TWI389683B - A therapeutic agent for an inflammatory bowel disease or an inflammatory bowel disease treatment using a 2-amino-1,3-propanediol derivative as an active ingredient - Google Patents
A therapeutic agent for an inflammatory bowel disease or an inflammatory bowel disease treatment using a 2-amino-1,3-propanediol derivative as an active ingredient Download PDFInfo
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- TWI389683B TWI389683B TW096102882A TW96102882A TWI389683B TW I389683 B TWI389683 B TW I389683B TW 096102882 A TW096102882 A TW 096102882A TW 96102882 A TW96102882 A TW 96102882A TW I389683 B TWI389683 B TW I389683B
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- Prior art keywords
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- inflammatory bowel
- bowel disease
- disease
- amino
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Classifications
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- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Description
本發明是關於以神經胺醇－1－磷酸受體致效劑之2－胺基－1,3－丙二醇衍生物或藥學容許之其鹽類及水合物作為有效成分之發炎性腸道疾病之治療劑或發炎性腸道疾病之治療方法。
發炎性腸道疾病主要以庫隆氏病及潰瘍性大腸炎為代表，由較輕年齡層開始發病，引起腹痛、發燒、下痢、出血等症狀的難治疾病。庫隆氏病定義為口腔到肛門間，全部的消化道非連續性地，於黏膜到腸管全層有潰瘍、纖維化、狹窄，及病變進展原因不明之肉芽腫性發炎性病變，造成腹痛、慢性下痢、發燒、營養不良等全身症狀。又，潰瘍性大腸炎主要侵襲黏膜，常常形成糜爛及潰瘍之大腸的不明原因之瀰漫性非特異性發炎，出現以出血性下痢為開端之種種全身症狀的疾病。除此之外的發炎性腸道疾病中，有指在小腸或大腸發病之腸炎、包含腸道型貝切多病(ehcet’s disease)、潰瘍性大腸炎、出血性直腸潰瘍或迴腸囊炎等。關於發炎性腸道疾病的原因，雖然可推測與免疫機能異常有關，其直接原因至今不明。(非專利文獻1、2)。
