TWI321472B - [[2-(amino-3,4-dioxo-1-cyclobuten-1-yl)amino]alkyl]-acid derivatives for the treatment of pain - Google Patents
[[2-(amino-3,4-dioxo-1-cyclobuten-1-yl)amino]alkyl]-acid derivatives for the treatment of pain Download PDFInfo
- Publication number
- TWI321472B TWI321472B TW091123270A TW91123270A TWI321472B TW I321472 B TWI321472 B TW I321472B TW 091123270 A TW091123270 A TW 091123270A TW 91123270 A TW91123270 A TW 91123270A TW I321472 B TWI321472 B TW I321472B
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- Prior art keywords
- pain
- pharmaceutical composition
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- amino
- compound
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- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940087652 vioxx Drugs 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 229940063674 voltaren Drugs 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
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Description
1321472 五、發明說明(1 ) 發明背景 疼痛已經於參考文獻決定其特徵且以多種不同方式說 明。例如疼痛之性質可能爲強烈、局部、銳痛或刺痛及 /或鈍痛、疼痛,彌漫性疼痛或燒灼感。疼痛也可能爲 中樞疼痛,發生於脊索,腦幹及腦部之背角;或爲周邊 疼痛出現於受傷部位及其周圍組纖。長時間出現之疼痛 (換言之持續性疼痛)通稱慢性疼痛。慢性疼痛例如包括 神經病變疼痛、發炎痛及癌症疼痛。此等疼痛可能與痛 覺過敏及/或痛覺異常有關,痛覺過敏表示對局部有害 刺激的敏感度增高;而痛覺異常表示對局部非有害刺激 之敏感度增高。 目前無法作適當藥理治療之一類型慢性疼痛爲神經病 變疼痛。神經病變疼痛通常被認爲由於周邊神經系統或 中樞神經系統受傷或病理變化引發的慢性疼痛。有關神 經病變疼痛之病理變化例如包括長期周邊神經元或中樞 神經元敏化、神經系統抑制功能及/或興奮功能受損相 關之中樞敏化、以及副交感神經系統與交感神經系統間 之異常交互作用。多種臨床疾病可能關聯或構成神經病 變疼痛的基礎,包括例如糖尿病、截肢之創傷後疼痛、 下背痛、癌症、化學品傷害或毒素、其它重大手術、因 創傷傷害壓迫造成的周邊神經損傷 '營養不良或感染例 如帶狀疤疹或HIV。 目前有多種藥劑用來治療疼痛例如非麻醉性止痛劑例 如阿斯匹靈、乙醯胺芬(acetaminophen)或伊布普芬 1321472 五、發明說明(2) (ibuprofen);非類固醇抗炎藥物(NSAID);麻醉性止痛 劑例如嗎啡、氫嗎琳酮、芬坦尼(fentanyl)、可待因或美 派利定(meperidine);類固醇例如普尼松(prednisone)或 德沙美沙松(d e X a m e t h a s ο n e );三環鬱劑例如亞米奇林 (amitriptyline)、德西普明(desipramine)或伊米普明 (imipramine);抗癲癇劑例如噶巴潘汀(gabapentin)、托 皮拉梅(topiramate)、維普酸鈉(valproate sodium)或癲通 (phenytoin);或此等不同藥劑的組合。但此等藥劑典型 用於治療慢性本質之疼痛未臻滿意,且可能有副作用例 如嗜眠、頭昏、口乾、體重增加、記億力受損及/或姿 態性低血壓。 更爲晚近令人感興趣者係使用N-甲基-D-天冬酸酯(「 NMDA」)接受器抑制劑來治療疼痛(後文稱作「NMDA 接受器拮抗劑」)。已知NMD A接受器涉及寬廣多項過 程包括缺血後神經元死亡、記億力形成關聯之突觸成形 、以及持績疼痛期間的中樞敏化。相信調節NMD A接受 器之麩胺酸鹽於疼痛特別於慢性疼痛扮演關鍵要角。 NMDA接受器局限於全部中樞神經系統。NMDA接受 器爲配位子-閘控之陽離子通道,NMDA接受器當藉麩胺 酸鹽絚合甘胺酸活化時,調節鈉、鉀及鈣離子通量。於 結構上相信NMDA接受器係由包含兩個主要亞單元(定 名爲NR1及NR2)之非同質多元體通道組成。此等亞單 元含有一個甘胺酸結合位置,一個魅胺酸鹽結合位置以 及一個多胺結合位置。對於NR1亞單元,已經識別出多 1321472 五、發明說明(3) 種剪接變異株;而對NR2亞單元識別四類型個別亞單元 (NR2A、NR2B、NR2C 及 NR2D)。NMDA 接受器含有一 個Mg + +結合位置位在NMDA接受器/通道複體之離子基團 之孔洞內部,其阻斷離子流。芬賽克利定(phencyclidine)及 其它化合物顯然結合此種Mg + +位置。爲了讓PCP可接 近PCP接受器,通道首先必須利用麩胺酸鹽及甘胺酸( 使用相依性)開啓通道。 已經發展出多種NMDA拮抗劑來與NMDA接受器之 此等位置交互作用。例如NMDA接受器麩胺酸鹽位置拮 抗劑表示可與NR2亞單元之麩胺酸鹽結合位置交互作用 之該等拮抗劑。於臨床前實驗模式已經顯示可抑制疼痛 之NMDA接受器麩胺酸鹽位置拮抗劑例如包括003-1 9 75 5 (色弗托(8611'〇161);順-4-膦基甲基-2-哌啶羧酸)、 CPP(3-(2-羧哌畊基-4-基)丙基-1-膦酸)以及AP5(D-2胺 基5 -膦基戊酸)。例如參考Karlsten及Gordh,藥物與 老化11; 398-412,(1997)。其它已經識別之NMDA接 受器拮抗劑,於番木繼鹼不敏感甘胺酸位置(甘胺酸#) 交互作用者例如爲L701324(7-氯-4-羥- 3-(3-苯氧)苯基-2(1H)-喹琳),以及於多胺位置交互作用者例如爲伊芬普 迪(ifenprodil)。已經發現可有效抑制疼痛之非競爭性 NMDA接受器通道阻斷拮抗劑包括德多美沙芬 (dextromethorphan)、K 它命(ketamine)、美曼汀 (memantine)及亞曼它定(amantadine)。例如參考Hao等 人,疼痛66: 279-285(1996); Chapian等人,藥理實驗 1321472 五、發明說明(4) 治療學期刊280: 829-838(1997); Suzuki等人,疼痛91 :1 0 1 - 1 09(2000); Bennetts,疼痛症狀管理期刊 19: S2(2000) ; Sang,疼痛症狀管理期刊 19(1) : S21,(2000)。 NMDA接受器拮抗劑已經用於臨床上治療疼通。例如 k它命已經用來治療治療後神經痛、幻肢痛、神經受傷 後疼痛、術後疼痛及燒傷疼痛。又例如德多美沙芬用於 治療糖尿病性神經病變疼痛及術後疼痛;以及亞曼它定 已經用來治療癌症病人的疼痛。 此等N M D A接受器拮抗劑之臨床用途受其副作用所限 ,其副作用例如爲頭痛、運動功能障礙例如運動失調、 鎭定及/或例如精神方面影響例如頭昏、幻覺、煩躁不 安、或於止痛劑量時造成認知功能障礙。例如參考Hao 等人,疼痛66: 2 79-2 8 5 ( 1 996); Chaplan等人,藥理實 驗治療學期刊280: 829-838(1997); Suzuki等人,疼痛 91 : 101-109,(2000): Bennett,疼痛症狀管理期刊 19 :S2(2000) ; Sang,疼痛症狀管理期刊 19(1) : S21, (2000)。