TWI591064B - 2-吡啶酮化合物 - Google Patents
2-吡啶酮化合物 Download PDFInfo
- Publication number
- TWI591064B TWI591064B TW102141288A TW102141288A TWI591064B TW I591064 B TWI591064 B TW I591064B TW 102141288 A TW102141288 A TW 102141288A TW 102141288 A TW102141288 A TW 102141288A TW I591064 B TWI591064 B TW I591064B
- Authority
- TW
- Taiwan
- Prior art keywords
- compound
- cyclopropyl
- phenyl
- ethyl
- difluoroethyl
- Prior art date
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- -1 2-pyridone compound Chemical class 0.000 title claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 168
- 239000002904 solvent Substances 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- 239000013078 crystal Substances 0.000 claims description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 238000004519 manufacturing process Methods 0.000 claims description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 25
- 206010012601 diabetes mellitus Diseases 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 21
- 239000008280 blood Substances 0.000 claims description 16
- 210000004369 blood Anatomy 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 16
- 230000004913 activation Effects 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
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- 239000012453 solvate Substances 0.000 claims description 9
- 229910017488 Cu K Inorganic materials 0.000 claims description 8
- 229910017541 Cu-K Inorganic materials 0.000 claims description 8
- 238000002844 melting Methods 0.000 claims description 8
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- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
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- ABERLDAQFUZISG-SJLPKXTDSA-N 3-cyclopropyl-6-[(1r)-1-[4-(1,1-difluoroethyl)phenyl]-2-[(2r)-5-oxopyrrolidin-2-yl]ethyl]-1h-pyridin-2-one Chemical compound C1=CC(C(F)(F)C)=CC=C1[C@H](C=1NC(=O)C(C2CC2)=CC=1)C[C@@H]1NC(=O)CC1 ABERLDAQFUZISG-SJLPKXTDSA-N 0.000 description 4
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- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- CMZUMMUJMWNLFH-UHFFFAOYSA-N sodium metavanadate Chemical compound [Na+].[O-][V](=O)=O CMZUMMUJMWNLFH-UHFFFAOYSA-N 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
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- 239000012085 test solution Substances 0.000 description 1
- 229950006667 tofogliflozin Drugs 0.000 description 1
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- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Description
本發明係關於具有葡萄糖激酶(glucokinase )活性化作用之新穎2-吡啶酮化合物及含有此作為有效成分之醫藥。此外,亦關於該化合物之結晶及其之製造方法。
2型糖尿病患者數目正處於世界性的增加階段,因病態的發展與併發症的發病而造成嚴重的疾病預測,因此期望開發新的預防藥或治療藥。2型糖尿病,一般認為其發病係與遺傳因素或年齡增長有所關聯,在此背景下,再加上先進國家的生活習慣,亦即相對於身體活動量而攝取能量過剩的狀態,可以推測到發病風險會大幅增加。此外,病態之基礎的代謝異常,係可列舉於骨骼肌或脂肪組織中之糖利用的降低、來自胰臟β細胞之胰島素分泌障礙、肝臟葡萄糖釋出之抑制不全等,將此等改善的藥劑係被認為有用於2型糖尿病之預防及治療。
對於骨骼肌或脂肪組織中之糖利用的降低,
一般認為藉由以四氫噻唑衍生物(例如,吡格列酮(Pioglitazone))為代表的胰島素抵抗性改善藥所致之藥物療法係有效,但報告有更加肥胖、體液聚積、心臟衰竭風險增大、膀胱癌之發病率增加等,故使用時需要慎重的判斷。此外,對於胰島素分泌障礙,一般認為磺醯脲藥(例如,格列美脲(Glimepiride)、格列本脲(Glibenclamide)、格列吡嗪(Glipizide))為有效,但由於會常常引起低血糖或體重過重,此外於長期使用時會有治療效果減弱而導致血糖控制不良(二次無效)的情況,因此在安全性與有效性兩方面仍殘留課題。對於食後高血糖,雖使用有α-葡萄醣苷酶抑制劑(例如,阿卡波糖(Acarbose)、伏格列波糖(Voglibose)、米格列醇(Miglitol))或列奈(Glinide)藥(例如,那格列奈(Nateglinide)、瑞格列奈(Repaglinide)、米格列奈(Mitiglinide)),但糖尿病治療效果係有所限定。於肝臟葡萄糖釋出之抑制方面,雖雙胍藥(例如,二甲雙胍)為有效,但隨著病態之發展,血糖控制會變得困難,而且會有因消化管副作用或乳酸酸血症風險等,而於使用時增加限制的情況。如依據上述主要藥劑相關的見解所明瞭般,既有的藥劑不能說是滿足醫療上之必要性者。尤其,獲得直接性的肝臟葡萄糖代謝之改善的藥劑,實際上就只有二甲雙胍,故能夠藉由新穎製作機制(mechanism)而改善肝臟葡萄糖代謝之藥劑的必要性非常大。