在發炎性腸道疾病之藥物療法方面，可使用免疫抑制劑、類固醇製劑、柳氮磺吡啶(Salazosulfapyridine)或美沙拉(Mesalazine)等。免疫抑制劑方面，特別是硫唑嘌呤(Azathioprine)及6－巰基嘌呤(6－Mercaptopurine)等代謝拮抗物質，雖說對庫隆氏病有效，但投予初期之臨床效果不佳，經常有過敏、胰臟炎、白血球減少等副作用。高用量之環孢菌素(Ciclosporin)雖說對發炎性及瘻孔性疾病有治療效果，因其長期使用有種種的毒性所以不使用。阻礙腫瘤壞死因子之單株抗體，因福利美(Infliximab)靜脈注射用於對其他治療有耐藥性之中度或重度庫隆氏病(特別是伴隨有瘻孔)，其長期之效果與副作用並未明瞭。其他強力之免疫抑制劑療法被嘗試使用，如介白素－1阻斷劑、介白素－12之抗體、抗CD4抗體、附著分子阻斷劑、低表達細胞激素或腫瘤壞死因子之單株抗體。這些多數是經驗療法，對於發炎性腸道疾病，今日之藥物療法尚不充足。因此，希望開發出更有效且安全性高之藥物。(非專文獻3、4、5)
已知本說明書之2－胺基－1,3－丙二醇衍生物作為免疫抑制劑，對組織移植之排斥反應有效(專利文獻1、2)。本說明書之2－胺基－1,3－丙二醇衍生物雖係神經胺醇－1－磷酸受體之致效劑，關於其在作為發炎性腸道疾病之治療劑的有效性則並未得知。
〔非專利文獻1〕厚生省特定疾患難治性炎症腸管障害調查研究班，平成9年度研究報告書〔非專利文獻2〕New Engl J Med,2002,347：417－429〔非專利文獻3〕Am J Gastroenterol,2001,96：1977－1997〔非專利文獻4〕Nucl Med Commun,2005,26：649－655〔非專利文獻5〕最新醫學，2004,59：1070－1075
〔專利文獻1〕W02003/029184文獻〔專利文獻2〕W02003/029205文獻
本發明之目的為提供一種發炎性腸道疾病之治療方法，其有效成分為2－胺基－1,3－丙二醇衍生物，或藥學容許之其鹽類及水合物。
本發明者們，發現神經胺醇－1－磷酸受體致效劑之2－胺基－1,3－丙二醇衍生物，或藥學容許之其鹽類及水合物作為發炎性疾病(庫隆氏病、大腸庫隆氏病、腸道型貝切多病(ehcet’s disease)、潰瘍性大腸炎、出血性直腸潰瘍或迴腸囊炎)之治療及預防係有效的，而完成本發明。
也就是說，本發明係1.一種發炎性腸道疾病之治療劑或預防劑，其特徵為：以化學式(1)所表示之2－胺基－1,3－丙二醇衍生物或藥學容許之鹽類及水合物為有效成分。
[式中，R1
為鹵素原子、三鹵化甲基、羥基、碳數1~7之低級烷基、有取代基亦可之苯基、芳烷基、碳數1~4之低級烷氧基、三氟甲氧基、苯氧基、環己基甲氧基、有取代基亦可之芳烷氧基、吡啶甲氧基、肉桂氧基、萘甲氧基、苯氧基甲基、羥甲基、羥乙基、碳數1~4之低級烷硫基、碳數1~4之低級烷基亞硫醯基、碳數1~4之低級烷基磺醯基、苄硫基、乙醯基、硝基或氰基；R2
為氫原子、鹵素原子、三鹵化甲基、碳數1~4之低級烷氧基、碳數1~7之低級烷基、苯乙基或苄氧基，R3
為氫原子、鹵素原子、三氟甲基、碳數1~4之低級烷氧基、羥基、苄氧基、碳數1~7之低級烷基、苯基、碳數1~4之低級烷氧甲基或碳數1~4之低級烷硫基；X為O、S、SO或SO2
，n為1~4之整數]，