例如具有高度親和力之NMDA接受器通道阻斷 劑k它命,偶而用於燒傷相關疼痛,據報告有不良影響 因而限制k它命用於病人之用途(Pal等人,燒傷23: 404-412’ 1997)。此外,NMDA接受器通道阻斷拮抗劑 第左西平(dizocilpine)(MK-801)的發展終止,原因在於 第左西平產生類似芬賽克利定(換言之PC P)引起的精神 作用影響。曾經提議親和力較低之通道阻斷劑例如德多 美沙芬 '亞曼它定及美曼汀可能副作用比高度親和力阻 1321472 五、發明說明(5 ) 斷劑少(Rogawski,藥理學趨勢1 4 : 32 5,1 998)。證實 此項論點,德多美沙芬用於患有糖尿病性神經病變病人 具有止痛效果,而副作用比k它命低(Sang,疼痛症狀 管理期刊19(1) : S21,2000)。同樣地,亞曼它定用於 癌症病人可解除手術神經病變疼痛而副作用較少(Hewitt ,臨床疼痛期刊16: 573,2000)。 但類似較高親和力之非競爭性拮抗劑,即使使用具較 低親和力之非競爭性NMD A接受器通道阻斷拮抗劑,也 有非期望之精紳作用影響因而障礙藥物的發展。例如於 臨床前實驗模式,具有不等親和力之NMDA接受器通道 阻斷劑用於經過受訓練可區分食鹽水與PCP之大鼠皆能 一致地產生類似PCP之區別刺激效果》美曼汀、k它命 及第左西平全部皆可於大鼠替代仿PC P區別刺激效果 (Nicholson 等人,行爲藥理學:9(3): 231-243,1998; Mori等人:行爲腦部硏究丨19 : 33_4〇,2〇〇1)。此外, 類似PCP ’美曼汀可於猴維持自我投藥,顯示美曼汀用 於人類可能造成濫用藥物傾向(Nicholson等人,行爲藥 理學:9(3): 231-243’ 1998)。使用依賴性NMDA接受 器通道阻斷劑也會增加心搏率及提高血壓,因而限制其 臨床用途。 雖然NMDA接受器麩胺酸鹽拮抗劑不具有於人類之精 神方面副作用、或於非人類之仿pcp區別刺激效果(例 如參考Baron及Woods,精神藥理學118(1): 42-51 ’ (1995); Mori 等人’行爲腦硏究 119: 33-40,(2〇〇1); 1321472 五、發明說明(6)
France等人,藥理實驗治療學期刊257(2): 727-734, (1991) ’ France 等人,歐洲藥理期刊 1 5 9(2) : 1 33 - 1 39, ( 1 9 8 9)) ’但NMD A接受器麩胺酸鹽拮抗劑也有多種非 期望的副作用。例如NMDA麩胺酸鹽拮抗劑CGS- 1 975 5 於行爲有效劑量顯示於小鼠及大鼠之扣帶皮質及脾後皮 質某些層可能一過性可逆性誘生空泡(換言之效果/空泡 形成比=1)。例如參考Herring等人,使用拮抗劑之興 奮性胺基酸臨床結·果,學術出版社出版,第1章(1 9 9 7 年)。雖然形成空泡之功能方面未明,但先前硏究提示 此種空泡之形成與NMD A接受器拮抗劑產生精神方面影 響有交互關聯(例如參考Olney等人,科學,224:1 630-1632’ 1989; Olney 等人,科學 254: 1515-1518,1991) ’如同第左西平之例可能導致有限神經元細胞死亡(Fix 等人,實驗神經學123: 204-215,1993)。 如此’希望找出其它可有效治療疼痛之化合物。較佳 此等化合物之不良副作用減少及/或治療疼痛之功效增 筒。
Kinney等人之美國專利第5,1 68,1 03號(後文稱作「 Kinney」)揭示某些[[2_(胺基_3,4_二酮基_;!_環丁烯基) 胺基]烷基]-酸衍生物可用作爲神經保護劑及抗痙攣劑。 此等揭示爲競爭性NMDA拮抗劑之[[2-(胺基-3,4-二酮 基-1-環丁烯-1-基)胺基]烷基]-酸衍生物可用於治療某些 中樞神經系統病症,例如痙攣、腦細胞損傷及相關神經 退化病症。 1321472 五、發明說明(7) Kinney專利案之揭示之化合物之一亦即[2-(8,9-二酮 基-2,6 -二氮雜雙環[5.2.0]壬-1(7-烯-2-基)乙基)膦酸之副 作用先前已經於歐洲進行的第I期硏究對健康自願者進 行評估。此項硏究係有關將此種化合物發展用於治療病 人之中風相關性缺血(Bradford等人,中風及腦循環摘 要,1 998 年)。 本發明人發現Kinney專利案之環丁烯衍生物可用於 多種臨床前期疼痛硏究模式治療疼痛。例如發明人發現 此種環丁烯衍生物於此處試驗之比較性NMDA接受器拮 抗劑無法緩解疼痛之情況下,前述環丁烯衍生物可緩解 疼痛。此外’出乎意外地,此等環丁烯衍生物不具有已 知NMDA接受器拮抗劑於疼痛緩解需要劑量時所呈現的 不良副作用程度。 例如(容後詳述),發明人發現Kinney專利案揭示之化 合物例如[2-(8,9-二酮基-2,6-二氮雜雙環[5_2.〇]壬-1(7-烯-2-基)乙基)膦酸於臨床前期硏究模式中,於緩解疼痛 所需劑量,比其它報告之競爭性麩胺酸鹽拮抗劑(C G S -19755)、競爭性多胺拮抗劑(伊芬普迪)以及使用依賴性 通道阻斷劑(MK-80 1、美曼汀;第左西平、k它命)較爲 不會產生運動失調或鎭定作用。此外,如前述,發現某 些N M D A接受器拮抗劑例如c G S - 1 9 7 5 5於小鼠及大鼠 之扣帶皮質及脾後皮質之若干層具有一過性可逆性空泡 誘生作用。與CGS- 1 975 5 (於行爲有效劑量形成空泡)相 反’環丁烯衍生物例如[2-(8,9 -二酮基-2,6 -二氮雜雙環 1321472 五、發明說明(8) [5.2.0]壬-1(7-烯-2-基)乙基)膦酸具有功效/成空泡比高 達1 6。此外,不似本文先前所述之NMDA接受器通道 阻斷拮抗劑,環丁烯衍生物例如[2-(8,9-二酮基- 2,6-二 氮雜雙環[5.2.0]壬-1(7-烯-2-基)乙基)膦酸不會放大鼠替 代PCP,表示此種化合物不會引起類似PCP之精神方面 影響、或含有類似PCP之藥物濫用情形。此外,[2-(8,9 -二酮基-2,6-二氮雜雙環[5.2.0]壬-1(7-烯-2-基)乙基)膦 酸用於缺血模式於高於有效劑量4-10倍之劑量時會顯 示多種類似PCP之影響。 發明槪述 本發明提供一種於哺乳動物體治療疼痛之方法,該方 法包括對需要此種治療之哺乳類投予醫藥有效量之至少 一種式(I )化合物: NH N—A—X R1 R2 (I) 此處: R1爲氫、含1至6個碳原子之烷基或含7至〗2個碳 原子之苯烷基; R2爲氫、含1至6個碳原子之烷基、含2至6個碳原 子之烯基或含7至12個碳原子之苯烷基;或 R1 及 R2 共同形成爲 Z,Z 爲-CH2CH2-、-CH2C(R6)(R7)CH2-、或-(^2(:(118)(119)-(:(11|。)(1^1)(:112-,此處116、118及 •10- 1321472 五、發明說明(9) 分別爲氫 '含1至6個碳原子之烷基或羥基以及R7、R9 及R11分別爲氫或含1至6個碳原子之烷基; A爲含1至6個碳原子之伸烷基或含2至6個碳原子 之伸烯基; . X 爲 C02R3、P(0)(〇R4)(〇R5)、3,5-二酮基-1,2,4-噚二 唑啶-2-基或5-四唑基,此處R3、R4及R5分別爲氫或含 1至6個碳原子之烷基; 或其醫藥可接受性鹽。 本發明也提供一種醫藥組成物,其含有:疼痛治療有 效量之式⑴化合物或其醫藥可接受性鹽;此處R1及R2 共同形成爲Z,其餘變數定義如前:以及至少一種醫藥 載劑。較佳具體實施例中,此種組成物也含有醫藥有效 量之至少一種疼痛緩解劑。也提供一種醫藥組成物,其 含有疼痛治療有效量之式(I)化合物或其醫藥可接受性 鹽,以及醫藥有效量之至少一種疼痛緩解劑。 本發明也提供一種呈單位劑型之醫藥組成物以及一種 含有呈單位劑量之式(I )化合物可用於哺乳類治療疼痛 之治療包裝。 