葡萄糖激酶(glucokinase:以下記載為GK)
係屬於己醣激酶系(Hexokinase Family),在胰臟β細胞或肝細胞等,催化(catalyze)引入細胞內的葡萄糖之磷酸化。肝臟與胰臟β細胞之GK,雖會分別因剪接(splicing)的差異而使N末端15胺基酸的序列有所差異,但在酵素學上係為同一。GK係對於葡萄糖之親和性S0.5高達10mM左右,且不會受到因生成物之葡萄糖6磷酸所致之抑制,因此,其反應速度係於血糖值之生理性的變動區域產生敏感反應。於胰臟β細胞,係調節葡萄糖依存性的胰島素分泌,另一方面,於肝臟,係調節解糖系統或肝糖合成,而維持、調節血糖值。因而,GK係被認為是作為用以恆常性維持血糖值之葡萄糖感測器而發揮功能(參照非專利文獻1)。
將GK作為生物體內葡萄糖感測器而發揮功能的假設,係藉由基因工程小鼠或人類基因變異之發現所支持。GK同型結合缺失小鼠,出生後即呈現高血糖而死亡,此外,於異質結合缺失小鼠中,係觀察有高血糖、耐糖功能不全(參照非專利文獻2)。另一方面,GK過剩表現小鼠,係確認有血糖降低(參照非專利文獻3)。進而,確認有GK基因變異的人類MODY2(maturity onset diabetes of the young),係從年輕開始糖尿病發病(參照非專利文獻4)。於此基因變異中,係確認有GK之活性降低。另一方面,亦報告有具有使GK活性亢進之基因變異的血統(參照非專利文獻5)。於此基因變異中,係對於GK之葡萄糖的親和性亢進,確認為伴隨血中胰島素濃
度上昇之絕食時低血糖症狀。
如上所述,GK係顯示在包含人類之哺乳類中作為葡萄糖感測器而發揮功能。
使GK活性增大的物質(以下,記載為GK活性化物質),係被認為能夠藉由增大在肝臟之糖代謝或肝糖合成、來自胰臟β細胞之葡萄糖應答性胰島素分泌,而改善高血糖。其中,使肝臟優先增大GK活性的物質,一般認為藉由胰島素非依存性地使在肝臟之糖代謝亢進,而改善高血糖。藉由改善高血糖,而治療及預防視網膜病變、腎臟病變、神經官能症、缺血性心臟病、動脈硬化等之糖尿病性慢性併發症,進而亦可期待關於肥胖症、高血脂症、高血壓症、代謝症候群等之糖尿病相關疾病的治療及預防。因而,增大GK功能之化合物,係可期待成為有效的糖尿病治療藥。
另一方面,GK係報告有並非僅於胰臟或肝臟,亦表現於攝食中樞,且於以葡萄糖所致之攝食抑制作用中具有重要的功能(參照非專利文獻6)。因而,GK活性化物質,亦被認為會作用於攝食中樞,且具有攝食抑制作用,而並非僅治療糖尿病,故亦可期待作為肥胖治療藥。
另外,GK活性化物質,雖報告有具有2-吡啶酮之化合物,但結構與本發明之化合物不同(參照專利文獻1及2)。此外,雖報告有結構性類似的2-吡啶酮化合物,但就無本發明化合物之具體的揭示(參照專利文獻3
及4),此外,亦無對於醫藥用途之記載,而目的為2-吡啶酮化合物之合成法的觀點而言,係與本發明不同(參照非專利文獻7)。進而,雖報告有將能夠得到擬似的環狀結構之某種醯基脲化合物作為GK活性化物質,但為非環狀之化合物,故與本發明化合物不同(參照專利文獻5及6)。
[非專利文獻1] Matschinsky F. M. and Magnuson M. A., Frontiers in Diabetes, 16, 2004
[非專利文獻2] Grupe A.et al. Cell, 83, 1, 69-78, 1995
[非專利文獻3] Ferre T. et al. Proc. Natl. Acad. Sci., 93, 14, 7225-7230, 1996
[非專利文獻4] Vionnet N. et al. Nature, 356, 6371, 721-722, 1992
[非專利文獻5] Glaser B. et al. N. Engl. J. Med. 338, 4, 226-230, 1998
[非專利文獻6] Kang L. et al, Diabetes, 55, 2, 412-420, 2006
[非專利文獻7] Latif R. et al. J. Chem. Soc. C. Organic, 17, 2140-2144, 1968
[專利文獻1] WO2008/079787號手冊
[專利文獻2] WO2010/013161號手冊
[專利文獻3] US4275069號說明書
[專利文獻4] WO2011/068211號手冊
[專利文獻5] WO2000/58293號手冊
[專利文獻6] WO2001/44216號手冊
本發明之目的在於提供一種具有優異的GK活性化作用而可用作為醫藥品的化合物。
本發明者們係鑑於上述記載的狀況,為了發現具有GK活性化作用的化合物而努力研究的結果,發現以下述式[1]所表示之2-吡啶酮化合物(化合物名:3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮)或該化合物之互變異構物、或者其藥學上所容許的鹽(以下,將該2-吡啶酮化合物或該化合物之互變異構物、或者此等之藥學上所容許的鹽稱為「化合物等」)、或者該化合物等之溶劑合物會達成此目的,因而完成本發明。
(I)本發明之1個樣態係提供以式[1]
所表示之2-吡啶酮化合物或該化合物之互變異構物、或者此等之藥學上所容許的鹽、或者該化合物等之溶劑合物。
(II)本發明之另一樣態,係提供如(I)記載之以上述式[1]所表示,且具有下述(a)之物性的3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮之結晶;
(a)於粉末X射線繞射圖(Cu-K α)中,於繞射角2θ=8.5、13.4、19.1及24.5°時具有峰值。
(III)本發明之另一樣態,係提供如(I)記載之以上述式[1]所表示,且具有下述(a)~(c)之物性的3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮之結晶;
(a)於粉末X射線繞射圖(Cu-K α)中,於繞射角2θ=8.5、13.4、19.1及24.5°時具有峰值;(b)於紅外線吸收光譜中,特性吸收光帶係於916、1146、1167、1295、1651、1664、2909、2955、3003及3146cm-1;(c)熔點為199~201℃。
(IV)本發明之另一樣態,係提供具有下述(a)~
(c)之物性的3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮之結晶的製造方法,其特徵為將以上述式[1]所表示之3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮加熱溶解於醇系溶劑之後,添加水溶劑並冷卻至5℃以下使其結晶化,使所得到的結晶在60℃以下乾燥;(a)於粉末X射線繞射圖(Cu-K α)中,於繞射角2θ=8.5、13.4、19.1及24.5°時具有峰值;(b)於紅外線吸收光譜中,特性吸收光帶係於916、1146、1167、1295、1651、1664、2909、2955、3003及3146cm-1;(c)熔點為199~201℃。
(V)本發明之另一樣態,係提供一種醫藥,其係含有如(I)記載之2-吡啶酮化合物或該化合物之互變異構物、或者此等之藥學上所容許的鹽、或者該化合物等之溶劑合物作為有效成分。
(VI)本發明之另一樣態,係提供如(V)記載之醫藥,其係用以預防或治療能藉由葡萄糖激酶活性化作用獲得改善的疾病或狀態。
(VII)本發明之另一樣態,係提供如(V)記載之醫藥,其係血糖降低作用藥。
(VIII)本發明之另一樣態,係提供如(V)記載之醫藥,其係糖尿病之預防或治療藥。
依據本發明,可提供一種具有優異的GK活性化作用之2-吡啶酮化合物。
此外,依據本發明,可提供可用作為醫藥品且具有新穎的結晶形態之3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮之結晶。該結晶係在室溫附近之溫度時為安定的結晶形,故保存安定性優異。
進而,依據本發明,可提供一種用以同一品質且安定、安全地得到上述結晶之新穎的製造方法。
[第1圖]係顯示本發明之3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮之結晶的粉末X射線繞射圖型。