2.第1項之發炎性腸道疾病之治療劑或預防劑，其中，該化學式(1)所表示之化合物為2-胺基-2-[4-(3-苄氧基苯硫基)-2-氯苯基]乙基-1,3-丙二醇。
3.第1項之發炎性腸道疾病之治療劑或預防劑，其中，該化學式(1)所表示之化合物為2-胺基-2-[4-(3-苄氧基苯硫基)-2-氯苯基]乙基-1,3-丙二醇之鹽酸鹽。
4.第1~3項之發炎性腸道疾病之治療劑或預防劑，其中發炎性腸道疾病係庫隆氏病、大腸庫隆氏病、腸道型貝切多病(ehcet’s disease)、潰瘍性大腸炎、出血性直腸潰瘍或迴腸囊炎。
5.一種發炎性腸道疾病之治療方法，其特徵為：以
使用化學式(1)所表示之2-胺基-1,3-丙二醇衍生物或藥學容許之其鹽類及水合物為有效成分。
[式中，R1
為鹵素原子、三鹵化甲基、羥基、碳數1~7之低級烷基、有取代基亦可之苯基、芳烷基、碳數1~4之低級烷氧基、三氟甲氧基、苯氧基、環己基甲氧基、有取代基亦可之芳烷氧基、吡啶甲氧基、肉桂氧基、萘甲氧基、苯氧基甲基、羥甲基、羥乙基、碳數1~4之低級烷硫基、碳數1~4之低級烷基亞硫醯基、碳數1~4之低級烷基磺醯基、苄硫基、乙醯基、硝基或氰基，R2
為氫原子、鹵素原子、三鹵化甲基、碳數1~4之低級烷氧基、碳數1~7之低級烷基、苯乙基或苄氧基，R3
為氫原子、鹵素原子、三氟甲基、碳數1~4之低級烷氧基、羥基、苄氧基、碳數1~7之低級烷基、苯基、碳數1~4之低級烷氧甲基或碳數1~4之低級烷硫基，X為O、S、SO或SO2
，n為1~4之整數]。
6.如第5項之發炎性腸道疾病之治療方法，其中，發炎性腸道疾病係庫隆氏病、大腸庫隆氏病、腸道型貝切多病(ehcet’s disease)、潰瘍性大腸炎、出血性直腸潰瘍或迴腸囊炎。
7.一種發炎性腸道疾病之治療劑或預防劑，其特徵為：以使用化學式(1)所表示之2-胺基-1,3-丙二醇衍生
物或藥學容許之其鹽類及水合物及更併用至少一種之發炎性腸道疾病用藥劑而成。
[式中，R1
為鹵素原子、三鹵化甲基、羥基、碳數1~7之低級烷基、有取代基亦可之苯基、芳烷基、碳數1~4之低級烷氧基、三氟甲氧基、苯氧基、環己基甲氧基、有取代基亦可之芳烷氧基、吡啶甲氧基、肉桂氧基、萘甲氧基、苯氧基甲基、羥甲基、羥乙基、碳數1~4之低級烷硫基、碳數1~4之低級烷基亞硫醯基、碳數1~4之低級烷基磺醯基、苄硫基、乙醯基、硝基或氰基，R2
為氫原子、鹵素原子、三鹵化甲基、碳數1~4之低級烷氧基、碳數1~7之低級烷基、苯乙基或苄氧基，R3
為氫原子、鹵素原子、三氟甲基、碳數1~4之低級烷氧基、羥基、苄氧基、碳數1~7之低級烷基、苯基、碳數1~4之低級烷氧甲基或碳數1~4之低級烷硫基，X為O、S、SO或SO2
，n為1~4之整數]。
8.本發明是關於如第7項之發炎性腸道疾病之治療劑或預防劑，其中，發炎性腸道用藥劑為柳氮磺吡啶(Sulfasalazine)類、類固醇類或免疫抑制劑。
本發明係提供一種含神經胺醇-1-磷酸受體致效劑之2-胺基-1,3-丙二醇構造之二芳基硫化物或二烯丙基醚衍生
物，或藥學容許之其鹽類及水合物作為有效成分之發炎性腸道疾病之治療劑或預防劑。又，根據本發明提供發炎性腸道疾病之庫隆氏病、大腸庫隆氏病、腸道型貝切多病(ehcet’s disease)、潰瘍性大腸炎、出血性直腸潰瘍或迴腸囊炎之治療或預防方法。
本發明之神經胺醇-1-磷酸受體之致效劑之2-胺基-1,3-丙二醇衍生物，其係如下述化學式(1)所示之化合物或藥學容許之其鹽類及水合物。
[式中，R1
