TWI426906B - 治療精神分裂症的醫藥組成物 - Google Patents
治療精神分裂症的醫藥組成物 Download PDFInfo
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- TWI426906B TWI426906B TW097125709A TW97125709A TWI426906B TW I426906 B TWI426906 B TW I426906B TW 097125709 A TW097125709 A TW 097125709A TW 97125709 A TW97125709 A TW 97125709A TW I426906 B TWI426906 B TW I426906B
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- Prior art keywords
- schizophrenia
- treatment
- effective amount
- therapeutically effective
- dichlorophenyl
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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- Inorganic Chemistry (AREA)
Description
本發明關於(硫代)-胺甲醯基-環己烷衍生物(尤其是反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺)及其藥學上可接受之鹽類於製造用於治療精神分裂症之藥品上的用途。再者,本發明關於透過投服(硫代)-胺甲醯基-環己烷衍生物(尤其是反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺)及其藥學上可接受之鹽類來治療精神分裂症。
精神分裂症為一種終生失能之精神病症,全世界報告之盛行率為約1%,包括320萬美國人(見,如:National Institute of Mental Health, Schizophrenia, http://www.nimh.nih.gov/healthinformation/schizophrenia menu.cfm 2006;Mueser and McGurk,Lancet 2004;363:2063-72,2004)。此病症通常在青少年期或青年時期即顯露;主要症狀分為三種區塊-陽性症狀(諸如妄想及幻覺)、陰性症狀(諸如缺乏幹勁及社交退縮)和認知症狀(諸如注意力及記憶之問題)。這些造成社交及職業機能障礙,其對家庭及受影響之個人在廣大社會中的地位必然有深遠之影響。除了精神症狀外,罹患精神分裂症之患者在既有疾病方面的風險亦較一般人為高。
在急性及殘留症狀期間,以多巴胺拮抗劑進行之藥物治療為精神分裂症處理的基礎。目前之指導原則建議以非典型抗精神病劑(包括:利培酮(risperidone)、奧氮平(olanzapine)、喹硫平(quetiapine)、齊拉西酮(ziprasidone)及阿立哌唑(aripiprazole))作為精神分裂症之第一線治療。這些藥物之一致持徵為其雙重作用模式:除了拮抗多巴胺D2
外,其亦為血清素5-HT2A
受體之強抑制劑。
雖然較傳統之抗精神分裂症藥改善,非典型之抗精神病劑在有效管理該疾病中仍有缺點。尤其是,這些藥物在高劑量下與副作用之高發生率有關(如高劑量時之錐體外徑症狀[EPSs]、鎮靜、心血管作用,諸如QTc延長、血液學上之改變、對性功能之影響、體重增加、代謝異常)。再者,治療抗性仍存在,有10%至30%患者對目前可用之抗精神病藥物僅有很小或無反應,另有至多之30%患者僅有部分治療反應(見,如Lehmanet al., Am. J. Psychiatry
, 161 (2 Suppl),1-56,2004)。此造成在一般臨床上實驗性使用高劑量之非典型、抗精神病多重用藥並以其他治療精神病之藥物加強效果(見,如:Zink et al., Eur. Psychiatry
, 19:56-58,2004;Stahl and Grady,Curr. Med. Chem
., 11,313-27,2004)。
根據用於治療精神分裂症之美國精神病協會指導原則,無維持治療時,60%至70%之患者在1年內復發且幾乎90%在2年內復發(見,如:Lehmanet al,. Am. J. Psychiatry
, 161 (2 Suppl),1-56,2004)。
總括而言,治療精神分裂症仍存在明顯未被滿足的醫療需求且在鑑定及研發改良之抗精神病劑上有許多努力仍在進行。
在此研究中,D3
多巴胺受體顯露出為抗精神病藥物治療之可能標的。此策略係植基於D3
受體(其在精神病病理學之核心區域的腹側紋狀體中具最高密度)在腦中之分佈及建議之角色(見,如Gurevich and Joyce,Neuropsychopharmacology
