TW200425914A - Pharmaceutical tablet composition comprising n-[(1-nbutyl-4-piperidinyl)methyl]-3,4-dihydro-2h-[1,3]oxazino[3,2-a]indole-10-carboxamide (sb 207266) or a salt thereof - Google Patents
Pharmaceutical tablet composition comprising n-[(1-nbutyl-4-piperidinyl)methyl]-3,4-dihydro-2h-[1,3]oxazino[3,2-a]indole-10-carboxamide (sb 207266) or a salt thereof Download PDFInfo
- Publication number
- TW200425914A TW200425914A TW93114682A TW93114682A TW200425914A TW 200425914 A TW200425914 A TW 200425914A TW 93114682 A TW93114682 A TW 93114682A TW 93114682 A TW93114682 A TW 93114682A TW 200425914 A TW200425914 A TW 200425914A
- Authority
- TW
- Taiwan
- Prior art keywords
- composition
- patent application
- scope
- atrial
- composition according
- Prior art date
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
200425914 A7 B7 五、發明説明( 10 15 經濟部智慧財產局員工消費合作社印製 20 本^明係勸某些化合物在治療或預防如:心房重建之 某些心血管疾病上的用途,及使用特定劑量及/或劑量攝取之 邊化合物在治療或預防,。I纖維性顫動的用途。 引言 心房纖維性顫動(AF)是臨床環境中最通常遇到的心律不 整。其為插塞性(embollM_主要危⑨,並且伴隨著必死 危險性的增力”AF(其症狀可包括心房的心悸等)是由引發物 心房心跳過速(不規則跳動),與基質的互相作用,如執掏之 間隙異原性或解剖位置的傳導阻塞。纖維性顫動由所在心房 周圍之連續環形通路中經過之刺激波前所組成。-旦被刺 文 房、、且、、我化些時間去回復到其可被再次刺.激的狀態, 此,間被稱為,,執拘時間(refract〇ry pen〇d),,(AER卜心房有 政^抝日守間)。因此若執抝時間大於刺激波前循環經過360。 2時間,則該波前遇到不可刺激的”執抝,,物質,並且纖維性 =動會停止,心臟回到靜脈竇性節律。否則,AF波進行,,再 =入,並且繼續心房纖維性顫動,有時幾乎是無盡的。有陣 發性AF的病患通常發展為慢性(持續性或永久性的)af。當 然,與上述引發物及基質互相依賴,促進因素歸因於疾病的 進展及永存。被稱為心房重建的促進者是由於現象再發 生之各種結構、細胞、電生理及神經元介質的改變所引起。 抗心律不整藥物通常部份起作用,是藉著增加心房執构時間 及/或減J〜房傳導速度(c〇nducti⑽、或這兩種致200425914 A7 B7 V. Description of the invention (10 15 Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 copies of ^ This is to advise the use of certain compounds in the treatment or prevention of certain cardiovascular diseases such as atrial reconstruction, and the use of specific Dose and / or dose of side compounds in the treatment or prevention of fibrillation. Introduction Atrial fibrillation (AF) is the most commonly encountered arrhythmia in clinical settings. It is pluggable (embollM_ Mainly dangerous, and accompanied by the danger of mortal strengthening, AF (its symptoms may include atrial palpitation, etc.) is caused by atrial atrial tachycardia (irregular beating), interaction with the matrix, such as the gap Heterogenous or anatomical conductive blockage. Fibrillation consists of stimulus wavefronts passing through a continuous annular pathway around the atrium.-Once you have been stabbed in the study room, and, take some time to return to what it can The state of being stabbed again, this time is called, the detention time (refract〇ry pen〇d), (AER, atrium has politics ^ 拗 day Mori). Therefore, if the hold time is longer than the stimulation wave The cycle goes through 360. 2 time, then the wavefront encounters an unstimulable, stubborn, material, and fibrous = movement will stop, the heart returns to sinus rhythm. Otherwise, the AF wave proceeds, and then = enter, And continued atrial fibrillation, sometimes almost endless. Patients with paroxysmal AF usually develop chronic (persistent or permanent) af. Of course, interdependence with the above-mentioned initiators and substrates, the contributing factors are attributed to Due to disease progression and perpetuity. The promoters of atrial reconstruction are caused by changes in various structural, cellular, electrophysiological, and neuronal mediators that cause the phenomenon to reoccur. Antiarrhythmic drugs usually work in part, by borrowing To increase atrial construction time and / or decrease J ~ atrial conduction velocity (c〇nducti⑽, or both
本紙張尺度適用標準(CNS (請先閱讀背面之注意事項存填寫本頁) 200425914 A 7 B7 五、發明説明(.) 力增加心房波長,並且因此減少再進入波的數目,並緩和/ 減少AF。 在AF病患上的研究顯示結構/組織上的改變會發生在趨 向於有AF的心房上,但結構重建與慢性心律不整之間的關 5係不被完全了解。該改變主要係關於適應(心肌細胞的細胞形 態消化)及適應不良(有替代性纖維性顫動的細胞退化)的特 性。(纖維性顫動意為例如:在連接性組織的增加)。心房擴張 及/或擴大也會發生。這些結構改變是一般的、而非經常地在 延長持續AF期間被觀察到。(見:丁hlJ ssen VL等人,[⑺必⑽% 10尸遍/ 2000 -月-二月;9⑴:17-28;及以⑽⑷,心"州 1997五月;18 Suppl c:cl2-8回顧)。在另一方面,在一個 研九中,於持續性心房纖維性顫動的環境下,重要的左心房 及左心房附生器官官能性及組織性重建(例如··擴張)被發現 是一或兩個月持續性心房纖維性顫動所發生的·結果,而為類 15似於在選擇性心律轉變法之前病患所經驗之進行肝素抗凝血 劑的期間(Weigiier MJ 等人,//ear/ 1999 十一月;82(5).555-8)。 心房重建為一種的方法,其為心房中產生機械及細胞改 變(結構/組織上改變)及/或在心房中電生理(電的)改變,通常 為AF發展的結果,雖然心房重建不總為心房纖維性顫動的 20結果,即:不是必然的結果,特別是在陣發性的AF病患上。 (見:Thijssen VL 等人,CaWv仍e 2000 —月-二月; 9(1):17,28 ; Tse HF 及 Lau CP,£印抑⑺·腳/ 1 998 五月:25(5):293-302 ; Lau cp 及 Tse 肝,c/,/7 £印 /^"7奶〇/ 以少川"1 998 五月;25(4):293-302 ;[抓 cp 及丁se 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) (請先閲讀背面之注意事 項再填· :寫本頁) 經濟部智慧財產局員工消f合作社印¾ 200425914 經濟部智慧財產局員工消費合作社印製 五、發明說明(專 k,Clm Exp phc^amacot physi〇h '州十二艿, 一4(1—).98>J,及 Jaws MJ //⑽/ J 1 997 五月;18 Suppl 2_8,心房纖維性顫動及心房重建來回顧)。這些改變通 ::趨向於持續的AF。結構/組織改變已如上述。在此所稱之 ' (兒的)〜房重建包括或意為:a)心房執抝時間(AERP) 或:房執抝的改變(特別是縮減);b)執抝時間之適應速率的 &艾(例如·叙適應速率的消失,使得接受心臟速率的減 緩,執抝時間不如預期地延長);及/或c)作用電位的改變(例 士 間的縮紐、形態的改變等)。較佳地,電生理(電的)心房 重建心為心房執抝時間(AERp)或心房執抝的改變(特別是縮 減、)。可廷擇地,電心房重建也可包括心房傳導速度的改變及 /或刀政上的改變(.特別是增加),例如:執抝的分散。”分散”意 為或夕個電現象之大小的差別,如:在組織接近區域之間的 執抝時間(例如:AERP)。 在人類及緒中,5-HT4受體存在於心房中(見例如:A.j. kaumam]等人,Naunyn-Schmiedeberg,s Arch Pharmaco 1(1 990), 324.619-622 ; A. J. Kaunmann 等人 Br J Pharmac〇l(1 990)100:879-855)。5-HT4 受體的次類(5-HT4A)近 來被鑑別為對人類心房及豬心房為特定的(〇· B|〇ndel等人, FEBS Letters,412, 1997,第 465-474 頁)。此 5-HT4A 受體不存 在於心室中。對5-HT受體一般的命名見:D. H〇yer, NeLirophanncicology^ 1997,36(4/5),41 9。WO 9 1/1 6045 (SmithKline Beecham)揭示心臟5-HT4受體拮抗劑可用於治 療心律不整,並且減少中風的發生。 ίο 15 20 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 請 先 閱 讀 背 面 之 注 意 事14?裝 本衣 頁 I w I I I 1 I I 訂 200425914 A7 ______B7 _ 五、發明說明() 請 先 閱 讀 背 Φ 之 注 意 事 項 再 填 寫 本 頁 WO 93/1 8036(SmitliKline Beecham)揭示大量的縮合口引哚 化合物,做為5-HT4受體拮抗劑,包括:在第]7-18頁實例3 白勺N-[(卜正丁基-4-六氫吡啶基)甲基]-3,4-二氫-2H-[1,3;K畊Applicable standards for this paper size (CNS (please read the notes on the back and fill in this page) 200425914 A 7 B7 V. Description of the invention (.) Force to increase the atrial wavelength, and therefore reduce the number of re-entry waves, and mitigate / reduce AF Studies in AF patients have shown that structural / tissue changes occur in the atria that tend to have AF, but the relationship between structural reconstruction and chronic arrhythmia is not fully understood. This change is mainly about adaptation (Cell morphological digestion of cardiomyocytes) and maladaptive (cell degradation with alternative fibrillation). (Fibrillation means, for example: an increase in connective tissue). Atrial expansion and / or enlargement can also occur These structural changes are generally, but not often, observed during prolonged continuous AF. (See: Ding HLJssen, VL et al., [⑺ 必 ⑽% 10 dead times / 2000-month-February; 9: 17] -28; and ⑽⑷, Heart " State 1997 May; 18 Suppl c: cl2-8 review). On the other hand, in a study nine, in the context of continuous atrial fibrillation, important left Atrium and left heart Atrial epiphyseal organ function and tissue reconstruction (eg, dilation) were found to occur as a result of persistent atrial fibrillation for one or two months, and class 15 resembles disease before the selective cardiac rhythm change method Patient experience during the administration of heparin anticoagulants (Weigiier MJ et al. // ear / November 1999; 82 (5) .555-8). Atrial reconstruction is a method that produces machinery in the atrium And cellular changes (structural / tissue changes) and / or electrophysiological (electrical) changes in the atrium, usually the result of AF development, although atrial reconstruction is not always the 20 result of atrial fibrillation, ie: not necessary Results, especially in patients with paroxysmal AF. (See: Thijssen VL et al., CaWv still e 2000-month-February; 9 (1): 17,28; Tse HF and Lau CP, Yin Yin脚 · Feet / 1 998 May: 25 (5): 293-302; Lau cp and Tse liver, c /, / 7 £ 印 / ^ " 7 奶 〇 / Yi Shaochuan " 1 998 May; 25 (4): 293-302; [Grasp cp and Ding se This paper size applies to Chinese National Standard (CNS) A4 specifications (210X 297 mm) (Please read the precautions on the back before filling in · : Write this page) Printed by the Cooperative of the Intellectual Property Bureau of the Ministry of Economy ¾ 200425914 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy 4 (1 —). 