為鹵素原子、三鹵化甲基、羥基、碳數1~7之低級烷基、有取代基亦可之苯基、芳烷基、碳數1~4之低級烷氧基、三氟甲氧基、苯氧基、環己基甲氧基、有取代基亦可之芳烷氧基、吡啶甲氧基、肉桂氧基、萘甲氧基、苯氧基甲基、羥甲基、羥乙基、碳數1~4之低級烷硫基、碳數1~4之低級烷基亞硫醯基、碳數1~4之低級烷基磺醯基、苄硫基、乙醯基、硝基或氰基，R2
為氫原子、鹵素原子、三鹵化甲基、碳數1~4之低級烷氧基、碳數1~7之低級烷基、苯乙基或苄氧基，R3
為氫原子、鹵素原子、三氟甲基、碳數1~4之低級烷氧基、羥基、苄氧基、碳數1~7之低級烷基、苯基、碳數1~4之低級烷氧甲基或碳數1~4之低級烷硫基，X為O、S、SO或SO2
，n為1~4之整數]。
本發明之化學式(1)中，「鹵素原子」表示氟原子、氯原子、溴原子、碘原子，「三鹵甲基」表示三氟甲基、三氯甲基，「碳數1~7之低級烷基」，舉例如甲基、乙基、丙基、異丙基、丁基、t－丁基、戊基、己基、庚基等之直鏈或支鏈的碳數1~7之碳水化合物。
「有取代基亦可之苯氧基」為苯環之任意位置上有氟原子、氯原子、溴原子、碘原子等之鹵素原子、三氟甲基、碳數1~4之低級烷基、碳數1~4之低級烷氧基。「芳烷基」、「芳烷氧基」之「芳烷基」為苄基、二苯甲基、苯乙基、苯丙基。又「碳數1~4之低級烷氧基」、「碳數1~4之低級烷硫基」，「碳數1~4之低級烷基亞硫醯基」，「碳數1~4之低級烷基磺醯基」等之「低級烷基」為，如甲基、乙基、丙基、異丙基、丁基等之直鏈或支鏈的碳數1~4之烴，「有取代基亦可之芳烷基」為苯環之任意位置上有氟原子、氯原子、溴原子、碘原子等之鹵素原子、三氟甲基、碳數1~4之低級烷基、碳數1~4之低級烷氧基。
本發明中化學式(1)所表示之化合物之藥理學所容許之鹽為鹽酸鹽、溴化氫酸鹽、醋酸鹽、三氟醋酸鹽、甲磺酸鹽、檸檬酸鹽、酒石酸鹽之酸附加鹽。
更具體之例子為2－胺基－2－[4－(3－苄氧基苯硫基)－2－氯苯基]甲基－1,3－丙二醇或其鹽酸鹽。
化學式(1)所示之本發明之化合物，已於WO03/029184文獻及WO03/029205文獻等中公開，可經由這些公報中公開之方法製造。
如此得到之本發明之化合物或藥學容許之其鹽類及水合物作為發炎性腸道疾病之治療劑為有效的。
本發明之治療劑為全身的或於局部的、經口的或非經口的被投用。化合物的劑型依化合物的性狀而能有所變更，可調製成經口製劑或非經口製劑。也就是說，有效成分與生理學上可容許之擔體、賦形劑、結合劑、稀釋劑等混合，可調製成顆粒劑、粉劑、錠劑、膠囊劑、糖漿劑、坐劑、懸濁劑、溶液劑等。
臨床上的使用量，依使用之用途、體重、年齡、接受治療之狀態而變化，通常一次量為一個人0.01~100mg，以0.1~5mg為佳，1日1~3次較適當。
進一步，此等之製劑中，可與一種以上作為發炎性腸道疾病之治療劑的藥物搭配使用。這樣之發炎性腸道疾病治療劑有柳氮磺吡啶(Sulfasalazine)類、類固醇類或免疫抑制劑。具體之柳氮磺吡啶類有美沙拉嗪(mesalazine)、奧抄拉寨、柳氮磺吡啶(sulphasalazine)、巴柳氮(balsalazide)等；類固醇類有氫皮質酮、甲基氫化保泰松、布地奈德(Budesonide)、磷酸倍他米松等；又免疫抑制劑有硫唑嘌呤(Azathioprine)、6－巰基嘌呤、環孢菌素、他克莫司(tacrolimus)、抗TNF－α抗體、抗α 4整合素(Integrin)抗體等。