[第2圖]係顯示本發明之3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮之結晶的紅外線吸收光譜(ATR法,晶體:金鋼石)。
[第3圖]係顯示本發明之3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮之結晶的示差熱分析/熱質量測定曲
線。
以下,雖針對本發明進行詳細地說明,但所例示者並無特別限定。
於本發明中,「n」係表示正,「i」係表示異,「s」及「sec」係表示二級,「tert」係表示三級,「c」係表示環,「o」係表示鄰,「m」係表示間,「p」係表示對。
首先,針對本發明化合物進行說明。
於本發明中,藥學上容許的鹽,係指例如:鹽酸鹽、氫溴酸鹽、氫碘酸鹽、磷酸鹽、硫酸鹽、硝酸鹽之類的無機酸鹽;甲磺酸鹽、乙磺酸鹽、苯磺酸鹽、p-甲苯磺酸鹽之類的磺酸鹽;草酸鹽、酒石酸鹽、檸檬酸鹽、馬來酸鹽、琥珀酸鹽、乙酸鹽、苯甲酸鹽、苦杏仁酸鹽、抗壞血酸鹽、乳酸鹽、葡萄糖酸鹽、蘋果酸鹽之類的羧酸鹽;甘胺酸鹽、賴胺酸鹽、精胺酸鹽、鳥胺酸鹽、麩胺酸鹽、天冬胺酸鹽之類的胺基酸鹽;或者是鋰鹽、鈉鹽、鉀鹽、鈣鹽、鎂鹽之類的無機鹽或銨鹽、三乙基胺鹽、二異丙基胺鹽、環己基胺鹽之類的有機鹼之鹽,較佳係可列舉:鹽酸鹽、氫溴酸鹽、磷酸鹽、硫酸鹽、甲磺酸鹽、p-甲苯磺酸鹽、草酸鹽、酒石酸鹽、檸檬酸鹽、乙酸鹽、乳酸鹽、麩胺酸鹽、天冬胺酸鹽、鈉鹽、鉀鹽、銨鹽、或者三乙基胺鹽。
於本發明中之溶劑合物,係指本發明之化合物或其鹽之醫藥上所容許的溶劑合物。本發明之化合物及其鹽,係藉由暴露於大氣中、或者進行再結晶等,吸收水分,而有帶有吸附水的情況或成為水合物的情況。於本發明之化合物中,亦含有如此之水合物。
本發明之化合物,雖具有2個不對稱中心,但本發明化合物為光學活性體,且本發明之化合物的2個不對稱中心絕對配置皆為(R)。本發明之化合物,係可藉由相對應的外消旋物或非鏡像異構物混合物之光學分割而得到。光學分割之方法,係可使用該業者所熟知的方法,例如分別結晶法或使用有掌性管柱的層析法。此外,本發明之光學活性體化合物,亦可藉由此目的所需之所周知的有機化學性手法而得到。此外,於用以得到本發明之化合物的合成中間體中,雖有(E)體、(Z)體等之幾何異構物存在,但此等異構物之比例為任意。
於本發明之化合物中,亦含有互變異構物。互變異構物係意味著:以上述式[1]所表示的化合物之酮-烯醇互變異構物。將以下顯示以上述式[1]所表示的化合物及其之互變異構物[1’]作為例子。
本發明之2-吡啶酮化合物,係可為其之藥學上所容許的鹽,或者亦可為該化合物等之溶劑合物。以下,包含本發明之2-吡啶酮化合物或該化合物之互變異構物、或者此等之藥學上所容許的鹽、或者該化合物等之溶劑合物,皆稱為「本發明化合物」。
此外,針對具有可化學性或代謝性分解的基,且藉由加溶劑分解或者在生理性條件下之in vivo(在活體內)中形成藥理性活性的本發明化合物之化合物,一般稱為前驅藥之化合物,亦包含於「本發明化合物」中。
本發明化合物係具有GK活性化作用。因而,本發明化合物,主要是藉由增大在肝臟的糖代謝,而可改善高血糖。因此,既存的糖尿病治療藥,係指可作為作用機制不同之新穎的藥物療法而利用。糖尿病,係指包含I型糖尿病、II型糖尿病、因特定原因所致之其他的糖尿病。進而,本發明化合物,對於酮酸症、微血管病(視網膜病變、腎臟病變)、動脈硬化症(粥狀性動脈硬化症、心肌梗塞、腦梗塞、周邊動脈阻塞等)、神經病變(感覺神經、運動神經、自律神經等)、足壞疽、感染症等之糖尿病性併發症的治療及預防亦為有效。
進而,亦能夠利用於肥胖症、高血脂症、高血壓症、代謝症候群、浮腫、高尿酸血症、痛風等之糖尿病相關疾病的治療及預防。
此外,本發明化合物,亦可與GK活性化作用
以外之相異的作用機制之糖尿病治療藥、糖尿病併發症治療藥、高血脂症治療藥、高血壓症治療藥等合併使用。藉由將本發明之化合物與其他的藥劑進行組合,而於上述疾病中,相較於分別以單劑所得到的效果,經併用的情況更可期待相加性的效果。
能夠併用的糖尿病治療藥、糖尿病併發症治療藥,係可列舉例如:胰島素製劑、胰島素抵抗性改善藥(PPARγ促效劑、PPARα/γ促效劑、PPARδ促效劑、PPARα/γ/δ促效劑等)(例如:吡格列酮(Pioglitazone)、羅格列酮(Rosiglitazone)、阿格列扎(Aleglitazar)、培格列扎(Peliglitazar)、AVE-0897、MBX-8025)、α-葡萄醣苷酶抑制劑(例如:伏格列波糖(Voglibose)、阿卡波糖(Acarbose)、米格列醇(Miglitol))、雙胍藥(例如:二甲雙胍、丁福明(Buformin)、苯乙雙胍)、胰島素分泌促進藥(例如:格列本脲(Glibenclamide)、格列美脲(Glimepiride)、瑞格列奈(Repaglinide)、那格列奈(Nateglinide)、米格列奈(Mitiglinide))、升糖素受體拮抗劑、胰島素受體激酶促進藥、雙胜肽蛋白水解酶IV抑制劑(例如:維格列汀(Vildagliptin)、阿格列汀(Alogliptin)、西他列汀(Sitagliptin)、利拉利汀(Linagliptin)、沙格列汀(Saxagliptin)、特力利汀(Teneligliptin)、阿拉格列汀(Anagliptin))、SGLT抑制劑(例如:達格列淨(Dapagliflozin)、魯格列淨(音譯;Luseogliflozin)、
卡納格列淨(Canagliflozin)、依帕列淨(Empagliflozin)、艾普格列淨(Ipragliflozin)、托格列淨(Tofogliflozin))、PTP1b抑制劑(例如:釩酸鈉)、葡萄糖6磷酸酶抑制劑、肝醣磷酸化酶抑制劑(例如:PSN-357、FR-258900)、FBPase抑制劑(例、MB-07803)、PEPCK抑制劑、丙酮酸脫氫酶激酶抑制劑、D-右旋肌醇、GSK3抑制劑、GLP-1促效劑(例如:利拉魯肽(Liraglutide)、艾塞那肽(Exenatide))、澱粉素促效劑(例如:普蘭林肽(Pramlintide))、糖皮質素受體拮抗劑、11 β HSD1抑制劑(例如:INCB-13739、LY-2523199、Ro-5027838、Ro-5093151、S-707106)、蛋白質激酶C抑制劑(例如:魯伯斯塔(Ruboxistaurin))、β 3腎上腺素受體促效劑、磷脂醯肌醇激酶抑制劑、磷脂醯肌醇磷酸酶抑制劑、ACC抑制劑、GPR40受體促效劑(例、TAK-875)、GPR119受體促效劑(例如:APD-597、PSN-821、MBX-2982、DS-8500)、GPR120受體促效劑、TGR5受體促效劑、AMPK活性化藥、醛醣還原酵素抑制劑(例如:依帕司他(Epalrestat)、雷尼司他(Ranirestat)、法地司他(Fidarestat))、AGE抑制劑等。
此外,能夠併用的糖尿病相關疾病之藥劑,係可列舉:HMG-CoA還原酵素抑制劑、鯊烯合成酵素抑制劑、膽酸吸附劑、IBAT抑制劑、CETP抑制劑、CPT抑制劑、微纖維酸(Fibrates)系藥劑、ACAT抑制劑、
MGAT抑制劑、DGAT抑制劑、膽固醇吸收抑制劑、胰脂酶抑制劑、MTP抑制劑、異菸鹼酸衍生物、LXR促效劑、LDL受體增多劑、血管張力素變換酵素抑制劑、血管張力素II拮抗劑、腎素受體拮抗劑、醛固酮拮抗劑、利尿劑、鈣拮抗劑、α阻斷劑、β阻斷劑、內皮素變換酵素抑制劑、內皮素受體拮抗劑、食欲抑制藥、尿酸生成抑制劑、尿酸排泄促進劑等。
本發明化合物係可單獨或與藥學上或者藥劑學上所容許的載體或稀釋劑一起投予。使用本發明化合物作為GK活性化物質時,亦可將本發明化合物直接經口投予,或者非經口投予。此外,含有本發明化合物作為有效成分的藥劑,亦可經口投予、或者非經口投予。非經口投予係可列舉:靜脈內投予、經鼻投予、經皮投予、皮下投予、肌肉內投予、舌下投予。
本發明化合物之投予量,雖依據投予對象、投予途徑、對象疾病、症狀等而異,但於例如對於成人之糖尿病患者進行經口投予時,一般1次量為約0.01~1000mg,較佳為0.1~100mg,以將此量進行1日1~3次投予者較為理想。
接著,針對本發明化合物之製造方法進行說明。