98 &J; and Jaws MJ // ⑽ / J 1 997 May; 18 Suppl 2_8, review of atrial fibrillation and atrial reconstruction). These changes pass :: towards a continuous AF. Structural / organizational changes have been described above. What is referred to herein as' (children's) ~ atrial reconstruction includes or means: a) atrial retention time (AERP) or: change (especially reduction) in atrial retention time; b) & Ai (for example, the disappearance of the Syrian adaptation rate makes it slower to accept the heart rate, and the duration of clinging is not as long as expected); and / or c) changes in the action potential (such as the contraction between scholars, changes in morphology, etc.). Preferably, the electrophysiological (electrical) atrial reconstruction of the heart is a change in atrial retention time (AERp) or atrial retention (especially reduction). Alternatively, electrical atrial reconstruction may also include changes in atrial conduction velocity and / or changes in politics (especially increases), such as the dispersion of entrapment. "Scattering" means the difference in the magnitude of electrical phenomena, such as the duration of time between tissue proximity areas (eg, AERP). In humans, the 5-HT4 receptor is found in the atrium (see, eg, Aj kaumam) et al., Naunyn-Schmiedeberg, s Arch Pharmaco 1 (1 990), 324.619-622; AJ Kaunmann et al. Br J Pharmac. l (1 990) 100: 879-855). The subclass of 5-HT4 receptors (5-HT4A) has recently been identified as being specific for the human atrium and pig atrium (Bonder et al., FEBS Letters, 412, 1997, pages 465-474). This 5-HT4A receptor does not exist in the ventricle. See the general nomenclature for 5-HT receptors: D. Hoyer, NeLirophanncicology ^ 1997, 36 (4/5), 41 9. WO 9 1/1 6045 (SmithKline Beecham) discloses that cardiac 5-HT4 receptor antagonists can be used to treat arrhythmias and reduce the incidence of stroke. ίο 15 20 This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) Please read the notes on the back 14? Install this page I w III 1 II Order 200425914 A7 ______B7 _ 5. Description of the invention ( ) Please read the notes on the back Φ before filling out this page. WO 93/1 8036 (SmitliKline Beecham) reveals a large number of condensed indole compounds as 5-HT4 receptor antagonists, including: on pages] 7-18 Example 3 N-[(n-butyl-4-hexahydropyridyl) methyl] -3,4-dihydro-2H- [1,3;
並[3,2-a]叫丨哚-1 0 -甲ϋ胺(SB 207266)及其較佳的鹽酸鹽(SB 5 207266-A)。這些化合物被揭示用於治療或預防腸胃、心血管 及CNS失調,特別是刺激性腸病症。w〇93/18036也在6-7 頁中以一般術語闡述一般性敘述:”特定心臟5-HT4受體拮抗 劑,其避免心房纖維性顫動及其他與‘ 5-HT相關的心律不整, 也預期減少中風的發生’’。也見US 5,852,014、EP 0 884 3 1 9 10 A2、L.M· Gaster 等人,A/ed Ckm., 1995,38,4760-4763 及對 SB 207266 的 撕 〇/ /心 Az/z/re, 1997,22(12), 1 3 25-1 332,其對5-HT4受體的高選擇性是超過5-HT受體。 (SB207266之效力及選擇性也由5-HT4受體拮抗劑顯示,並 且選擇性測試造成在本專利申請書所稍後呈現的)。對改進之 15 SB 207266 合成,見 WO· 98/07 72 8、WO 98/1 1067、WO 00/03983 ;及 WO 00/03984。 SB 207266的結構如下: 經濟部智慧財產局員工消費合作社印製 ο 2And [3,2-a] is called indole-1 0 -formamide (SB 207266) and its preferred hydrochloride (SB 5 207266-A). These compounds are disclosed for the treatment or prevention of gastrointestinal, cardiovascular and CNS disorders, especially irritating bowel disorders. W〇93 / 18036 also elaborates general descriptions in general terms on pages 6-7: "Specific cardiac 5-HT4 receptor antagonists, which avoid atrial fibrillation and other 5-HT-related arrhythmias, also Expected to reduce the occurrence of strokes ''. See also US 5,852,014, EP 0 884 3 1 9 10 A2, LM Gaster et al., A / ed Ckm., 1995, 38, 4760-4763 and tearing of SB 207266. Heart Az / z / re, 1997, 22 (12), 1 3 25-1 332, its high selectivity for 5-HT4 receptor is higher than that of 5-HT receptor. (The efficacy and selectivity of SB207266 are also determined by 5 -HT4 receptor antagonists are shown, and selective tests have been made later in this patent application). For improved 15 SB 207266 synthesis, see WO 98/07 72 8, WO 98/1 1067, WO 00 / 03983; and WO 00/03984. The structure of SB 207266 is as follows: Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 2
N-N-
J SB 207266 其他的5-HT4抬抗劑被揭示於94/27965(Syntex)及這 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公爱) 9200425914 A7 B7 五、發明說明() 些化合物之一 :RS 100302( Roc he),其名為 N-(2-(4-(3-8-胺基 -7 -氣基-2,3 -二氫-1,4 -苯並二σ等烧-5-基)-3-氧丙基)六氫σ比σ定 -卜基)乙基)-甲石黃基醯胺,被建議在治療豬模式之心房不規則 跳動及心房纖維性顫動為有效的(Μ.Μ· Rahme等人 1999,100 (19)冊,2010-2017 頁)。 其他5 - ΗΤ4結抗劑被揭不於RD C1 ark等人的万/ ο 〇 rg yV/e C/7em Le" 1994,4(20),248卜4 ; Clark 同前述,1 995,5(1 8), 2119-2122(例如:RS100235)。 * WO 93/05038(SmitliKline Beecham)揭示一系列的 5-HT4 拮抗劑,包括實例1中高活性及選擇性的5-HT4拮抗劑SB 204070 ’其為8-胺基-7-氯基-1,4-苯並二呤烷-5-羧酸(1-丁基 -4-六氫吡啶基)甲酯。對此化合物之鹽酸鹽(SB 204070-A)見 L.M. Gaster 等人,J. Med. C/zem. 1993,36,4121-4123。揭示 於WO 93/05038中的其他5-HT4拮抗劑包括SB 2077 10[8-胺 基-7-碘基-1,4-苯並二呤烷-5-羧酸(1-丁基-4-六氫吡啶基)甲 S旨]及其鹽酸鹽,如在實例52中所示;及SB 205800[N-(卜 丁基-4-六氫吡啶基)甲基胺基-7-氯基-1,4-苯並二4烷-5-曱醯胺,如在實例14中所示。SB 204070、SB 207710及SB 205800的結構如下: 10 15 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 20J SB 207266 Other 5-HT4 antagonists were disclosed at 94/27965 (Syntex) and this paper size applies Chinese National Standard (CNS) A4 specifications (210 X 297 public love) 9200425914 A7 B7 V. Description of the invention () One of these compounds: RS 100302 (Roc he), its name is N- (2- (4- (3-8-amino-7-amino-2,3-dihydro-1,4-benzodi σ isothiophene-5-yl) -3-oxopropyl) hexahydroσσσσ-buyl) ethyl) -methoxanthanamine, it is suggested to treat atrial irregular beat and atrial fibers in pig mode Sexual fibrillation is effective (M.M. Rahme et al. 1999, 100 (19), 2010-2017 pages). Other 5-ΤΤ4 binding agents were not disclosed in RD C1 ark et al. / Ο rg yV / e C / 7em Le " 1994, 4 (20), 248 4; Clark Ibid, 1 995, 5 ( 1 8), 2119-2122 (for example: RS100235). * WO 93/05038 (SmitliKline Beecham) discloses a series of 5-HT4 antagonists, including the highly active and selective 5-HT4 antagonist SB 204070 in Example 1, which is 8-amino-7-chloro-1, 4-Benzodiuridine-5-carboxylic acid (1-butyl-4-hexahydropyridyl) methyl ester. For the hydrochloride salt of this compound (SB 204070-A), see L.M. Gaster et al., J. Med. C / zem. 1993, 36, 4121-4123. Other 5-HT4 antagonists disclosed in WO 93/05038 include SB 2077 10 [8-amino-7-iodo-1,4-benzodiurin-5-carboxylic acid (1-butyl-4 -Hexahydropyridyl) methyl] and its hydrochloride, as shown in Example 52; and SB 205800 [N- (bubutyl-4-hexahydropyridyl) methylamino-7-chloro- 1,4-Benzodi-4alk-5-fluorenamine, as shown in Example 14. The structure of SB 204070, SB 207710 and SB 205800 is as follows: 10 15 (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20
Nil·Nil ·
本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200425914 A7 B7 五、發明説明()SB 204070 SB 207710 SB 205800 10 15 經濟部智慧財產局員工消費合作社印製 揭示5-HT4拮抗劑的其他SmithKline Beecham出版品包 括 WO 93/1 6072、WO 94/10174、WO 94/27987、WO 95/04737 〇 GR 1 1 3808,其名為1-甲基-1H-口引哚-3-羧酸(卜(2-((甲磺 醯基)胺基)乙基)-4-六氫吡啶基)甲酯或另外[1-(2-[(甲磺醯基: 胺基]乙基)-4-六氫吡啶基]甲基1-甲基-1H-吲哚-3-羧酸酯, 為另一個有效力及選擇性的5-HT4拮抗劑,來自 Glaxo Wellcome。GR 125487其名為5-氟基-2-甲氧基-1H-吲哚-3-羧酸[1-[2-[(曱磺醯基)胺基]乙基]-4-六氫吡啶曱酯,為另一個 有效力及選擇性的5-HT4拮抗劑:其在5-HT4a及5-HT3A受體 的 pKi 分別=10.0 及 <6.5。對 GR 1 13808 及 G.R 125487, 見:Grossman 等人,召厂· 乂 1994,111,332 ; EP 501 322 A1 及 EP 501322 B1。對 GR 1 13808 見 EP 501322 B1 的實例1,及對GR 125487及其鹽酸鹽、甲烷磺酸鹽及順丁 烯二酸鹽見 EP 5013 22 B1 之實例 12、21 及 22。GR 1 13808 及GR 125487之化學結構如下: /—NHS02MeThis paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200425914 A7 B7 V. Description of the invention () SB 204070 SB 207710 SB 205800 10 15 Printed by the Consumers ’Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 5-HT4 Other SmithKline Beecham publications of the antagonist include WO 93/1 6072, WO 94/10174, WO 94/27987, WO 95/04737 〇GR 1 1 3808, which is named 1-methyl-1H-ordoline-3 -A carboxylic acid (((((methanesulfonyl) amino) ethyl) -4-hexahydropyridyl) methyl) or another [1- (2-[(methanesulfonyl: amino) ethyl ) -4-hexahydropyridyl] methyl 1-methyl-1H-indole-3-carboxylic acid ester, is another potent and selective 5-HT4 antagonist from Glaxo Wellcome. GR 125487 Named 5-fluoro-2-methoxy-1H-indole-3-carboxylic acid [1- [2-[(fluorenylsulfonyl) amino] ethyl] -4-hexahydropyridinium ester, Is another potent and selective 5-HT4 antagonist: its pKi at the 5-HT4a and 5-HT3A receptors = 10.0 and < 6.5. For GR 1 13808 and GR 125487, see: Grossman et al., Zhaochang · 乂 1994,111,332; EP 501 322 A1 and EP 501322 B1. For GR 1 13808 See Example 1 of EP 501322 B1, and for GR 125487 and its hydrochloride, methanesulfonate and maleate see examples 12, 21 and 22 of EP 5013 22 B1. GR 1 13808 and GR 125487 The chemical structure is as follows: / —NHS02Me
CH3CH3
GR 125487 NHS02Me (請先閱讀背面之注意事項再填寫本頁)GR 125487 NHS02Me (Please read the notes on the back before filling this page)
項再填A 20 GR 1 1 3808 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐)Fill in the items A 20 GR 1 1 3808 This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm)
I 200425914 A7 B7____ 五、發明説明() GR 1 3 8897其名為[1-[2-[(甲磺醯基)胺基]乙基]-4-六氫吡 σ定基]曱基[2-(3 -甲基-1,2,4-4二唑-5-基)苯基]胺基甲酸酯, 為另一個有效力及選擇性的5-HT4拮抗劑,來自GlaxoI 200425914 A7 B7____ 5. Description of the invention () GR 1 3 8897 Its name is [1- [2-[(methylsulfonyl) amino] ethyl] -4-hexahydropyridine stilbyl] fluorenyl [2- (3-methyl-1,2,4-4diazol-5-yl) phenyl] carbamate is another potent and selective 5-HT4 antagonist from Glaxo
Wellcome:其在 5-HT4A& 5-HT3A 受體的 pKi 分別二 10.0 及 5 <5.0。對GR1 38897見WO 93/20071之實例1及3和申請專 利範圍第 8-10 項,及 US 5,6 1 8,827、EP 0 640 081 B1 及對 (Z)-2-丁烯二酯及甲烷磺酸鹽見w〇93/20071之實例2及4 和申請專利範圍第9-10項。GR13 8897之化學結構如下: (請先閱讀背面之注意事 項再填· :寫本頁} ΗWellcome: Its pKi at the 5-HT4A & 5-HT3A receptor are 10.0 and 5 < 5.0, respectively. For GR1 38897, see Examples 1 and 3 of WO 93/20071 and patent application items 8-10, and US 5,6 1 8,827, EP 0 640 081 B1 and (Z) -2-butene diester and methane For sulfonates, see Examples 2 and 4 of WO 93/20071 and the scope of patent applications No. 9-10. The chemical structure of GR13 8897 is as follows: (Please read the notes on the back before filling in:: Write this page} Η
