TW201144279A - New azabicyclo[3.2.0]hept-6-yl compounds, a process for their preparation and pharmaceutical compositions containing them - Google Patents
New azabicyclo[3.2.0]hept-6-yl compounds, a process for their preparation and pharmaceutical compositions containing them Download PDFInfo
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Abstract
Description
201144279 六、發明說明: 【發明所屬之技術領域】 本發明係關於一種新穎氮雜雙環[3·2.0]庚-6-基化合物、 其製備方法及包含其之醫藥組合物。 從藥理學觀點講,本發明化合物由於可活體内與中樞組 胺能系統相互作用而尤具價值。 【先前技術】 由於出生時預期壽命增加而導致之人口老齡化已隨之大 幅度增加與年齡相關之神經病理及特定言之阿茲海默病 (Alzheimer's disease)之發生率。腦老化及特定言之與年齡 相關之神經病理之主要臨床表現為缺乏記憶及認知功能’ 其可導致癡呆。 神經藥理學研究已顯示,在中樞神經系統中,組胺經由 中樞組胺能系統在生理或生理病理狀況中發揮神經傳遞質 或神經調節物質的作用(Pell及Green ’ Annu. Rev. Neurosci. ’ 1986,9,209-254 ; Schwartz 等,Physiol. Rev. ’ 1991, 71,1 -5 1)。因此,已顯示組胺涉及多種生理及行為過程, 例如體溫調節、神經内分泌調節、傷害性知覺、畫夜節 律、強直狀態 '運動性、侵佔性、進食行為、學習及記 憶、及突觸可塑性(Hass 等,Histaminergic neurones : morphology and function,Boca Raton,FL : CRC 出版社, 1991,196-208 頁;Brown等,Prog. Neurobiology,2001, 63 > 637-672 ; Smith 等,Neuroimmunomodulation 2007, 14 , 317-325頁)。 152492.doc 201144279 動物研究已顯示增加組胺之内源性突觸外含量可促進警 覺狀態、學習及s己憶過程’及調節攝食(Br〇wn等,pr〇g.201144279 VI. Description of the Invention: [Technical Field] The present invention relates to a novel azabicyclo[3.2.0]hept-6-yl compound, a process for the preparation thereof and a pharmaceutical composition comprising the same. From a pharmacological point of view, the compounds of the present invention are of particular value because they can interact with the central histamine system in vivo. [Prior Art] The aging of the population due to an increase in life expectancy at birth has greatly increased the incidence of age-related neuropathology and the specific case of Alzheimer's disease. The main clinical manifestations of brain aging and, in particular, age-related neuropathology are the lack of memory and cognitive function, which can lead to dementia. Neuropharmacological studies have shown that in the central nervous system, histamine exerts neurotransmitters or neuromodulators in physiological or physiological pathologies via the central histaminergic system (Pell and Green ' Annu. Rev. Neurosci. ' 1986, 9, 209-254; Schwartz et al., Physiol. Rev. '1991, 71, 1 -5 1). Thus, histamine has been shown to be involved in a variety of physiological and behavioral processes such as thermoregulation, neuroendocrine regulation, nociceptive perception, night rhythm, tonic state 'exercise, encroachment, eating behavior, learning and memory, and synaptic plasticity ( Hass et al, Histaminergic neurones: morphology and function, Boca Raton, FL: CRC Press, 1991, pp. 196-208; Brown et al, Prog. Neurobiology, 2001, 63 >637-672; Smith et al, Neuroimmunomodulation 2007, 14 317-325). 152492.doc 201144279 Animal studies have shown that increasing the endogenous extrasynaptic content of histamine promotes alertness, learning and sufficiency processes and regulates feeding (Br〇wn et al., pr〇g.
Neurobiol.,2000,63,637-672 ; Passani 等,Neurosci. Biobehav· Rev· ’ 2000,24,107-113)。因此,可增加組胺 ’ 之中樞含量之更新或釋放之化合物的潛在治療適應症係與 ' 腦老化相關、與急性及慢性神經退化性疾病相關及與精神 ***症相關之認知缺陷之治療及情感障礙、妥瑞氏症候群 (Tourette’s Syndrome)(Gulhan Ercan-Sencicek 等人,New England Journal of Medicine,May 20,2010,1901- 1908)、精神***症、睡眠障礙、睡眠-覺醒節律障礙及注 意力不足過動症之治療。此外,研究已顯示將組胺注入饱 腹調節所涉及之丘腦下部核中減弱大鼠之餵食。另外,組 胺旎傳導之機能不足已在遺傳型肥胖大鼠中表現出來 (Machidod等,Brain Research,1992,590,180-186)。因 此,進食行為障礙及肥胖症亦為本發明化合物之潛在治療 適應症。 【發明内容】 本發明係關於一種新穎氮雜雙環化合物,其與申請案 . W〇2〇〇5/089747所述之化合物不同之處在於卜氮雜雙環 . [3.2·0]庚烷環系統之存在。 精神醫學水平之㈣新職合物提供與腦老化相關、與 神經退化性疾病相關或與顱腦損傷相關之認知障礙之新穎 治療’及與例如睡眠障礙H炎漠及/或抑t狀態之彼 等病理相關之心理-行為障礙的治療的解決辦法。此外, 152492.doc 201144279 本發明化人^札 瘅 ^藥學特徵亦可設想精神領域的新穎治 睡眠障礙針對於妥瑞氏症候群、精神***症、情感障礙或 更明確而令,士 &4 發月係關於式(I)化合物,其等對映體及 非對映異構其與醫藥上可接受酸或鹼之加成鹽: ALK-0Neurobiol., 2000, 63, 637-672; Passani et al, Neurosci. Biobehav· Rev. ’ 2000, 24, 107-113). Therefore, potential therapeutic indications for compounds that increase the release or release of histamine's central content are associated with treatment and emotions associated with 'cerebral aging, associated with acute and chronic neurodegenerative diseases, and cognitive deficits associated with schizophrenia. Obstacle, Tourette's Syndrome (Gulhan Ercan-Sencicek et al, New England Journal of Medicine, May 20, 2010, 1901- 1908), schizophrenia, sleep disorders, sleep-wake rhythm disorders, and lack of attention Treatment of hyperactivity. In addition, studies have shown that inhalation of histamine into the subthalamic nucleus involved in satiety regulation attenuates rat feeding. In addition, the insufficiency of histamine conduction has been demonstrated in hereditary obese rats (Machidod et al, Brain Research, 1992, 590, 180-186). Therefore, eating behavioral disorders and obesity are also potential therapeutic indications for the compounds of the invention. SUMMARY OF THE INVENTION The present invention relates to a novel azabicyclo compound which differs from the compound described in the application. W〇2〇〇5/089747 in the azabicyclo ring. [3.2·0]heptane ring system Existence. (4) The new level of psychology provides novel treatments related to brain aging, neurodegenerative diseases or cognitive impairments associated with head injury, and with, for example, sleep disorders, hyperinflammation, and/or t-state Solutions to the treatment of pathologically relevant psycho-behavioral disorders. In addition, 152492.doc 201144279 The present invention can also be used to envisage a novel treatment of sleep disorders in the spiritual field for Tori's syndrome, schizophrenia, affective disorder or more specifically, and &4; The addition of a compound of formula (I) to its enantiomers and diastereomers to a pharmaceutically acceptable acid or base: ALK-0
\«-·— ①, 其中: ALK代表伸院基鏈,\«-·— 1, where: ALK stands for the base chain of the hospital.