本發明化合物,雖可藉由以下所示的方法進行合成,但下述製造法係顯示一般性製造法的例子,並非限定製造法。
本發明化合物之合成,亦可使用於化學領域中自體周知的方法,或者經過類似於此之一個或二個以上之製程的方法。如此之方法係可列舉例如:於有機官能基製劑(ORGANIC FUNCTIONAL GROUP PREPARATIONS )第2版ACADEMIC PRESS公司(ACADEMIC PRESS,INC.)1986年刊、綜合.有機.變換(Comprehensive Organic Transformations)VCH Publishers Inc.1989年刊、胜肽合成之基礎與實驗 丸善股份有限公司刊1985年等所記載的方法等。
於本發明化合物之合成中,起始原料或中間體等所含有的官能基之適當的保護及去保護之方法,係可依據該業者所周知的方法,例如:於Greene’s有機合成中的保護基(Greene’s Protective Groups in Organic Synthesis)John Wily and Sons公司2006年刊等所記載的方法來實施。
雖於流程(scheme)1~2顯示本發明化合物之一般性的製造法,但並不限定製造法。亦可使用變更實施步驟的順序、於羥基等施以保護基來實施反應而在之後的步驟中實施去保護、或於各步驟途中追加新的步驟等之對於該業者而言為周知的方法來製造本發明化合物。
流程1:來自化合物(1-a)之本發明化合物[1]的合成法
(流程中,G1係表示羥基吡啶基中之羥基的保護基,R1係表示2-苯并噻唑基或1-苯基-1H-四唑-5-基)。
另外,步驟(1-4)使用的化合物(1-g),係可作為市售化合物、周知化合物、或者使用該業者所周知的各種有機合成手法,由容易取得的化合物所合成之化合物而取
得。
化合物(1-b)之製造方法:可藉由進行於化合物(1-a)使用三氟化N,N-二甲氧基乙基胺基硫(雙(2-甲氧基乙基)胺基硫三氟化物、Deoxo-Fluor(註冊商標))等之氟化試劑的「氟化反應」而製造化合物(1-b)。
該氟化反應係可列舉例如:藉由於無溶劑或惰性溶劑中,在0℃至100℃之溫度下,使Deoxo-Fluor(註冊商標)等之氟化試劑與化合物(1-a)反應,而賦予化合物(1-b)的方法。
化合物(1-d)之製造方法:係可藉由使化合物(1-b),於惰性溶劑中,在乙酸鉀等之鹼及鈀觸媒存在下,與化合物(1-c)產生作用,而製造化合物(1-d)。
化合物(1-f)之製造方法:係可藉由使化合物(1-e),於惰性溶劑中,在與n-丁基鋰或n-丁基鎂氯化物等之鹼產生作用之後,與N,N-二甲基甲醯胺產生作用,而製造化合物(1-f)。
另外,作為起始物質之化合物(1-e),係可藉由
WO2011/068211號手冊所記載的方法或依據此之方法而取得。
化合物(1-h)之製造方法:可使藉由進行使用有羰基化合物(1-f)與化合物(1-g)之「偶合反應」所得到的(5R)-5-[2-(5-環丙基-6-甲氧基吡啶-2-基)乙烯基]吡咯啶-2-酮(E/Z混合物),於惰性溶劑中,與溴產生作用,接著,與1,8-二氮雜雙環[5.4.0]十一-7-烯(DBU)等之鹼產生作用,藉此而製造化合物(1-h)。
該偶合反應係可列舉例如:使藉由以化合物(1-g)為基質,且於惰性溶劑中,在-78℃至100℃之溫度下,使用n-丁基鋰、sec-丁基鋰、tert-丁基鋰等之有機金屬試劑或六甲基二矽胺化鋰、六甲基二矽胺化鉀等之鹼所產生的陰離子與羰基化合物(1-f)產生反應,藉此而賦予化合物(1-h)的方法。所得到的烯烴化合物,一般雖可得到為E/Z混合物,但藉由使用二氧化矽凝膠管柱層析或HPLC等,進行分割而可各自分離。
另外,於偶合反應所使用之化合物(1-g),係可藉由WO2011/068211號手冊所記載的方法或依據此之方法而取得。
化合物(1-i)之製造方法:係可藉由以化合物(1-
h)為基質,在鈀觸媒存在下,進行與苯基硼化合物(1-d)之「偶合反應」,而製造化合物(1-i)。
該偶合反應係可列舉例如:在20℃至160℃之溫度下,於惰性溶劑中,在鈀觸媒與鹼存在下,使化合物(1-h)與苯基硼化合物產生反應的方法。反應亦可使用微波。
偶合反應所使用的鈀觸媒係可列舉:肆三苯基膦鈀(0)、雙(二亞苄基丙酮(dibenzylideneacetone ))鈀(0)、參(二亞苄基丙酮)二鈀(0)、雙(三苯基膦)鈀(II)二氯化物、雙(三苯基膦)鈀(II)乙酸酯或者[1,1’-雙(二苯基膦基(diphenylphosphino))二茂鐵]鈀(II)二氯化物二氯甲烷錯合物(1:1)等之該業者所周知的鈀觸媒。此外,亦可於鹼存在下,將參(二亞苄基丙酮)二鈀(0)與三(2-呋喃基)膦使用於反應中。
化合物(1-j)之製造方法:係可以化合物(1-i)為基質,在0℃至80℃之溫度下,於惰性溶劑中,在氧存在下或非存在下,藉由使用有觸媒量之鈀-活性碳、銠-活性碳、或鉑-活性碳等的接觸氫化反應進行還原,藉此而製造化合物(1-j)。
化合物(1-k)之製造方法:係可藉由進行化合物(1-j)所具有之保護基G1的「去保護反應」,而製造化合物(1-k)。
該去保護反應,例如:(i)於保護基G1為烷基.烯丙基的情況中,係可列舉:在0℃至200℃之溫度下,於惰性溶劑中,藉由在酸或者強酸存在下水解反應而去除的方法,或使用有三甲基矽烷基碘化物等的方法或使用有氯化鋁與烷硫基(alkylthiol)的方法等之去保護反應;(ii)於保護基G1為苄基、4-甲氧基苄基、2,4-二甲氧基苄基、苄基氧代羰基、或者二苯甲(benzhydryl)(二苯基甲基)基等的情況中,係可列舉:在0℃至80℃之溫度下,於惰性溶劑中,在酸存在下或非存在下,藉由使用有觸媒量之鈀-活性碳、或銠-活性碳等的氫化分解反應進行去除的方法、或者使用硝酸鈰(IV)銨或2,3-二氯-5,6-二氰基-p-苯醌等之氧化劑的方法。
本發明化合物[1]之取得方法:可藉由對於化合物(1-k),使用例如HPLC等,將非鏡像異構物進行分割,而取得本發明化合物[1]。
另外,在上述流程1作為原料化合物所使用的化合物(1-a)及化合物(1-c),係可藉由市售或藉由本身周知的方法來取得。
(流程中,G1及R1係與上述相同。G2係表示經側氧基所取代的吡咯啶基中之氮原子的保護基)。
化合物(2-b)之製造方法:化合物(2-b)係可藉由WO2008/103185號手冊所記載的方法或依據此之方法而取得。
化合物(2-c)之製造方法:可藉由進行使用有化合物(2-b)與雜芳基鋰等之鋰試劑、雜芳基鎂溴化物等之格林納(Grignard)試劑等的陰離子之「加成反應」,將所得到的化合物以鹽酸等之酸進行處理而製造化合物(2-c)。
該加成反應係可列舉例如:使藉由以化合物(1-e)為基質,且於惰性溶劑中,在-78℃至100℃之溫度下,使用n-丁基鋰、sec-丁基鋰、tert-丁基鋰、異丙基鎂溴化物等之有機金屬試劑或鎂等之金屬試劑或六甲基二矽胺化鋰、六甲基二矽胺化鉀等之鹼所產生的陰離子與化合物(2-b)反應的方法。
化合物(2-d)之製造方法:係可藉由進行使用有羰基化合物(2-c)與化合物(1-g)的「偶合反應」,而製造化合物(2-d)。
該偶合反應係可列舉與步驟(1-4)中已敘述之「偶合反應」相同的反應。
藉由上述方式所得到的化合物(2-d),係可利用已敘述的流程1之步驟(1-7)~(1-9)所記載的方法,而導至本發明化合物[1]。
此外,亦可依據以下所示的方法,製造本發明化合物[1]。
化合物(2-e)之製造方法:可藉由使具有經側氧基取代的吡咯啶基之化合物(2-d),與二碳酸二-tert-丁基酯等產生作用,而製造具有保護基G2之化合物(2-e)。
化合物(2-f)之製造方法:係可藉由以化合物(2-e)為基質,且在0℃至80℃之溫度下,於惰性溶劑中,在氧存在下或非存在下,藉由使用有觸媒量之鈀-活性碳、銠-活性碳、或鉑-活性碳等的接觸氫化反應進行還原,而製造化合物(2-f)。
化合物(2-g)之製造方法:係可藉由進行化合物(2-f)所具有之保護基G2的「去保護反應」而製造化合物(2-g)。
該去保護反應係可列舉使用有如鹽酸或三氟乙酸之類的酸的方法。
本發明化合物[1]之製造方法:係可藉由進行化合物(2-g)所具有之保護基G1的「去保護反應」而製造本發明化合物[1]。
該去保護反應係可列舉與步驟(1-8)中已敘述之「去保護反應」相同的方法。