, 20,60-80,1999)。多巴胺D3
受體顯示出參與調節運動活性(見,如Shafer and Levant,Psychopharmacology
(Berl), 135,1-1,1998)及認知功能(見,如Ukaiet al., Eur. J. Pharmacol
., 324,147-51,1997;Smith et al.,Pharmacol. Biochem. Behav
., 63,201-11,1999)。在齧齒動物模型中,受體之選擇性拮抗劑調整或甚至徹底破壞由D2
拮抗劑誘導之運動擾亂(全身僵硬症(catalepsy))(見,如Millanet al., Eur. J. Pharmacol
., 321,R7-9,1997;Gyertyánet al
., [abstract].Int. J. Neuropsychopharmacol
., 5 Suppl. 1,174,2002)且當單獨投藥時不會造成運動副作用或增加乳泌素之量(見,如Reavillet al., A. J. Pharmacol. Exp. Ther
., 294,1154-65,2000;Millanet al., J. Pharmacol. Exp. Ther
., 293,1063-73,2000)。此暗示大為降低錐體外徑副作用之傾向。D3
拮抗劑顯示出改良齧齒動物(見,如Sigalaet al., Eur. J. Pharmacol
., 336,107-12,1997;Laszyet al., Psychopharmacology
(Berl), 179,567-75,2005)及靈長動物中由不同作用劑引起之認知
不良,此暗示一種治療精神分裂症中之認知障礙的可能方法。多巴胺D3
受體拮抗劑增加動物在習慣環境中的運動活性(見,如Waterset al., J. Neural. Transm. Gen. Sect
., 98,39-55,1994;Sautelet al., J. Pharmacol. Exp. Ther
., 275, 1239-46,1995;Gyertyán and Sághy, Behav.Pharmacol
., 15,253-62,2004)。此活化作用可證明對該疾病之陰性症狀有益。
然而,目前為止,用來評估(人類)抗精神病作用之多種不同動物模型中選擇性D3
拮抗劑作用之欠缺暗示單獨之“純”D3
拮抗劑可能無足夠強大之抗精神病效果來辯明臨床發展。其顯示出為了在臨床中取得抗精神病作用,多巴胺D2
受體之佔有率必須達約60%至80%(見,如:Nyberget al., Br. J. Psychiatry. Suppl
., (29),40-4,May 1996;Seeman,Clin. Neurosci. Res
., 1,53-60,2001)。後種現象提供D2
拮抗性對抗精神病作用而言為必要之觀點的基礎。因此,在D2
拮抗性中加入D3
拮抗性被認為可在精神分裂症之治療中提供超越現存之抗精神病劑的明確益處,亦即,無EPSs、認知增強潛力及對陰性症狀的強化作用。
美國專利公開第2006/0229297號中揭示作為D3
及D2
多巴胺受體亞型較佳配體之具有式(I)的(硫代)-胺甲醯基-環己烷衍生物:
其中R1
、R2
、X和n如其中之定義。
匈牙利專利申請案第P0700339號中揭示反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺之鹽類。其中揭示之一種特殊化合物為反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺氫氯酸鹽,其亦稱為反式-1{4-[2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基]-環己基}-3,3-二甲基-脲氫氯酸鹽,其結構式顯示於下:
這些(硫代)-胺甲醯基-環己烷衍生物為口服活性及非常強之多巴胺D3
/D2
受體拮抗劑,其以明顯較與D2
受體結合力高出很多之效力與D3
結合。該D3
受體拮抗性較D2
受體拮抗性的強度約高一數量級,據信其可抗衡一些由D2
受體拮抗劑產生之錐體外徑副作用。如:反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺氫氯酸鹽除了對D3
之親和力較D2
增加外,其在其他受體位置(諸如5-HT2c
、組織胺H1
及腎上腺受體位置)處的效力亦低,此暗示發生副作用(諸如EPSs及增加體重)的可能性較低。
因此,對於可有效治療精神分裂症之症狀及與精神分裂症相關之認知作用,且無一些與傳統治療相關之副作用的治療持續存在著需求。