以下舉實施例來具體說明本發明。本實施例中特別關於化學式(1)之化合物中，2－胺基－2－[4－(3－苄氧基苯硫基)－2－氯苯基]甲基－1,3－丙二醇之鹽酸鹽(以下縮寫為「KRP－203」)論述，但本發明並不因此等實施例而受任何限定。
對於右旋葡聚醣硫酸鈉誘發小鼠大腸炎之治療效果給BALB/C系雄性小鼠餵給含右旋葡聚醣硫酸鈉(平均分子量5000)之5%水溶液7天，製造大腸炎[Kitajima,S.et.al.,Exp Anim,Vol.49,No.1：9－15(2000)]。KRP－203(0.01、0.03、0.1mg/kg)以蒸餾水溶解，在投予右旋葡聚醣硫酸鈉溶液飲水的前日開始，一日一次經口投用八天，而溶劑投予組則投用蒸餾水。
右旋葡聚醣硫酸鈉溶液飲水開始第八天，將小鼠以二乙基醚深度麻醉，做下頸椎脫臼使其死亡，取出大腸(結腸到肛門)。餵給小鼠右旋葡聚醣硫酸鈉之水溶液後，已知因腸炎會造成大腸長度的縮短[Okayasu,I.et.al.,Gastroenterology,Vol.98：694－702(1990)]取出之大腸之結腸到肛門的長度以游標尺測定。接著，將大腸縱切露出管腔，以生理食鹽水洗淨內容物。藉測定腸炎之炎症標記之大腸組織中過氧化骨髓酶活來比較[Grisham,MB.et.al.,Methods Enzymol,Vol.186：729－742(1990)]。
大腸之長度比較如表1所示。KRP－203對腸炎造成之大腸長度的縮短抑制有統計學上的意義。
大腸組織中過氧化骨髓酶活性測定結果如表2所示。KRP－203對於腸炎造成之大腸組織中過氧化骨髓酶活性上升之抑制有統計學上的意義。
右旋葡聚醣硫酸鈉所誘發之小鼠大腸炎，常被用作為人類發炎性腸道疾病之病態模型[Elson,CO.et.al.,Gastroenterology,Vol.109：1344－1367(1995)][Hibi,T.et.al.,J Gastroenterol,Vol.37：409－417(2002)]。所以，此實驗結果說明了KRP－203對於作為發炎性腸道疾病之治療劑是有效的。
(比較例)在發炎性腸道疾病的藥物治療上，種種藥物被使用。於器官移植用於抑制排斥反應的免疫抑制劑也是一種選擇。與評估KPR－203同樣地，評估代表免疫抑制劑之環孢菌素、他克莫司之作用。
環孢菌素(10、30mg/kg)溶於大豆油，在投予右旋葡聚醣硫酸鈉溶液飲水的前日開始，一日一次經口投用八天。而溶劑投予組則投用大豆油。相對於溶劑投予組之大腸組織中過氧化骨髓酶活性上升，環孢菌素之10mg/kg投予組有54%，30mg/kg投予組有73%之抑制率。
他克莫司(3mg/kg)於0.5%羧酸甲基纖維素鈉水溶液中懸濁，在投予右旋葡聚醣硫酸鈉溶液飲水的前日開始，一日一次經口投用八天。而溶劑投予組則投予0.5%羧酸甲基纖維素鈉水溶液。相對於溶劑投予組之大腸組織中過氧化骨髓酶活性上升，他克莫司3mg/kg投予組有37%之抑制率。
代表免疫抑制劑之環孢菌素及他克莫司之對於右旋葡聚醣硫酸鈉所誘發之小鼠大腸炎之作用與KRP－203之作用比較，相對於溶劑投予組之大腸組織中過氧化骨髓酶活性上升，KRP－203之0.01mg/kg投予組有51%、0.03mg/kg投予組有69%、0.1mg/kg投予組有62%之抑制率(表2)。這些結果表示出，作為發炎性腸道疾病之治療劑，使用少量KRP－203即有與環孢菌素及他克莫司之同樣或以上之效果之可能性。