另外,在上述流程2作為原料化合物使用的化合物(2-a),係可藉由市售或藉由本身周知的方法來取得。
最後,針對本發明之3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮之結晶及其製造方法進行說明。
本發明之化合物3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮之結晶(以下,有時稱為「本發明結晶」),係具有上述式[1]所示之化學結構式。此外,本發明結晶,係如上所述般,可再現性良好地得到具有一定品質的單一結晶,且能夠安定地供給作為用於醫藥品之製造的原料藥之結晶,且保存安定性優異者。
本發明結晶係具有接下來的(a)~(c)之物性;(a)於粉末X射線繞射圖(Cu-K α、測量方法:透過法)中,於繞射角2θ=8.5、10.8、11.2、11.6、13.4、16.8、17.0、17.9、18.5、18.8、19.1、19.4、22.6、23.1、23.2及24.5°時具有峰值,尤其,於繞射角2θ=8.5、13.4、19.1及24.5°時具有特徵性的峰值;(b)於紅外線吸收光譜(ATR法,晶體:金鋼石)中,特性吸收光帶於916、1146、1167、1295、1375、
1614、1625、1651、1664、2837、2866、2909、2955、2986、3003、3088及3146cm-1,尤其,於916、1146、1167、1295、1651、1664、2909、2955、3003及3146cm-1時具有特徵性的特性吸收光帶;(c)熔點為199℃~201℃。
另外,以粉末X射線結晶繞射所致之特徵性的峰值,有時會依據測量條件而變動。因此,關於本發明化合物之粉末X射線結晶繞射的峰值,會有產生誤差,或不明確的情況。
本發明結晶之粉末X射線繞射圖型係如第1圖所示,紅外線吸收光譜(ATR法、晶體:金鋼石)係如第2圖所示,示差熱分析/熱質量測定曲線係如第3圖所示。
本發明結晶,係藉由使用醇系溶劑,使3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮結晶化,而進行製造。
於醇系溶劑中,溶解前的原料之3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮,係非結晶或結晶。
藉由使用有醇系溶劑之結晶化或再結晶而得到本發明結晶時之將3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮溶解於醇系溶劑及來自醇溶劑之結晶化,係可
利用一般的方法進行。例如,使用有於醇系溶劑中,使非晶質之3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮加熱溶解之後,進行冷卻的方法。
具有與醇系溶劑混合的性質之溶劑,係可列舉水溶劑或庚烷等之烴溶劑等。
另外,具有與醇系溶劑混合的性質之溶劑、與醇系溶劑的混合溶劑中之混合比係可進行適當地變更。
所使用的醇系溶劑,較佳為甲醇、乙醇、1-丙醇、異丙基醇、tert-丁基醇、1-丁醇、2-丁醇、2-乙氧基乙醇、2-甲氧基乙醇、三氟乙醇、乙二醇、丙二醇等碳數為1至4之醇,更佳為甲醇、乙醇、異丙基醇或丙二醇,再更佳為甲醇或乙醇。
使3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮溶解的濃度為1至50質量%,較佳為17至25質量%。在此,質量%係指溶液中之3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮之質量百分比。
可列舉:3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮之結晶化溫度,雖能夠在從-78℃至溶劑之回流溫度為止的溫度下實施,但較佳為將3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡
咯烷-2-基]乙基}吡啶-2(1H)-酮,於醇系溶劑中,從55℃加熱至75℃進行溶解之後,依據情況而添加具有與水等之醇系溶劑混合的性質之溶劑,並冷卻至5℃以下而使結晶析出的方法。
冷卻的時間,雖只要10秒鐘以上則無特別限制,但一般為10分鐘至24小時,較佳為30分鐘至5小時。就工業上製造的觀點而言,較佳為2小時至4小時。
所析出的結晶,係將懸浮液過濾,並藉由離心分離等與溶液分離之後,在60℃以下進行乾燥。
此外,結晶化時係可使用種晶。種晶,係可藉由以刮勺(Spatula)來摩擦添加有用以晶析的溶液之容器的壁等該業者所熟知的方法而取得。
本發明化合物之一般性製造方法的反應溫度,係指-78℃至250℃,較佳為-20℃至80℃。反應時間係5分鐘至3日,較佳為30分鐘至18小時。本製造方法係可在常壓下、加壓下、微波照射下等實施。
雖針對本發明化合物之一般製造法的記載中之鹼、酸、及惰性溶劑,進一步具體地記載,但並不限定於以下的例示。此外,雖亦針對可使用的分離手法進行具體地記載,但相同地並不限定於以下的例示。
所謂「鹼」係可列舉例如:鹼金屬或鹼土類金屬之氫化物(氫化鋰、氫化鈉、氫化鉀、氫化鈣等)、鹼金屬或鹼土類金屬之醯胺類(胺化鋰、胺化鈉、二異丙基醯胺鋰、二環己基醯胺鋰、六甲基二矽胺化鋰、六甲基
二矽胺化鉀等)、鹼金屬或鹼土類金屬之C1-C6烷氧化物(甲氧化鈉、乙氧化鈉、tert-丁氧化鉀等)、鹼金屬或鹼土類金屬之氫氧化物(氫氧化鈉、氫氧化鉀、氫氧化鋰、氫氧化鋇等)、鹼金屬或鹼土類金屬之碳酸鹽(碳酸鈉、碳酸鉀、碳酸鈣、碳酸銫等)、鹼金屬之碳酸氫鹽(碳酸氫鈉、碳酸氫鉀等)、鹼金屬或鹼土類金屬之磷酸鹽(磷酸三鉀等)等之無機鹼、胺類(三乙基胺、二異丙基乙基胺、N-甲基嗎啉等)、鹼性雜環化合物(吡啶、4-二甲基胺基吡啶、DBU(1,8-二氮雜雙環[5.4.0]十一-7-烯)、DBN(1,5-二氮雜雙環[4.3.0]壬-5-烯)、咪唑、2,6-二甲基吡啶(2,6-Lutidine)等)。
所謂「酸」係可列舉例如:無機酸(鹽酸、氫溴酸、硫酸、硝酸、磷酸等)、有機酸(p-甲苯磺酸、甲磺酸、三氟乙酸、甲酸、乙酸、樟腦磺酸等)、路易士酸(三氟化硼、三溴化硼、氯化鋁、三氟甲磺酸鈧(scandium triflate)、三氟甲磺酸鐿(ytterbium triflate)等)。
「惰性溶劑」方面,只要不阻礙反應,而將起始原料進行某種程度溶解者則無特別限定,可列舉例如:腈系溶劑、醯胺系溶劑、鹵化碳系溶劑、醚系溶劑、芳香族系溶劑、烴系溶劑、酯系溶劑、醇系溶劑、亞碸系溶劑、水,此等係可以適當的比例將二種以上混合使用。
腈系溶劑係可列舉例如:乙腈、丙腈。醯胺系溶劑係可列舉例如:N,N-二甲基甲醯胺(以下,有時亦
略稱為DMF)、N,N-二甲基乙醯胺、N-甲基吡咯啶酮。鹵化碳系溶劑係可列舉例如:二氯甲烷、氯仿、1,2-二氯乙烷、四氯化碳。醚系溶劑係可列舉例如:二乙基醚(以下,有時亦略稱為“醚”)、四氫呋喃(以下,有時亦略稱為THF)、1,4-二噁烷、1,2-二甲氧基乙烷。芳香族系溶劑係可列舉例如:苯、甲苯、二甲苯、吡啶。烴系溶劑係可列舉例如:己烷、戊烷、環己烷。酯系溶劑係可列舉例如:乙酸乙酯、甲酸乙酯。醇系溶劑係可列舉例如:甲醇、乙醇、異丙基醇、tert-丁基醇、乙二醇。亞碸系溶劑係可列舉例如:二甲基亞碸(以下,有時亦略稱為DMSO)。
藉由上述製造法所得到的化合物,係可藉由周知的手段,例如溶劑萃取、液性變換、轉溶、結晶、再結晶、各種層析法而進行分離純化。
以下雖記載可使用本發明化合物之一般製造中的化合物之保護基,但並不限定於此例示,其他亦可進行適當地選擇。
保護基G2,可列舉例如:於胜肽合成時一般所使用的C1-C6醯基(甲醯基、乙醯基、丙醯基等)、C2-C15烷氧基羰基(甲氧基羰基、乙氧基羰基、tert-丁氧基羰基、苄氧基羰基、9-茀基亞甲氧基羰基等)、芳基羰基(苯甲醯基等)、三苯甲基、鄰苯二甲醯基、N,N-二甲基胺基亞甲基、取代矽烷基(三甲基矽烷基、三乙基矽烷基、二甲基苯基矽烷基、tert-丁基二甲基矽烷基、tert-丁基二
乙基矽烷基等)、C2-C6烯基(1-烯丙基等)。此等之基係可以由鹵素原子、C1-C6烷氧基(甲氧基、乙氧基、丙氧基等)、及硝基所選出的1個以上之取代基所取代。