本發明關於式(I)之(硫代)-胺甲醯基-環己烷衍生物(尤其是反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺)及其藥學上可接受之鹽類於製造用於治療精神分裂症之藥品上的用途。再者,本發明關於透過投服式(I)之(硫代)-胺甲醯基-環己烷衍生物(尤其是反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺)及其藥學上可接受之鹽類來治療精神分裂症。
本發明關於式(I)之(硫代)-胺甲醯基-環己烷衍生物及/或其幾何異構物及/或立體異構物及/或非對映異構物及/或鹽類及/或水合物及/或溶劑化物及/或多形物於製造用於治療精神分裂症之藥品上的用途,
其中
R1
和R2
各自獨立地為氫、烷基、烯基、芳基、環烷基、芳醯基,或者R1
和R2
與該相鄰之氮原子一起形成雜環;X為O或S; n為1或2。
於某些較佳體系中,當R1
及/或R2
代表烷基時,該烷基部分為經取代或未經取代之飽和的烴基,其可為直鏈型或支鏈型,含有約1至約6個碳原子(尤其是1至4個碳原子),且隨意地經一或多個C1-6
烷氧羰基、芳基(如:苯基)或(C1-6
烷氧羰基)-C1-6
烷基或其組合所取代。
於其他較佳體系中,R1
和R2
與該相鄰之氮原子一起形成雜環,此雜環可為飽和或不飽和,經隨意取代之單環或雙環(其可含有選自O、N或S之其他雜原子)。例如:該雜環可為吡咯烷、六氫吡六氫吡啶或嗎啉。
於其他較佳體系中,當R1
及/或R2
代表烯基時,該烯基部分可具有2至7個碳原子及1至3個雙鍵。
於其他較佳體系中,當R1
及/或R2
代表芳基時,該芳基部分可選自經隨意取代之單環、二環或三環芳基,諸如,但不限於苯基、萘基、茀基或蒽醌基團(如:苯基或萘基)。該芳基部分可被一或多個C1-6
烷氧基、三氟-C1-6
烷氧基、C1-6
烷氧羰基、C1-6
烷醯基、芳基、C1-6
烷硫基、鹵素、氰基或其組合所取代。
於其他較佳體系中,當R1
及/或R2
代表環烷基時,該環烷基部分可選自經隨意取代之單環、二環或三環形環
烷基,諸如環己基或金剛基。
於其他較佳體系中,當R1
及/或R2
代表芳醯基時,其中該芳基部分之定義如上(如苯基)。
藥學上可接受之鹽類包括那些經由將作為鹼之主要化合物與無機或有機酸反應所取得之鹽,例如:氫氯酸、硫酸、磷酸、甲磺酸、樟腦磺酸、草酸、順丁烯二酸、琥珀酸、檸檬酸、甲酸、氫溴酸、苯甲酸、酒石酸、反丁烯二酸、水楊酸、扁桃酸及碳酸之鹽類。藥學上可接受之鹽類亦包括那些其中該作為酸之主要化合物與合適之鹼反應所形成之鹽,如:鈉、鉀、鈣、鎂、銨及膽鹽。那些熟習本技藝之人士將進一步察知該所主張專利之化合物的酸加成鹽可藉由多種已知方法中之任一種,將化合物與合適之無機或有機酸反應來製備。或者,可將本發明之化合物與合適之鹼藉由多種已知方法反應來製備鹼及鹼土金屬鹽類。
下列為可經由以無機或有機酸反應來製備之酸性鹽的其他實例:醋酸鹽、己二酸鹽、藻酸鹽、檸檬酸鹽、天門冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、亞硫酸鹽、丁酸鹽、樟腦酸鹽、二葡萄糖酸鹽、環戊烷丙酸鹽、十二烷基硫酸鹽、乙磺酸鹽、葡糖庚酸鹽、甘油磷酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、反丁烯二酸鹽、氫溴酸鹽、氫碘酸鹽、2-羥基-乙磺酸鹽、乳酸鹽、順丁烯二酸鹽、甲磺酸鹽、菸鹼酸鹽、2-萘磺酸鹽、草酸鹽、棕櫚酸鹽、果膠酸鹽、過硫酸鹽、3-苯基丙酸鹽、苦味酸鹽、三甲基乙酸鹽、丙酸鹽、琥珀酸鹽、酒石酸鹽、硫代氰酸鹽、甲苯磺酸鹽、甲
磺酸鹽及十一烷酸鹽。
於一較佳體系中,該藥學上可接受之鹽為氫氯酸鹽。
可用於本發明之一些化合物可以不同之多形型存在。如本技藝所知,多形性為化合物以超過一種不同之結晶型結晶化或為“多形”物種之能力。多形物為一種化合物之固態結晶相,該化合物分子在固態時具有至少二種不同之排列或多形型。任何指定之化合物的多形型的定義為相同之化學式或組成物而在化學結構上之區別則如同二種不同化學化合物之結晶型結構。這類多形物之用途係在本發明之範圍內。
可用於本發明之一些化合物可以不同之溶劑化物型存在。在結晶化過程中,當溶劑分子被併入化合物分子之晶格構造時亦可形成本發明化合物之溶劑化物。例如:合適之溶劑化物包括水合物,如一水合物、二水合物、倍半水合物及半水合物。這類溶劑化物之用途係在本發明之範圍內。
再者,本發明特別關於反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺及其藥學上可接受之鹽類之用途,更特別的是關於反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺氫氯酸鹽於製造用於治療精神分裂症之藥品上的用途。
再者,本發明關於經由給予有此需要之患者治療上有效量之作為活性成分之式(I)化合物及/或其幾何異構物及/