發明之詳細說明 本發明可用於治療疼痛之化合物包括式(I)環丁烯衍 生物 Ο. ,Ο (I) -11- 1321472 五、發明說明(1〇) 此處: R1爲氫、含1至6個碳原子之烷基或含7至12個碳 原子之苯烷基; R2爲氫、含1至6個碳原子之院基、含2至6個碳原 子之烯基或含7至12個碳原子之苯烷基;或 R1 及 R2 共同形成爲 z,Z 爲-ch2ch2-、-ch2c(r6)(r7)ch2-、或,此處 R6、R8 及 R1Q分別爲氫、含1至6個碳原子之烷基或羥基以及R7 、R9及R11分別爲氫或含1至6個碳原子之烷基; A爲含1至6個碳原子之伸烷基或含2至6個碳原子 之伸烯基; X 爲 C02R3' P(0)(0R4)(0R5)' 3,5-二酮基-1,2,4-噚二 唑啶-2-基或5-四唑基,其中R3、R4及R5分別爲氫或含 1至6個碳原子之烷基; 或其醫藥可接受性鹽。 R1·11之烷基以及A之伸烷基例如爲直鏈或分支基團例 如甲基、乙基、丙基(例如正丙基、異丙基)、丁基(例如 正丁基、異丁基)、戊基(例如正戊基、異戊基)或己基。 較佳本發明之烷基含有1至4個碳原子。R2之烯基以及 A之伸烯基例如爲直鏈或分支一-、二-或多未飽和基團 例如乙烯基、丙-1-烯基、丙烯基 '甲基丙烯基、丁 -1-烯基、丁 -2-烯基或丁 -3-烯基。 R1及R2之苯烷基例如爲其中烷基部分爲含1至6個 碳原子之直鏈或分支碳鏈,例如苄基、苯乙基、3-苯丙 -12- 1321472 五、發明說明(11) 基或4-苯丁基。 R1及R2之較佳値分別爲氫、甲基、乙基、丙烯基、 甲基丙烯基或苄基。 其它較佳値爲當R1及R2共同形成爲式(II)之Z部分 時: NH N-A—X\7/ z (II) 此處 Z 爲-CH2CH2-、-CH2C(R6)(R7)CH2-、或 -ch2c(r8)(r9)-c(r1())(ru)ch2-,且較佳爲-ch2c (r6)(r7)ch2-,此處R6、R8及Rl()分別爲氫、含1至6個碳原子之烷 基或羥基而R7、R9及R11分別爲氫或含1至6個碳原子 之烷基。較佳R6至R"爲氫。 就A而言,伸烷基較佳例如爲含1至4個碳原子之直 鏈或分支鏈基團例如:-CH2-、-CH2CH2-、-CH(CH3)CH2-、 -CH2CH(CH3)-、-(CH2)3-、或- (CH2)4-。A 之伸烯基較佳 例如爲含2至4個碳原子之順式或反式基團例如-<:112-CH=CH-、-CH=C(CH3)-、-C(CH3)=CH-、 -CH= CH-CH2- ' -CH2-CH= CH-CH2 -CH2-CH= C(CH3)-。較佳A爲含1至4個碳原子之伸烷基或反-2-伸丁基 。X之較佳取代基爲羧基、膦基或5-四唑基。 本發明之最佳具體實施例中,本發明有用之化合物具 有式(皿): -13- 1321472 五、發明說明(12 )
X (III) 此處A及X定義如前❶ 本發明有用之化合物也包括式(I )化合物之醫藥可接 受性鹽。「醫藥可接受性鹽」一詞表示經由醫藥可接受 性鹼或酸與式(I )化合物加成形成之對應鹽。「醫藥可 接受性」一詞表示一種物質其由毒理學觀點視之可用於 醫藥用途,且不會與活性成分產生不良交互作用。較佳 醫藥可接查性鹽爲式(I )化合物之鹼金屬(鈉、鉀、鋰) 或鹼土金屬(鈣 '鎂)鹽、或式(I )化合物與衍生肖氨或 鹼性胺之醫藥可接受性陽離子形成之鹽。後述例包括但 非限於銨、一-或二-或三甲基銨、一-、二-或三乙基銨 、一-、二-或三丙基銨(異及正)、乙基二甲基銨、苄基 二甲基銨、環己基銨、苄基銨、二苄基錶、哌啶_、嗎 啉鐵、吡咯@鐵、哌畊鑷、1-甲基哌啶鏺、1-異丙基吡 咯啶鐵、1,4-二甲基哌哄鑰、1-正丁基哌啶鑰' 2-甲基 峨陡鐵、1-乙基-2 -甲基峨陡鐵、一-、二-、或三乙醇錢 、參-(羥甲基)甲基銨或苯基一乙醇銨。 此處所述化合物可藉美國專利第5,1 68,1 03號(Kinney 等人)核發日期19 92年12月1日所述方法製備,其全 部內容以引用方式倂入此處。本發明化合物也可經由美 -14- 1321472 五、發明說明(13) 國專利第 5,240,946 號(Kinney 等人),5,99〇,3〇7(Asselin 等人),或6,011,168號(Asselin等人)所述方法製備;此 等專利案之內容以引用方式倂入此處。 本發明有用之較佳化合物包括下列化合物或其醫藥可 接受性鹽: N-(2 -胺基-3,4-二酮基-1-環丁烯-1-基)/5-丙胺酸; 2-[2-[(2-胺基- 3,4-二酮基-1-環丁烯-1-基)胺基]乙基]· 1,2,4-噚二唑啶·3,5-二酮; Ν-(2-胺基- 3,4-二酮基-1·環丁烯-1-基)-Ν-(2-丙烯基)甘 胺酸; [2-[(2-胺基- 3,4-二酮基-1-環丁稀-I-基)胺基]乙基]膦酸 [(Ε)-4-[(2-胺基-3,4-二酮基-卜環丁烯-1-基)胺基]-2_丁 烯基]膦酸; [2-[(2 -胺基-3,4 -二酮基-卜環丁嫌-卜基)甲基胺基]乙基] 膦酸; [2-(7,8-二酮基_2,5-二氮雜雙環[4.2.0]辛-1(6)_烯_2-基) 乙基]膦酸; [2-(8,9-二酮基-2,6-二氮雜雙環[5.2.0]壬_1(7)_烯_2_基) 氮雜雙環[5.2.0]壬-1(7)-烯_ 乙基]膦酸; [2-(4-羥-8,9-二酮基-2,6-2-基)乙基]膦酸; ‘ 8,9-二酮基-2,6-二氮雜雙環[5.2.〇]壬_1(7)-烯_2-乙馱, 2-[(lH-四唑-5-基)甲基]-2,6-二氮雜雙環[5.2.〇]壬1 -1 5 - 1321472 五、發明說明(14) (7)-8,9-二酮;或 [2-(9,10-二酮基-2,7_二氮雜雙環[6,2_0]癸-1(8)-烯-2-基) 乙基]膦酸。 本發明之更佳具體實施例中,用於治療疼痛之化合物 爲[2-(8,9-二酮基-2,6-二氮雜雙環[5.2.0]壬-1(7)-烯-2-基) 乙基]膦酸具有式:
或其醫藥可接受性鹽形式》 雖然不欲受理論所限,但信本發明之環丁烯衍生物對 NMDA接受器之某些結合位置具有獨特親和力及選擇性。 此種獨特親和力及選擇性相信可於較低劑量提供疼痛的 有效治療,及/或於緩解疼痛需要劑量引起較少副作用。 此處所述環丁烯衍生物根據本發明方法可用於哺乳動物治 療疼痛。「治療」一詞用於此處表示部分或完全消除、抑制 、改善及/或緩解疼痛。例如「治療」一詞用於此處包括部 分或完全消除、抑制或緩解疼痛經歷一段時間。「治療」也 包括完全改善疼痛。 本發明有用之化合物可用於治療哺乳類包括人類經驗的多 種不同類型之疼痛。例如本發明化合物可有效治療急性疼痛 -16- 1321472 五、發明說明(15) (持績時間短)或慢性疼痛(規則性復發或持續疼痛)。此種疼 痛也可爲中樞或爲周邊疼痛。 急性或慢性且可根據本發明方法治療之疼痛例如包括發炎 痛、肌肉骨骼痛、骨胳痛、腰椎薦椎疼痛、頭痛或上背痛、 內臟痛、軀體痛、神經病變疼痛、癌症痛、受傷或手術引起 的疼痛例如燒傷痛、或頭痛例如偏頭痛或緊張性頭痛或此等 疼痛的組合。熟諳技藝人士了解此等疼痛可能彼此重疊。例 如發炎造成的疼痛本質上可能爲內臟痛或肌肉骨骼痛。 本發明之較佳具體實施例中,本發明有用之化合物投予哺 乳類治療慢性疼痛例如與周邊神經系統或中樞神經系統損傷 或病理變化關聯之神經病變疼痛;癌症痛;例如與腹腔、骨 盆腔及/或會陰區或胰炎相關之內臟痛;例如與上背或下背 '脊椎、纖維肌痛、顳顎關節或肌筋膜疼痛症候群關聯之肌 肉骨骼痛;例如與骨骼或關節退化病症(例如骨關節炎、類 風濕性關節炎、或僵直性脊椎炎)關聯之骨骼痛;頭痛例如 偏頭痛或緊張性頭痛;或感染(如HIV、鐮刀型血球貧血、 自體免疫病、多發性硬化症)或發炎(例如骨關節炎或類風濕 性關節炎)關聯之疼痛。 較佳具體實施例中,本發明有用之化合物可根據此處 所述方法用於治療慢性疼痛、換言之神經病變疼痛、Θ 臟痛、肌肉骨骼痛、骨痛、頭痛、癌症痛或發炎痛或其 組合。發炎痛可能與多種醫事情況有關,例如骨關節炎 、類風濕性關節炎、手術或受傷。神經病變疼痛可能關 聯糖尿病性神經病變 '周邊神經病變 '疱疹後神經痛、 -17- 1321472 五、發明說明(16) 二叉神經痛、腰椎或頸椎神經根病變、纖維肌肉痛、舌 咽神經痛、反射性交感神經萎縮、意外疼痛、丘腦症候 群 '神經根撕裂或因受傷引起神經損傷造成周邊及/或 中樞敏化例如幻肢痛、反射性交感神經萎縮或胸廓造口 術後疼痛、癌症、化學品傷害、毒素 '營養不良或病毒 性或細菌性感染例如帶狀疱疹或HIV或其組合。