本發明雖藉由以下的實施例及試驗例進一步詳細地說明,但此等並不限定本發明,此外,亦可在不脫離本發明之範圍內進行改變。
於以下之實施例中,NH二氧化矽凝膠管柱層析,係指表示使用有NH2型二氧化矽膠(Chromatorex(註冊商標)NH2型、Biotage(註冊商標)SNAP KP-NH Cartridge)的管柱層析分離純化。溶出溶劑之比只要不特別限定則表示容量比。
於二氧化矽凝膠管柱層析中,係使用有關東化學「二氧化矽膠60」或Fuji Silysia「PSQ60B」或填充管柱(YAMAZEN Hi-FlashTM Column或MORITEX Purif Pack或Biotage(註冊商標)SNAP KP-Sil Catridge)。
本說明書中所使用的簡稱係表示下述的意思。
S:單重峰(singlet)
d:二重峰(doublet)
t:三重峰(triplet)
q:四重峰(quartet)
dd:雙二重峰(double doublet)
m:多重峰(multiplet)
br:寬峰(broad)
J:偶合常數(coupling constant)
Hz:赫茲(Hertz)
CDCl3:重氯仿
1H-NMR(質子核磁共振光譜)係以下述的傅立葉轉換型NMR進行測量。
300MHz:JNM-ECP300(JEOL),JNM-ECX300(JEOL)
600MHz:JNM-ECA600(JEOL)
解析係使用ACD/SpecManager ver.12.01(商品名)等。
MS(質量光譜)係利用以下的裝置進行測量。
micromass ZQ(Waters)
LTQ XL(Thermo Fisher Scientific)
LCMS-2010EV(Shimadzu)
LCMS-IT-TOF(Shimadzu)
Agilent 6150(Agilent)
LCQ Deca XP(Thermo Fisher Scientific)
離子化法,係使用ESI(Electrospray Ionization,電噴灑離子化)法或者ESI與APCI(Atmospheric Pressure Chemical Ionization,大氣壓化學離子化)法之雙重離子化法。
旋光度測量係使用日本分光公司製、旋光計
(型號:P-1020)來進行。
粉末X射線繞射測量係使用PANalytical公司製,X'Pert PRO MPD(線源:Cu.K α)來進行。
紅外線吸收光譜測量,係利用Thermo Fisher Scientific公司製,Nicolet iS5,並以ATR法(attenuated total reflection,衰減全反射法)來進行。
熔點測量係使用Mettler Toledo公司製之MP90自動熔點測定系統來進行。
分取用HPLC管柱係使用Daicel Chemical Industries,LTD.CHIRALPAK IB 5μm(I.D.20mm、Length 250mm)等。
分析用HPLC管柱係使用Daicel Chemical Industries,LTD.CHIRALPAK IB 5μm(I.D.4.6mm、Length 250mm)等。
化合物名係使用ACD/Name ver.12.01(商品名)等來命名。
(1)1-溴-4-(1,1-二氟乙基)苯
於1-(4-溴苯基)乙烷(20.0g)中,加入Deoxo-Fluor(註冊商標)(22.2g),在85℃下進行攪拌15小時。冰冷下,於反應液中加入冰水及碳酸鉀水溶液,以氯仿萃取。在減壓下餾除溶劑,使用二氧化矽凝膠管柱層析(己烷)將所得到的殘渣純化,藉此而得到黃色油狀物質之標題化合物(13.0g,產率59%)。
1H NMR(600MHz,CDCl3)δ ppm 1.91(t,J=18.2Hz,3H),7.50(d,J=8.3Hz,2H),7.86(d,J=8.3Hz,2H)。
(2)2-[4-(1,1-二氟乙基)苯基]-4,4,5,5-四甲基-1,3,2-二氧雜硼烷(dioxaborolane)
於在實施例1-(1)所合成的1-溴-4-(1,1-二氟乙基)苯(9.80g)之1,4-二噁烷(60mL)溶液中,加入雙二硼酸酯(22.5g)與[1,1’-雙(二苯基膦基)二茂鐵]鈀(II)二氯化物二氯甲烷錯合物(904mg)與乙酸鉀(8.70g),在90℃下攪拌10小時。將反應液加入水中,以氯仿萃取。在減壓下餾除溶劑,使用二氧化矽凝膠管柱層析(己烷)將所得到的殘渣純化,藉此而得到無色固體之標題化合物(7.87g,產率66%)。
1H NMR(600MHz,CDCl3)δ ppm 1.35(s,12H),1.91(t,J=18.2Hz,3H),7.50(d,J=7.8Hz,2H),7.86(d,J=7.8Hz,2H)。
(3)5-環丙基-6-甲氧基吡啶-2-甲醛(carbaldehyde)
於甲苯(433mL)-四氫呋喃(116mL)混合溶劑中,在氬環境下,加入2M n-丁基鎂氯化物之四氫呋喃溶液(74.5mL)。在-12℃下滴下1.6M n-丁基鋰之四氫呋喃溶液(186mL)進行攪拌40分鐘之後,加入6-溴-3-環丙基-
2-甲氧基吡啶(34.0g)。進一步攪拌1小時之後,滴下N,N-二甲基甲醯胺(32.7g)。進一步攪拌1個半小時之後,將反應液添加至13%檸檬酸水溶液中萃取之後,利用水洗淨有機層。在減壓下餾除溶劑,使用二氧化矽凝膠管柱層析(己烷:乙酸乙酯=95:5→90:10)將所得到的殘渣純化,藉此而得到黃色油狀物質之標題化合物(21.2g,產率80%)。
1H NMR(600MHz,CDCl3)δ ppm 0.73-0.78(m,2H),1.03-1.08(m,2H),2.14-2.21(m,1H),4.07(s,3H),7.19(d,J=7.4Hz,1H),7.49(d,J=7.4Hz,1H),9.92(s,1H)。
MS(+):178[M+H]+。
(4)、(5)(5R)-5-[(Z)-2-溴-2-(5-環丙基-6-甲氧基吡啶-2-基)乙烯基]吡咯啶-2-酮
(4)於(5R)-5-[(1,3-苯并噻唑-2-基磺醯基)甲基]吡咯啶-2-酮(30.0g)與氯化鋰(8.58g)之四氫呋喃溶液(1.2L)中,在-78℃下滴下1M六甲基二矽胺化鉀之四氫呋喃溶液(405mL)之後,進行攪拌1小時。
滴下在實施例1-(3)所合成的5-環丙基-6-甲氧基吡啶-2-甲醛(carbaldehyde)(17.9g)之四氫呋喃溶液(600mL),進一步攪拌0.5小時。於反應溶液中加入飽和氯化銨水溶液(500mL),以乙酸乙酯萃取,利用飽和食鹽水洗淨有機層之後,加入硫酸鎂使其乾燥,濾除乾燥劑之後,在減壓下餾除溶劑。將所得到的殘渣,以二氧化矽凝膠管柱層析(己烷:乙酸乙酯=100:0→70:30)進行2次純化,得到黃色油狀物質之(5R)-5-[(Z)-2-(5-環丙基-6-甲氧基吡啶-2-基)乙烯基]吡咯啶-2-酮(8.40g,產率34%)。
1H NMR(600MHz,CDCl3)δ ppm 0.62-0.68(m,2H),0.93-0.99(m,2H),1.89-1.97(m,1H),2.03-2.09(m,1H),2.33-2.56(m,3H),3.98(s,3H),5.53-5.55(m,1H),5.70(dd,J=11.56,7.84Hz,1H),5.94-6.03(br.s.,1H),6.34(dd,J=11.56,1.24Hz,1H),6.70(d,J=7.43Hz,1H),7.07(d,J=7.43Hz,1H)。
MS(+):259[M+H]+。
(5)於在實施例1-(4)所合成的(5R)-5-[(Z)-2-(5-環丙基-6-甲氧基吡啶-2-基)乙烯基]吡咯啶-2-酮(8.40g)之氯仿(126mL)溶液中,在0℃下滴下溴(1.33mL)。進行攪拌1小時之後,耗費30分鐘滴下1,8-二氮雜雙環[5.4.0]十一-7-烯(9.7mL)之氯仿溶液(42mL),進行攪拌15分鐘。於反應溶液中加入1M鹽酸(200mL),以乙酸乙酯萃取,利用飽和食鹽水洗淨有機
層之後,加入硫酸鎂使其乾燥,濾除乾燥劑之後,在減壓下餾除溶劑。將所得到的殘渣,以二氧化矽凝膠管柱層析(己烷:乙酸乙酯=50:50→0:100)進行純化,而得到黃色固體之標題化合物(7.50g,產率68%)。