♦W代表基團-·Ν_ R, C "1—Ν—R, Ο R* 其中R及R·彼此獨立地代表氫原子或視需要經選自鹵 素、經基及院氧基之一或多個基團取代之直鏈或支鏈(匸^ C6)烧基, 應瞭解: -術語「伸烷基」表示含2至6個碳原子之直鍵或支鏈二價 基團; -術語「烷氧基」表示烷基-氧基基團,其中烷基鏈為直 键或支鍵’且含有1至6個碳原子; 在醫藥上可接受酸中,可提及,但未意味任何限制,氫 氣酸、氫溴酸、硫酸、膦酸、乙酸、三氟乙酸、乳酸、丙 酮酸、丙二酸、琥珀酸、戊二酸、富馬酸、酒石酸、馬來 酸、檸檬酸、抗壞血酸、草酸、曱磺酸、樟腦酸等。 152492.doc 201144279 在醫藥上可接受鹼中,可提及,但未意味任何限制,氣 氧化鈉、氫氧化鉀、三乙胺、第三丁胺等。 較佳之式(I)化合物為w基團係位於對位之彼等化合物。 ALK較佳代表含2至6個碳原子之直鏈二價基團,諸如, 例如,伸乙基或伸丙基’甚至更佳為伸丙基。 本發明之一特定實施例係關於式⑴化合物,其中貨代表 基團 1· 一 N——R。 Ο R· 本發明之另一特定實施例係關於式⑴化合物,其中玫代 表基團 -N一~r——R。♦W represents a group -·Ν_ R, C "1—Ν—R, Ο R* wherein R and R· independently of each other represent a hydrogen atom or, if desired, one selected from the group consisting of halogen, thiol and alkoxy A linear or branched (匸^ C6) alkyl group substituted with a plurality of groups, it is understood that: - the term "alkylene" means a straight or branched divalent group having 2 to 6 carbon atoms; - the term "Alkoxy" means an alkyl-oxy group in which the alkyl chain is a straight bond or a bond 'and contains 1 to 6 carbon atoms; among pharmaceutically acceptable acids, mention may be made, but does not mean any Restriction, hydrogen acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid , oxalic acid, sulfonic acid, camphoric acid, etc. 152492.doc 201144279 Among the pharmaceutically acceptable bases, mention may be made of, but not meant to be any limitation, sodium oxyhydroxide, potassium hydroxide, triethylamine, tert-butylamine and the like. Preferred compounds of formula (I) are those in which the w group is in the para position. ALK preferably represents a linear divalent group having 2 to 6 carbon atoms, such as, for example, an ethyl group or a propyl group, and even more preferably a propyl group. A particular embodiment of the invention is directed to a compound of formula (1) wherein the cargo represents a group 1 · a N - R. Ο R· Another specific embodiment of the invention pertains to compounds of formula (1) wherein the rose represents a group -N-~r-R.