本發明 化合物之用法進一步包括用於治療神經病變疼痛屬於轉 移性浸潤、痛性肥胖症、燒燙傷或丘腦疾病相關之中樞 疼痛繼發之情況。 如前述,本發明方法可用於治療屬於軀體病及/或內 臟痛本質的疼痛。例如根據本發明方法可治療之軀體痛 包括手術、牙科處理、燒燙傷或外傷性身體受傷所遭遇 之結構或軟組纖受傷引發的疼痛。根據本發明方法可治 療之內臟痛例如包括與內部器官疾病關聯的或導致的該 種類型疼痛’內部器官疾病例如潰瘍性結腸炎、激躁性 腸症群、剌激性膀胱、克隆氏症、風濕症(關節痛)、腫 瘤 '胃炎、胰炎、器官感染或膽道疾病或其組合。熟諳 技藝人士了解根據本發明方法治療之疼痛也有關痛覺過 敏、痛覺異常或二者之相關病情。此外,慢性疼痛可帶 有或未帶有周邊或中樞敏化。 本發明有用之化合物也可用於治療與女性疾病關聯之 急性及/或慢性疼痛,也稱作爲女性特有疼痛。此種疼 痛族群包括女性所獨有或主要出現於女性之疼痛包括月 經、排卵、妊娠或分娩、流產、子宮外孕、逆行性月經 -18- 1321472 五、發明說明(17) 、濾泡或黃體囊破裂、骨盆內臟刺激、子宮纖維硬化、 腺肌病、子宮內膜炎、感染與發炎、骨盆腔器官缺血、 梗阻、腹內沾黏、骨盆腔內臟解剖扭曲、卵巢膿腫、骨 盆腔喪失支撐、腫瘤、骨盆腔充血等關聯的疼痛或來自 於非婦科起因之疼痛。 本發明可用之環丁烯衍生物可以多種方式投藥包括例 如經口、肌肉、腹內 '硬膜外、鞘內、靜脈、皮下、黏 膜內例如舌下或鼻內或經皮投藥。本發明之較佳具體實 施例中,本發明有用之化合物可經口、經黏膜或經靜脈 投藥。 本發明有用之化合物可以疼痛治療有效量投予需要治 療疼痛的哺乳類。用於此處,「疼痛治療有效量」爲可 治療該種疼痛之至低用量之環丁烯衍生物或其醫藥可接 受性鹽形式。爲了決定用於治療疼痛時投予之疼痛治療 有效量之化合物,醫師例如可藉遞增劑量例如口服劑量 且較佳由約3毫克/千克至約1 000毫克/千克評估環丁烯 衍生物給予病人的效果,直到達成所需症狀緩解程度爲 止。隨後之用法用量可據此修改來達成所需效果,口服 劑量較佳係由約1 5 0毫克/日至約9 0 0毫克/日之範圍。 對其它投藥途徑例如靜脈或肌肉途徑決定有效劑量範圍 也可遵照類似技術基於生物利用率資料決定劑量。例如 估計靜脈劑量較佳於約3毫克/日至約5 0毫克/日之範圍。 雖然環丁烯衍生物可根據本發明方法投予作爲治療疼 痛之唯一活性成分,但發明人發現環丁烯衍生物也可組 -19- 1321472 五、發明說明(18) 合一或多種其它疼痛緩解劑投藥。「疼痛緩解劑」—詞 表示任何可直接或間接治療疼痛症狀之藥劑。間接疼痛 緩解劑包括例如消炎劑例如抗類風濕劑。 一或多種其它疼痛緩解劑可同時投予(例如同時個別 投予或一起於一種醫藥組成物投予),及/或接續一或多 種本發明有用之環丁烯衍生物投予。較佳,環丁烯衍生 物以及一或多種疼痛緩解劑之投藥方式讓二者可於哺乳 動物體內存在一段可供治療疼痛的時間。 其它疼痛緩解劑之投藥方法可與用於環丁烯衍生物之 投藥途徑相同或相異。例如其它疼痛緩解劑可經口、肌 肉、腹內、硬膜外、鞘內、靜脈、黏膜內例如鼻內或舌 下、皮下或經皮投藥。較佳投藥途徑將依據選用之特定 疼痛緩解劑熟諳技藝人士已知之推薦投藥途徑決定。例 如鴉片劑較佳係經口、靜脈或肌肉投藥途徑投藥。 熟諳技藝人士了解其它疼痛緩解劑投予哺乳動物體之 劑量將依據選用之特定疼痛緩解劑以及期望投藥途徑決 定。如此,其它疼痛緩解劑可根據熟諳技藝人士已知之 劑量及投藥規範投予,例如揭示於參考文獻例如醫師桌 面手冊,55版,2001年,醫學經濟公司出版,紐澤西 州,蒙特維爾。 可連同本發明有用之環丁烯衍生物一起投藥之疼痛緩 解劑例如包括止痛劑例如非麻醉性止痛劑或麻醉性止痛 劑;抗炎劑例如非類固醇抗炎劑(NSAID)、類固醇或抗 風濕劑;偏頭痛製劑例如/3腎上腺激性阻斷劑' 麥角衍 -20- 1321472 五、發明說明(19) 生物或艾索美賽汀(isometheptene);三環抗鬱劑例如亞 米奇林、德西普明或伊米普明;抗癲癇劑例如噶巴潘汀 、卡巴美奇平、托皮拉梅、維普酸鈉或癲通;α2促效 劑;或選擇性血淸素再吸收抑制劑/選擇性新腎上腺素 吸收抑制劑或其組合。熟諳技藝人士了解後文所述某些 藥劑可用來緩和多種情況例如疼痛與發炎,而其它藥劑 則只能緩和一種症狀例如疼痛。具有多重性質之藥劑特 例爲阿斯匹靈,此處阿斯匹靈以高劑量投藥時具有抗炎 作用’但於較低劑量時只能止痛。疼痛緩解劑也包括前 述藥劑之任一種組合,例如疼痛緩解劑可爲非麻醉性止 痛劑組合麻醉性止痛劑。 本發明有用之非麻醉性止痛劑包括例如水楊酸鹽類如 阿斯匹靈、伊布普芬(摩琴(MOTRIN®),阿德維(ADVIL®) 奇托普芬(ketoprofen)(歐路迪斯(ORUDIS®))、納普洛森 (naproxen)(納普洛辛(NAPROSYN®))、乙醯胺芬、印多 美沙辛(indomethacin)或其組合。可組合環丁烯衍生物 使用之麻醉性止痛劑例如包括鴉片類止痛劑例如芬坦尼 、沙芬坦尼(s u f e n t a n i 1)、嗎啡、氫嗎啡酮、可待因、經 可待因、布普諾芬(buprenorphine)或其醫藥可接受性鹽 或其組合。可與環丁烯衍生物組合使用之抗炎劑例如包 括但非限於阿斯匹靈;伊布普芬;奇托普芬;納普洛森 :伊托多來(etodolac)(洛定(LODINE®) ; C0X-2抑制劑 例如希雷克夕(celecoxib)(希樂葆(CELEBREX®))、洛費 克夕(rofecoxib)(偉適(VIOXX®)、瓦德克夕(valdecoxib) -21 - 1321472 五、發明說明(20 ) (貝克采(BEXTRA®)、帕瑞克夕(parecoxib)、伊托利克 夕(etoricoxib)(MK663®)、德拉克夕(deracoxib)、2-(4-乙氧-苯基)-3-(4-甲烷磺醯基-苯基)-吡唑并[l,5-b]嗒畊 、4-(2-酮基-3-苯基-2,3-二氫噚唑-4-基)苯磺醯胺、達布 費隆(darbufelone)、弗洛沙來(flosulide)、4-(4-環己基-2-甲基-5-噚唑基)-2-氟苯磺醯胺)、美洛西坎(meloxicam) 、尼美沙來(nimesulide)、1-甲基磺醯基-4-(1,1-二甲基-4-(4-氟苯基)環戊-2,4-二烯-3-基)苯、4-(1,5-二氫-6-氟-7-甲氧- 3-(三氟甲基)-(2)-苯并硫吡喃并(4,3-c)吡唑-1-基)-苯磺醯胺' 4,4-二甲基-2-苯基-3-(4-甲基磺醯基)苯 基)環·丁烯酮、4-胺基-N-(4-(2-氟-5-三氟甲基)-噻唑-2-基)-苯磺醯胺、1-(7-第三-丁基-2,3-二氫·3,3-二甲基-5-苯并呋喃基)-4-環丙基丁 -1-酮或其生理可接受性鹽、酯 類或溶劑合物;沙林達(sulindac)(克林諾里(CLINORIL®)) ;代克洛芬(diclofenac)(弗他倫(VOLTAREN®);派洛西坎 (piroxicam)(費爾定(FELDENE®));地夫路尼沙(diflunisal) (多洛必(DOLOBID®)) '納布美東(nabumetone)(瑞拉芬 (RELAFEN® ))、歐沙普琴(oxaprozin)(待普洛(DAYPRO®)) 、印多美沙辛(印多辛(INDOCIN®));或類固醇例如佩代 亞培(P EDI APED®));普尼松鈉磷酸鹽口服液、索路-美 德羅(SOLU-MEDROL®)甲基普尼松鈉丁二酸鹽注射劑、 普利隆(PRELONE®)品牌普尼松糖漿劑。 較佳用於治療類風濕性關節炎之抗炎劑之進一步實例 包括納普洛森市面上可以艾克納普洛辛(EC-NAPROSYN®) -22- 1321472 五、發明說明(21) 遲釋放錠、納普洛辛(NAPROSYN®)、亞納普洛斯 (ANAPROX®)及亞納普洛斯DS錠及納普洛辛懸浮液得 自羅氏公司、希樂葆品牌之希雷克夕錠、偉適品牌之洛 費克夕、希樂斯東(CELE STONE®)品牌之貝他美沙松、 久普拉明(CUPRAMINE)品牌之青黴胺膠囊劑、第片 (DEPEN®)品牌之可滴定青黴胺錠劑、待波-美德羅 (DEPO-MEDROL)品牌之甲基普尼松乙酸鹽注射用懸浮 液劑、亞拉瓦(ARAVATM)雷夫路諾麥(leflunomide®)錠 劑 '亞助費定(AZULFIDINEEN-tabs®)品牌之沙法沙拉 琴(sulfasalazine)延遲釋放錠、費爾定品牌之派洛西坎 膠囊劑、卡他弗蘭(CATAFLAM®)品牌之代克洛芬鉀錠 劑、弗他倫代克洛芬鈉延遲釋放錠、代克洛芬-XR代克 洛芬鈉延遲釋放錠、或安布瑞(ENBREL®)安他內塞 (etanerecept)產品。 