ch3 10 GR138897 [丫《〇5〇4〇〇其名為1-(1-曱基乙基)-]^-(2-(4-((三環(3.3.1.1) 癸-1-基载基)胺基)-1 -六氫σ比σ定基)乙基)_ 1 Η— , σ坐-3 -甲龜胺、 經濟部智慧財產局8工消費合作社印製ch3 10 GR138897 [Ya "0505400 its name is 1- (1-fluorenylethyl)-] ^-(2- (4-((tricyclic (3.3.1.1) dec-1-yl Base) amine group) -1-hexahydro σ ratio σ fixed base) ethyl group) _ 1 Η —, σ sitting -3 -metachloramine, printed by the 8th Industrial Cooperative Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs
或1-(1-甲基乙基)-Ν-(2-(4-(三環(3.3丄1)上標(3,7)癸-卜基羰 基)胺基)-1-六氫吡啶基)乙基)-1Η-口引唑-3-甲醯胺、或1-(1-甲 15基乙基)-N-(2-(4-((三環(3.3.1.1。、7)癸小基幾基)胺基)-1-六氫 吡啶基)乙基)-1 H-吲唑-3-甲醯胺,為一個有效力選擇性的 5-HT4 结抗劑,由 Eli Lilly 發展,見:Cohen ML 等人,Drwg· Deve/opme/?/ 43:193-199,1 988 年四月(包括 LY 353433之活性氫氧化代謝物LY-34303 1及LY-343032的揭 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 200425914 A7 B7 五、發明説明( 10 15 經濟部智慧財產局員工消費合作钍印製 20 示)’ Cohen ML 專九,j pharmacology and Experimental 7/7e/Y//^z///d 277:97-104,1996 四月,及也見:EP 732333 A1。 理想的疋發現新的化合物或新一類的化合物,其可被用 於心房重建療法(例如:治療或預防)。 快速〜房速率,特別是慢性的快速心房速率(pacing)(或 在動物實驗設定中的慢性心房節律)是一種其中心房重建(特 別疋兒重建)發生的情況,其中心房有效執抝時間(AERp)被 減J。貫驗地,此電重建顯示在加速AF發生上扮演一個重 要的角色。現在我們已經發現5七丁4受體拮抗劑(抑制劑卜 特別是SB 207266能夠至少部份反轉在心房有效執抝時間 (AERP)的此項減少,即:能夠增加aerp。因此,預期:像沾 207266的5-HT4受體拮抗劑會緩和心房重建及/或保護心房 免於重建,特別是電重建。 一因此,根據本發明之第一個觀點,是提供SHI受體拮 抗劑在製造藥劑上的用㉟,用來預防或治療心房重建,例如: 在哺乳動物上,如:人類。 本發明也對需要其之喃乳動物(例如:人類)提供一種治療 或預防心房重建的方法,其包含對該哺乳動物施用有效 之5-HT4受體拮抗劑。 里 本發明也提供5媽受體结抗劑,用於預防或治療心房 重建’例如:在哺乳動物上,如:人類。 較佳地,本發明牽涉到預防或治療 重建,如上所述。 廢%生理(電的)心房 本發明在其所有觀點上,牽涉到 人-Xw口燎由心房纖維 請 先 閲 讀 背 面 意 事 項 再 填 寫 本 頁 10 本紙張尺度適用中國國家標準(CNS )八4規格(2丨〇χ 297公釐) 200425914 A7 B7 五、發明說明(9) 性顫動成為可能的心房重建,例如:由再發性由心房纖維性顫 動成為可能的心房重建。在本發明的所有觀點上,被治療的 哺乳動物(如:人類)為心房纖維性顫動的患者或疑為患者,特 別是持續性或永久性心房纖維性顫動的患者[例如:長期(如>1 5 年或>5年)患者]。持續或永久性心房纖維性顫動的長期(例 如:>1年或>5年)患者最可能具有心房重建的問題,如上所 述。 較佳地或另外地,在本發明所有觀點中,治療或預防的 藥劑/方法/5-HT4受體拮抗劑(例如:SB 207266或其醫藥上可 10 接受之鹽類)是用於抑制持續性或永久性AF(較佳為永久性 AF)病患之心房纖維性顫動的症狀再發性。 “陣發性AF”包括或意為有個別<48小時現象之平均期間 的AF現象。持續性AF現象可自動停止或可以5-HT4拮抗 劑及/或其他抗心律不整藥物轉化成一般的靜脈竇性節律 15 (NSR),陣發性AF的主要部分是單獨的AF,其沒有潛在的 心血管疾病並且無心房重建。若其不快速地中止,持續性 AF會轉成永久性AF。 經濟部智慧財產局員工消費合作社印製 “持續性AF”,例如:症狀性的永久AF,通常比持續性 AF有更長的時間,並且包括或意為個別248小時且S1年現 20 象之平均期間的AF現象,例如:症狀性現象,或更佳地為平 均期間個別<48小時且<6個月。永久性AF通常不會自動停 止並且經常需要電或藥理上的心律轉變法而轉成NSR。心 房電重建通常出現,會發生在左心房擴張及左心室官能不 良。 25 “永久性AF”包括或意為個別現象之平均期間長於持續 -11- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200425914 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明説明() ' "' _ ⑽見象’例如:>丨年或>5年的期間、或水久期間。 "^书對電心律轉變法無反應,並且與完全的電重建相關, 且逍t伴隨著進行中的C V疾病(局部貧血性心臟病、心肌症 及/或兩血壓等)。 口軚铨地,本發明牽涉到預防或治療由快速心房速率成為 可能的心房重建(例如:實驗之慢性心房節律)。被治療之哺乳 動物(例如:人類)可以是快速心房速率的患者或疑為患者,例 如:不正常的快速心房速率。 用方、本%明之5-HT4受體拮抗劑可包括任何那些在引言 ^所柄的。因此,例如:用於本發明之5-HT4受體拮抗劑劑可 匕括在引δ中所稱之任何專利出版品的任何申請專利範圍中 所涵蓋的任何化合物(例如:申請專利範圍第i項等),揭示為 :)-HT4 X體拮抗劑(例如:w〇93/18〇36、w〇、w〇 93/1 6072、WO 94/10Π4、W〇 94/27987、W〇 95/04737、W〇 93/2007 1、EP 501322 B1、WO 94/27965 及/或 EP 732333 A1)、及/或例如可包括在引言中所稱之任何專利或期刊出版 品中所特定示範的任何5-HT4受體拮抗劑,揭示為5_Ht4受 體括抗劑。其他的5-HT4受體拮抗劑可使用此後詳述之5_Ητ4 结抗背j測試而被發現。5 _ΗΤ4受體拮抗劑之醫藥上可接受鹽 類(例如:HC1鹽)、溶劑化物、水合物、錯合物及/或前藥及類 似衍生物被包括於UT4受體括抗劑’’的定義範嘴中。適當 的醫藥上可接受鹽類對習知此藝者為明顯的,並且包括例如 與無機酸及有機酸所形成之酸加成鹽類,.該無機酸例如:鹽 s是氫’臭岐、硫酸、硝酸或墻酸,該有機酸例如:丁二酸、順 10 15 20 12 本纸張尺度適用中國國家標準(CNS)A4規格(210X 297公釐) (請先閱讀背面之注意事項再填寫本頁) 項再填亡 200425914 經濟部智慧財產局員工消費合作社印製 五、發明說明( 丁烯一酸、醋酸、反丁烯二酸、檸檬酸、酒石酸、苯甲酸、 對_曱苯磺酸、甲烷磺酸或萘磺酸。 ^ΗΊ%叉體拮抗劑較佳的是%HT4A受體的拮抗劑,例如 在〇.Blondel 等人 FEBS Letters,412, 1 997, 465·474 頁中所 鑑別的。 罕父仏地’ 5-ΗΤ4受體拮抗劑是心臟的5-ΗΤ4受體拮抗劑, 思為那些存在於人類心房中之5-ΗΤ4受體的拮抗劑,較佳意 為在人類心臟中基本上只存在於人巔心房中之那些5_Η 丁4受 體的拮抗劑。(見例如:Kaumanil 等人 Naunyn_Schmiedeberg,s Arch Pharmacol (199〇),342·619·622 ;八丄 Kaumann 等人 Br J Pharmacol (1 990) 100:879-885),〇 B1〇ndel 等人,叩⑽ Letters,412, 1 997,第 465-474 頁)。5_Ht4a 受體是如此之受 體。 較隹地,5-HT4(或5-HT4A)受體拮抗劑是選擇性的 _ 丁4(或5 HT4A)党骨豆结抗劍。此結抗劑可例如鍵結到及/或 抑制>HT4(或5-HT4A)受體至少1〇倍強於任何其他5-ht受 骨豆’ k佳為至少25倍,更佳為至少1 〇〇倍。該選擇性可以已 知的測試來測量。見:例如見D H〇yer, 1997, 36(4/5),419及其中對5-HT受體命名的所引述之參照。 k佳地’ 5-ΗΊ:4(或5-HT4a)受體拮抗劑包含揭示於w〇 9j/18036之敘述(包括實例)及/或申請專利範圍中的化合物。 例如.根據W〇93/1 803 6之申請專利範圍第[項,5-HT4受體 才吉抗劑可包含式⑴之化合物或其醫藥上可接受之鹽類·· ίο 15 20 13 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 請 先 閱 讀 背 之 注 意 事 項 再 填 寫 本 頁 200425914 A7 B7 五、發明說明(Or 1- (1-methylethyl) -N- (2- (4- (tricyclic (3.3 丄 1) superscript (3,7) dec-butylcarbonyl) amino) -1-hexahydropyridine (Yl) ethyl) -1H-oripazol-3-carboxamide, or 1- (1-methyl15ylethyl) -N- (2- (4-((tricyclic (3.3.1.1., 7 ) Decyl small group, aminyl group) amine group) -1-hexahydropyridyl group) ethyl group) 1 H-indazol-3-carboxamide, a potent and selective 5-HT4 binding inhibitor by Eli Development of Lilly, see: Cohen ML et al., Drwg · Deve / opme /? / 43: 193-199, April 1988 (including the uncovered active hydroxide metabolites LY-34303 1 and LY-343032 of LY 353433) Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 200425914 A7 B7 V. Invention description (10 15 printed by the Intellectual Property Bureau, Ministry of Economic Affairs, Employee Consumption Cooperation, printed 20) 'Cohen ML Special Nine, j pharmacology and Experimental 7 / 7e / Y // ^ z /// d 277: 97-104, April 1996, and also see: EP 732333 A1. Ideally, a new compound or a new class of compounds is found, which can be used in the atrium Reconstructive therapy (eg, treatment or prevention). Fast ~ atrial rate, especially chronic fast atrial Pace (or chronic atrial rhythm in animal experimental settings) is a situation in which the reconstruction of the central room (especially child reconstruction) occurs, and the effective execution time (AERp) of the central room is reduced. This electrical reconstruction has been shown to play an important role in accelerating the onset of AF. Now we have found that the 5-buta-4 receptor antagonist (inhibitor BU, especially SB 207266, can at least partially reverse the effective atrial effective time (AERP) This reduction of, that is, the ability to increase aerp. Therefore, it is expected that 5-HT4 receptor antagonists like 207266 will moderate atrial reconstruction and / or protect the atrial from reconstruction, especially electrical reconstruction.-Therefore, according to the present invention The first aspect is to provide a medicament for the use of SHI receptor antagonists in the manufacture of a medicament for the prevention or treatment of atrial remodeling, such as in mammals, such as humans. The present invention is also applicable to lactating animals in need thereof (Eg, human) A method for treating or preventing atrial remodeling, which comprises administering a 5-HT4 receptor antagonist effective to the mammal. The present invention also provides a 5M receptor antagonist for prevention 'Treatment of atrium reconstruction', for example: on mammals, such as humans. Preferably, the present invention involves preventive or therapeutic reconstruction, as described above. Waste% Physiological (Electrical) Atrial The present invention, in all its aspects, involves the Human-Xw mouth is made of atrial fiber. Please read the notice on the back before filling out this page. 10 This paper size is applicable to China National Standard (CNS) 8 4 specifications (2 丨 〇χ 297 mm) 200425914 A7 B7 V. Description of the invention (9 Atrial reconstruction is possible with sexual fibrillation, for example: atrial reconstruction with atrial fibrillation possible from recurrent. In all aspects of the invention, the mammal to be treated (eg, human) is a patient or suspected atrial fibrillation patient, especially a patient with persistent or permanent atrial fibrillation [eg: long-term (eg > 15 years or > 5 years) patients]. Long-term (e.g. > 1 year or > 5 years) patients with persistent or permanent atrial fibrillation are most likely to have problems with atrial remodeling, as described above. Preferably or additionally, in all aspects of the invention, a therapeutic / preventive agent / method / 5-HT4 receptor antagonist (eg, SB 207266 or a pharmaceutically acceptable salt thereof) is used to inhibit persistence Symptoms of atrial fibrillation in patients with persistent or permanent AF (preferably permanent AF) are recurrent. "Paroxysmal AF" includes or means AF phenomenon with an average period of individual < 48 hours phenomenon. The persistent AF phenomenon can be stopped automatically or can be converted into general sinus rhythm 15 (NSR) by 5-HT4 antagonists and / or other antiarrhythmic drugs. The main part of paroxysmal AF is AF alone, which has no potential Of cardiovascular disease and no atrial reconstruction. If it is not stopped quickly, continuous AF will be converted to permanent AF. The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs prints "continuous AF", for example: symptomatic permanent AF, which usually has a longer time than continuous AF, and includes or means 248 hours individually and 20 years in S1 The AF phenomenon in the average period, for example, is a symptomatic phenomenon, or more preferably the individual period is <48 hours and <6 months. Permanent AF does not usually stop automatically and often requires electrical or pharmacological heart rate conversion to NSR. Atrial electrical reconstruction usually occurs, and it can occur with left atrial dilatation and left ventricular dysfunction. 