R' C 有利地,R及R,彼此獨立地代表氫原子、甲基或乙基, 該等基團視需要經甲氧基取代。 更特定言之,W代表基團-CO-NH-CH3、-(:0-Ν((:ϋ3)2、 -CO-NH2 ^ -CO-N(CH2CH3)2 ^ -NH-CO-CH3 > -N(CH3)-C〇-CH3 或-NH-C〇-CH2-OCH3。 甚至更特定言之,本發明係關於為以下之式(I)化合物、 及其等對映體、及其等與醫藥上可接受酸或社加成鹽: -4-[3-(順式_6_氮雜雙環[32〇]庚基)_丙氧基]苯甲醯 胺、 -N-(4-{3_(順式·6_氮雜雙環[3 2 〇]庚·6-基)丙氧基}苯 基)乙酿胺、 • 順式_6_氮雜雙環[3 2 〇]庚·6•基)丙氧基}Ν,Ν< 曱基笨甲醯胺、 I52492.doc 201144279 -4-{3-(順式-6-氮雜雙環[3.2.0]庚-6-基)丙氧基}·Ν,Ν-二 乙基笨甲酿胺、 -Ν-(4-{3-(順式-6-氮雜雙環[3.2.0]庚-6-基)丙氧基}笨 基)-Ν-曱基乙醯胺。 在與醫藥上可接受酸之加成鹽中,較佳更特定言之為鹽 酸鹽、草酸鹽及檸檬酸鹽。 本發明亦係關於一種製備式(I)化合物之方法,該方法之 特徵為使用式(II)化合物作為起始物質: w (II), 其中W係如式(I)所定義, 在鹼性介質中,使式(11)化合物與式(111)化合物縮合: ⑽,R' C Advantageously, R and R, independently of one another, represent a hydrogen atom, a methyl group or an ethyl group, which groups are optionally substituted by a methoxy group. More specifically, W represents a group -CO-NH-CH3, -(:0-Ν((:ϋ3)2, -CO-NH2^-CO-N(CH2CH3)2^-NH-CO-CH3 > -N(CH3)-C〇-CH3 or -NH-C〇-CH2-OCH3. Even more specifically, the present invention relates to compounds of the formula (I) below, and their enantiomers, and And pharmaceutically acceptable acid or co-addition salt: -4-[3-(cis_6_azabicyclo[32〇]heptyl)-propoxy]benzamide, -N-(4 -{3_(cis-6-azabicyclo[3 2 fluorene]heptyl-6-yl)propoxy}phenyl)ethinamide, • cis_6_azabicyclo[3 2 〇]g 6•yl)propoxy}Ν,Ν< 曱基笨甲甲胺胺, I52492.doc 201144279 -4-{3-(cis-6-azabicyclo[3.2.0]hept-6-yl)propyl Oxy}·Ν, Ν-diethyl stearamine, -Ν-(4-{3-(cis-6-azabicyclo[3.2.0]hept-6-yl)propoxy} In the case of a pharmaceutically acceptable acid addition salt, it is preferably more specifically referred to as a hydrochloride, an oxalate and a citrate. The invention also relates to a preparation A process for the compound of formula (I), characterized in that a compound of formula (II) is used as starting material: w (II), wherein W is a compound of formula (11) condensed with a compound of formula (111) in an alkaline medium as defined by formula (I): (10),
Br—ALK-〜C| 其中ALK係如式(I)所定義 以獲得式(IV)化合物:Br-ALK-~C| wherein ALK is as defined in formula (I) to obtain a compound of formula (IV):
(IV), 其中W與ALK係如文中之前所定義 使其與式(V)化合物縮合:(IV), wherein W and ALK are condensed with a compound of formula (V) as previously defined herein:
(V) 以產生如文中之前所定義之式(1)化合物:(V) to produce a compound of formula (1) as defined before:
152492.doc 201144279 可根據傳統分離技術進行純化,且如需要,轉化為其與醫 藥上可接受酸或鹼之加成鹽;且合宜時,根據傳統分離技 術,分離成其光學異構體。 式(II)、(III)及(V)化合物可購得或可利用文獻中描述之 傳統化學反應由熟悉此項技術者製得。 或者,式(VI)化合物可作為式(I/a)化合物之合成中間 物,尤其就W代表-CONRR'基團之式(I)化合物而言,可藉 由與式NHRR'(其中R及IT如式(I)所定義)胺偶合152492.doc 201144279 Purification can be carried out according to conventional separation techniques and, if desired, converted to a pharmaceutically acceptable acid or base addition salt; and, where appropriate, separated into its optical isomers according to conventional separation techniques. Compounds of formula (II), (III) and (V) are commercially available or can be prepared by those skilled in the art using conventional chemical reactions described in the literature. Alternatively, a compound of formula (VI) can be used as a synthetic intermediate of a compound of formula (I/a), especially in the case of a compound of formula (I) wherein W represents a -CONRR' group, by virtue of formula NHRR' (wherein R IT as defined by formula (I) amine coupling
其中ALK基團係如文中之前所定義。 同樣,可利用式(VII)化合物作為式(I/a)化合物之合成中 間物,尤其就W代表-CONRR'基之式(I)化合物而言,可藉 由與式NHRR’(其中R及R’如式(I)所定義)胺偶合Wherein the ALK group is as previously defined herein. Similarly, a compound of the formula (VII) can be utilized as a synthetic intermediate of the compound of the formula (I/a), especially in the case of a compound of the formula (I) wherein W represents a -CONRR' group, by virtue of the formula NHRR' (wherein R R' as defined in formula (I)) amine coupling
其中ALK基團係如文中之前所定義。 此外,亦可利用式(VIII)化合物,藉由胺NHRR'(其中R 及R’如式(I)所定義)之縮合,獲得式(I/a)化合物,尤其就W 代表-CONRR’基之式(I)化合物而言:Wherein the ALK group is as previously defined herein. Further, a compound of the formula (VIII) can also be used to obtain a compound of the formula (I/a) by condensation of an amine NHRR' (wherein R and R' are as defined in the formula (I)), in particular, W represents a -CONRR' group. For the compound of formula (I):