或立體異構物及/或非對映異構物及/或鹽類及/或水合物及/或溶劑化物及/或多形物來治療精神分裂症的方法。再者,本發明特別關於經由給予有此需要之患者治療上有效量之作為活性成分之反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺或其藥學上可接受之鹽(更特別的是治療上有效量之反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺氫氯酸鹽)來治療精神分裂症的方法。
於某些較佳體系中,該活性成分之投服量為約0.1毫克、約0.2毫克、約0.3毫克、約0.4毫克、約0.5毫克、約1毫克、約1.5毫克、約2毫克、約2.5毫克、約3毫克、約3.5毫克、約4毫克、約4.5毫克、約5毫克、約5.5毫克、約6毫克、約6.5毫克、約7毫克、約7.5毫克、約8毫克、約8.5毫克、約9毫克、約9.5毫克、約10毫克、約10.5毫克、約11毫克、約11.5毫克或約12毫克。而於其他較佳體系中,該活性成分之投服量係介於這些劑量中之任何二個劑量間的範圍內。例如:於一較佳體系中,該活性成分之投服量為約1.5毫克至約4.5毫克。於另一較佳體系中,該活性成分之投服量為約6毫克至約12毫克。再於另一較佳體系中,該活性成分之投服量為約0.5毫克至約12毫克。
於示範之較佳體系中,該活性成分之投服量為約0.5毫克、約1.0毫克、約1.5毫克、約3毫克、約4.5毫克、約6毫克、約9毫克或約12毫克,例如:該投服量
為約1.5毫克、約3毫克、約4.5毫克、約6毫克、約9毫克或約12毫克。
所需之劑量可在一天中,以一或多個每日之次劑量,於合適之時間間隔內投服,或者,可以,例如:供早上或晚上投服之單次劑量投服。例如:該每日劑量可分割成一、二、三或四個分割之日劑量。
治療期可為數十年、數年、數月、數週或數日,只要其效益持續。
於一較佳體系中,本發明關於經由給予有此需要之患者約0.5毫克之反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺或其藥學上可接受之鹽來治療精神分裂症的方法。
於一較佳體系中,本發明關於經由給予有此需要之患者約1.0毫克之反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺或其藥學上可接受之鹽來治療精神分裂症的方法。
於一較佳體系中,本發明關於經由給予有此需要之患者約1.5毫克之反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺或其藥學上可接受之鹽來治療精神分裂症的方法。
於另一較佳體系中,本發明關於經由給予有此需要之患者約3毫克之反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺或其藥學上可接受之鹽來治療精神分裂症的方法。
於另一較佳體系中,本發明關於經由給予有此需要之患者約4.5毫克之反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺或其藥學上可接受之鹽來治療精神分裂症的方法。
再於另一較佳體系中,本發明關於經由給予有此需要之患者約6毫克之反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺或其藥學上可接受之鹽來治療精神分裂症的方法。
於另一較佳體系中,本發明關於經由給予有此需要之患者約9毫克之反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺或其藥學上可接受之鹽來治療精神分裂症的方法。
再於另一較佳體系中,本發明關於經由給予有此需要之患者約12毫克之反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺或其藥學上可接受之鹽來治療精神分裂症的方法。
於其他較佳體系中,投服之活性成分為反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺氫氯酸鹽。
於一較佳體系中,該活性成分係以一或二個分割之日劑量投服。
於一較佳體系中,投服活性成分可於治療精神分裂症之認知症狀時提供療效。於另一較佳體系中,投服活性成分可於治療精神分裂症之陽性症狀時提供療效。再於另一
較佳體系中,投服活性成分可於治療精神分裂症之陰性症狀時提供療效。
於其他較佳體系中,投藥可於治療精神分裂症之情感性症狀、精神分裂症之殘留症狀或類精神分裂性疾患(schizophreniform disorder)時提供療效。
式(I)之化合物可單獨投服或以醫藥組成物之活性成分形式來投服。
用於製備適合投服本發明化合物之不同配方的程序之描述可在多種標準參考資料中取得。例如:在Handbook of Pharmaceutical Excipients, American Pharmaceutical Association(目前版本);Pharmaceutical Dosage Forms: Tablets(Lieberman, Lachman and Schwartz,編者)目前版本由Marcel Dekker, Inc.出版,以及Remington's Pharmaceutical Sciences(Arthur Osol,編者),1553-1593(目前版本)中包含可能之配方及製備方法的實例。