25 “Permanent AF” includes or means that the average period of individual phenomena is longer than lasting -11- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200425914 A7 B7 Employee Consumer Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs Printed 5. Description of Invention () '"' _ Seeing Elephants' Example: > 丨 year or > 5 year period, or Shuijiu period. " ^ The book is non-responsive to electrocardiocardia and is associated with complete electrical reconstruction, and is accompanied by ongoing CV disease (local anemia heart disease, cardiomyopathy, and / or both blood pressure, etc.). Orally, the present invention relates to the prevention or treatment of atrial reconstruction made possible by rapid atrial rates (for example, experimental chronic atrial rhythms). The mammals being treated (eg, humans) can be patients with or suspected of rapid atrial rate, such as abnormal rapid atrial rate. The use of the present invention may include any of the 5-HT4 receptor antagonists described in the introduction. Thus, for example, the 5-HT4 receptor antagonist used in the present invention may be included in any compound covered by any patent application of any patent publication referred to in δ (for example: patent application Items, etc.), revealed as:)-HT4 X-body antagonists (for example: WO93 / 18〇36, WO, WO93 / 1 6072, WO 94 / 10Π4, WO94 / 27987, WO95 / 04737, WO93 / 2007 1, EP 501322 B1, WO 94/27965 and / or EP 732333 A1), and / or any 5 that may be specifically exemplified in any patent or journal publication that may be included in the introduction, for example -HT4 receptor antagonist, revealed as a 5-Ht4 receptor antagonist. Other 5-HT4 receptor antagonists can be found using the 5-Ητ4 junction anti-backup test detailed later. 5 _T4 receptor antagonists are pharmaceutically acceptable salts (eg, HC1 salts), solvates, hydrates, complexes and / or prodrugs and similar derivatives are included in the UT4 receptor antagonists '' Define Fan in the mouth. Appropriate pharmaceutically acceptable salts are obvious to those skilled in the art, and include, for example, acid addition salts formed with inorganic and organic acids. The inorganic acids such as: salt s is hydrogen, odor, Sulfuric acid, nitric acid or wall acid. The organic acids such as: succinic acid, cis 10 15 20 12 This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) This page) was refilled 200425914 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the invention Methanesulfonic acid or naphthalenesulfonic acid. ^% Prokaryotic antagonists are preferably antagonists of the% HT4A receptor, such as identified in Blooms et al. FEBS Letters, pages 412, 1 997, 465 · 474. Rather, the 5-ΗΤ4 receptor antagonist is a 5-ΗΤ4 receptor antagonist of the heart, which is thought to be an antagonist of the 5-ΗΤ4 receptor present in the human atrium, preferably in the human heart. Of those 5-receptor 4 receptors that are basically present in the atrium of humans (See for example: Kaumanil et al. Naunyn Schmiedeberg, s Arch Pharmacol (199〇), 342 · 619 · 622; Hachiman Kaumann et al. Br J Pharmacol (1 990) 100: 879-885), 〇B1Ondel, etc. People, 叩 ⑽ Letters, 412, 1 997, pp. 465-474). The 5_Ht4a receptor is such a receptor. In a nutshell, 5-HT4 (or 5-HT4A) receptor antagonists are selective. This anti-binding agent can, for example, bind to and / or inhibit the> HT4 (or 5-HT4A) receptor at least 10 times stronger than any other 5-ht affected bone bean'k, preferably at least 25 times, more preferably at least 25 times 100 times. This selectivity can be measured by known tests. See: See, for example, D Hoyer, 1997, 36 (4/5), 419 and the references cited therein for the nomenclature of 5-HT receptors. k-Jadi '5-ΗΊ: 4 (or 5-HT4a) receptor antagonists include compounds disclosed in the description (including examples) of WO9j / 18036 and / or patent applications. For example, according to item # 05 of the scope of patent application of WO93 / 1 803 6, the 5-HT4 receptor talent inhibitor may include a compound of formula (I) or a pharmaceutically acceptable salt thereof. 15 20 13 This paper Standards are applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) Please read the precautions before filling in this page 200425914 A7 B7 V. Description of the invention (
(I) 其中 X 為 0、S、SO、S02、CH2、CH 或 ’NR,其中 R 為氫或 C 火完基; 5 A為飽和或不飽和之2-4個碳原子的聚亞甲基鏈; R!及R2為氫或CN6烧基; 為氫、鹵基' Cu烷基、胺基、硝基或Cn6烷氧基; R4為氫、鹵基、C!—6烷基或Cw烷氧基; Y為〇或NH ; ίο Z為次級式(a)、(b)或(c): (CH2)q(I) where X is 0, S, SO, S02, CH2, CH, or 'NR, where R is hydrogen or C fluorenyl; 5 A is a polymethylene of 2-4 carbon atoms, saturated or unsaturated R! And R2 are hydrogen or CN6 alkyl; are hydrogen, halo 'Cu alkyl, amine, nitro or Cn6 alkoxy; R4 is hydrogen, halo, C! -6 alkyl or Cw alkyl Oxygen; Y is 0 or NH; ίο Z is a secondary formula (a), (b) or (c): (CH2) q
I ------------裝 (請先閱讀背面之注意事項再填寫本頁) 訂--- # 經濟部智慧財產局員工消費合作社印製 ⑷ (CH2)n2、 R7I ------------ Installation (Please read the precautions on the back before filling this page) Order --- # Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs ⑷ (CH2) n2, R7
I 14 (b) 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200425914I 14 (b) This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) 200425914
A7 ----— 五、發明說明() 10 其中 (CH2)n3—A7 ----— V. Description of the invention () 10 of which (CH2) n3—
(c) 11 為 1、2、3 或 4 ; η2 為 1、2、3 或 4 ; η3 為 2、3、4 或5; Rs為齒素、Cl-12烧基、芳烷基或R5為(CH2)Z-RI0,其中z為2或3,且(c) 11 is 1, 2, 3, or 4; η2 is 1, 2, 3, or 4; η3 is 2, 3, 4, or 5; Rs is dentin, Cl-12 alkyl, aralkyl, or R5 is (CH2) Z-RI0, where z is 2 or 3, and
Rio是選自氰基、羥基、烷氧基、苯氧基、c(〇)Ci_6 犬兀基、COC6H5、-C〇NRur12、NRllC0Rn、s〇2NRllRl2 或NRl]S〇2Rl2、其中Rii及R12為氫或Ci_6烷基;且 R6、R7及R8獨立為氫或Cl_6烷基;且 R9為氫或Ci_1Q烷基; 請 先 閱 讀 背 δ 之 注 意 事 項 填 寫 本 頁 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 或式(I)之化合物,其中C0_Y連結被雜環生物等排物置換。 其中CO-Y連結被雜環生物等棑物置換,該生物等排物 可為如wo 93/1 8036第3頁第n-25行所揭示的。然而,較 I5佳的是此生物等棑物不存在;g卩:較佳地¥為〇或NH。 •較佳地,X為〇。較佳地,A為_(0%)3…較佳地,r】及I 獨立為鹵素或甲基。較佳地,L為氫且I為氫或齒基。(比 較:WO 93/18036之申請專利範圍第2-5項)。 芳基(例如:當R5為芳烷基)包括苯基及萘基,可選擇地以 20 =或多個選自_基、Ci·6烷基及Cm烷氧基之取代基取代。 當I為芳烷基時,此可包括可選擇之經取代的苄基,例如. ^基其中的苯環是以一或多個選自齒基、Cm烷基及Cm烷 氧基之取代基取代。(比較:WO 93/1 8036之申請專利範圍第9 15 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200425914 五、發明説明( 員及第3頁6-7行)。偶”2 ’Z為切式⑷。在次級式⑷中 騎的石炭原子。較佳illUl。較佳地 (CH2)nl是附於 q = 3,使得次級 式(a)包含 個 偶氮環,即:Ζ為 Ν—R5 ,主 、J从喷,外:ζ马 '-/ 車 二^兄為(CH2)nl是附於偶氮環的4-位置。仍更佳地,Z j 、^比咬基甲基 '以R5做N-取代(即:Z J 八/ \ r5 取d )。其中Z為4-六氫吡啶基甲基、以Rs做N 的是N-取代的I為C2或C3或更大的烷基(即:C2 疋基或Cl丨2烷基、或可選擇地為經取代之苄基; 2-^ 10的是以EP-A-501322之式⑴中所定義的(CH2)nR4置換^ 且與EP-A-501 322之特定實例相關。最佳地,z為〇气正了 ~\ N—*nguRio is selected from the group consisting of cyano, hydroxy, alkoxy, phenoxy, c (〇) Ci_6 cannonyl, COC6H5, -C〇NRur12, NRllC0Rn, so2NRllRl2, or NR1] S〇2R12, where Rii and R12 are Hydrogen or Ci_6 alkyl; and R6, R7, and R8 are independently hydrogen or Cl_6 alkyl; and R9 is hydrogen or Ci_1Q alkyl; please read the notes on δ first and fill out this page Or a compound of formula (I), in which the C0_Y linkage is replaced by an isostere of heterocyclic organisms. The CO-Y link is replaced by a heterocyclic organism such as a heterocyclic organism, which is as disclosed in wo 93/1 8036, page 3, lines n-25. However, it is better than I5 that this organism is not present; g 卩: preferably ¥ or NH. • Preferably, X is 0. Preferably, A is _ (0%) 3 ... Preferably, r] and I are independently halogen or methyl. Preferably, L is hydrogen and I is hydrogen or a dentate. (Comparison: the scope of patent application of WO 93/18036 items 2-5). Aryl (for example: when R5 is aralkyl) includes phenyl and naphthyl, optionally substituted with 20 = or more substituents selected from Ci, Ci · 6 alkyl, and Cm alkoxy. When I is an aralkyl group, this may include an optionally substituted benzyl group, for example, a phenyl group where the phenyl ring is one or more substituents selected from the group consisting of halo, Cm alkyl, and Cm alkoxy. To replace. (Comparison: WO 93/1 8036 patent application scope No. 9 15 This paper size applies to Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 200425914 V. Description of invention (members and lines 6-7 on page 3) . Even "2'Z is tangent ⑷. Carbon atoms riding in secondary ⑷. Better illUl. Preferably (CH2) nl is attached to q = 3, so that secondary (a) contains an even Nitrogen ring, that is: Z is N-R5, the master and J are sprayed, and the outer: Zema '-/ Che Eryi is (CH2) nl is the 4-position attached to the azo ring. Still more preferably, Z J and ^ are N-substituted by R5 (that is, ZJ ba / \ r5 is d). Where Z is 4-hexahydropyridylmethyl and Rs is N-substituted I C2 or C3 or greater alkyl (ie: C2 fluorenyl or Cl2 alkyl, or optionally substituted benzyl; 2- ^ 10 is in the formula of EP-A-501322) The defined (CH2) nR4 substitution ^ is related to a specific instance of EP-A-501 322. Optimally, z is 0 gas is correct ~ \ N— * ngu