KRP－203對於IL－10基因敲除小鼠之作用使用B6.129P2－IL10<tm1Cgn>/J(IL－10基因敲除小鼠)(雄，5~6週齡)做試驗。以蒸餾水將KRP－203溶解，由取得動物後第八週起之四週，以每日一次每次0.1mg/kg之用量經口投予。溶劑投予組只投用蒸餾水。投予完成後，將動物解剖，摘出其大腸。藉由福馬林固定大腸後做組織切片，進行蘇木素伊紅染色。遵循評分基準(BergDJ,et al.,Gastroenterology,123：1527－1542(2002))做近端大腸、中端大腸、遠端大腸之評分，合計各部份之評分，作為個體之Histological Score。結果以平均值±標準誤差表示。
如表3所示，經由KRP－203之投予，Histological Score對溶劑投予組來說其抑制有統計學上的意義，而對於IL－10基因敲除小鼠之大腸炎有抑制作用。此結果說明被試驗物質KRP－203對於發炎性腸道疾病之治療有效。
處方例：膠囊劑(1膠囊中)組成化合物(KRP－203) 0.1mg D－甘露醇 247.5mg硬酯酸鎂 2.5mg
也就是說，化合物與D－甘露醇混合，再與硬酯酸鎂混合調製成混合粉末。將此混合粉末充填於膠囊中即製成膠囊劑。
如上所述，本發明之化合物在人類發炎性腸道疾病之病態模型中有良好之治療效果，又在基因敲除小鼠之組織病變上看到顯著之改善。所以本發明之2－胺基－1,3－丙二醇衍生物或藥學容許之其鹽類及水合物可用作發炎性腸道疾病之治療劑或預防劑。本發明提供了發炎性腸道疾病之庫隆氏病、大腸庫隆氏病、腸道型貝切多病(ehcet’s disease)、潰瘍性大腸炎、出血性直腸潰瘍或迴腸囊炎等之治療劑、治療方法及預防劑、預防方法。
Claims (8)
- 一種發炎性腸道疾病之治療劑，其特徵為以2-胺基-2-[4-(3-苄氧基苯硫基)-2-氯苯基]乙基-1,3-丙二醇或其藥學上所容許之鹽作為有效成分。
- 如申請專利範圍第1項之發炎性腸道疾病之治療劑，其係以2-胺基-2-[4-(3-苄氧基苯硫基)-2-氯苯基]乙基-1,3-丙二醇之鹽酸鹽作為有效成分。
- 如申請專利範圍第1或2項之發炎性腸道疾病之治療劑，其中發炎性腸道疾病係指庫隆氏病、大腸庫隆氏病、腸道型貝切多病(ehcet’s disease)、潰瘍性大腸炎、出血性直腸潰瘍或迴腸囊炎。
- 如申請專利範圍第1或2項之發炎性腸道疾病之治療劑，其中發炎性腸道疾病係指庫隆氏病或潰瘍性大腸炎。
- 一種2-胺基-2-[4-(3-苄氧基苯硫基)-2-氯苯基]乙基-1,3-丙二醇或其藥學上所容許之鹽之用途，其特徵係用作為製造治療發炎性腸道疾病用藥劑之有效成分。
- 如申請專利範圍第5項之用途，其中，發炎性腸道疾病係指庫隆氏病、大腸庫隆氏病、腸道型貝切多病(ehcet’s disease)、潰瘍性大腸炎、出血性直腸潰瘍或迴腸囊炎。
- 一種發炎性腸道疾病之治療劑，其特徵為組合2- 胺基-2-[4-(3-苄氧基苯硫基)-2-氯苯基]乙基-1,3-丙二醇或其藥學上所容許之鹽與至少一種之發炎性腸道疾病用藥劑而成。
- 如申請專利範圍第7項之發炎性腸道疾病之治療劑，其中，發炎性腸道疾病用藥劑為柳氮磺吡啶(Sulfasalazine)類、類固醇類或免疫抑制劑。
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