毫莫耳)中,同時使該反應溫度維持在低於-70℃。在-75℃下再攪拌該反應混合物1小時,然後再以2小時之時間逐滴加入N-苯基-雙(三氟甲磺醯亞胺)(236克,661毫莫耳)於四氫呋喃(950毫升)中之溶液,同時再次使該反應溫度維持在低於-70℃。接著使該反應隔夜回溫至室溫,再逐份加入2 M氫氧化鈉水溶液(800毫升)。分離各層,並以額外之2 M氫氧化鈉水溶液(600毫升)清洗該有機層,然後再蒸發至乾。將該所得之固體溶於乙醚中,再以水進行清洗。接著使該有機層通過矽藻土過濾,以硫酸鈉去水,再蒸發至乾,以產生標題化合物(140克,61%),其不經進一步之純化即用於下一階段。
{2-[(4-六氫吡啶-4-基苯甲醯基}胺基]苯基}胺基甲酸第三丁酯(替代方法)
在{2-[4-吡啶-4-基苯甲醯基)胺基]苯基}胺基甲酸第三丁酯(20克,51.35毫莫耳;如述於下文方法5A或5B中者製備)、10%鈀被碳(3.17克)及檸檬酸(4.75克,24.65毫莫耳)中,加入水(80毫升)及IPA(80毫升)。將該反應混合物置於4巴壓力之氫氣下,並加熱至70℃ 5小時。使該反應混合物冷卻至50℃,並通過矽藻土墊過濾。將該混合物加熱至70℃,然後再以10分鐘之時間加入20% w/w之氫氧化鈉水溶液(15毫升)至pH 10-11。加入額外之水(30毫升),再以1小時之時間使該混合物冷卻至40℃,接著再次加熱至60℃ 30分鐘,然後在冷卻回到室溫。過濾收集所得之沈澱物,以水(2x20毫升)清洗,再在真空下乾燥(50℃),以產生標題化合物(17.6克,84%);NMR光譜
:(DMSO-d6
)δ 1.45(s,9H),1.53(m,2H),1.70(m,2H),2.58(m,1H),2.66(m,2H),3.03(m,2H),3.31(br s,1H),7.17(m,2H),7.35(d,2H),7.54(m,2H),7.89(d,2H),8.65(br s,1H),9.75(br s,1H)。
質譜
:M+H+
396。
{2-[4-吡啶-4-基苯甲醯基)胺基]苯基}胺基甲酸第三丁酯
在乙腈(300毫升)中之4-(4-吡啶基)苯甲酸鈉(55.2克,236.2毫莫耳)、boc鄰-苯二胺(45.7克,217.6毫莫耳)及N-甲基嗎啉(24毫升)中,以3小時之時間,加入2-氯-4,6-二甲氧基-1,3,5-三嗪(48.5克,270.5毫莫耳)於乙腈(152毫升)中之過篩溶液。攪拌該混合物22小時,然後加入水(460毫升)。過濾收集所得之沈澱物,以50%之乙腈水溶液(3x100毫升)清洗,再在真空下乾燥(50℃),以產生標題化合物(75.6克,90%);NMR光譜
:(DMSO-d6
):δ 1.45(s,9H),7.17(m,2H),7.56(m,2H),7.81(d,2H),7.99(d,2H),8.11(d,2H),8.69(d,2H),9.94(br s,1H)。
質譜
:M+H+
390。
{2-[4-吡啶-4-基苯甲醯基)胺基]苯基}胺基甲酸第三丁酯
將乙腈(60毫升)中之4-(4-吡啶基)苯甲酸鈉(10克,45.2毫莫耳)加熱至70℃,接著加入亞硫醯氯(6.6毫升,90.4毫莫耳)。使該反應物在回流溫度下加熱5小時,然後再冷卻至室溫。小心加入三乙胺(12.6毫升,90.4毫莫耳),然後再以10分鐘之時間加入Boc鄰-苯二胺(9.42克,45.2毫莫耳)於乙腈(15毫升)中之溫溶液。加入氫氧化鈉(8.6克,109毫莫耳)於水(60毫升)中之溶液,過濾收集所得之固體,以水(20毫升)清洗,再在真空下乾燥(50℃),以產生標題化合物(12.6克,68%);NMR光譜
:(DMSO-d6
):δ 1.45(s,9H),(7.17(m,2H),7.56(m,2H),7.81(d,2H),7.99(d,2H),8.11(d,2H)8.69(d,2H),9.94(br s,1H)。
質譜
:M+H+
390.