經濟部智慧財產局員工消費合作社印說 15 基)-4-六氫吡啶基)曱基,即: 一 。ν π (比罕父:W〇 93/1 8036之申請專利範圍第1及7_9項及第4頁6行至第5 頁10行)。 較佳地,在本發明中,5-HT4受體拮抗劑包含選自下列的 化合物: ⑷如WO 93/1 8036所述的實例1至46之一、 (b) 如WO 93/05038所述的實例1至54之一、 (c) 如WO 93/2007 1之申請專利範圍第6項或實例丨至% 20 所述的化合物之 或 16 本紙張尺度適用中國國家標隼(CNS ) A4規格(210><297公釐) (請先閲讀背面之注意事項再填寫本頁)The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs said that 15-based) -4-hexahydropyridyl) fluorenyl, that is, one. ν π (Bihan's father: WO 93/1 8036's patent application scope items 1 and 7-9 and page 4 line 6 to page 5 line 10). Preferably, in the present invention, the 5-HT4 receptor antagonist comprises a compound selected from: ⑷ one of Examples 1 to 46 described in WO 93/1 8036, (b) as described in WO 93/05038 One of Examples 1 to 54, (c) As described in item 6 or example of WO 93/2007 1 or the compound described in% 20 or 16 of this compound, this paper size applies to China National Standard (CNS) A4 (210 > &297; 297mm) (Please read the notes on the back before filling in this page)
200425914 η , Α7 ; _____Β7 五、發明説明(’) (d)如ΕΡ 5013 22 Β]之申請專利範圍第9項或實例}至 23所述的化合物之一, (請先閲讀背面之注意事項再填寫本頁) 為游離鹼形式或其醫藥上可接受之鹽類。 另外地’在本發明中,SHI受體拮抗劑可包含選自下列 5 的化合物: (a) 如WO 94/27965所述之實例1至15所述的化合物之 一、或 RS 100235 或 RS100302,或 (b) 如EP 73 233 3 A1所述的實例1至38之一、 為游離驗形式或其醫藥上可接受之鹽類。 10 在本發明中,特佳的是5-HT4受體拮抗劑包含: (〇义[(卜正丁基-4-六氫吡啶基)甲基]-3,4-二氫-211-[1,3]啐 畊並[3,2-a]吲哚-10-甲醯胺(SB 207266); (ii)N-(2-(4-(3-(8-胺基-7 -氯基-2,3-二氫-1,4-苯並二喝烧 -5-基)-3-氧丙基)六氫吡啶-卜基)乙基)-甲磺基醯胺(RS 15 1 00302); (iii) l -甲基-1H-吲哚-3 -羧酸(1-(2-((曱磺醯基)胺基)乙 基)-4-六氫吡啶曱酯(GR 1 13808);或 經濟部智慧財產局P、工消費合作社印¾ 20 (iv) l-(l -甲基乙基)-N-(2-(4_((三環(3.3.1.1)癸-1-基羰基) 胺基)-1 -六氫吡咬基)乙基)-1 H-吲唑-3 -曱醯胺(LY-353433); 也就是1-(1-甲基乙基)-N-(2-(4-((三環(3.3.1.13,7)癸-1_基羰基) 胺基)-1 -六氫吡咬基)乙基)-1Η-吲唑-3 -甲醯胺; 或其w藥上可接受之鹽類。 另外地,較佳的是5 -HT4受體结抗劑包含: (v) 8-胺基-7-氣基-1,4-苯並二哼烷-5-羧酸(1-丁基-4_六氫 17 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 2Q0425914 A7 B7 經 部 智 慧 財 產 局 消 費 合it 社 印 製 五、發明説明(-) ~ 口比啶基)甲酯(SB 204070)或其醫藥上可接受之鹽類,例如.其 鹽酸鹽; ^ (v〇8-胺基-7-碘基-1,4-苯並二呤烷羧酸丁基— 氫吡啶基)甲酯(SB 207710)或其醫藥上可接受之鹽類,例如 5 其鹽酸鹽; (vH)N-(l-丁基-4-六氫吡啶基)甲基胺基·7_氯基-〗,4-苯 並二哼烷-5-甲醯胺(SB 205800)或其醫藥上可接受之鹽類'(vni)[l-[2-[(甲磺醯基)胺基]乙基卜仁六氫吡啶基]甲基 [2 (j甲基1,2,4。号一哇-5-基)笨基]胺基曱酸醋(gr 13 8897) 或其醫藥上可接受之鹽類,例如:其(2>2_ 丁烯二酯或甲烷磺 酸鹽;或 dx)5-氟基_2_曱氧基-1H“引嘴1羧酸[H2_[(甲磺醯基) 胺基]乙基卜仁六氫吡啶曱酯(GR 125487)或其醫藥上可接受 之鹽類,例如:其鹽酸鹽、曱烷磺酸鹽、或順丁烯二酸鹽。 更佳的拮抗劑包括··⑴SB 207266、(v)SB 2〇4〇7()、(V1)SB 2077 10、(VU)SB 205800 及(vili)GR 13δ897 ;或其醫藥上可接 受之鹽類。 最佳的5-ΗΤ4受體拮抗劑為Ν_[(ρ 丁基_4_六氮π比啶)甲基]-3,4-二氫_2Η_Π,3]啐畊並[3,2_a]吲呼_ι〇_曱醯胺⑽ 207266)或其醫藥上可接受之鹽類’特別是其鹽酸;鹽⑽ 207266-A)。 ,本设明之第—個觀點提供5·ΗΤ4受體括抗劑在製造藥劑 上的用途’用來預防或治療除了心房纖維性顫動之外的疾病 或健康狀況,是關於減少心房有效執构時間(AERP)及/或不想 10 15 20 本紙張尺度適财關家縣 1.^ϋ 1: -1 — I - --* I 匪 5 · (請先閱讀背面之注意事項再填寫本頁) 訂 i# 18 200425914 A7 B7 五、發明説明( 10 15 經濟部智慧財產局員工消費合作社印製 20 要的心房執拉7改變。 β本發明之第二個觀點也在需要其之哺乳動物(如:人類)上 種治療或預防除了心房纖維性顫動外之疾病或健康狀 況的方法’關於減少心房有效執抝時間(AERP)及/或不想要的 心房執抝改變’其中包含對該哺乳動物施用有效份量之 5-HT4受體拮抗劑。 本發明之第二個觀點士拇你c ττπ # 提七、5-ΗΤ4受體拮抗劑,用於除 了心房纖維性顫動之外的疾病或健康狀況,是㈣減少心房 有效執构時間(AERP)及/或不想、要的心房㈣改變。 本發明之第三個觀點提供5_叫受體拮抗劑在製造藥劑 勺用帛來加L房有效執构時間(AERp)及/或有效地改 變遭遇該㈣或健康狀況之患者或疑為患者之哺乳動物(如. =的除了心房纖維性顫動外的心房執构,其中此 變是想要的。 本發明之第三個觀點也在需要其之哺乳動物(如:人類) t,提供—種增加心房有效執柄時間(A啊及/或有效地改變 1該疾病或健康狀況之患者或疑為患者之哺乳動物的除了 心房纖維性顫動外的心房執抝,其中台各 七^ \曰 u °對4 _乳動物施用 有效伤置之5-ΗΤ4受體拮抗劑。 力三個觀點也提供5-ΗΤ4受體拮抗劑,用來辦 加心房有效執枚/時問^AFR Ρ、β / > 士 曰 t間(AERP)及/戏有效地改變遭遇竽 健康狀況之患者或疑為患者之哺乳動物(如:人類二口或 居滅維性顫動外的心房⑽,其中此增加或改變是 、 本發明之第四個觀點提供5邮受體拮抗劑在製造藥劑 19 _ j y 本紙張尺度適用中晒家標 (請先閱讀背面之注意事項再填寫本頁) 200425914 經濟部智慧財產局員工消費合作社印製 五、發明說明() i 上的用途’用來預防或治療心房節律(例除了心房纖維性顫動夕卜的疾病或健康狀況,·斑,、、〜房^律)或 象(例如:慢性心房節律)相關的。 人匕房筇律的現 較U也在本毛明之第二、三及四個觀$中 5健康狀況是除了心律不整之外。較佳祕, ,邊疾病或 本'發'明之Μ - ·α三個觀點中,該疾病或健康狀況是心臟(例如 : 健康狀況 '及/或哺乳動物-如··人類-的疾病或健康狀況病或 為了使用5-ΗΤ4受體拮抗劑,其一般會根準 施而調配成醫藥組合物。 +W木具 通4受體拮抗劑可習用地以任何習用於藥物施用的路 聽用’例如:腸胃外用、口服、局部或吸入。抑制劑可以制 備成習用劑量形式施用’根據習用之步驟與標準醫藥載體: 合之。抑制劑也可與已知的第二個治療性活性化合物組合, :習用劑量而被施用。這些步驟可牽涉到混合、成微粒及壓 縮或溶解原料成為適當的所要製劑。要明白:醫藥上可接受載 體的形式及特性,被與之組合之活性原料的份量、施用的路 徑及其他已熟知的變數所指定。該載體必須是,,可接受的”, 逼理是與調配物的其他原料是可相容的,並且對其接受者為 不傷害的。 W樂上可接受載體可以是例如:固體或液體。固體載體的 粑例為乳糖、白土、蔗糖、滑石 '凝膠、洋菜、果膠、阿杈 伯樹膠、硬脂酸鎂、硬脂酸及類似物。液體載體的示範為糖 桌、花生油、橄;f覽油、水及類似物。類似地,載體或稀釋劑 可包括此藝中已熟知的時間延遲物質,如:單硬脂酸甘油酯或 10 15 20 20 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 請 先 閱 背 之 注 意 事 項 再 填 寫 本 頁 200425914 經 濟 部 智 慧 財 產 局 員 工 消 費 合 社 印 製 五、發明說明() 二硬脂酸甘油酯單獨、或與蠟混合。 可使用廣泛種類的般磁# 制— ' 硝的西^形式。因此,若使用固體載體, 衣剖可為成旋的、被置於硬踢囊中的粉末或贫劑形式、或作 f检制的形<。固體載體的份量可廣泛地變化,但較佳# 將勺2 5元克至約1克。當使用液體載體時,製劑可以是米 ::、乳化劑、軟膠囊、經消毒之可注射液體,如;瓶或非 生的液態懸浮液。 、、卩制“車乂侄地疋鈿胃外施用的,也就是靜脈注射、肌读 皮下庄射、异内、直腸内、陰道内或腹膜内施用。靡 ,外施用的靜脈注射形式是通常較佳的。此 可以習用技術來製備。 ”抑制劑也可以口服施用。對此施用的適當劑量形式可以 白用技術來製備。 抑制劑也可以吸入來施用,也就是鼻内及口腔吸入的施 用。對此施用的適當劑量形式_如:噴霧調配物,可以習用技 術來製備。 抑制劑也可以局部施用’也就是非系統性的施用。此包 2抑制劑的外部塗敷到表皮或D腔孔洞、及此化合物灌入耳 木'眼晴及鼻子,使得該化合物基本上不進人血流中。 對如:SB 207266或其醫藥上可接受鹽類之抑制劑的在此 句不所有方法而言,每日口服劑量攝取較佳是從約。.i至約 80宅克/公斤之總體重,較佳是從約〇 2至3〇毫克/公斤’更 :是,至〇.5約1 5毫克/公斤。每曰非腸胃用(例如:靜脈注 射)制量攝取較佳是從約(U至約80毫克/公斤之總想重,較 10 15 20200425914 η, Α7; _____ Β7 V. Description of the invention (') (d) One of the compounds described in the patent application scope item 9 or example} to 23 of EP 5013 22 Β] (Please read the precautions on the back before (Fill in this page) is either the free base form or a pharmaceutically acceptable salt thereof. Additionally, in the present invention, the SHI receptor antagonist may include a compound selected from the following 5: (a) one of the compounds described in Examples 1 to 15 described in WO 94/27965, or RS 100235 or RS 100302, Or (b) one of the examples 1 to 38 described in EP 73 233 3 A1, which is a free test form or a pharmaceutically acceptable salt thereof. 10 In the present invention, it is particularly preferred that the 5-HT4 receptor antagonist comprises: (〇yi [(Bu n-butyl-4-hexahydropyridyl) methyl] -3,4-dihydro-211- [1, 3] Pyrene [3,2-a] indole-10-carboxamide (SB 207266); (ii) N- (2- (4- (3- (8-amino-7-chloro- 2,3-dihydro-1,4-benzodiazepine-5-yl) -3-oxopropyl) hexahydropyridine-butyl) ethyl) -methanesulfonamide (RS 15 1 00302) (Iii) l-methyl-1H-indole-3 -carboxylic acid (1- (2-((fluorenylsulfonyl) amino) ethyl) -4-hexahydropyridinium ester (GR 1 13808) ; Or printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Industrial and Consumer Cooperatives ¾ 20 (iv) l- (l -methylethyl) -N- (2- (4 _ ((tricyclo (3.3.1.1) dec-1--1-yl Carbonyl) amino) -1-hexahydropyridyl) ethyl) -1 H-indazole-3 -amidoamine (LY-353433); that is, 1- (1-methylethyl) -N- (2- (4-((tricyclic (3.3.1.13,7) dec-1-ylcarbonyl) amino) -1 -hexahydropyridyl) ethyl) -1'-indazole-3 -formamidine Or a pharmaceutically acceptable salt thereof. Additionally, it is preferred that the 5-HT4 receptor binding agent comprises: (v) 8-amino-7-amino-1,4-benzodihum Alk-5-carboxylic acid (1-butyl-4_hexahydro 17 paper sizes Printed in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 2Q0425914 A7 B7 Ministry of Intellectual Property Bureau Consumption Co. Ltd. V. Invention Description (-) ~ Methylpyridyl) methyl ester (SB 204070) or its medicine Acceptable salts, such as its hydrochloride; ^ (v〇8-amino-7-iodo-1,4-benzodiuridine carboxylic acid butyl-hydropyridyl) methyl ester (SB 207710) or a pharmaceutically acceptable salt thereof, such as 5 or its hydrochloride; (vH) N- (l-butyl-4-hexahydropyridyl) methylamino · 7-chloro-, 4 -Benzodihenane-5-carboxamide (SB 205800) or a pharmaceutically acceptable salt thereof '(vni) [l- [2-[((Methanesulfonyl) amino) ethyl] renal Hydropyridyl] methyl [2 (jmethyl1,2,4. No. 1-Wa-5-yl) benzyl] aminoacetic acid (gr 13 8897) or a pharmaceutically acceptable salt thereof, such as : Its (2 > 2-butene diester or methane sulfonate; or dx) 5-fluoro-2-_2-methoxy-1H "injection 1 carboxylic acid [H2 _ [(methylsulfonyl) amino] ethyl Pyridyl hexahydropyridine (GR 125487) or a pharmaceutically acceptable salt thereof, such as its hydrochloride, pinanesulfonate, or maleic acid Salt. Better antagonists include: ⑴SB 207266, (v) SB 2040 (7), (V1) SB 2077 10, (VU) SB 205800, and (vili) GR 13δ897; or a pharmaceutically acceptable salt thereof class. The best 5-ΗΤ4 receptor antagonist is N _ [(ρ butyl_4_hexaazapipyridine) methyl] -3,4-dihydro_2Η_Π, 3] and [3,2_a] ind _Ιο_ 曱 醯 amine⑽ 207266) or its pharmaceutically acceptable salts', especially its hydrochloric acid; salt ⑽ 207266-A). The first aspect of this article provides the use of a 5ΗΤ4 receptor antagonist in the manufacture of a medicament. It is used to prevent or treat diseases or health conditions other than atrial fibrillation. It is about reducing the effective construction time of the atrium. (AERP) and / or do not want 10 15 20 This paper size is suitable for financial affairs in Guanjia County 1. ^ ϋ 1: -1 — I--* I Band 5 · (Please read the notes on the back before filling this page) Order i # 18 200425914 A7 B7 V. Description of the invention (10 15 Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives, 20 Atrial Tension 7 Change. β The second aspect of the