152492.doc 201144279 其中,ALK基團係如文中之前所定義且R"代表直鏈或支鏈 (CrC6)烷基或苯曱基, 式(VIII)化合物係經由文中之前所示的相應羧酸(VI)或醯 基氣(VII)製得。 最後’亦可藉由使式(IX)化合物水解來獲得式(I/a)化合 物:152492.doc 201144279 wherein the ALK group is as previously defined and R" represents a linear or branched (CrC6) alkyl or phenyl fluorenyl group, and the compound of formula (VIII) is via the corresponding carboxylic acid previously shown herein ( VI) or bismuth based gas (VII). Finally, the compound of the formula (I/a) can also be obtained by hydrolyzing the compound of the formula (IX):
其中ALK基團係如文中之前所定義。 精神醫學水平之本發明化合物可用於與腦老化或與神經 退化性疾病’諸如阿茲海默症(Alzheimer's disease)、帕金 森氏症(Parkinson's disease)、皮克氏症(Pick's disease)、 雷維體失智症(Lewy body dementias)、額葉及皮質下視失 智症、額顳葉失智症、血管性失智症、亨廷頓氏舞蹈症 (Huntington、disease)及多發性硬化症相關之認知障礙之Wherein the ALK group is as previously defined herein. The psychiatric level of the compounds of the invention can be used in conjunction with brain aging or with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Pick's disease, Levi. Knowledge of Lewy body dementias, frontal and subcortical dementia, frontotemporal dementia, vascular dementia, Huntington's disease (Downase, disease) and multiple sclerosis Obstacle
森氏症相關之睡眠障礙,例如日間過度嗜睡Sjogren's disease-related sleep disorders, such as excessive daytime sleepiness
痛,及治療睡眠障礙、 v狀心、女^氏症候群(Tourette's 1及與其相關之認知障礙、及疼 睡眠-覺醒節律障礙與注意力不足 152492.doc 201144279 過動症(通D)。在該障财,可㈣提及發作性 嗜睡症及㈣Μ症。亦針對㈣目輯礙,例如阻塞性睡 眠暫停综合症或注意力不足過動症中發生之嗜睡症,及曰 間嗜睡症。 本發明亦係關於一種醫藥组人物 带?且。物其包含與一或多種醫 藥上可接受之賦形劑組合之一種式(1)化合物。 在本發明之醫藥組合物中 Τ活性成份之重量比(活性成 份重量除以組合物總重量)為1至5 〇%。 本發明醫藥組合物中’可特別提及適於經口、非經 腸、經鼻、經皮或穿皮、經直腸、經舌、經眼或吸入投與 之彼等物’尤其鍵劑或糖衣、舌下錠劑、藥囊、藥包、膠 囊舌下鍵、含片、栓劑、乳膏、軟膏、皮膚凝膠、及可 飲用或可注射安瓶。 使用劑量隨患者性別、年齡及體重、投與途徑、治療適 應症之特性,及任何相關治療而改變;且 與治療中,於每24小物5mg至別mg之範圍内。 式(I)化合物與乙醯膽鹼酯酶抑製劑之聯合亦形成本發明 之組成部分’且更特定言之式⑴化合物與多奈哌齊 (donepezil)雷斯替明(nvastigmine)或加蘭他敏⑽—⑽) 之聯合。此類型之聯合可用於治療阿茲海默症之認知障 礙0 【實施方式】 "以:實例閣述本發明,但不以任何方式限制。根據一般 光4光度測量技術(紅外線法、NMR、質譜法等)確定實例 152492.doc 201144279 中所描述之化合物之結構。 .歪由-貝Λ *F文化合物相當於順式組態之消旋物;換言 之,該等化合物相當於(1/?,5/〇_6_氮雜雙環[3 2川庚_6基 構架與(1㈣-6-氮雜雙環[3·2.〇]庚·6_基構架《消旋混合 物。 如下文貫例所述,可藉由HPLC柱(例如chiralcel OF、CHIRALPACK AS-H或 CHIRALPACK AD-H型)之手性 分離技術分離消旋混合物以獲得純對映體。 實例1,合成路線A : 4-[3-(順式-6-氮雜雙環[3.2.0】庚-6- 基)-丙氧基】苯甲酿胺 步驟1 : 4-(3-氣丙氧基)苯甲醯胺 在回流下,加熱1〇 ml乙腈中包含〇 〇〇4 m〇l 4_羥基苯甲 醯胺、0.004 mol 1-溴-3-氣丙烷及〇.006 m〇i碳酸鉋之混合 物5小時。 步驟2 : 4-[3-(順式-6-氮雜雙環[3.2.0]庚-6-基)丙氧基]苯曱 酿胺 在周溫下,將0.004 mol順式-6-氮雜雙環[3.2.0]庚烷(出 版品 J. Chem. Soc· Perkin Trans. 1 1979,1770-1773 頁中描 述其合成)及0.002 mol碘化鈉添加至步驟1之反應混合物 中。隨後,繼續回流下加熱,進行16小時。過濾出沈澱物 並以乙腈沖洗。將濾液濃縮至乾。將殘留物溶於二氣甲烷 中。用氫氧化鈉溶液並隨後用水萃取所得溶液,然後經硫 酸鎂乾燥並濃縮至乾。在Lichroprep RP-18相上利用製備 型色譜技術純化殘留物。 152492.doc 201144279 元素微量分析 % C % Η 70·〇4 8.08 70.06 8.1 1 % Ν 10.21 10.00 計算值 測得值 實例1,路線Β: 4_[3_(順式_6_氛雜雙環[3.2()】庚冬基丙 氧基】苯甲酿胺 步驟1 : 4-{3-(順式冬氮雜雙環[3 2 ()]庚_6基)丙氧幻笨 甲腈 實驗步驟與實m之合成路線Α相同,其中步驟艸以心 羥基苯甲腈替代4-羥基笨甲醯胺。 步驟2 : 4-[3-(順式-6-氮雜雔援丨^ Ί ηΊ Λ 亂雜又f衣[3.2.0]庚_6•基)丙氧基]苯甲 醯胺 將以上步驟所得之化合妨j 〇 . 〈化口物(2.2g)溶於9〇ml乙醇中,並在 5.1 g KOH存在下回流下加埶 …、小夺。將該混合物傾入90 ml水中並隨後真空濃縮至—本 丰體積。過濾出所得固體, 田工g、:《b冼并陡仫紅,„ J m 異丙醚沖洗並隨後乾燥 元素微量分析: % C % Η % Ν 計算值 70.04 8.08 10.21 測量值 69.64 8.01 10.17 又艰Μ.2.01庚-6-基)-丙 氧基】苯甲酿胺 步驟1 : 4-{3-(順式-6-氮雜雙環丨 酸甲醋 ^3·2·0]庚+基)丙氧基}苯甲 152492.doc 201144279 實驗步驟與實例1之合成路線A相同,其中步驟丨中以4· 羥基苯曱酸曱酯替代4_經基苯曱醯胺。 步驟2 : 4-{3-(順式-6-氮雜雙環[3.2.0]庚-6-基)丙氧基}笨 甲酸 使含3.5 g步驟1化合物的12.7 ml 2 Ν氫氧化鈉溶液與8 ml甲醇之混合物在回流下加熱1小時。將12.7 ml 2 N HCL· 加入在冰浴中冷卻之該反應混合物中。以水沖洗沈丨殿物並 真空乾燥。 步驟3 : 4-{3-(順式-6-氮雜雙環[3.2.0]庚-6-基)丙氧基}苯甲 酿氣鹽酸鹽 使1.8 g步驟2所述之產物與2〇 ml亞硫醯氯之混合物在回 ί/IL下加熱2小時。真空濃縮該反應混合物,並與曱苯共蒸 發兩次。使固體殘留物在***中均質化,過濾並真空乾 燥。 步驟4 : 4-[3-(順式-6-氮雜雙環[3 2 〇]庚_6_基)丙氧基]苯甲 醢胺 在〇 C下,將4 ml 2 N氨甲醇逐滴加入含j g步驟3中所述 產物之二氣甲烧溶液中。隨後,在周溫下,將該混合物樓 摔1小時,并用2 N氫氧化納溶液及隨後用水沖洗。有機相 ’生爪^鎮乾燥並濃縮。過據出所得固體,以異丙驗沖洗旅 隨後乾燥。 元素微量分析: 〇/〇 C % Η % Ν 計算值 70 04 〇 ηο ^ 8-〇8 10.21 測得值 69 90 〇 υ 8·〇5 10.19 152492.doc 201144279 實例2 : 4-{2-(順式-6-氮雜雙環[3.2.0]庚-6-基)乙氧基}笨 甲醯胺 實驗步驟與實例1之合成路線A相同,其中步驟1中以卜 溴-2-氯乙烷替代1-溴-3-氣丙烷。 元素微量分析: % C % Η % Ν 計算值 69.21 7.74 10.76 測得值 68.99 7.71 10.28 實例3 : N-(4-{3-(順式-6-氮雜雙環[3.2.〇]庚_6_基)丙氧基} 苯基)乙醯胺草酸鹽 實驗步驟與實例1之合成路線A相同,其中步驟1中以Ν· (4-羥苯基)乙醯胺替代4-羥基笨甲醯胺。隨後將〇 36 g草酸 加入含0.40 g所得化合物之6 ml乙醇中。過濾出所得產 物’以***沖洗並隨後真空乾燥。 