其它可用於治療發炎之藥劑特別類風濕性關節炎之藥 劑例如包括免疫抑制劑如珍格拉夫(gengraftm)品牌之 環孢靈膠囊劑、尼歐拉(NEORAL®)品牌之環孢靈膠囊劑 或口服溶液劑、或伊姆蘭(IMURAN®)品牌之亞查普林 (a z a t h i 〇 p r i n e)銳劑或靜脈注射劑;印多辛品牌之印多美沙 辛膠囊劑、口服懸浮液劑或栓劑;普拉奎尼(PLAQUENIL®) 品牌之海左克洛奎(hydroxychloroquine)硫酸鹽;或雷米 凱(REM IC ADE)因夫利西梅(infliximab)重組株供靜脈注 射;或金化合物例如奧拉諾芬(a u r a η o f i η)或密歐克利辛 (MYOCHRISYINE®)金鈉硫代蘋果酸鹽注射劑。 •23- 1321472 五、發明說明(22) 本發明有用之環丁烯衍生物也可與一或多種其它醫藥 活性劑一起投藥,其它醫藥活性劑例如用於治療哺乳類 存在之任何與疼痛相關或不相關之醫療病情之藥劑。此 等醫藥活性劑例如包括抗血管新生劑、抗腫瘤劑、抗糖 尿病劑、抗感染劑或胃腸道作用劑或其組合。 醫藥活性劑包括疼痛緩解劑之更完整淸單可參考醫師 桌面手冊,第55版,2001年,醫學經濟公司出版,紐 澤西州,蒙特維爾》各藥劑可根據業界已知之醫藥有效 用法用量投予,例如述於醫師桌面手冊,第55版,2001 年’醫學經濟公司出版,紐澤西州,蒙特維爾對各產品 相關用法用量之說明。 本發明之較佳具體實施例中,至少一種環丁烯衍生物 可根據前述所述方法與至少一種鴉片類止痛劑一起投藥 。出乎意外地發現本發明有用之環丁烯衍生物當與至少 一種鴉片類止痛劑例如嗎啉一起投藥時具有協同性降低 痛覺、延長疼痛緩解時間及/或減低副作用至比其它比 較性NMDA拮抗劑更高的程度等有利效果。 本發明有用之環丁烯衍生物可淨(換言之就此)投藥或 呈醫藥組成物投藥。本發明有用之醫藥組成物可呈熟諳 技藝人士已知之任一種劑型例如液體劑型或固體劑型。 醫藥組成物除了含有醫藥有效量之一或多種本發明之 環丁烯衍生物外,也可包括一或多種熟諳技藝人士已知 用於調配醫藥組成物之成分。此等成分包括例如載劑 (例如呈固體或液體形式)、矯味劑、潤滑劑、增溶劑、 -24- 1321472 五、發明說明(23) 懸浮液劑、塡充劑、滑動劑、壓縮助劑、黏結劑、錠 劑-崩散劑、包囊劑、乳化劑、緩衝劑、保藏劑、甜味 劑、增稠劑、著色劑、黏度調節劑、安定劑或滲透壓調 節劑、或其組合。 固體醫藥組成物較佳含有一或多種固體載劑以及視情 況需要含有一或多種其它添加劑例如矯味劑、潤滑劑、 增溶劑、懸浮劑、塡充劑、滑動劑、壓縮助劑、黏結劑 或錠劑-崩散劑或包囊材料。適當固體載劑包括例如磷 酸鈣、硬脂酸鎂、滑石、糖類、乳糖、糊精、澱粉、明 膠、纖維素、甲基纖維素、羧甲基纖維素鈉、聚乙烯基 吡咯啶酮、低熔點蠟或離子交換樹脂或其組合。粉末醫 藥組成物中,載劑較佳爲經過精細分割之固體其與經過 精細分割之活性成分混合。錠劑中,活性成分以適當比 例混合具有所需壓縮性質之載劑以及視情況需要混合其 它添加劑且壓縮成爲期望形狀及大小。固體醫藥組成物 例如散劑及錠劑較佳含有高達9 9 %活性成分。 液體醫藥組成物較佳含有一或多種環丁烯衍生物以及 一或多種液體載劑俾形成溶液劑、懸浮液劑、乳液劑、 糖漿劑、酏劑或加壓組成物。醫藥可接受性液體載劑包 括例如水、有機溶劑、醫藥可接受性油類或脂肪或其組 合。液體載劑含有其它適當醫藥添加劑例如增溶劑、乳 化劑、緩衝劑、保藏劑、甜味劑、矯味劑、懸浮劑、增 稠劑、色料、黏度調節劑、安定劑或滲透壓調節劑或其 組合。 -25- 1321472 五、發明說明(24) 適合經口或經腸道外投藥之液體載劑例如包括水(較 佳含有添加劑例如纖維素衍生物如羧甲基纖維素鈉)、 醇類或其衍生物(包括一元醇或多元醇例如二醇類)或油 類(例如分餾椰子油或花生油)。供腸道外投藥用,載劑 也可爲油酯例如油酸乙酯或肉豆蔻酸異丙醇。加壓組成 物用之液體載劑可爲鹵化烴類或其它醫藥可接受性推進 劑。 無菌溶液劑或無菌懸浮液劑之液體醫藥組成物可經腸 道外投藥,例如經由肌肉、腹內、硬膜外、鞘內、靜脈 或皮下注射投藥。口服或經黏膜投藥之醫藥組成物可呈 液體或固體組成物形式。 本發明之較佳具體實施例中,醫藥組成物除了含有環 丁烯衍生物外,也可含有醫藥有效量之一或多種前述疼 痛緩解劑,及/或醫藥有效量之一或多種前述其它醫藥 活性劑。如此’本發明也提供治療疼痛之醫藥組成物其 含有疼痛治療有效量之至少一種本發明有用之環丁烯衍 生物以及醫藥有效量之至少一種前述疼痛緩解劑。更佳 具體實施例中,疼痛緩解劑包括鴉片類止痛劑。 較佳醫藥組成物係呈單位劑型,例如錠劑或膠囊劑。 於此種劑型,組成物被再分割成爲含有適量活性成分之 單位劑量。單位劑型可爲包裝組成物例如包裝散劑、小 瓶、安瓿、預塡充注射器或含液體之舉袋。單位劑型例 如可爲錠劑或膠囊劑的本身,或可爲任何適量組成物之 包裝形式。 -26- 1321472 五、發明說明(25) 如此,本發明也提供呈單位劑型之醫藥組成物用於哺 乳類治療疼痛,其含有疼痛治療有效單位劑量之至少一 種本發明之環丁烯衍生物。如熟諳技藝人士已知,較佳 疼痛治療有效單位劑量係依據例如投藥方法決定。例如 口服投藥之單位劑量較佳爲約7 5毫克至約3 0 0毫克, 更佳約100毫克至約3 00毫克本發明有用之環丁烯衍生 物。 本發明也提供一種配送本發明有用之環丁烯衍生物給 欲治療疼痛之哺乳類之治療包裝。較佳治療包裝含有一 或多單位劑量環丁烯衍生物,以及一個容器含有一或多 單位劑量,以及標示指導包裝如何用於哺乳動物治療疼 痛。較佳具體實施例中,單位劑型爲錠劑或膠囊劑劑型》 較佳具體實施例中,各單位劑量爲疼痛治療有效量。 實施例 本發明有用之環丁烯衍生物評估其用於治療疼痛之效 果。已知可用於緩解疼痛之NMDA接受器拮抗劑也一起 試供比較用。 此處使用之試驗方法由熟諳技藝人士用於評估化合物 緩解疼痛的效果。例如參考BennettGJ及XieTK,大 鼠之周邊單一神經病變產生如同人類之痛覺病症,疼痛 33 : 87- 1 07(1 988) ; Chaplan SR, Bach RW, Pogrel JW, Chung JM及Yaksh TL,大鼠足掌觸感痛覺異常之量化評 估,神經科學方法期刊53 : 5 5-63(1994);以及Mosconi T 及Kruger L’固定直徑聚乙稀袖套施加放大鼠坐骨神經 -27-· 1321472 五、發明說明(26) 誘發疼痛性神經病變:軸突變化之超結構形態學分析, 疼痛 64 : 37-57(1996)。 主旨 個別圈養之史柏格拉秉大鼠(Spraque Dawley rats)可 自由進食鼠及飲水。接受12小時亮/12小時暗的周期 (由上午6點至夜間6點點燈)。動物的維護及硏究係根 據美國國家衛生院實驗動物資源委員會提供的指南進 行。此等個體用於下列各試驗。 試驗化合物 實施例中試驗之環丁烯衍生物爲: A. [2-(8,9-二酮基-2,6-二氮雜雙環[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸(稱作化合物a);以及 Β. 2-[(1Η-四唑-5-基)甲基]-2,6-二氮雜雙環[5·2.0]-壬-l(7)-烯-8,9-二酮(稱作化合物B)。 化合物A及化合物B分別係根據as selin等人之美國 專利第5,990,307號以及Kinney等人之美國專利第5,168,1〇3 號所述合成方法製造。 本發明之環丁烯衍生物與以下已知可緩解疼痛之NMd A 拮抗劑之一或多者作比較: 美曼汀(memantine) ’得自RBI(麻省,拿提克) 第左西平(dizocilipine),得自RBI(麻省,拿提克) k它命(ketamine) ’得自福特多吉(Fort Dodge)(福特多 吉,愛荷華州) 伊芬普迪(ifenprodil) ’得自西格瑪藥廠(蒙大拿州, -28- 1321472 五、發明說明(27) 聖路易) CGS- 1 97 5 5,得自托克利斯(Tocris)(蒙大拿州,艾利 斯維) k它命及第左西平爲高度親和使用依賴性NMDA接受 器通道阻斷劑,美曼汀爲中等親和力使用依賴性NMD A 接受器通道阻斷劑。