present invention is also in mammals that require it (eg: (Human) The above method for treating or preventing diseases or health conditions other than atrial fibrillation 'About reducing atrial effective hold time (AERP) and / or unwanted changes in atrial hold', which includes effective administration to the mammal Serving amount of 5-HT4 receptor antagonists. A second aspect of the present invention is that you c ττπ # Tiqi, 5-ΗΤ4 receptor antagonists for diseases or health conditions other than atrial fibrillation, is ㈣ Reduce effective atrial execution (AERP) and / or unwanted or desired atrial dysplasia. A third aspect of the present invention provides a method for the use of receptor antagonists in the manufacture of pharmaceutical spoons to increase the effective room time (AERp) and / or Effectively change the atrial architecture of patients suffering from this disease or health condition or mammals suspected of being a patient (eg, atrial fibrillation other than atrial fibrillation, where this change is desired. The third aspect of the invention also In mammals (eg, humans) who need it, provide a type of atrial fiber that increases the effective atrial handle time (A and / or effectively alters 1 patient or suspected patient ’s mammal) Atrial perseverance outside of sexual fibrillation, in which each of them is administrated to a 5- 乳 T4 receptor antagonist that is effective in treating 4- lactating animals. The three viewpoints also provide 5-ΗΤ4 receptor antagonists, which Adding effective atriums / times ^ AFR P, β / > Shi T t (AERP) and / play effectively change the patient's health condition or mammal suspected to be a patient (such as human second mouth) Or atrial fibrillation outside of dimensional fibrillation, where this increase or change is, The fourth aspect of the present invention provides a 5-post receptor antagonist in the manufacture of pharmaceuticals. 19 _ jy This paper is suitable for standard printing (please read the precautions on the back before filling out this page) 200425914 Employee Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Printed 5. Description of the Invention (i) Uses to prevent or treat atrial rhythm (except for diseases or health conditions of atrial fibrillation fibrillation, plaques, ..., ~ atrial rhythm) or elephants (for example: Chronic Atrial Rhythm) is related to the current rhythm of the human heart and the rhythm of the heart. The health status of the second, third, and fourth perspectives of Mao Maoming is in addition to arrhythmia. In the three perspectives, the disease or the health condition is the heart (eg, the health condition) and / or the mammal or the human disease or health. Conditional disease or for the use of 5-HT4 receptor antagonists, which are generally formulated into a pharmaceutical composition. + W 木 具 通 4 receptor antagonists can be used conventionally in any of the conventional methods for drug administration. For example: parenteral, oral, topical or inhalation. Inhibitors can be prepared in conventional dosage forms and administered according to customary procedures with standard pharmaceutical carriers: In combination. Inhibitors can also be combined with a second known therapeutically active compound, : Conventional doses are used. These steps may involve mixing, granulating and compressing or dissolving the raw materials into the appropriate desired formulation. It should be understood that the form and characteristics of the pharmaceutically acceptable carrier, the amount of active ingredients combined with it, The route of application and other well-known variables are specified. The carrier must be, "acceptable", the reasoning is that it is compatible with the other ingredients of the formulation, and its recipient is Harmful. W Le acceptable carriers can be, for example: solid or liquid. Examples of solid carriers are lactose, white clay, sucrose, talc 'gel, agar, pectin, arbor gum, magnesium stearate, Stearic acid and the like. Examples of liquid carriers are sugar table, peanut oil, olive; oil, water and the like. Similarly, the carrier or diluent may include time delay substances well known in the art, such as: Glyceryl stearate or 10 15 20 20 This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) Please read the precautions before filling out this page 200425914 Employees ’Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs Printed 5. Description of the invention () Glyceryl distearate alone or mixed with wax. A wide variety of general magnetic systems can be used-the form of nitrate. Therefore, if a solid carrier is used, the section can be made into Rotating, powdered or lean formulations placed in a hard kick capsule, or shaped for inspection. The amount of solid carrier can vary widely, but it is better to #spoon 2 5 yuan to about 1 gram When using a liquid carrier Preparations can be rice :: emulsifiers, soft capsules, sterilized injectable liquids, such as; bottles or non-liquid liquid suspensions. 卩, "car 乂 nephew 疋 钿 外 administered parenterally, that is intravenously Injection, intramuscular subcutaneous injection, heterogeneous, intrarectal, intravaginal or intraperitoneal administration. Intravenous injection forms are generally preferred. This can be prepared by conventional techniques. "Inhibitors can also be administered orally. Appropriate dosage forms for this application can be prepared using techniques. Inhibitors can also be administered by inhalation, that is, intranasal and oral inhalation. Appropriate dosage forms for this application _ such as spray formulations, can be used conventional techniques to Preparation. Inhibitors can also be administered topically, that is, non-systemic. The exterior of this pack 2 inhibitor is applied to the epidermis or D cavity cavity, and the compound is infused into the fungus' eyes and nose, so that the compound does not substantially enter the human blood stream. For all methods in this sentence such as SB 207266 or a pharmaceutically acceptable salt inhibitor thereof, the daily oral dose intake is preferably from about. The total weight is from .i to about 80 g / kg, preferably from about 02 to 30 mg / kg 'and more preferably from about 0.5 to about 15 mg / kg. For non-parenteral use (for example: intravenous injection), the total intake is preferably from about (U to about 80 mg / kg total weight, compared with 10 15 20
請 先 閲 讀 背 之 注 意 事 項 再 填 寫 本 頁 200425914 五、發明說明() 佳是從約0.2至約30毫克/公斤,且更佳 笔克,公斤。每日局部用劑量攝取較佳是從約二]二古5至L 耄克,每天施用一至四次,較佳為-至_二.1笔克至15< 攝取較佳是每天從約〇 〇1亳克/八‘斤 每日吸入劑量| 5基於上述較佳的劑量範圍‘斤。 你豬實驗的活體結果,其中劑量為0.3及二::中顯示之迷| 207266靜脈注射施用,有效地治療心房纖維性毛寵/公斤的SB 建,下列的劑量範圍較佳地用預、'庵f、動及心房重 ίο 吞/八6A斤之紅體重(例如:0.1至1 〇真 更佳是從約。.2 η。毫克,公斤(例如:。…; 克:是從°.3至毫克,公斤,且最佳是從 毛克/公斤(例如:0 5至〗〇哀 15 乳動物上,如:人類。對人 ·. △斤),特別是在哺 i °服或非腸胃用(例如:,r : ·"重約7〇-7:)公斤,每曰Please read the memorandum items on the back and fill in this page. 200425914 V. Description of the invention () It is preferably from about 0.2 to about 30 mg / kg, and more preferably a pen gram and a kilogram. The daily topical dose intake is preferably from about two] Ergu 5 to L 耄 grams, administered one to four times a day, preferably-to _.2.1 grams to 15 < the intake is preferably from about 0.00 1 kg / eight 'kg inhaled daily dose | 5 based on the above preferred dose range' kg. In vivo results from your pig experiment, in which the dose is 0.3 and two :: 207266 shown in the intravenous injection | 207266 is administered intravenously to effectively treat atrial fibrous hair pets / kg of SB. The following dose ranges are preferably used for pre-, '庵 f, movement and atrial weight ίο swallow / eight 6A pounds of red body weight (for example: 0.1 to 10 is more preferably from about .. 2 η. Milligrams, kilograms (for example: ...; grams: from ° .3 To milligrams, kilograms, and preferably from gross grams / kg (for example: 0 5 to 〇〇 15 on dairy animals, such as: humans. To humans .. △ pounds), especially in feeding or non-gastrointestinal Use (for example:, r: · " about 7〇-7 :) kg, each