投服模式及劑型與所需之化合物或組成物的治療量及其在指定之治療應用上之效力密切相關。
合適之劑型包括,但不限於用於經由口、直腸、舌下、黏膜、鼻、眼、皮下、肌肉內、靜脈內、透皮、脊椎、鞘內、關節內、動脈內、蜘蛛網膜下腔、支氣管、淋巴及子宮內投服之劑型,以及其他用於系統性遞送活性成分之劑型。宜為適合用於口服之配方。
該活性成分係根據習知之藥學化合技術與藥學載體充分混合以製備這類藥學劑型。該載體可根據投藥所需之製
劑形式而有多種形式。
製備口服劑型之組成物時可使用任何常用之藥學介質。因此,在液態口服製劑(諸如懸浮液、弛劑及溶液)方面,合適之載體及添加劑包括水、甘醇、油、醇、調味劑、防腐劑、染色劑,等。在固態口服製劑(諸如粉末、膠囊及錠劑)方面,合適之載體及添加劑包括澱粉、糖、稀釋劑、粒化劑、潤滑劑、結合劑、崩散劑,等。錠劑及膠囊因易於投服,所以代表最有利之口服劑量單位形式。若需要時可藉由標準技術以糖塗覆或以腸衣包覆錠劑。
在經由腸胃道外途徑投服之配方方面,該載體通常包括無菌水,但亦可包括其他成分,例如協助溶解或用於保存之成分。亦可製備其中可使用適當之助溶劑的注射溶液。
在某些應用中,使用“向量化”形式(vectorized form)之活性劑可能有所助益,諸如將活性劑包囊在微脂粒或其他密封劑介質中或將活性劑藉由,如共價鍵結、螯合作用或聯合配位固定在合適之生物分子(諸如選自蛋白質、脂蛋白、糖蛋白及多醣者)上。
利用適合口服之配方的本發明治療法可以不連續單位(諸如膠囊、小藥囊、錠劑或喉糖)呈現,其中各含有預定量之為粉末或顆粒狀的活性成分。可選擇性地使用在水性液體或非水性液體中之懸浮液,諸如弛劑、乳劑或飲用液。
錠劑可藉由緊壓或鑄型或濕性粒化,並隨意地加上一
或多種附加成分來製造。緊壓之錠劑可經由將為自由流動形式之活性化合物(諸如粉末或顆粒)在合適之機器中緊壓來製備,其中該活性化合物係隨意地與,例如結合劑、崩散劑、潤滑劑、惰性稀釋劑、界面活性劑或釋出劑(discharging agent)混合。包含粉狀活性化合物與合適載體之混合物的模型錠劑可經由在合適之機器中鑄型來製造。
糖漿可經由將活性化合物加入糖(例如蔗糖)之濃縮水性溶液中來製造,該溶液中亦可加入任何附加成分。這類附加成分可包括調味劑、合適之防腐劑、阻止糖結晶化之作用劑、增加任何其他成分之溶解度的作用劑,諸如聚羥基醇(例如:甘油或山梨糖醇)。
適合經由腸胃道外途徑投服之配方通常包含活性化合物之無菌水性製劑,此製劑宜與接受者之血液等張(如:生理食鹽水溶液)。這類配方可包含懸浮劑及增濃劑和微脂粒或其他被設計成將該化合物瞄準血液成分或一或多種器官的微粒系統。該配方可以單一劑量或複數劑量形式呈現。
經由腸胃道外途徑投藥可包含任何合適之系統遞送形式或可直接遞送至CNS。例如:可經由靜脈內、動脈內、鞘內、肌肉內、皮下、肌肉內、腹部內(如:腹膜內),等途徑投藥且可藉注入唧筒(外用或植入的)或任何其他適合所需之投藥模式的合適工具來使其作用。
鼻及其他黏膜噴霧配方(如:吸入形式)可包含具有防
腐劑及等張劑之純化的活性化合物水溶液。這類配方宜調整為與鼻或其他黏膜相容之pH及等張狀態。或者,其可為懸浮於氣體載體中之精細分割的固態粉末形式。這類配方可藉任何合適之工具或方法(如:藉由噴霧器、霧化器、計量之劑量吸入器,等)遞送。
用於直腸投藥之配方可以具合適之載體(諸如可可脂、氫化之脂肪或氫化之脂肪羧酸)的栓劑形式呈現。
透皮配方可經由將活性成分併入流動減黏或膠化之載體(諸如纖維素介質,如甲基纖維素或羥乙基纖維素)中來製備,然後,可將所產生之配方包裝在適合確保與使用者之皮膚作皮膚接觸的透皮裝置中。
除了上述成分外,本發明之配方可進一步包含一或多種選自下列之附加成分:稀釋劑、緩衝劑、調味劑、結合劑、崩散劑、界面活性劑、增濃劑、潤滑劑、防腐劑(包括抗氧化劑),等。
本發明之配方可具有熟習本技術之人士所已知之立即釋出、持續釋出、延遲開始釋出或任何其他釋出變化形廓。
於本發明之一較佳體系中係投服反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺或其藥學上可接受之鹽作為一或多種附加治療劑(如:抗精神病劑、抗抑鬱劑)的輔助治療。於另一較佳體系中可將反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺或其藥學上可接受之鹽
與一或多種附加治療劑(如:抗精神病劑、抗抑鬱劑)共同投藥來作為組合治療。