CGS- 1 975 5爲競爭性NMDA拮抗劑 以及伊芬普迪爲競爭性多胺拮抗劑。 試驗方法1 : 前列腺素E2-誘生熱過敏。 尾部末端10厘米置於含有溫熱至38、42、46、50、 54或5 8°C水之熱水瓶中。動物將尾部由水中移開之延 遲時間(秒數)用來測量疼痛感覺。若動物在20秒以內未 移開尾端,則實驗者將動物尾端移開且記錄最大延遲時 間=20秒。 評估基準線熱敏感度之後,將50微升0. 1毫克前列 腺素E2(PGE2)注射於尾端1厘米位置,造成熱過敏。於 PGE2注射前(基準線)以及注射後(15、30、60、90及 120分鐘)產生熱效應曲線。先前對其它種屬的硏究(例 如猴;Brandt等人,醫理實驗治療學期刊296: 939, 2 00 1 )以及由本硏究結果證實PGE2可產生劑量-相依性 及時間-相依性熱過敏,尖峰出現於注射後1 5分鐘,而 於2小時後消失。 單一化合物硏究。藥物逆轉PGE2誘生熱過敏之能力 係使用單劑量時程程序評估。此種程序中,單劑試驗化 -29- 1321472 五、發明說明(28) 合物係於PGE2注射前30分鐘經腹內(IP)、口服(P〇)或 鼻內(IN)投藥。於PGE2注射後30鐘評比觸覺敏感度。 組合藥物硏究。進行NMDA接受器拮抗劑連同#瑪片 劑促效劑嗎啡之組合硏究。最低有效量嗎啡(5.6毫克/千 克)單獨以及組合無效劑量之NMDA接受器拮抗劑投予 進行溫水-尾部抽回檢定分析。化合物係於試驗前3 〇分 鐘同時經腹內投予。 也於PGE2誘生熱過敏檢定分析進行NMDA接受器拮 抗劑連同//鴉片劑促效劑嗎啡之組合硏究。可完全逆轉 熱過敏(換言之返回基準線値)之嗎啡劑量(5.6毫克/千克) 單獨或組合NMDA接受器拮抗劑劑量用於pgE2誘生溫 水尾部抽回檢定分析。於PGE2同時,亦即試驗前30分 鐘腹內投予化合物。 試驗方法1資料分析…可於尾端抽回延遲時間產生半 最大値增高之溫度(換言之,T1())由各溫度-效應曲線算 出。T1C係由溫度-效應曲線上1〇秒上方該點或下方該 點劃一直線藉內插法測定。由此硏究,熱過敏定義爲於 溫度效應曲線向左位移,以及T i 〇値減少。熱過敏之逆 轉定義爲返回溫度效應曲線及T, 〇値之基準線値,且係 根據如下方程式計算: %ΜΡΕ= [(τ10 缀物 H PGE2卜(Ti〇PGE2)]/[(Ti〇 8 準線卜(T|〇PGE2)] xlOO 其中Tl〇 *物+ PGE2爲藥物組合PGE2後之T10,T丨/GE2爲 單獨PGE2後之τ丨〇 ’以及T]〇Su爲於控制條件下之 -30- 1321472 五、發明說明(29) Τιο。%MPE値=100指示完全返回未注射PGE2時觀察 得之基準線熱敏感度。%MPE値大於1 00%,指示試驗 化合物降低熱敏感度大於未經PGE2注射時的基準線熱 敏感度。 試驗方法2 :慢性收縮傷害 大鼠使用3 · 5 %鹵烷於氧氣以1升/分鐘麻醉,手術期 間維持於1 · 5 %鹵烷於氧氣。經修改之慢性坐骨神經收縮 傷害(Mosconi & Kruger,1996 ; Bennett & Xie,1988)係利 用皮膚切開以及切割臀肌曝露出坐骨神經造成傷害。PE 90聚乙嫌管(因多美第(Intramedic),克雷亞當(Clay Adams);貝克坦狄金森(Becton Dickinson)公司)管套(長 2毫米)於中臀高度位置套住坐骨神經。傷口使用4-0絲 線縫線以傷口釘針關閉。手術後6-1 0日進行試驗。 ί 動物置於高舉之金屬線網籠內,讓動物適應房間45- | 60分鐘。手術前0-3日使用一系列經過校準的von Frey 單絲線(史多汀(Stoelting);伊利諾州,伍代爾)評估觸 覺敏感度基準線値。von Frey單絲線視需要以上升或下 降順序循序施用於後足掌中腳底,俾儘可能接近反應之 臨限價。臨限値係以刺激可激發輕快的回縮反應的最小 力量表示。如此,有回縮反應則下個刺激減輕,若無回 縮反應則下個刺激增強。帶有基準線臨限値小於1 0克 力之大鼠由實驗中排除。約在CCI手術後一周,再度評 r 估觸覺敏感度,出現運動缺陷(換言之腳掌在地面拖行) 1 以及無法產生隨後之觸覺過敏(臨限値大於1 〇克力)之動 -31 - 1321472 五、發明說明(3〇) 物由進一步試驗中排除。於副量累進條件下,每3 0分 鐘以1 /2 log單位增量累進遞增劑量投予化合物。每次 投藥後評比觸覺過敏20-30分鐘。 試驗方法2資料分析--計算Dixon非參數試驗(Chaplan 等人,1 994)之5〇%臨限値(1克力爲單位)表示,使用I5 克力作爲最大力。對各大鼠由各實驗條件生成劑量-效 應曲線。平均求出個別觸覺過敏臨限値獲得平均値(± 1 SEM)。觸覺過敏之逆轉係定義爲返回觸覺敏感度基準線 値,且係根據如下方程式計算: % 逆轉=[(5 0 % 薄物 + c c 1) — (5 0 % c c 1) ] / [ ( 5 0 % 基準線)一 (50%CCI)]x 100其中50%藥物+ cc丨爲CCI手術後約1周對 動物投藥後之50%値,50%CC1爲單獨CCI手術後約1周 之50%値,以及50%基準線爲CCI手術前之50%値。最大 效應逆轉100%表示返回該個體於該實驗條件下之平均 手術前臨限値。 試驗方法3 :排程控制反應。 大鼠於實驗中以每周5曰接受多週期試驗程序。各個 訓練週期係由1 〇分鐘的處理前期,接著1 〇分鐘反應期 組成。處理前期,尙未照射刺激光,反應也未產生排程 結果。反應期間,照射左或右刺激光(個體間之相對平 衡),延長反應槓桿,個體在固定30週期給予食物。整 個試驗期由3個連績週期組成。試驗期與訓練期完全相 同,但第一週期開始時給予單劑藥物。 資料分析。個別動物之操作反應率係對每個試驗期間 -32- 1321472 五、發明說明(31) 之3個週期求平均,且換算成占對照反應率之百分比, 使用試驗前當日之平均反應率作爲對照値(換言之三個 週期的平均)》資料係以平均(± SEM)反應率以占對照之 百分比表示。如此,例如試驗値1 〇〇%指示投予試驗化 合物後之反應率同對照反應率,且未出現試驗化合物之 不良影響。 結果 試驗方法1 :基準線熱疼痛感覺及PGE2-誘生熱過 敏。 於基準線條件下,典型使用3 8、4 2及4 6 °c溫度獲得 尾回縮延遲(亦即20秒)。水溫升高至50°C時,各頭大 鼠之尾回縮延遲典型爲5至1 5秒。最高溫度54°C對全 部大鼠產生的尾回縮延遲皆少於1 0秒。平均基準線T,。 値(1 0秒回縮)爲4 9 °C至5 1 °C。 一劑〇· 1毫克PGE2產生之劑量相依性及時間相依性 熱過敏,表現爲溫度效應曲線的向左位移以及Τ,ο値的 降低。最大尾回縮延遲的縮短出現於投藥後15分鐘, 注射後120分鐘尾回縮延遲返回基準線値。 表1顯示PGE2組合比較性NMDA拮抗劑化合物之效 果。直到產生可觀察之鎭定以及運動失調徵兆之劑量 (換言之比較例1< 10毫克/千克,比較例2< 100毫克/ 千克,比較例3 < 0.3毫克/千克,比較例4-6 < 30毫克/ 千克),比較性化合物包括美曼汀(比較例1及2)、第左 西平(比較例3)、k它命(比較例4)、伊芬普迪(比較例5) -33- 1321472 五、發明說明(32) 或003- 1 975 5 (比較例6)皆未產生大於25%?0£2誘生熱 過敏的逆轉。比較上,[2-(8,9-二酮基-2,6·二氮雜雙環 [5·2·0]壬-1(7)-烯-2-基)乙基膦酸亦即本發明有用之環丁 烯衍生物(化合物Α),於腹內注射1 0毫克/千克後產生 79%逆轉,口服投予1 00毫克/千克後產生87%逆轉。此 種劑量(高達1 7 8毫克/千克)並未造成如比較性化合物之 鎭定或運動失調副作用。此外,1毫克或3毫克化合物 Α經鼻內分別產生37%或7 9%逆轉。由個體體重求出之 平均劑量分別表示2.6及7.5毫克/千克劑量。同理,本 發明有用之另一種環丁烯衍生物亦即2-[(1H-四唑-5-基) 甲基]-2,6-二氮雜雙環[5.2.0]-壬-1(7)-烯-8,9-二酮(化合 物B)產生完全逆轉PGE2誘生熱過敏。 本發明有用之環丁烯衍生物如化合物A及B用於緩解 疼痛如熱過敏之效果係驚人且出人意外的。例如全部根 據試驗方法1試驗之化合物皆爲NMDA接受器拮抗劑’ 但化合物A及B之表現實質上且顯然優於比較性化合 物。特別重要地須注意化合物A及B類似比較性化合物 CGS-19755爲競爭性麩胺酸鹽NMDA接受器拮抗劑,但 化合物A及B之表現顯然且實質較佳。 一· ^ -34- 1321472