公斤,應每=二:)=::广.°毫克J 克/公斤至!.0毫方/八片卜 )笔克;,約〇.2毫| 毫克·々勺二A ’相對應於每天從(約14-15)至(70-75) 35_37 5)至(7。:=心 量是胃隊祕_她聰每曰劑 丄旦 寸疋20*克)、5〇毫克及80毫克〇 2〇J1^!^.;b 207266 ^ SBj ° 添加到游離鹼之任何酸的重量被棑除 22 20 200425914 經濟部智慧財產局員工消費合作社印製 五、發明說明(_) 因此,本發 ' 之第五個觀點提供N_[(1_正丁基冬六氮口比。定 二二]甘氫2Η·[1,3] 口亏啡並[3,2-a] 口引口朵-1〇_甲酿胺(SB -07266)或其醫藥上可接受赜制、 现犬員在衣仏樂劑上的用途,用來 治療或預防在哺乳動物上(如· 、 人"貞)的〜房緘維性顫動,藉著 5動物每日口服或非腸胃用劑量攝取是從總體重的每公 斤約〇·1毫克至約1〇臺吞的 見勺SB 207266或其鹽類(以游離驗 測量)。 、T啡_ 本發明之第五個觀點4對需要其之哺乳動物提供—種治 療或預防心房纖維性顫動的方法,其包含㈣哺乳動物施用 母日口服或非腸胃用劑量攝取總體重的每公斤從約ο」毫克 至1.0笔克的N-[(l-正丁基_4_六氫吡啶基)曱基卜3,4-二氡 -2H-[1,3]。等畊並[3,2_aWh朵·1〇_ 甲醯胺(SB 2〇7266)或其醫 ^ 上可接受之鹽類(以游離鹼測量)。 ^ π 也提供丁基冰六氫吡啶基)甲基]·3,心二氫 -2Η-[1,3;Κ畊並[3,2-a]吲哚_1〇_甲醯胺(SB 2〇7266)或其醫華 上可接X之鹽類,用於治療或預防哺乳動物(例如:人類)的心 房纖維性顫動,藉著對哺乳動物施用每曰口服或非腸胃用劑 量攝取為總體重的每公斤約〇.丨毫克至1〇毫克的SB 2〇72^ 或其鹽類(以游離驗測量)。 在本發明之所有觀點(第一至第五個觀點)中,每日口服或 非腸胃用劑量攝取較佳的是總體重的每公斤從約〇.丨亳克至 1.0笔克的SB 207266或其鹽類,更佳是從約0.2毫克/公斤 至1,〇毫克/公斤,仍更佳是0.3至丨.0毫克/公斤,例如是約 0.5毫克/公斤至ΐ·〇毫克/公斤。 10 15 20 23 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 請 先 閱 讀 背 δ 之 注 意 事 項 再 填 寫 本 頁 裝 I I I I I 訂 修 200425914 五、發明說明( 10 15 經濟部智慧財產局員工消費合作社印製 20 更佳地,在本發 包含口服或非腸胃施用 δ〇毫克的SB 207 266咬兑 疋:。50毛克或 以每天一次單1量來:鹽雄游離驗測置)。每日劑量可 ▲、 β來、七14、或可在該曰之相同或不同時間 以一或夕久罕父小劑量仏盘Α、丄 旦。 、° ”的廷些,其總共產生該特定每曰劑 因此,本發明之第六個觀點提供N-[(l-正丁基-4-六氫π比咬 基)甲基Η,4-二氫_2Η·Π,3Μ。井並[3,2-aH丨Ή0-甲酿胺(SB 207266)或其醫華上可垃為 、 $上了接又之鹽類在製造藥劑上的用途,用來 療或預防在人類上的心房纖維性顫動,藉著對人類施用每 =口服或非腸胃用(較佳為口服)劑量2〇毫克、5〇毫克或8〇 笔克的SB 207266或其鹽類(以游離鹼測量)。 也對需要其之人類提供—種治療或預防心房纖維性顏動 的方π,其包含對泫人施用每曰口服或非腸胃用劑量是2〇 宅克、)〇宅克或80毫克的SB 2〇7266或其鹽類(以游離鹼測 量)。 也供疋SB 207266或其醫藥上可接受之鹽類用來治療 或預防人類之心房纖維性顫動,藉著對人類施用每日口服或 非腸胃用劑量20毫克、50毫克或80毫克的SB 2〇7266或其 鹽類(以游離鹼測量)。 在本發明之所有觀點中,較佳的是5-HT4受體拮抗劑(例 如:SB 207266或其醫藥上可接受之鹽類)被用於/對有症狀性 心房纖維性顫動(AF)、及/或持續或永久性(較佳為永久性 的)AF之病患施用。 24 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200425914 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明(.) 一 也克50毛克及/或80毫克的人類口服劑量及約〇 2 也克a斤至1 ·〇毛克/公斤每曰劑量被設計為將施用如 207266之心血管及/或其他副作用減至最小。 較佳地’在本發明之所有觀財,藥繼療或預防的方 5法/5-HT4受體拮抗劑(例如:SB 2〇7266或其醫藥上可接受之 鹽類)被用於持續或永久性A F (較佳為永久性a f )病患之心房 纖維性顫動症狀再發生的抑制。使用SB 2〇7266於永久性AF 病患上抑^ I纖維性顫動症狀再發生的較佳方法被詳細敛 述於此後之實例3中。 對使用/施用SB 207266,通常理想的是達到更迅速的完 整治療反應。為了達到此,相信:可起初使用較大負載劑量⑽ 如:口服劑量)之SB 207266或其鹽類’來更快速達到治療濃 度。 已經發現:SB 207266的穩定態血衆.濃度以一日一劑量的 後續約5天達到,與移除半生期T1/2約2〇_24小時一致。相 信:此達到穩定態濃度的長時間是不理想的’因為有心房纖維 性顏動/重建、而已轉換(心臟轉換)成一般靜脈f性節律續以 AF現象的病患,更可能在心臟轉換之後很快有入17再發生。 相信:接續一日口服一劑量之累積程度是約丨5倍。因此,施 用之SB 207266為第一天施用日劑量約15倍,必會造成立 刻達到假穩定恶血漿濃度,在心臟轉換之後對AF有治療優 點。 初步之人口醫樂動力學模式結果為圖5,其顯示對兩次 攝取之模擬SB 207266血漿濃度對時間作圖(第丨天]2〇毫 10 15 20 25 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐)Kilograms should be every = 2:) = :: wide. ° mg Jg / kg to! .0 milligrams / eight tablets) Pico ;, about 0.2 milligrams | milligrams · two spoons A 'corresponding to (about 14-15) to (70-75) 35_37 5) to (7) per day. : = Heart weight is the secret of the stomach team_ She Cong (20 * grams per day), 50 mg and 80 mg 〇2〇J1 ^! ^ .; b 207266 ^ SBj ° Any acid added to the free base The weight has been eliminated. 22 20 200425914 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the invention (_) Therefore, the fifth aspect of the present article provides N _ [(1_n-butyl winter six nitrogen ratio. Ding 22] Glycogen 2Η · [1,3] Moutine and [3,2-a] Mouth Induced Mouth-10 ~ Methylamine (SB -07266) or its pharmaceutically acceptable preparation, The use of canine members in clothing tinctures, for the treatment or prevention of atrial fibrillation in mammals (such as ·, human " Zhen), through oral or parenteral doses of 5 animals It is SB 207266 or its salt (measured by free test) from about 0.1 milligrams to about 10 units per kilogram of the total weight. T-Fine_The fifth aspect of the present invention 4 requires it Mammal provides-a treatment or prevention of atrial fiber A method of sexual tremor comprising ㈣ administering a mammal to a parenteral oral or parenteral dose ingesting from about ο 」mg to 1.0 g of N-[(l-n-butyl_4_hexahydropyridine) per kg of total body weight Base) 曱 Kib 3,4-difluorene-2H- [1,3]. Etc. and [3,2_aWh Do · 1〇_ formamidine (SB 207266) or a pharmaceutically acceptable salt thereof Class (measured as free base). ^ Π also provides butyl ceyl hexahydropyridyl) methyl] · 3, cardiodihydro-2Η- [1,3; K 耕 [3,2-a] indole_ 1_ Formamidine (SB 2007266) or its salt that can be used in X for treatment or prevention of atrial fibrillation in mammals (eg, humans). Oral or parenteral doses are from about 0.1 mg to 10 mg of SB 207 2 ^ or its salts (measured by free test) per kilogram of the total weight. In all aspects (first to fifth aspects) of the present invention, the daily oral or parenteral dosage intake is preferably from about 0.1 g to 1.0 g of SB 207266 per kilogram of total weight or The salt thereof is more preferably from about 0.2 mg / kg to 1.0 mg / kg, still more preferably from 0.3 to 1.0 mg / kg, for example, from about 0.5 mg / kg to 100 mg / kg. 10 15 20 23 This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) Please read the notes on δ before filling in this page. IIIII Repair 200425914 V. Description of invention (10 15 Ministry of Economic Affairs Wisdom Printed by the Property Bureau's Consumer Cooperatives. 20 More preferably, this hair contains oral or parenteral administration of δ0 mg of SB 207 266 bitumen: .50 gross or in a single dose once a day: salt male free test Setting). The daily dose can be ▲, β, VII, 14, or at the same or a different time, the small dose of the plate A, 旦, or 久 will be used in the day or night. , ° ”, which produces the specific agent in total. Therefore, the sixth aspect of the present invention provides N-[(l-n-butyl-4-hexahydroπ-ratio) methylphosphonium, 4- Dihydro_2Η · Π, 3M. The use of wells [3,2-aH 丨 Ή0-methyl amine (SB 207266) or its medicinal use, and the use of glutamate salts in the manufacture of pharmaceuticals For the treatment or prevention of atrial fibrillation in humans, by administering to humans an oral or parenteral (preferably oral) dose of 20 mg, 50 mg, or 80 grams of SB 207266 or Its salts (measured by free base). It is also provided to humans in need-a formula for the treatment or prevention of atrial fibrosis, which comprises administering to humans an oral or parenteral dose of 20 grams per day. ) 〇 2 grams or 80 mg of SB 207266 or its salts (measured as free base). It is also used for SB 207266 or its pharmaceutically acceptable salts to treat or prevent atrial fibrillation in humans. By administering to humans a daily oral or parenteral dose of 20 mg, 50 mg or 80 mg of SB 207266 or its salts (measured as free base). In all aspects of the invention, it is preferred that 5-HT4 receptor antagonists (eg, SB 207266 or a pharmaceutically acceptable salt thereof) are used / for symptomatic atrial fibrillation (AF), and / Or continuous or permanent (preferably permanent) AF patients. 24 (Please read the precautions on the back before filling out this page) This paper size applies to Chinese National Standard (CNS) A4 (210 X 297) (Mm) 200425914 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the invention (.) Yield of 50 g and / or 80 mg of human oral dose and about 0.2 g to 1 kg. The gross weight per kg is designed to minimize the cardiovascular and / or other side effects of administration such as 207266. Preferably, in all the methods of the present invention, drug treatment or prevention methods 5-5- HT4 receptor antagonists (such as SB 2007266 or a pharmaceutically acceptable salt thereof) are used to suppress the recurrence of atrial fibrillation symptoms in patients with persistent or permanent AF (preferably permanent af). Use of SB 2 07266 in patients with permanent AF ^ I fibrillation symptoms The preferred method of recurrence is detailed in Example 3 that follows. For use / administration of SB 207266, it is usually desirable to achieve a more rapid complete therapeutic response. To achieve this, it is believed that a larger loading dose may be used initially Such as: oral dose) of SB 207266 or its salts' to reach the therapeutic concentration more quickly. It has been found that: SB 207266 is a steady-state blood mass. The concentration is reached in one subsequent day for about 5 days, and the half-life is removed T1 / 2 is about 20-24 hours consistent. It is believed that this long time to reach steady state concentration is not ideal because of atrial fibrous facial movement / reconstruction, which has been converted (cardiac conversion) to general venous f sex rhythm continued. Patients with the AF phenomenon are more likely to reappear 17 soon after a heart switch. It is believed that the cumulative degree of one oral dose on the next day is about 5 times. Therefore, the application of SB 207266 is about 15 times the daily dose on the first day, which will surely cause the pseudo-stable plasma concentration to be reached immediately, and AF has a therapeutic advantage after cardiac conversion. The results of the preliminary population medical music dynamics model are shown in Figure 5, which shows the simulated SB 207266 plasma concentration versus time for two intakes (day 丨) 2 0 0 10 15 20 25 This paper scale applies the Chinese national standard (CNS ) A4 size (210 X 297 mm)
1 閱 背 面 之 注 意 事 項 再鲁重裝 頁I I I 訂 # 200425914 © A7 B7 10 15 r<··濟部智慧財產局員工消費合作社印製 20 五、發明說明(.. 克 '續以7天每天—次80毫克,對δ天每天一次80毫克)。 =圖5中的模擬指出接續15倍負載攝取之維持劑量, 心健康狀况以24小時更快速達到,因此減少對每—個病1 Read the precautions on the back and re-install the page III Order # 200425914 © A7 B7 10 15 r < ·· Printed by the Consumers 'Cooperatives of the Ministry of Economic Affairs and Intellectual Property Bureau 20 V. Description of the invention (.. 克' continued for 7 days a day— 80 mg once, 80 mg once daily for δ days). = The simulation in Fig. 5 indicates that after 15 times the maintenance dose of the load intake, the heart health condition is reached more quickly in 24 hours, thus reducing the effect on each disease.