(2-{[4-(1-{1,3-二甲基-1H
-吡唑-4-基甲基}六氫吡啶-4-基)苯甲醯基]胺基}苯基)胺基甲酸第三丁酯
將2-[(4-六氫吡啶-4-基苯甲醯基)胺基]苯基胺基甲酸第三丁酯(6.83克,17.3毫莫耳)及1,3-二甲基-1H
-吡唑-4-甲醛(3.0克,24.2毫莫耳)溶於二氯甲烷(150毫升)中。接著加入醋酸(996微升,17.3毫莫耳),並使該反應混合物在室溫下攪拌4小時。接著加入三乙醯氧基硼氫化鈉(5.49克,25.9毫莫耳),並再攪拌該反應混合物18小時。接著小心加入飽和之碳酸氫鈉水溶液(300毫升),再加入二氯甲烷(100毫升)。分離該有機層,再以更多之二氯甲烷(150毫升)再次萃取該水層。以硫酸鎂對該結合之有機萃取物進行去水,過濾,再蒸發至乾。在矽膠上,以閃蒸層析純化該所得之殘餘物,以甲醇於二氯甲烷中之5%(v/v)溶液溶析,接著再以甲醇於二氯甲烷中之5-10%(v/v)漸增梯度溶析,以產生一澄清膠體,將其溶於乙醚中,再蒸發至乾,以產生標題化合物(7.61克,87%);NMR光譜
:(DMSO d6
)δ 1.43(s,9H),1.69(m,4H),1.98(m,2H),2.10(s,3H),2.56(m,1H),2.92(m,2H),3.26(s,2H),3.70(s,3H),7.15(m,2H),7.40(m,3H),7.52(m,2H),7.87(d,2H),8.60(s,1H),9.73(s,1H);質譜
:M+H+
504。
(2-{[4-(1-{1,3-二甲基-1H
-吡唑-4-基甲基}六氫吡啶-4-基)苯甲醯基]胺基}苯基)胺基甲酸第三丁酯
將2-[(4-六氫吡啶-4-基苯甲醯基)胺基]苯基胺基甲酸第三丁酯(如述於上文方法4中者製備;108.1克,273.3毫莫耳)、1,3-二甲基-1H
-吡唑-4-甲醛(35.6克,287毫莫耳)及鈀被碳(3.09克,1.37毫莫耳)加入適當之壓力瓶中。加入四氫呋喃(920毫升)、水(54毫升)及醋酸(32.8克,546.7毫莫耳),並在3巴氫氣下,將該攪拌混合物加熱至60℃,直到反應被認為完成為止。接著將該混合物冷卻至40℃,再加入2 M氫氧化鈉溶液(410毫升,820毫莫耳)。在冷卻至25℃時,過濾該混合物以除去催化劑,然後再加入四氫呋喃(650毫升),並分離該有機相。蒸餾以部分濃縮該有機相,然後加入甲苯(575毫升)。繼續進行蒸餾,同時藉由進一步加入甲苯(690毫升)而維持該反應體積。以約3小時之時間,使該反應混合物冷卻至室溫,期間結晶出該產物。過濾收集該固體,以甲苯(460毫升)清洗,接著以乙酸乙酯(230毫升)清洗,然後再在45℃於真空下乾燥至恆定重量,,以產生標題化合物(114.9克,83%)。
光譜
:(DMSO d6
),δ 1.434(s,9H),1.70(m,4H),1.98(m,2H),2.11(s,3H),2.56(m,1H),2.93(m,2H),3.28(s,2H),3.71(s,3H),7.16(m,2H),7.40(m,3H),7.52(m,2H),7.87(d,2H),8.60(s,1H),9.73(s,1H);質譜
:M+H+
504。
{2-[(4-{1-[(1,5-二甲基-1H
-吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯基)胺基]苯基}胺基甲酸第三丁酯
將1,5-二甲基-1H