元素微量分析: % C % Η % Ν 60.31 6.92 7.40 60.47 6.71 7.26 苯基)乙醯胺草酸鹽 計算值 測量值 實例4 · Ν·(4-{2·(順式-6·氮雜雙環丨3 2 ()】庚_6基)乙氧基} 實驗步驟與實例2相同,其中步驟i中以Ν-(4-經苯基)乙 過濾出所得產物,以***沖洗 醯胺替代4,基笨甲酿胺。隨後將0.36 g草酸加入含0.38 g 所得化合物之6 ml乙醇中 並隨後真空乾燥。 152492.doc 201144279 元素微量分析: % C % Η % Ν 計算值 59.33 6.64 7.69 測量值 58.89 6.30 7.51 實例5:4-{3-(順式_6-氮雜雙環[3.2.〇]庚_6-基)丙氧基}_ N,N-二甲基苯甲醯胺鹽酸鹽 實驗步驟與實例1之合成路線A相同,其中步驟丨中以4_ 羥基-N,N-二甲基苯曱醯胺替代4·羥基苯甲醯胺。Pain, and treatment of sleep disorders, v-shaped heart, female syndrome (Tourette's 1 and its associated cognitive impairment, and pain sleep-wake rhythm disorder and attention deficit 152492.doc 201144279 hyperactivity (pass D). Difficulty can be (4) mentioning narcolepsy and (4) snoring. It is also directed to (4) dysfunction, such as apnoea in obstructive sleep apnea syndrome or attention deficit hyperactivity disorder, and diurnal narcolepsy. Also contemplated is a pharmaceutical group of persons comprising a compound of formula (1) in combination with one or more pharmaceutically acceptable excipients. The weight ratio of active ingredient in the pharmaceutical composition of the invention ( The weight of the active ingredient divided by the total weight of the composition is from 1 to 5% by weight. The pharmaceutical composition of the present invention can be specifically mentioned for oral, parenteral, nasal, transdermal or transdermal, transrectal, menstrual. Tongue, eye or inhalation of them, especially key agents or sugar coatings, sublingual tablets, sachets, sachets, sublingual labels, lozenges, suppositories, creams, ointments, skin gels, and Drinkable or injectable ampoules. Dosage The patient's gender, age and weight, the route of administration, the characteristics of the treatment indication, and any related treatment changes; and in the treatment, within the range of 5 mg to other mg per 24 small items. Compound of formula (I) and acetaminophen The combination of an alkali esterase inhibitor also forms a combination of a compound of the invention 'and more specifically a compound of formula (1) with donepezil nvastigmine or galantamine (10)-(10)). This type of combination can be used to treat cognitive impairment of Alzheimer's disease. [Embodiment] " By way of example, the invention is described, but is not limited in any way. The structure of the compound described in the example 152492.doc 201144279 is determined according to the general photo 4 photometric technique (infrared method, NMR, mass spectrometry, etc.).歪由-贝Λ *F-form compound corresponds to the cis-configured racemate; in other words, these compounds correspond to (1/?,5/〇_6_azabicyclo[3 2川庚_6 base Framework and (1(tetra)-6-azabicyclo[3.2.]]g-6-yl framework "racemic mixture. As described in the following examples, it can be by HPLC column (eg chiralcel OF, CHIRALPACK AS-H or The chiral separation technique of CHIRALPACK AD-H) separates the racemic mixture to obtain the pure enantiomer. Example 1, Scheme A: 4-[3-(cis-6-azabicyclo[3.2.0]heptane- 6-yl)-propoxy]benzamide A Step 1 : 4-(3-Actyloxy)benzamide is heated under reflux, containing 1 〇ml of acetonitrile containing 〇〇〇4 m〇l 4_ a mixture of hydroxybenzamide, 0.004 mol of 1-bromo-3-aeropropane and 〇.006 m〇i carbonate for 5 hours. Step 2: 4-[3-(cis-6-azabicyclo[3.2. 0]hept-6-yl)propoxy]benzoquinone at a temperature of 0.004 mol cis-6-azabicyclo[3.2.0]heptane (published J. Chem. Soc· Perkin Trans 1 1979, 1770-1773 describes its synthesis) and 0.002 mol of sodium iodide is added to the reaction mixture of step 1. Subsequently, Heating was continued under reflux for 16 hours. The precipitate was filtered off and washed with acetonitrile. The filtrate was concentrated to dryness. The residue was dissolved in methane methane. Dry and concentrate to dryness. Purify the residue on a Lichroprep RP-18 phase using preparative chromatographic techniques. 