抗精神病劑可為非典型或典型之抗精神病劑,宜為非典型之抗精神病劑。非典型之抗精神病劑的實例包括,但不限於:奧氮平(olanzapine)、氯氮平(clozapine)、利培酮(risperidone)、舍吲哚(sertindole)、喹硫平(quetiapine)、阿立哌唑(aripiprazole)、齊拉西酮(ziprasidone)及曲米帕明(surmontil)。典型之抗精神病劑的實例包括,但不限於:乙醯丙(acepromazine)、苯哌利多(benperidol)、溴西泮(bromazepam)、溴哌利多(bromperidol)、氯丙(chlorpromazine)、氯普噻噸(chlorprothixene)、氯噻平(clotiapine)、腈異丁(cyamemazine)、二氮平(diazepam)、地西拉(dixyrazine)、氟哌利多(droperidol)、氟哌噻噸(flupentixol)、氟奮乃靜(fluphenazine)、氟斯必噻(fluspirilene)、氟哌啶醇(haloperidol)、庚胺醇(heptaminol)、異丙碘胺(isopropamide iodide)、左美丙(levomepromazine)、左舒必利(levosulpiride)、洛沙平(loxapine)、美哌隆(melperone)、美索達(mesoridazine)、嗎茚酮(molindone)、奧苷哌汀(oxypertine)、奧普西平(oxyprothepine)、五氟利多(penfluridol)、丙拉(perazine)、哌氰(periciazine)、奮乃靜(perphenazine)、匹莫齊特(pimozide)、匹泮哌隆(pipamperone)、哌泊噻(pipotiazine)、丙氯拉(prochlorperazine)、丙(promazine)、異丙(promethazine)、丙硫噴地(prothipendyl)、吡哆醇(pyridoxine)、舒必利(sulpiride)、舒托必利(sultopride)、丁苯那(tetrabenazine)、硫丙拉(thioproperazine)、硫利達(thioridazine)、硫必利(tiapride)、替沃噻噸(tiotixene)、三氟拉(trifluoperazine)、三氟丙(triflupromazine)、苯海索(trihexyphenidyl)及氯哌噻噸(zuclopenthixol)。
“藥學上可接受”一詞意指在動物或人類體內使用時為生物學或藥學上相容,且宜指由聯邦或州政府之管理機構核准或列於美國藥典或其他一般認可之用於動物(尤其是人類)的藥典中者。
“精神分裂症”一詞欲包括其特徵為思考及感知瓦解的一群心理障礙,包括精神分裂症(及所有其子類別;偏執型、僵直型、欠組織、殘留、未分類型)及其他精神疾患(如:Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, Washington, D. C (1994): American Psychiatric Association, or The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines, Geneva (1992):World Health Organization),諸如類精神分裂性疾患及分裂情感性疾患、暫時性精神病,等。
在臨床評估中,精神分裂症通常以“陽性症狀”,諸如幻覺(尤其是常以為是聲音之聽覺上的幻覺)、欠組織之思考過程和妄想症),以及“陰性症狀”(其包括情感表現平板、貧語症、無動機及性快感缺乏)為特徵。
“精神分裂症之陰性症狀”一詞係指一類精神分裂症之症狀,其可被視為反應官能上、指導思想或活性上之“損失”。精神分裂症之陰性症狀為本技藝所熟知且包括情感表現平板(其特徵為,例如:固定及/或無反應之臉部表情、少有眼睛接觸及減少之身體語言)、貧語症(言詞貧乏或簡短、簡明及/或空洞之回應)、無動機(其特徵為減少或無能力開始及進行目的性行為)、性快感缺乏(喪失興趣或樂趣)、社會孤立(減少社交驅動力及互動)、冷淡及其他熟習本技藝之人士已知的陰性症狀。精神分裂症之陰性症狀可利用任何本技藝已知之方法評估,包括,但不限於:簡明精神分級量表(Brief Psychiatric Rating Scale)(BPRS)及陽性和陰性症狀量表(PANSS)。BPRS及PANSS具有可用來測量陰性症狀之分量表或因子。其他已設計用來具體發表陰性症狀之量表為,例如,評估陰性症狀之量表(the Scale for the Assessment of Negative Symptoms)(SANS)、陰性症狀評估法(the Negative Symptoms Assessment)(NSA)及缺陷型精神分裂症診斷量表(the Schedule for the Deficit Syndrome)(SDS)。BPRS及PANSS之分量表亦可用來評估陽性症狀,雖然亦可使用用於具體評估陽性症狀的方法(如:評估陽性症狀之量
表(the Scale for the Assessment of Positive Symptoms或SAPS))。