1H NMR(600MHz,CDCl3)δ ppm 0.65-0.68(m,2H),0.95-1.00(m,2H),1.96-2.10(m,2H),2.40-2.59(m,3H),4.00(s,3H),4.80(q,J=7.4Hz,1H),5.68-5.70(br.s.,1H),7.10(d,J=7.8Hz,1H),7.15(d,J=7.8Hz,1H),7.24(d,J=7.8Hz,1H)。
MS(+):337[M+H]+。
(6)(5R)-5-{(E)-2-(5-環丙基-6-甲氧基吡啶-2-基)-2-[4-(1,1-二氟乙基)苯基]乙烯基}吡咯啶-2-酮
在氮環境下,於在實施例1-(5)所合成的(5R)-5-[(Z)-2-溴-2-(5-環丙基-6-甲氧基吡啶-2-基)乙烯基]吡咯啶-2-酮(1.0g)之1,4-二噁烷(50mL)溶液中,加入在實施例1-(2)所合成的2-[4-(1,1-二氟乙基)苯基]-4,4,5,5-四甲基-1,3,2-二氧雜硼烷(dioxaborolane)(1.59g)、碳酸銫(1.92g)、參(二亞苄基丙酮)二鈀
(0)(271mg)、三(2-呋喃基)膦(412mg)、蒸餾水(10mL),在90℃下進行攪拌2小時。於反應溶液中加入水,以乙酸乙酯萃取之後,於有機層中加入無水硫酸鎂使其乾燥,濾除乾燥劑之後,在減壓下餾除溶劑。將所得到的殘渣,以二氧化矽凝膠管柱層析(己烷:乙酸乙酯=100:0→0:100),進一步以NH二氧化矽凝膠管柱層析(己烷:乙酸乙酯=100:0→0:100)進行純化,而得到無色非晶質狀物質之標題化合物(1.13g,產率96%)。
1H NMR(600MHz,CDCl3)δ ppm 0.56-0.64(m,2H),0.90-0.97(m,2H),1.93-2.09(m,5H),2.20-2.34(m,2H),2.37-2.45(m,1H),4.04(s,3H),4.07-4.16(m,1H),5.73-5.75(br.s.,1H),6.23(d,J=7.4Hz,1H),6.90(d,J=9.9Hz,1H),6.92(d,J=7.8Hz,1H),7.24(d,J=8.3Hz,2H),7.57(d,J=7.8Hz,2H)。
MS(+):399[M+H]+。
(7)(5R)-5-{2-(5-環丙基-6-甲氧基吡啶-2-基)-2-[4-(1,1-二氟乙基)苯基]乙基}吡咯啶-2-酮
在氮環境下,於在實施例1-(6)所合成的(5R)-5-
{(E)-2-(5-環丙基-6-甲氧基吡啶-2-基)-2-[4-(1,1-二氟乙基)苯基]乙烯基}吡咯啶-2-酮(1.1g)之甲醇(44mL)溶液中,加入10%鈀-活性碳(110mg),在氫環境下,於室溫進行攪拌1小時。矽藻土(Celite;註冊商標)過濾反應液之後,在減壓下餾除溶劑而得到無色非晶質狀物質之標題化合物(1.10g,產率99%)。
MS(+):401[M+H]+。
(8)3-環丙基-6-{1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮
於在實施例1-(7)所合成的(5R)-5-{2-(5-環丙基-6-甲氧基吡啶-2-基)-2-[4-(1,1-二氟乙基)苯基]乙基}吡咯啶-2-酮(1.1g)之乙腈(30mL)溶液中,加入氯三甲基矽烷(707μL)及碘化鉀(1.37g),在60℃下進行攪拌1小時。將反應液加入水中,以乙酸乙酯萃取。以飽和食鹽水洗淨有機層,加入無水硫酸鎂使其乾燥,濾除乾燥劑之後,在減壓下餾除溶劑。將所得到的殘渣,以二氧化矽凝膠管柱層析(氯仿:甲醇=100:0→80:20)進行純化,而得到無色非晶質狀物質之標題化合物(880mg,
產率83%)。
MS(+):387[M+H]+。
(9)3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮
將在實施例1-(8)所合成的3-環丙基-6-{1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮之RS混合物(180mg),以掌性HPLC管柱(CHIRALPAK IB,己烷:乙醇=70:30v/v,40℃,12mL/min,254nm)進行分取,將標題化合物(70mg)製成無色非晶質狀物質,而得到無色非晶質狀物質之標題化合物的非鏡像異構物(67mg)。
1H NMR(600MHz,CDCl3)δ ppm 0.54-0.67(m,2H),0.90-0.98(m,2H),1.68-1.75(m,1H),1.88(t,J=18.2Hz,3H),2.07-2.14(m,1H),2.14-2.40(m,5H),3.43-3.52(m,1H),4.07-4.12(m,1H),6.00(d,J=7.0Hz,1H),6.92(d,J=7.0Hz,1H),7.41-7.47(m,4H),7.60-7.68(m,1H),12.28-12.49(br.s.,1H)。
MS(+):387[M+H]+。
CHIRALPAK IB 4.6×250mm 5μm(DAICEL),己烷:乙醇=70:30v/v,40℃,1.0mL/min,210nm,Rt=7.5min。
非鏡像異構物
1H NMR(600MHz,CDCl3)δ ppm 0.54-0.66(m,2H),0.95-1.05(m,2H),1.75-1.84(m,1H),1.90(t,J=18.0Hz,3H),2.15-2.41(m,6H),3.54-3.64(m,1H),4.16(dd,J=10.1,5.57Hz,1H),6.01(s,1H),6.96(d,J=7.0Hz,1H),7.39(d,J=8.26Hz,2H),7.47(s,2H),7.83-7.92(m,1H),13.14-13.34(br.s.,1H)。
MS(+):387[M+H]+。
CHIRALPAK IB 4.6×250mm 5μm(DAICEL),己烷:乙醇=70:30v/v,40℃,1.0mL/min,210nm,Rt=18.9min。
(1)(5-環丙基-6-甲氧基吡啶-2-基)[4-(1,1-二氟乙基)苯基]甲酮
在氮環境下,於-78℃中,於6-溴-3-環丙基-2-甲氧基吡啶(41.5g)之四氫呋喃(273mL)溶液中,耗費50分鐘滴下1.6M n-丁基鋰之四氫呋喃溶液(127mL)之後,在-78℃下進行攪拌1小時。接著,直接於-78℃的反應溶液中,耗費75分鐘滴下4-(1,1-二氟乙基)苯甲腈(24.3g)之四氫呋喃(137mL)溶液,進一步進行攪拌1小時。使反應溶液昇溫至0℃後,依序滴下1M鹽酸(437mL)、四氫呋喃(365mL)、1M鹽酸(146mL)。
將反應液分離成有機層與水層之後,以乙酸乙酯(1000mL)萃取出水層。於合併的有機層中加入無水硫酸鎂使其乾燥,濾除乾燥劑之後,在減壓下餾除溶劑。將所得到的殘渣,以二氧化矽凝膠管柱層析(己烷:乙酸乙
酯=100:0→95:5)進行純化,而得到無色油狀物質之標題化合物(34.0g,產率74%)。
1H NMR(300MHz,CDCl3)δ ppm 0.72-0.81(m,2H),1.00-1.10(m,2H),1.96(t,J=18.2Hz,3H),2.10-2.25(m,1H),3.95(s,3H),7.24(d,J=6.9Hz,1H),7.59(d,J=9.0Hz,2H),7.67(d,J=7.8Hz,1H),8.21(d,J=8.6Hz,2H)。
MS(+):318[M+H]+。
(2)(5R)-5-{2-(5-環丙基-6-甲氧基吡啶-2-基)-2-[4-(1,1-二氟乙基)苯基]乙烯基}吡咯啶-2-酮
在氮環境下,於-78℃中,於在實施例2-(1)所得到的(5-環丙基-6-甲氧基吡啶-2-基)[4-(1,1-二氟乙基)苯基]甲酮(33.5g)與(5R)-5-[(1,3-苯并噻唑-2-基磺醯基)甲基]吡咯啶-2-酮(37.5g)之二氯甲烷(1007mL)溶液中,耗費50分鐘滴下1.0M六甲基二矽胺化鋰之四氫呋喃溶液(317mL),在-78℃下進行攪拌4小時40分鐘。
將反應液昇溫至0℃後,滴下飽和氯化銨水溶液