152492.doc 201144279 Elemental microanalysis % C % Η 70·〇4 8.08 70.06 8.1 1 % Ν 10.21 10.00 Calculated value Example 1, route Β: 4_[3_(cis_6_heterobicyclo[3.2()]heptylpropoxy]benzamide Step 1: 4-{3-(cis-aza-bicyclo[ The experimental procedure of 3 2 ()]g _6 yl)propoxy acetonitrile is the same as the synthetic route of the real m, wherein the step 艸 is substituted with 4-hydroxy carbamide by hydroxybenzonitrile. Step 2 : 4- [3-(cis-6-azaindole 丨^ Ί ηΊ Λ 杂 杂 杂 [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ 〇. <Chemical substance (2.2g) is dissolved in 9〇ml of ethanol, and added in the presence of 5.1 g KOH under reflux, and the mixture is poured into 90 ml of water and then Concentrate to - Benfeng volume. Filter out the solid obtained, Tiangong g,: "b冼 and steep blush, „ J m isopropyl ether rinse and then dry elemental microanalysis: % C % Η % Ν Calculated value 70.04 8.08 10.21 Measured value 69.64 8.01 10.17 Difficult. 2.01 G to 6-yl)-propoxy] Benzoylamine Step 1: 4-{3-(cis-6-azabicyclodecanoic acid methyl ketone ^3·2 ·0]heptyl + yl)propoxy}benzene 152492.doc 201144279 The experimental procedure is the same as that of the synthetic route A of Example 1, in which the hydrazine 4 hydroxy benzoate is substituted for the 4 hydrazinamide in the step 丨. Step 2: 4-{3-(cis-6-azabicyclo[3.2.0]hept-6-yl)propoxy} benzoic acid 12.7 ml of 2 Ν sodium hydroxide solution containing 3.5 g of the compound of Step 1. The mixture with 8 ml of methanol was heated under reflux for 1 hour. 12.7 ml of 2 N HCL· was added to the reaction mixture which was cooled in an ice bath. Rinse the sinking hall with water and dry in a vacuum. Step 3: 4-{3-(cis-6-azabicyclo[3.2.0]hept-6-yl)propoxy}benzaldehyde-hydrochloric acid hydrochloride 1.8 g of the product described in step 2 A mixture of 〇ml sulfite chloride was heated under ί/IL for 2 hours. The reaction mixture was concentrated in vacuo and evaporated twice with benzene. The solid residue was homogenized in diethyl ether, filtered and dried in vacuo. Step 4: 4-[3-(cis-6-azabicyclo[3 2 fluorene]heptyl-6-yl)propoxy]benzamide can be used to dilute 4 ml of 2 N ammonia in 〇C Add to the dioxazole solution containing the product of step 3 in step 3. Subsequently, the mixture was dropped for 1 hour at ambient temperature and rinsed with a 2 N sodium hydroxide solution followed by water. The organic phase was dried and concentrated. The solid obtained was taken out, and the rinse was washed with isopropyl and then dried. Elemental microanalysis: 〇/〇C % Η % Ν Calculated value 70 04 〇ηο ^ 8-〇8 10.21 Measured value 69 90 〇υ 8·〇5 10.19 152492.doc 201144279 Example 2: 4-{2-(Shun The experimental procedure of the formula-6-azabicyclo[3.2.0]hept-6-yl)ethoxy}benzamide is the same as the synthetic route A of Example 1, wherein the step 1 is bromo-2-chloroethane. Replace 1-bromo-3-aeropropane. Elemental microanalysis: % C % Η % Ν Calculated value 69.21 7.74 10.76 Measured value 68.99 7.71 10.28 Example 3: N-(4-{3-(cis-6-azabicyclo[3.2.〇]g]_6_ The experimental procedure of the phenyloxy}phenyl)acetamide oxalate is the same as that of the synthetic route A of Example 1, in which the hydroxy-(4-hydroxyphenyl)acetamamine is substituted for the 4-hydroxy carbamide in the first step. amine. Then, 36 g of oxalic acid was added to 6 ml of ethanol containing 0.40 g of the obtained compound. The resulting product was filtered off and washed with diethyl ether and then dried in vacuo. Elemental microanalysis: % C % Η % Ν 60.31 6.92 7.40 60.47 6.71 7.26 Phenyl) acetamidine oxalate calculated value Example 4 · Ν·(4-{2·(cis-6-azabicycloindole) 3 2 ()] Gg-6 group) Ethoxy} The experimental procedure is the same as in Example 2, in which step i is filtered with Ν-(4-phenyl)ethyl, and the amine is washed with diethyl ether instead of 4. Then, 0.36 g of oxalic acid was added to 6 ml of ethanol containing 0.38 g of the obtained compound and then dried under vacuum. 152492.doc 201144279 Elemental microanalysis: % C % Η % Ν Calculated value 59.33 6.64 7.69 Measured value 58.89 6.30 7.51 Example 5: 4-{3-(cis-6-azabicyclo[3.2.oxime]hept-6-yl)propoxy}_ N,N-dimethylbenzamide hydrochloride experimental procedure and The synthetic route A of Example 1 is the same, in which the step 丨 is replaced by 4-hydroxy-N,N-dimethylbenzamide as the 4-hydroxybenzamide.