五、發明說明(μ )
*欄中顯示估値;實際平均劑量爲2.6毫克/千克 μ欄中顯示估値;實際平均劑量爲7.5毫克/千克 本發明有用之環丁烯衍生物也使用鴉片類止痛胃 試驗’來決定環丁烯衍生物組合鴉片類止痛劑嗎啡用於 減低熱敏感度之能力。最小有效劑量之嗎啡單獨或組合 -35- 1321472 五、發明說明(34) 無效劑量之試驗化合物投藥。表I-2顯示溫水尾回縮檢 定分析範例。5.6毫克/千克嗎啡IP (比較例1 1)產生小但 明顯的T10增高(51.2 ±0.7),比較媒劑T,。(48.9 士 0.1)。組合5.6毫克/千克嗎啡投藥時,無效劑量之18 毫克/千克k它命ΙΡ(比較例12)產生Τ1β增高不顯著 (52·8 ± 0.5),比較單獨嗎啡(比較例I3)。相反地,無 效劑量之10毫克/千克化合物ΑΙΡ(實施例14)組合嗎啡 可顯著且出乎意外地提升Τ1β (55.8 ± 1.3),比較單獨d馬 啡(實施例15)。 表1 - 2 :溫水尾回縮組合硏究 實施例 試驗化合物 劑量(毫克/千克) 與基準線之 變化 比較例,11 嗎啡 5.6 ’ + 2.3 比較例12 k它命 18.0 -0.3 比較例13 嗎啡+k它命 5.6+18.0 + 3.9 實施例14 A 10.0 '----- •0.3 實施例15 嗎啡+ A 5.6+10.0 + 6.9 本發明有用之環丁烯衍生物也與鴉片類止痛劑試驗環 丁烯衍生物組合鴉片類止痛劑嗎啡之降低PGE2誘生熱 過敏能力。表】-3顯示PGE2_生熱過敏檢定分析範 例。PGE2注射入尾端可顯著降低τ1〇 (44.8 ± 0.1),比 較媒劑Τ10 (50.3 ±0.4;比較例16)。一劑5.6晕克/千 -36- λ々1472 五、發明說明(35) 克嗎啡(比較例17)可顯著逆轉Τ1β値至類似媒劑(50.6 ±G· 5)。組合5.6毫克/千克嗎啡投藥時,無效劑量之18 毫克/千克實施例3 IP (比較例18)造成T1Q之升高不顯著 〇1·7 ±0.2),比較單獨嗎啡(比較例19.)。相反地,有 效劑量之1 0毫克/千克實施例6 IP (T丨〇 = 4 8.8 ± 0.2 ;實 施例20)組合嗎啡可顯著且出乎意外地提升T|G (55.3 土 〇_2),比較單獨嗎啡(實施例21)❶ 表1-3 : PGE2誘生熱過敏組合硏究 實施例 試驗化合物 劑量(毫克/千克) 基準線之變化 比較例1 6 媒劑 -5.6 比較例1 7 嗎啡 5.6 + 0.3 比較例1 8 k它命 18.0 -5.5 比較例1 9 嗎啡+k它 5.6+18.0 + 1.4 命 實施例20 A 10.0 -1.5 實施例21 嗎啡+A 5.6+10.0 + 5.0 試驗方法2結果:慢性收縮傷害 表2顯示本發明有用之環丁烯衍生物用於試驗前一周 已經接受CCI手術之動物逆轉CCI誘生觸覺過敏之效 果。NMDA接受器拮抗劑美曼汀(比較例22)及CGS-1975 5(比較例23)也接受試驗供比較。至產生觀察得鎭 定及運動失調徵兆之劑量(換言之比較例22 < 10毫克/千 -37- 1321472 五、發明說明(36) 克’比較例23 < 3 0毫克/千克)前,比較性化合物皆未造 成CCI誘生觸覺過敏的逆轉。相對地,化合物A(實施 例24)於IP投藥後產生97%逆轉,化合物B(實施例25) 於IP投藥後產生40%逆轉。如比較性化合物所見,化 合物A及B之劑量不會引起鎭定或運動失調。 表2 :慢性收縮傷害誘生觸覺過敏 實施例 試驗化合物 投藥 方法 %逆轉劑量(毫克/千克) 1 3 10 30 比較例2 2 美曼汀 IP -2 5 % -4 5 % 比較例2 3 CGS- 1 9755 IP • -9% -5% -1 7 % 實施例24 A IP 13% 4 5% 97% 實施例2 5 B IP 13% 14% 40% 12% 本發明有用之環丁烯衍生物例如化合物A及B緩解疼 痛例如CCI誘生觸覺過敏之效果是驚人且出乎意外的。 例如化合物A及B之表現顯著且實質優於已知NMD A 接受器拮抗劑美曼汀及CGS-1 795 5。 試驗方法3結果 爲了評比本發明有用之環丁烯衍生物可能引發之副作 用,化合物A係以食物給予排程投予動物。NMDA接受 器拮抗劑美曼汀及第左西平作比較。表3顯示美曼汀 (比較例26)及第左西平以劑量相依性降低反應率。此劑 量不會逆轉PGE2誘生熱過敏或CCI誘生觸覺過敏。相 反地,經腹內(實施例28)或經口(實施例29)投予化合物 -38- 1321472 五、發明說明(37) A,於可逆轉PGE2誘生熱過敏或CCI誘生觸覺過敏之 劑量不會顯著改變反應率。 表3 :操作反應 實施例 試驗化合 物、 投藥 方法 - - 、 劑量(毫克/千克) 0.1 0.3 3 10 30 1 00 比較例26 美曼汀 IP 93% 2% 比較例27 第左西平 IP 63% 16% \ 實施例28 A IP 111% 86% 實施例29 A PO 1 12% 97% 100% -39-
Claims (1)
1321472 煩請/;1f — -—1:、申請專利範圍 — 第91123270號「用於治療疼痛之[[2-(胺基-3,4-二酮基-h 環丁烯-1-基)胺基]烷基]-酸衍生物」專利案 (93年10月修正) A申請專利範圍 1.一種用於治療疼痛之醫藥組成物,包括醫藥有效量之至 少一種式(I )化合物: 〇、 Ο NH N-A—X (I) -r/ ',-ν'1·Γ質内容 此處: R1爲氫、含1至6個碳原子之烷基或含7至12個碳原 子之苯院基; R2爲氫、含1至6個碳原子之烷基、含2至6個碳原 子之烯基或含7至12個碳原子之苯烷基;或 R1 及 R2 共同形成爲 Z,Z 爲-CH2CH2-、-CH2C(R6)(R7)CH2-、或,此處 R6、R8 及 R1。分 別爲氫 '含1至6個碳原子之烷基或羥基以及R7、R9及 Rn分別爲氫或含1至6個碳原子之烷基; A爲含1至6個碳原子之伸烷基或含2至6個碳原子 之伸烯基; X 爲 C02R3、P(0)(0R4)(0R5)、3,5-二酮基-1,2,4-噚二 1321472 、申請專利範圍 唑啶-2-基或5-四唑基,此處R3、R4及R5分別爲氫或含 1至6個碳原子之烷基; 或其醫藥可接受性鹽;以及一種醫藥載劑。 2 ·如申請專利範圍第1項之醫藥組成物,其中: R1及R2分別爲氫、甲基、乙基、丙烯基 '甲基丙烯基 或苄基,或R1及R2共同形成爲Z,且爲-CH2CH2-、 -CH2C(R6)(R7)CH2-、或; A爲直鏈或分支鏈伸院基選自-(^2-、-(:112(:112-、-CH(CH3)CH2- 、 -CH2CH(CH3)- 、 -(CH2)3- ' 或-(Ch2)4-;以 及 X係選自羧基、膦基或5 -四唑基; 或其醫藥可接受性鹽形式。 3 .如申請專利範圍第1項之醫藥組成物,其中: R 及 R2 共问形成爲 Z’ 且爲- CH2CH2-、_ 、或-CH2C(R8)(R9)-C(R10)(Rn)CH2.; A爲直鏈或分支鏈伸烷基選自- CH2-、_eH2(:H2_、 -ch(ch3)ch2-、-ch2ch(ch3)· ' -(ch2)3-、或-(CH2)4_ ; 以及 X係選自羧基、膦基或5 -四唑基。 