(335g),使反應停止。將反應液分離成有機層與水層之後,以氯仿(339mL)萃取出水層,以水(502g)洗淨合併的有機層。於有機層中加入無水硫酸鎂使其乾燥,濾除乾燥劑之後,在減壓下餾除溶劑。將所得到的殘渣,以二氧化矽凝膠管柱層析(己烷:乙酸乙酯=50:50→0:100)進行純化,而得到淡黃色非晶質狀物質之混合物(42.7g,E:Z=50:50)的標題化合物。
但,混合比係以液體層析法之面積百分率而決定。
以下顯示液體層析法之條件。
L-Column ODS,CH3CN:0.01M乙酸鹽緩衝液(acetate buffer)(0.01M乙酸水溶液:0.01M乙酸鈉水溶液=8:1)=80:20v/v,1.0mL/min,40℃,254nm,
E:Rt=5.40min、Z:Rt=5.08min。
MS(+):399[M+H]+。
以下,可以實施例1之(7)~(9)記載的方法或依據此等的方法,而將標題化合物導至化合物[1]。
於75℃中,於3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮(14.4g)之乙醇(72g)溶液中滴下水
(29g)。從75℃緩緩地冷卻,在內溫成為40℃的時點加入一片種晶,冷卻至室溫。進一步冷卻至0℃,攪拌整夜,藉此而製成懸浮液。
返回室溫,濾取所得到的固體,進行水洗淨、乾燥(50℃、6小時),藉此而得到8.7g(回收率60%)的無色結晶。
(a)於粉末X射線繞射圖(Cu-K α、測量方法:透過法)中,於繞射角2 θ=8.5、10.8、11.2、11.6、13.4、16.8、17.0、17.9、18.5、18.8、19.1、19.4、22.6、23.1、23.2及24.5°時具有峰值。
(b)於紅外線吸收光譜(ATR法,晶體:金鋼石)中,特性吸收光帶係於916、1146、1167、1295、1375、1614、1625、1651、1664、2837、2866、2909、2955、2986、3003、3088及3146cm-1。
(c)熔點為199℃~201℃。
(d)比旋光度為[α]D 23=+36(c 0.1、MeOH)。
本發明化合物之GK活性化作用的評估,係可依據例如試驗例所記載的方法等周知的手法來進行。
使用以下之試驗例所記載的方法來測量本發明化合物[1]以及WO2011/068211號手冊所揭示之化合物A(實施例4-302)、化合物B(實施例4-248)及化合物C(實施例4-340)的GK活性化作用。
另外,以下顯示WO2011/068211號手冊所揭示的化合物A、化合物B及化合物C之結構。
試驗化合物之GK活性化試驗,係將Van Schaftingen等之方法(Eur.J.Biochem.179:179-184,1989)進行一部分改變而實施。GK活性,係於以葡萄糖為基質並將藉由GK所產生的葡萄糖6磷酸藉由G6PDH(葡萄糖6磷酸脫氫酵素)進行脫氫時,測量作為基於由thio-NAD+(硫代菸鹼醯胺腺嘌呤二核苷酸(Thio-Nicotinamide Adenine Dinucleotide))所轉換的還原型生成物之thio-NADH量的吸光度之變化。
本檢定(assay)所使用的酵素源人類肝臟型GK,係作為於胺基末端加成GST(Glutathione S-transferase)的融合蛋白質而使大腸菌表現,並使用Glutathione Sepharose 4B(Amersham Bioscience公司)進行純化。
試驗係使用平底之96孔Half Area微孔盤(Corning公司)來進行。於盤的各孔中,添加試驗化合物之二甲基亞碸(DMSO)溶液,以及作為對照之DMSO,以使DMSO終濃度成為1%。進而,分別添加
25mM Hepes-KOH(pH=7.1)、25mM KCl、2mM MgCl2、2mM thio-NAD+、4mM葡萄糖、1mM DTT(二硫蘇糖醇)、0.01units/μL G6PDH、2μg/mL人類肝臓型GK作為終濃度。接著,以終濃度成為2mM的方式添加ATP而開始反應,並於室溫靜置。反應開始15分鐘後,使用微孔盤用吸光度計,測量於405nm時之吸光度。
依據試驗化合物將最大活性化的GK活性作為最大活性化能,將其之50%活性化所需的試驗化合物濃度(nM)表記為EC50值。
將結果顯示於下。
確認試驗化合物之血糖降低作用的試驗,係依據以Grimsby等方法(Science 301:370-373,2003)所代表之一般所使用的方法來實施。
於試驗前測量自由攝取食物後之C57BL6/J小鼠(N=6)的體重。將被驗化合物以0.06-20mg/mL的濃
度懸浮或溶解於投予基劑(0.5%甲基纖維素)中。對於小鼠經口投予藥液(相當於被驗化合物0.3-100mg/kg)或者對照(僅投予基劑)5mL/kg。於即將投予被驗化合物之前及投予被驗化合物後0.5、1、2、4、6小時後,以毛細管從尾靜脈採取血液約60μL。將經採取的血液進行離心分離之後,測量血漿葡萄糖濃度。依據投予被驗化合物後之血漿葡萄糖濃度的經時推移算出曲線下面積(AUC),而算出對照群對於AUC之降低率(%)。依據採取AUC降低率為縱軸,用量為橫軸的用量反應曲線,算出AUC降低率為顯示20%的用量(ED20值;mg/kg)。
將結果顯示於下。
依據以上之試驗結果,可確認出本發明化合物係由低的用量區域顯示良好的血糖降低作用。因而,本發明化合物係可用作為糖尿病等之預防、治療藥,且其治療領域可說明顯地較其他化合物更為廣泛。
而且可知,相較於WO2011/068211號手冊所揭示的3化合物,本發明化合物係具有更強力的血糖降低
作用。
另外,本發明化合物,係具有作為醫藥品所期望的性質。可列舉例如,藉由顯示良好的物性或藥物動態(例如,肝臟代謝安定性等),而顯示良好的血糖降低作用等之性質。
本發明化合物,係具有優異的GK活性化作用,可提供不僅是糖尿病治療,連肥胖治療、高血脂症等之糖尿病相關疾病、或者視網膜病變、腎臟病變、動脈硬化等之糖尿病慢性併發症的治療及預防藥。
Claims (8)
- 一種以式[1]
- 如請求項1所記載之以上述式[1]所表示,且具有下述(a)之物性的3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮之結晶;(a)於粉末X射線繞射圖(Cu-K α)中,於繞射角2θ=8.5、13.4、19.1及24.5°時具有峰值。
- 如請求項1所記載之以上述式[1]所表示,且具有下述(a)~(c)之物性的3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮之結晶;(a)於粉末X射線繞射圖(Cu-K α)中,於繞射角2θ=8.5、13.4、19.1及24.5°時具有峰值;(b)於紅外線吸收光譜中,特性吸收光帶係於916、1146、1167、1295、1651、1664、2909、2955、 3003及3146cm-1;(c)熔點為199℃~201℃。
- 一種具有下述(a)~(c)之物性的3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮之結晶的製造方法,其特徵為將以上述式[1]所表示之3-環丙基-6-{(1R)-1-[4-(1,1-二氟乙基)苯基]-2-[(2R)-5-氧代吡咯烷-2-基]乙基}吡啶-2(1H)-酮加熱溶解於醇系溶劑之後,添加水溶劑並冷卻至5℃以下,使其結晶化,使所得到的結晶在60℃以下乾燥,(a)於粉末X射線繞射圖(Cu-K α)中,於繞射角2θ=8.5、13.4、19.1及24.5°時具有峰值;(b)於紅外線吸收光譜中,特性吸收光帶係於916、1146、1167、1295、1651、1664、2909、2955、3003及3146cm-1;(c)熔點為199℃~201℃。
- 一種醫藥,其係含有如請求項1所記載之2-吡啶酮化合物或該化合物之互變異構物、或者此等之藥學上所容許的鹽、或者該化合物等之溶劑合物作為有效成分。
- 如請求項5所記載之醫藥,其係用以預防或治療能藉由葡萄糖激酶活性化作用獲得改善的疾病或狀態。
- 如請求項5所記載之醫藥,其係血糖降低作用藥。
- 如請求項5所記載之醫藥,其係糖尿病之預防或 治療藥。
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