將所付產物浴於其中添加有2 ml 2 N HC⑽溶液的i〇 W 乙醇中。過渡出結晶產物’以乙醇沖洗並真空乾燥。 元素微量分析 % C % Η % Ν % Cl- 計算值 63.80 8.03 8.27 10.46 測量值 63.22 7.60 7.94 10.49 實例6 : M3-(順式-6-氮雜雙環丨3.2 〇]庚·6基)丙氧基) Ν,Ν-二乙基苯甲醯胺草酸鹽 以4-羥基-Ν,Ν-二 實驗步驟與實例3相同,其中步驟j中 乙基笨曱醯胺替代Ν-(4-羥笨基)乙酿胺。 元素微量分析 % C % Η % Ν 計算值 62.84 7.67 6.66 測量值 61.97 7.51 6.74 實例7: 4·{3·(順式·6-氮雜雙環[32()】庚_6基)丙氧基卜ν _ 甲基苯甲醯胺鹽酸鹽 152492.doc -16- 201144279 實驗步驟與實例5相同,其中步驟1中以4-羥基-N-曱基 苯曱醯胺替代4-羥基-N,N_二曱基苯甲醯胺。 元素微量分析 % C % Η % Ν % Cl* 計算值 62.86 7.76 8.62 10.91 測量值 62.58 7.65 8.65 10.87 實例8 : N-(4-{3-(順式·6-氮雜雙環[3.2.0]庚-6-基)丙氧基} 苯基)-Ν-曱基-乙酿胺鹽酸鹽 實驗步驟與實例5相同,其中步驟1中以ν·(4-羥笨基)-Ν-甲基乙醯胺替代4-羥基-Ν,Ν-二甲基苯曱醯胺。 元素微量分析 % C % Η % Ν % Cl- 計算值 63.80 8.03 8.27 10.46 測量值 63.47 7.81 8.00 1 1.09 實例8a : Ν-(4-{3-(順式-6-氮雜雙環【3.2.0】庚-6-基)丙氧 基}苯基)-Ν-甲基-乙醯胺鹽酸鹽(對映體1) 對映體1係藉由手性柱CHIRALCEL OF 60X(600 mm,20 μιη)之製備性分離來獲得。 實例813:1^(4-{3-(順式-6-氮雜雙環[3.2.0】庚_6-基)丙氧 基}苯基)-Ν-甲基乙醯胺鹽酸鹽(對映體2) 對映體2係藉由手性柱CHIRALCEL OF 60X(600 mm,20 μιη)之製備性分離來獲得。 實例9 : Ν-(4-{3-(順式_6·氮雜雙環【3.2.〇】庚·6-基)丙氧基} 笨基)-2-甲氧基-乙醯胺鹽酸鹽 152492.doc 201144279 實驗步驟與實例5相同’其中步驟1中以N-(4-羥笨基)_2_ 曱氧基乙醌胺替代4-經基-N,N-二曱基苯曱醯胺。 元素微量分析(1.2 HCI) % C % Η % Ν % cr 計算值 59.70 7.57 7.74 11.75 測量值 58.19 7.83 6.94 12.07 藥理學研究 實例A : NMRI小鼠中之甲基組胺之大腦含量 根據 Tay丨0r 等之方法(Biochem. Pharm·,1992,44 » 1261 _1 267)進行之研究的目的係評價本發明化合物作為出 型中樞組胺受體之拮抗劑之活體外活性。在測試化合物經 口途徑處理後,藉由測量Ντ_甲基組胺(組胺之主要代謝物) 之中樞含量來顯示該活性。;曱基組胺之大腦含量之增 力員示因%型中樞組胺受體的阻斷而增加組胺轉換。 NMRI小鼠(18_20 g)係以本發明化合物或其等載體 r^/lcg)經π途徑處理。在藥理學處理後i小時,將該等動物 處死;移除大腦,冷;東於液氮中,稱4並在代下於〇ι N hcio4中均質。離心(15_ g,17分鐘,4。〇經均質之產 物。回收上清液並分成若干諸。將該料份料於液氮 中並儲存於-sot下直至用以分析。 β Ντ-甲基 利用毛細管電泳測定N:_ P基組胺之大腦含量 組胺之組織含量係以_新鮮大腦表達。利用單因素方差 分析比較經載體(對照)處理之動物 之動物的ΝΤ-甲基組胺之大腦含量 與經本發明化合物處理 ’如需要,隨後進行互 -J 8 - 152492.doc 201144279 補分析(Dunnett's測試),。 結果顯示,在3 mg/kg PO劑量下’本發明化合物可顯著 增加Ντ-甲基組胺之内源性大腦含量80%以上。 藉由實例,實例1、3、6、8及5之化合物當以3 mg/kg PO投與時Ντ-甲基組胺之内源性大腦含量增加程度分別如 下: 實例1之化合物:+125% 實例3之化合物:+111 % 實例6之化合物:+86% 實例8之化合物:+87% 實例5之化合物:+81% 此等結果顯示本發明化合物係Η3型中樞組胺受體之有效 拮抗劑。 實例Β :對小鼠Η3受體之親和力 該目的係測量本發明化合物對轉染至Ch〇細胞中之^型 小鼠組胺受體之親和力。 在經轉染之CHO細胞、作爲放射標記型配位體之對%受 體具特異性的之i〇d〇pr〇Xyfan、及閃爍珠粒存在下,使該 等化合物以不同濃度在室溫下培養24 h。 培養結束時,測量以測試化合物取代之配位體的特異性 結合,並測定彼等化合物對小鼠Η;受體之親和力常數。 結果顯示本發明化合物對H 3型組胺受體具有極大親和力 (Ki<40 ηΜ) 〇 例如: 實例6之化合物:Ki=21 ηΜ 152492.doc -19- 201144279 實例8之化合物:Ki = 14 nM 實例5之化合物:Ki = 35 nM 實例C :醫藥組合物 製備1000粒各含100 mg活性成份之錠劑之配方: 實例1之化合物....................................................1〇〇 g 羥丙基纖維素.......................................................20 g 聚乙烯吡咯啶酮....................................................20 g 小麥澱粉.............................................................1 50 g ....................................................................900 g 硬脂酸鎂..............................................................30 g 152492.doc 20-The product was bathed in i〇W ethanol to which 2 ml of 2 N HC(10) solution was added. The transitional crystalline product was rinsed with ethanol and dried under vacuum. Elemental trace analysis % C % Η % Ν % Cl- Calculated value 63.80 8.03 8.27 10.46 Measured value 63.22 7.60 7.94 10.49 Example 6: M3-(cis-6-azabicycloindole 3.2 〇]heptanyl 6-propoxyl Ν,Ν-diethylbenzamide oxalate is the same as in Example 3 in the 4-hydroxy-indole, Ν-two experimental procedure, in which the ethyl cumamine in step j is substituted for Ν-(4-hydroxy stupid) Base) Ethylamine. Elemental trace analysis % C % Η % Ν Calculated value 62.84 7.67 6.66 Measured value 61.97 7.51 6.74 Example 7: 4·{3·(cis-6-azabicyclo[32()]g--6-)propoxy ν _ Methyl benzamide hydrochloride 152492.doc -16- 201144279 The experimental procedure is the same as in Example 5, in which step 1 replaces 4-hydroxy-N,N with 4-hydroxy-N-mercaptophenylamine. _ Dimercaptobenzamide. Elemental trace analysis % C % Η % Ν % Cl* Calculated value 62.86 7.76 8.62 10.91 Measured value 62.58 7.65 8.65 10.87 Example 8: N-(4-{3-(cis-6-azabicyclo[3.2.0]g The experimental procedure of -6-yl)propoxy}phenyl)-fluorenyl-indenyl-ethanoic acid hydrochloride is the same as in Example 5, wherein in step 1, ν·(4-hydroxyphenyl)-hydrazine-methyl Acetamine replaces 4-hydroxy-indole, hydrazine-dimethylbenzamide. Elemental trace analysis % C % Η % Ν % Cl- Calculated value 63.80 8.03 8.27 10.46 Measured value 63.47 7.81 8.00 1 1.09 Example 8a : Ν-(4-{3-(cis-6-azabicyclo[3.2.0] Hept-6-yl)propoxy}phenyl)-indole-methyl-acetamide hydrochloride (enantiomer 1) Enantiomer 1 by chiral column CHIRALCEL OF 60X (600 mm, 20 μιη Prepared by preparative separation. Example 813: 1^(4-{3-(cis-6-azabicyclo[3.2.0]hept-6-yl)propoxy}phenyl)-indole-methylacetamide hydrochloride ( Enantiomer 2) Enantiomer 2 was obtained by preparative separation of a chiral column CHIRALCEL OF 60X (600 mm, 20 μιη). Example 9: Ν-(4-{3-(cis-6-azabicyclo[3.2.