4 ·如申請專利範圍第1項之醫藥組成物,其中該式(i }化 合物包括下列之至少一者: N-(2-胺基·3,4-二酮基-卜環丁烯-1-棊)@_丙胺酸; 2-[2-[(2-胺基- 3,4-二酮基-1-環丁烯、丨基)胺基]乙 1321472 六、申請專利範圍 基]-1,2,4 -噚二唑啶-3,5 -二酮;N-(2-胺基_3,4_二酮基―丨-環丁烯·;! ·基)_N_(2_丙烯基) 甘胺酸; [2-[(2-胺基_3,4-二酮基·1-環丁烯-i_基)胺基]乙基] 膦酸;[”)-4-[(2-胺基-3,4-二酮基-1-環丁烯_1_基)胺基]_ 2 - 丁燃基]膦酸;或 [2'[(2-胺基-3,4-二酮基-1-環丁稀-1_基)甲基胺基] 乙基]膦酸; 或其醫藥可接受性鹽形式。 5 .如申請專利範圍第1項之醫藥組成物,其中式(I )化合 物包含[2-(7,8 -二酮基-2, 5·二氮雜雙環[4.2.0]辛· 1(6) -烯-2-基)乙基〕膦酸,或其醫藥可接受性鹽形式。 6 ·如申請專利範圍第1項之醫藥組成物,其中式(〗)化合 物包含[2-(8,9-二酮基-2,6 -二氮雜雙環[5.2.0]壬-1(7)-烯-2-基)乙基]膦酸,或其醫藥可接受性鹽形式。 7 ·如申請專利範圍第1項之醫藥組成物,其中式(I )化合 物包含[2-(4-羥-8,9·二酮基-2,6-二氮雜雙環[5.2.0]壬 -1(7)-烯-2-基)乙基]膦酸,或其醫藥可接受性鹽形式。 8 .如申請專利範圍第1項之醫藥組成物,其中式(I )化合 物包含8,9-二酮基-2,6-二氮雜雙環[5.2.0]壬-1(7)-烯 -2 -乙酸,或其醫藥可接受性鹽形式。 9 .如申請專利範圍第1項之醫藥組成物,其中式(1 )化合 1321472 六、申請專利範圍 物包含2-[(1Η-四唑-5 -基)甲基]-2,6 -二氮雜雙環 [5.2.0] -壬-1-(7) -烯-8,9 -二酮,或其醫藥可接受性鹽 形式。 。 10.如申請專利範圍第1項之醫藥組成物,其中式(I )化合 物包含[2·(9, 10 -二酮基-2,7 -二氮雜雙環[6.2.0]癸-1(8)-烯-2-基)乙基]膦酸,或其醫藥可接受性鹽形式。 11 .如申請專利範圍第1項之醫藥組成物,其中該疼痛爲急 性疼痛或慢性疼痛。 1 2 .如申請專利範圍第1 1項之醫藥組成物,其中該疼痛爲發 炎痛、肌肉骨骼痛、骨痛、腰椎薦椎痛 '頸或上背痛、 內臟痛、軀體痛、神經病變性疼痛、癌症疼痛、受傷或 手術引起的疼痛、或頭痛或其組合。 1 3 ·如申請專利範圍第11項之醫藥組成物,其中該疼痛爲慢 性疼痛。 1 4 ·如申請專利範圍第1 3項之醫藥組成物,其中該慢性疼痛 係與痛覺異常、痛覺過敏或二者有關。 15. 如申請專利範圍第13項之醫藥組成物,其中該慢性疼痛 爲神經病變性疼痛;癌症疼痛;內藏痛;肌肉骨骼痛; 骨痛;頭痛;或感染 '鐮刀細胞型貧血、自體免疫病、 多發性硬化症、或發炎關聯之感染或其組合。 16. 如申請專利範圍第1項之醫藥組成物,其中該疼痛包含 神經病變性疼痛。 1 7 ·如申請專利範圍第1 6項之醫藥組成物,其中該神經病變 1321472 六、申請專利範圍 性疼痛係與糖尿病性神經病變、周邊神經病變、疱疹後 神經痛、三叉神經痛、腰椎或頸椎神經根病變、纖維肌 肉痛、舌咽神經痛、反射性交感神經性萎縮、意外性疼 痛、丘腦症候群、神經根撕裂、幻肢痛、反射性交感神 經性萎縮、胸廓造口術後疼痛'癌症、化學品傷害、毒 素、營養不良或病毒性或細菌性感染、或其組合。 1 8 _如申請專利範圍第丨項之醫藥組成物,其進—步包含醫 藥有效量之至少一種疼痛緩解劑。 19.如申請專利範圍第is項之醫藥組成物,其中該疼痛緩解 劑包含一或多種止痛劑;抗炎劑;偏頭痛製劑;三環抗 鬱劑;抗癲癇劑;α 2促效劑;或選擇性血淸素再吸收抑 制劑/選擇性新腎上腺素吸收抑制劑;或其組合。 20·如申請專利範圍第19項之醫藥組成物,其中該疼痛緩解 劑包含鴉片類止痛劑。 21 ·如申請專利範圍第1 8項之醫藥組成物,其中該疼痛 緩解劑包括COX-2抑制劑。 2 2 ·如申請專利範圍第2 1項之醫藥組成物,其中COX - 2 抑制劑係選自希雷克夕(celecoxib)、洛費克夕 (rofecoxib) ' 瓦德克夕(valdecoxib)、帕瑞克夕 (parecoxib)、伊托利克夕(etoricoxib)、德拉克夕 (deracoxib)、2-(4 -乙氧-苯基)-3-(4 -甲院擴醯基· 苯基)-吡唑并[l,5-b]嗒畊、4-(2-酮基-3-苯基-2,3-二氫of 唑-4-基)苯磺醯胺、達布費隆 1321472 六、申請專利範圍 (darbufelone)、弗洛沙來(fl〇sunde)、4_(4 -環己 基-2-甲基-5-曙哩基)_2_氟苯磺醯胺、美洛西坎 (meloxicam)、尼美沙來(nimesulide)'卜甲基磺醯 基-4-(1,1_二甲基'4-(4-氟苯基)環戊-2,4-二烯-3-基)苯、4-(1,5-二氫-6_氟_7_甲氧_3_(三氟甲基)· (2) -苯并硫壯喃并(4,3c)吡唑-丨基)苯磺醯胺、 4,4-二甲基-2-苯基_3_(4_甲基磺醯基)苯基)環丁烯 酮、4 -胺基- N- (4-(2 -氟-5_三氟甲基卜噻唑_2_基卜 苯磺醯胺、1-(7 -第三·丁基_2,3_二氫·3,3二甲基_ 5 -苯并咲喃基)·4 -環丙基丁-丨_酮或其生理可接受性 鹽、酯類或溶劑合物。 23.如申請專利範圍第ιδ項之醫藥組成物,其中該疼痛 緩解劑包括至少一種選擇性血淸素再吸收抑制劑,選 擇性新腎上腺素吸收抑制劑,或其組合。 24 .如申請專利範圍第1 8項之醫藥組成物,其中該疼痛 緩解劑包括至少一種選自亞米奇林 (amitryptyline)、德西普明(desiprannine)或伊米普 明(imipramine)之三環抗鬱劑;或選自嘻巴潘汀 (gabapentin)、卡巴美奇平(carbarn azepine)、托皮 拉梅(topiramate)、維普酸鈉(sodium valproate)或 癲通(phenytoin)之抗癲癇劑,或其組合。 2 5 .如申請專利範圍第1 8項之醫藥組成物,其中該疼痛 緩解劑包括至少一種阿斯匹靈,伊布普芬 1321472 六、申請專利範圍 (ibuprofen),奇托普芬(ketoprofen),納普洛森 (naproxen),乙酷胺芬(acetaminophen)' 印多美沙 辛(indomethacin),或其組合。 26 .如申請專利範圍第1項之醫藥組成物,其中該醫藥組 成物呈單位劑型。 27 .如申請專利範圍第 1項之醫藥組成物,其中該式(I )化 合物具有式(Π ):
(III) 其中A及X定義如申請專利範圍第1項。 28 .如申請專利範圍第1項之醫藥組成物,其中該組成物係 呈錠劑或膠囊劑劑型。
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ATE391498T1 (de) * | 2002-11-22 | 2008-04-15 | Gruenenthal Gmbh | Verwendung von (1rs,3rs,6rs)-6- dimethylaminomethyl-1-(3-methoxy-phenyl)- cyclohexan-1,3-diol zur behandlung von entzündungsschmerz |
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ATE481103T1 (de) | 2003-04-09 | 2010-10-15 | Wyeth Llc | Derivate von 2-(8,9-dioxo-2,6- diazabicyclo(5.2.0)non-1(7)-en-2- yl)alkylphosphonsäure und deren verwendung als n- methyl-d-aspartat- (nmda-) rezeptorantagonisten |
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JP2008515904A (ja) * | 2004-10-08 | 2008-05-15 | ワイス | [2−(8,9−ジオキソ−2,6−ジアザビシクロ[5.2.0]ノン−1(7)−エン−2−イル)アルキル]ホスホン酸の誘導体およびその製造方法 |
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