“與精神分裂症相關之認知障礙”一詞係指精神分裂症患者中之認知障礙。精神分裂症中之認知損壞為該疾病之核心特性(即,非治療結果或臨床症狀)。認知障礙包括,但不限於:注意力/警覺性、工作記憶、語言學習及記憶、視覺空間記憶、推理/解決問題和社會認知。用於測量精神分裂症中之認知障礙的神經精神學試驗有多種,諸如威斯康辛卡片分類試驗(Wisconsin Card Sorting Test)(WCST)。
“治療”("treat"、"treatment"、"treating")一詞係指下列之一或多項:(a)減輕或緩和個體內至少一種病症之症狀,包括,如過敏性及發炎性病症,諸如氣喘及COPD;(b)減輕或緩和個體所經歷之病症表現的強度及/或期間,包括,但不限於那些回應所指定之刺激(如:壓力、組織傷害、低溫,等)者;(c)遏制、延遲病症開始(即,病症臨床表現前之期間)及/或降低病症發展或變壞之風險。
“有效量”一詞係指活性成份之量,當將其給予患者(如:哺乳動物)以用於治療疾病時(即,精神分裂症)可足夠使這類對疾病之治療生效的量,或係指足夠調整多巴胺受體(如:多巴胺D2
及/或多巴胺D3
受體)以達到本發明目的的量。“有效量”將根據該化合物、該疾病和其嚴重性
以及欲治療之患者的年齡、重量、反應性,等而有變化。
投服該對於疾病或病症而言為有效之治療性攝生法的治療性化合物的個體或患者宜為人類,但亦可為任何動物,包括在試驗或篩選或活性實驗中的實驗室動物。因此,本技藝之一般技術人士可輕易地察知本發明之方法、化合物及組成物特別適合給予任何動物,尤其是哺乳動物且包括,但不限於:人類、家畜(諸如貓科或犬科個體)、農場動物(諸如,但不限於:牛、馬、山羊、綿羊及豬類之個體)、野生動物(不論是在野外園地或動物園中)、研究動物(諸如小鼠、大鼠、兔子、山羊、綿羊、豬、狗、貓,等)、禽類(諸如雞、火雞、鳴鳥,等),即,用於獸醫學用途之動物。
“約”或“近似”一詞係指在由本技藝之一般技術人士所測定之特定數值之可接受的誤差範圍內,此將部分取決於該數值是如何測量或測定,即,該測量系統之限制。例如:本技藝每次操作時,“約”可指在1個標準差之內或超過1個標準差。或者,與該組成物相關之“約”可指加或減至多20%,宜為至多10%,更宜為至多5%。或者,尤其是與生物系統或過程相關時,該詞可指在數值之一數量級範圍內,宜為在5倍以內,更宜為在2倍以內。在申請案及申請專利範圍中所記述之特殊值中,除非另外指明,該“約”一詞係指在該特定數值之可接受的誤差範圍內。
下列實例僅用於說明本發明而不應被理解為在任何方面限制本發明,熟習此技術之人士在閱讀本揭示內容時可清楚明白本發明所包含之多種不同的變化及其均等物。
本臨床研究將以多中心、隨機化、雙盲、安慰劑對照、平行試驗、彈性劑量研究之形式進行。利用包含如下述之患者的標準選出共約375位住院患者:(i)目前符合或過去符合the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)對精神分裂症之標準的患者,此標準係根據"Structured Clinical Interview for DSM-IV (SCID)"定義精神分裂症(295.30偏執型、295.10錯亂型、295.20僵直型或295.90未分類型),(ii)在第1及2次訪視中,PANSS總積分≧70及≦120之患者,(iii)在第1及2次訪視中,PANSS之P1(妄想)或P3(幻覺行為)項目中積分≧4(中度)之患者,及(iv)在第1及2次訪視中,PANSS之P2(思考欠組織)或P6(懷疑/困擾)項目中積分≧4(中度)之患者。
本研究期間將為10週;6週之雙盲治療及4週之安全性追踪。在隨機選擇前先進行至多7天之無藥物沖洗期。篩檢執行期間患者需住院。在隨機選擇及開始雙盲藥物治療後患者將持續住院至少21天。評估時間表顯示於表1中。
第1次訪視時符合所有合格標準之患者將參加至多7天之無藥物沖洗期。在藥物沖洗期後,第2次訪視時符合所有合格標準之患者將被隨機分配一個編號並分配對應於雙盲研究之鋁箔包裝藥物,進行第1週之雙盲治療。
將符合所有合格標準之患者隨機(1:1:1)分至三組治療組中之一:(I)安慰劑(II)1.5-4.5毫克之反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺氫氯酸鹽,或(III)6-12毫克之反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺氫氯酸鹽。
患者將被供應外表一致之含有1.5毫克、3.0毫克或6.0毫克之反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺氫氯酸鹽或安慰劑的膠囊。
所有研究藥物將被分裝在鋁箔包裝中,每週一份。各卡將含有30個以10行、3排方式排列之膠囊,適用於一週7天再多加3天。鋁箔包裝之配製提供於表2中。所有研究藥物將以單次每日劑量形式在睡前投服。若有耐受性問題,給藥可改在早晨;然而,任何改變均需容許二個連續劑量間至少相隔24小時。