〇]heptan-6-yl)propoxy} phenyl)-2-methoxy-acetamide hydrochloride Salt 152492.doc 201144279 The experimental procedure is the same as in Example 5, wherein in step 1, N-(4-hydroxyphenyl)_2_methoxyacetamide is substituted for 4-transyl-N,N-dimercaptobenzamide . Elemental microanalysis (1.2 HCI) % C % Η % Ν % cr Calculated value 59.70 7.57 7.74 11.75 Measured value 58.19 7.83 6.94 12.07 Pharmacological study Example A: Brain content of methyl histamine in NMRI mice according to Tay丨0r et al The method (Biochem. Pharm., 1992, 44 » 1261 _1 267) was conducted to evaluate the in vitro activity of the compounds of the present invention as antagonists of the exogenous central histamine receptor. This activity is shown by measuring the central content of Ντ-methylhistamine (the major metabolite of histamine) after oral administration of the test compound. The increase in brain content of thiol histamine increased histamine conversion due to blockade of the % central histamine receptor. NMRI mice (18-20 g) were treated with the compound of the invention or its vector r^/lcg) via the π route. The animals were sacrificed 1 hour after the pharmacological treatment; the brain was removed, cold; in liquid nitrogen, weighed 4 and homogenized in 〇ι N hcio4. Centrifuge (15 g, 17 min, 4. homogenized product. The supernatant was recovered and divided into several portions. The fraction was taken up in liquid nitrogen and stored under -sot until analyzed. β Ντ-methyl Determination of brain content of N:_P-based histamine by capillary electrophoresis The tissue content of histamine was expressed as _ fresh brain. One-way analysis of variance was used to compare ΝΤ-methylhistamine in animals of vehicle treated with control (control). The brain content was treated with the compound of the invention', if necessary, followed by a cross-J 8 - 152492.doc 201144279 supplemental analysis (Dunnett's test). The results show that the compound of the invention can significantly increase the Ντ- at a dose of 3 mg/kg PO. The endogenous brain content of methyl histamine is more than 80%. By way of example, the compounds of Examples 1, 3, 6, 8, and 5 are endogenous to Ντ-methylhistamine when administered at 3 mg/kg PO. The levels of brain content increase were as follows: Compound of Example 1: +125% Compound of Example 3: +111 % Compound of Example 6: +86% Compound of Example 8: +87% Compound of Example 5: +81% These results Shows that the compound of the present invention is a central histamine receptor of type Η3 An Effective Antagonist. Example Β: Affinity to Mouse Η3 Receptor This objective measures the affinity of a compound of the invention for a histamine receptor of a mouse transfected into Ch〇 cells. Transfected CHO cells In the presence of i〇d〇pr〇Xyfan, which is specific for the % receptor of the radiolabeled ligand, and the scintillation beads, the compounds were cultured at different concentrations for 24 h at room temperature. At the time, the specific binding of the ligands substituted with the test compound was measured, and the affinity constants of the compounds against the mouse oxime; receptor were determined. The results show that the compound of the present invention has a great affinity for the H 3 type histamine receptor (Ki< 40 ηΜ) 〇 For example: Compound of Example 6: Ki=21 ηΜ 152492.doc -19- 201144279 Compound of Example 8: Ki = 14 nM Compound of Example 5: Ki = 35 nM Example C: Preparation of 1000 tablets of pharmaceutical composition Formulation of each lozenge containing 100 mg of active ingredient: Compound of Example 1 .................................. ..................1〇〇g Hydroxypropylcellulose....................... ................................20 g polyvinylpyrrolidine ketone................................................. ...20 g wheat starch........................................... ..................1 50 g ............................. .................................900 g magnesium stearate..... .................................................. .......30 g 152492.doc 20-
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