-吡唑-4-甲醛(114毫克,0.92毫莫耳)加入2-[(4-六氫吡啶-4-基苯甲醯基)胺基]苯基胺基甲酸第三丁酯(289毫克,0.73毫莫耳)於二氯甲烷(6毫升)中之溶液,再加入醋酸(50微升,0.87毫莫耳)。在氮氣下,使該反應混合物攪拌2.5小時。加入三乙醯氧基硼氫化鈉(233毫克,1.10毫莫耳),再在室溫下使該反應混合物攪拌18小時(隔夜)。接著在該反應中加入飽和之碳酸氫鈉水溶液(10毫升),並使其攪拌15分鐘。分離該有機相,再以二氯甲烷(10毫升)再次萃取該水相。以水清洗該結合之有機物,以硫酸鎂去水,再蒸發至乾,以產生呈無色膠體之產物(308毫克,84%),其不經進一步之純化即予使用;質譜
:M+H+
504。
Claims (17)
- 一種式(IA)之化合物,
- 如請求項1之化合物,其中至少一個選自R2 、R3 及R5 之基團係不為氫。
- 如請求項1之化合物,其係N -(2-胺基苯基)-4-{1-[(1-甲基-1H -吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺,或其醫藥可接受之鹽。
- 如請求項1之化合物,其係N -(2-胺基苯基)-4-{1-[(1,3-二甲基-1H -吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺,或其醫藥可接受之鹽。
- 如請求項1之化合物,其係N -(2-胺基苯基)-4-{1-[(1,3,5-三甲基-1H -吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺,或其醫藥可接受之鹽。
- 如請求項1之化合物,其係N -(2-胺基苯基)-4-{1-[(1,5-二甲基-1H -吡唑-4-基)甲基]六氫吡啶-4-基}苯甲醯胺,或其醫藥可接受之鹽。
- 一種醫藥組合物,其包含如請求項1至6中任一項之化合物,或其醫藥可接受之鹽,結合醫藥可接受之稀釋劑或載體。
- 如請求項1至6中任一項之化合物,或其醫藥可接受之鹽,其作為藥物。
- 如請求項1至6任一項之化合物,或其醫藥可接受之鹽,其用於治療癌症。
- 如請求項1至6任一項之化合物,或其醫藥可接受之鹽,其用於治療肺癌、結腸直腸癌、乳癌、列腺癌、淋巴瘤及/或白血病。
- 如請求項1至6中任一項之化合物,或其醫藥可接受之鹽,係用於在溫血動物體內產生HDAC抑制作用。
- 如請求項1至6任一項之化合物,或其醫藥可接受之鹽,其用於治療癌症,其中該化合物係與選自一或多種下列抗腫瘤劑類型之化療藥劑經同時、順序或分別投藥:(i)抗增殖劑/抗腫瘤藥物;(ii)細胞抑制劑;(iii)可抑制癌細胞侵染之試劑;(iv)生長因子功能之抑制劑;(v)抗血管生成劑;(vi)血管損傷劑;(vii)反義物治療;(viii)基因治療方法;(ix)免疫治療方法; (x)細胞循環抑制劑;及(xi)分化劑。
- 一種如請求項1至6中任一項之化合物或其醫藥可接受之鹽於製造藥物之用途,該藥物係用於在溫血動物體內產生細胞循環抑制(抗細胞增殖)作用。
- 一種如請求項1至6中任一項之化合物或其醫藥可接受之鹽於製造藥物之用途,該藥物係用於治療癌症。
- 一種製備如請求項1之化合物或其醫藥可接受之鹽之方法,該方法包含:(a)使式(II)化合物
- 一種製備式(II)化合物之方法,
- 一種製備式(II)化合物之方法,
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