在第1天和第2天,給予所有患者一個來自鋁箔包裝之第1排的膠囊。第3天時可將劑量增加至2個膠囊(第1和2排),若反應不夠則無耐受性之問題。根據反應及耐受性,自第5天開始,可經由增加一個膠囊至最多3個膠囊(第1、2及3排)來增加劑量。在隨機分配至第Ⅱ組(1.5-4.5毫克之反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺氫氯酸鹽)之患者方面,第5天前可達到4.5毫克之最高劑量,然而,在隨機分配至第Ⅲ組(6-12毫克之反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺氫氯酸鹽)之患者方面,第9天前可達到12毫克之最高劑量。任何劑量之增加將以增加一個膠囊的方式完成。
利用已確立之分級方法進行的評估,包括:
PANSS總積分(見,如:Kay et al., Schizophr. Bull., 13,261-76,1987)
CGI-S:臨床總體印象-嚴重性(見,如:Guy ECDEU Assessment Manual for Psychopharmacology. Rockville, Md: US Department of Health, Education, and Welfare,218-22,Publication ADM 76-338,1976)
CGI-I:臨床總體印象-改善(見,如:Guy ECDEU Assessment Manual for Psychopharmacology. Rockville, Md: US Department of Health, Education, and Welfare,218-22,Publication ADM 76-338,1976)
CDSS:用於精神分裂症之Calgary抑鬱量表(見,如:Addington et al., Schizophr. Res., 19,205-12,1996)
在第14、21、28、35、42、56及70天收集血液樣本。
與以安慰劑治療之患者相較下,以反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺氫氯酸鹽進行上述治療攝生法來治療精神分裂症時預料將顯示出顯著效力。
本發明並不侷限於由此處所描述之特殊較佳體系的範圍。確實,熟習此技術之人士從先前之描述及附圖即可察
知除了此處所描述者外之多種不同的本發明之修改體。這類修改係意欲涵蓋於後附之申請專利範圍內。且需了解,所有數值皆為近似值且僅供用於描述。
前文及下文中所列舉之所有申請案、專利及刋物之全部揭示內容均併為此文之參考資料。
Claims (17)
- 一種反式-4-{2-[4-(2,3-二氯苯基)-六氫吡-1-基]-乙基}-N,N-二甲基胺甲醯基-環己胺及/或其鹽類之用途,其呈治療上有效量,係用於製造治療精神分裂症之藥品,其中,該治療上有效量為1.5至6毫克。
- 如申請專利範圍第1項之用途,其中該鹽類為氫氯酸鹽。
- 如申請專利範圍第1項之用途,其中該治療上有效量為1.5毫克。
- 如申請專利範圍第2項之用途,其中該治療上有效量為1.5毫克。
- 如申請專利範圍第1項之用途,其中該治療上有效量為3.0毫克。
- 如申請專利範圍第2項之用途,其中該治療上有效量為3.0毫克。
- 如申請專利範圍第1項之用途,其中該治療上有效量為4.5毫克。
- 如申請專利範圍第2項之用途,其中該治療上有效量為4.5毫克。
- 如申請專利範圍第1項之用途,其中該治療上有效量為6毫克。
- 如申請專利範圍第2項之用途,其中該治療上有效量為6毫克。
- 如申請專利範圍第1-10項中任一項之用途,其 中該治療上有效量係分割成一、二、三或四個之每日劑量。
- 如申請專利範圍第1-10項中任一項之用途,其中該藥品係用於治療精神分裂症之認知症狀。
- 如申請專利範圍第1-10項中任一項之用途,其中該藥品係用於治療精神分裂症之陰性症狀(negative symptoms)。
- 如申請專利範圍第1-10項中任一項之用途,其中該藥品係用於治療精神分裂症之陽性症狀。
- 如申請專利範圍第1-10項中任一項之用途,其中該藥品係用於治療精神分裂症之情感性及殘留症狀。
- 如申請專利範圍第1-10項中任一項之用途,其中該藥品係用於治療精神分裂症之繼發性社會及職業機能障礙。
- 如申請專利範圍第1-10項中任一項之用途,其中該藥品係用於治療類精神分裂性疾患(schizophreniform disorder)及分裂情感性疾患(schizoaffective disorder)。
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US7875610B2 (en) * | 2007-12-03 | 2011-01-25 | Richter Gedeon Nyrt. | Pyrimidinyl-piperazines useful as D3/D2 receptor ligands |
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