遙測監視期間’同時在10%目標穩定狀態之内仍維持SB 2 0 7 2 66 ^聚濃度的最大值。以負載攝取可能減少遙測監視期 門θ心'。午病患《 %院内較早治療出院,伴隨著醫療花 病患方便的優點。 、 t這些理由’較佳的SB 2〇7266或其醫藥上可接受之鹽 Si:::用的負載劑量、約丨,2至約2·。倍(較佳約為 1…5至、.勺1 · 7 5倍,例士口 ·的1 $及、一 例如·約1·5倍)之每日維持劑量,並且 後在後續天數施用維持日劑量。 因此’在本發.明之所有觀點中,藥劑、方法或拮抗兩” 使用SB 207266或其鹽類的施用,在第―天的 γ 至約2.G倍之每日維持劑量,接著在後續天數施用SB2〇726 或其鹽類的維持曰劑量。較佳地,負載劑量是約1 ::=之每日維持劑量,更佳地約I.5倍之每日維持劑量 牧佳地,母日維持劑量包括每天σ服或非腸胃㈣量^ 發明之*五及/或六個觀點中所定義之劑量攝取。〆 用於人類口服施用之SR αΑ:/ 如下: β 2〇7266的兩個特佳口服組合物 26 本紙張尺度適用中國國家標準(CNS)A4規格(2i_〇 X 297公爱) 200425914 五、發明說明() SB-207266 /(政結晶纖維素 甘露糖醇 硬脂酸Mg 5·0亳克 30.0毫克 11 2.0毫克 3.〇亳克 S山 B,207266 微結晶纖維素hpmc ;殿粉二醇納 碟酸二舞 硬脂酸Mg 錠劑會 150亳克 5.0毫克 30.0亳克 1 2.5毫克 12.5亳克 1 67.5毫克 2.5亳克 250亳克 HPMO經丙基甲基纖維素 10 經濟部智慧財產局員工消費合作社印^ 15 第二個(右手邊)組合物的劑量可容易被增 第二個組合物是微粒化製程的結果。 所有的出版品包括但不限於:專利及專利申請書、在此說 明書所m都在此併於本文為參考,如果各出版品為特 定且個別被指出在此併於本文為參考,一如完全提出的。 現在本發明參考下列實例來敘述,其只為說明用並不 解釋為本發明之範疇的限制。一些實例以圖示來說明,其中 圖1標題為”5-HT4拮抗劑在心房纖維性顫動/心房重建 心房節律;方法—麻醉有心房模擬電極之迷你豬,,,顯示在. 你猪上用於實驗產生5-HT引發心房纖維性顫動及心房重建 之方法的流程輪廓,及根據實例i及2,其以5-HT4拮抗劑(S# 207266)治療; 圖2標題為”5-HT4拮抗劑在心房纖維性顫動/心房重建 心房節律;媒介物治療組(ηθ),,,顯示心房ERP的改變及口 快速心房節律及5-ΗΤ所引發/導致之心房纖維性顫動的 加到20毫克。 I I I 訂 # 27 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200425914 五、發明說明( 生’在媒介物治療組中有7隻迷你豬; 圖3標題為”5-HT4拮抗劑於心房纖維性顫動/心房重建/ 匕房節律;SB 207266治療組(n=7),,,顯示心房ERP的改變 及由快速心房節律及5-Ητ所引發/導致之心房纖維性顫動的 ^弘生,以SB 2〇726ό治療組中有7隻迷你豬; 圖4顯示在逑你豬上弘ητ所引發之心房纖維性顫動及心 房重建之方法流程輪廓的不同呈現版本,如實例2中所述; 及 圖5顯示為兩個攝取(第1天12〇毫克、續以7天每天一 10次80愛克,對8天每天一次80亳克)之模擬SB-207266血漿 濃度對時間作圖。 實例 SB 207266 -N-[(l’丁基-4-六氫吡啶基)甲基]-3,4-二氫 15 經濟部智慧財產局員工消費合作社印製 20During the telemetry monitoring period, the maximum value of the SB 2 0 7 2 66 concentration was maintained within 10% of the target steady state. Taking up with load may reduce the telemetry monitoring period gate θ '. Noon patients <% of patients discharged early in the hospital, accompanied by the advantages of convenient medical patients. For these reasons, the preferred SB 207266 or its pharmaceutically acceptable salt Si ::: is used in a loading dose of about 2 to about 2 ·. Times (preferably about 1 ... 5 to,. Spoon 1.75 times, for example, $ 1 and one, for example, about 1.5 times) daily maintenance dose, and then apply maintenance on subsequent days Daily dose. Therefore, 'in all viewpoints of the present invention, agents, methods, or antagonists' use the administration of SB 207266 or its salts at a daily maintenance dose of γ to about 2.G times on the first day, followed by subsequent days A maintenance dose of SB20726 or a salt thereof is administered. Preferably, the loading dose is a daily maintenance dose of about 1 :: =, and more preferably about 1.5 times the daily maintenance dose of Mujiadi, on the mother's day Maintenance doses include daily sigma or parenteral doses ^ Inventive * 5 and / or six doses as defined in the viewpoint. SR αA for oral administration in humans: / as follows: two special features of β 2 07266 Best oral composition 26 This paper size is applicable to Chinese National Standard (CNS) A4 specifications (2i_〇X 297 public love) 200425914 V. Description of the invention () SB-207266 / (Crystalline crystalline cellulose mannitol stearic acid Mg 5 0 g 30.0 mg 11 2.0 mg 3.0 g S B, 207266 Microcrystalline cellulose hpmc; Dianfen diol Nadisic acid digalo stearic acid Mg Lozenges 150 g 5.0 mg 30.0 g 1 2.5mg 12.5 亳 g 1 67.5mg 2.5 亳 g 250 亳 g HPMO via propyl methylcellulose 10 Ministry of Economy Wisdom The property bureau staff consumer cooperatives printed 15 15 The dose of the second (right-hand side) composition can be easily increased. The second composition is the result of the micronization process. All publications include but are not limited to: patents and patent applications, All of the descriptions herein are hereby incorporated herein by reference. If each publication is specific and individually identified herein and incorporated herein by reference, as if fully set forth. The invention is now described with reference to the following examples, which are merely The explanation is not to be construed as a limitation of the scope of the present invention. Some examples are illustrated graphically, in which FIG. 1 is titled "5-HT4 Antagonist in Atrial Fibrillation / Atrial Reconstruction Atrial Rhythm; Method-Anesthesia with Atrial Simulated Electrode Miniature pigs, are shown in the outline of the process on your pig for experimentally producing 5-HT-induced atrial fibrillation and atrial reconstruction, and according to Examples i and 2, it uses a 5-HT4 antagonist (S # 207266) treatment; Figure 2 titled "5-HT4 antagonist in atrial fibrillation / atrial remodeling atrial rhythm; vehicle treatment group (ηθ)," showing changes in atrial ERP and rapid atrial rhythm The atrial fibrillation induced / caused by 5-ΗΤ was increased to 20 mg. III Order # 27 This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200425914 V. Description of the invention There are 7 mini-pigs in the vehicle-treated group; Figure 3 is titled "5-HT4 antagonists in atrial fibrillation / atrial reconstruction / atrial rhythm; SB 207266 treatment group (n = 7), showing atrial ERP. Changes and atrial fibrillation induced / induced by rapid atrial rhythm and 5- 的 τ, Hongsheng, there are 7 mini pigs in the SB 20726 treatment group; Figure 4 shows the Different renderings of the atrial fibrillation and atrial reconstruction method process contours, as described in Example 2; and Figure 5 shows two ingestions (120 mg on day 1, continued 10 days a day for 80 days, 80 gram The simulated SB-207266 plasma concentration was plotted against time for 8 days once a day (80 g). Example SB 207266 -N-[(l'butyl-4-hexahydropyridyl) methyl] -3,4-dihydro 15 Printed by the Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs 20
請 先 閱 讀 背 之 注 意 事 項 再· 寫裝 本 · 頁I 一 I 1 I I I I 訂 嫌 I I -2H-[〗,3]噚畊並[3,2-a],引哚jo-甲醯胺-使用在引言中所敘述 之合成方法而製成。 貫例1-以SB 207266實驗心房纖維性顫動/心房重建的測試 結果 在5-HT-引發之心律不整的麻醉Yucatan迷你豬模式上, SB 207266之抗心律不整效力(0·3及1〇毫克/公斤,靜脈注 身ί )被評估AF的引發性。如圖1所示,在af引發之前,動 物以3小時的快速心房節律(200毫秒周期長度)而變得敏 感,並伴隨在心房模擬位置局部塗敷5_ΗΤ(4毫克/小時)。心 28 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200425914 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明() 房有效執构時間(八廣)及AF引發性在安排模 節律期間被測量。 子 在媒介及藥物治療的兩個組中,快速心房節律及5_H丁的 =敷造f EARP&丨11.6 土2.6至9〇.〇±2」毫秒的減少,在媒 )物或樂物塗敷之前—見圖1中的黑菱形(♦)及圖2中的左手 ‘長彳本圖。g 5-H丁被添加而無心房節律時,可見aerp的 較小減少-見圖1中的白菱形(◊)。如圖2及3中的右手邊長 =圖所示,由10個連續突然之節律(2〇亳秒周期長度的2秒 突發)所導致的前藥AF引發性(八[發生%)是穩定的,並且可 10再產生的(在圖2之媒介物組中為76±8、69±7、73±4%,n=7)。 如圖3所示’ SB-207266在心房節律及5-HT塗敷之後的 施用’導致AERP.之依賴劑量的增加,分別在ο」及ίο毫 克/公斤(對照於ρ<〇.〇1媒介物)下從9〇·1±2·7到1〇2.3土2.7及 Π0.0±3·6毫秒。同時,Af引發性在缺乏藥物下,分別在ο」 15 及1.〇毫克/公斤(ρ<0.01)下從64土6%減少到46±11及30 土 9%。 這些結果建議SB-207266在預防或治療由快速心房節律 導致之心房重建或AF上的具有有效性質,伴隨著選擇性心 房執抝(AERP長度)的延長。 20 實例2-用SB-207266之更詳細實驗心房纖維性顫動/心房重 建的測試結果 下列更詳細地敘述在上述實例1所產生之實驗步驟、、结 果及討論及結論。再次參照圖1 - 3及另外的圖4。 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公爱) Γ 清先閱讀背面之注意事項再填寫本頁) 裝 訂----- 華 200425914 @ Λ7 ___B7 _______ 五、發明說明() 貫例2 -材料及測試系統 #存。下列技術設備被用來進行此研究: (請先閱讀背面之注意事項再填寫本頁) •麻醉蒸發器:Boyle International 2,Medishield,Harlow, England 〇 5 ·人工呼吸泵:Model 613,Harvard,South Natick,MA, USA 〇 •加熱塾水栗:Model TP-420,Gaymar Industries,NY,US A。 •血液氣體分析計:ABL 500,Radiometer,Copenhagen NV, Denmark 〇 10 ·壓力轉換器:Model P23 ID,Gould Electronics,Cleveland, 〇H, USA。 ^ 樂物注射:B Braun Melsungen AG,Germany •電生理刺激器:S8800刺激器及SIU-5刺激器分離單元, Grass Instrument Co.,Quincy, MA,USA。 15 •圖表紙張紀錄器:TA-5000多元記錄器,Gould Electonics。 •數位帶紀錄器:DTR 1800 Biologic,Claix,France。 經濟部智慧財產局員工消費合作社印製 參勿。雄性Yacatan迷你豬(丨2-17公斤重)從Charles Rivei(Saint-Aubin les Elboeuf,France)獲得,並且在實驗之前 維持休息2週的環境適應。 20 喬翁的手街孝#。在25% 02及75% ΝΑ混合物中,在 以異氟甲氧氟烷吸入劑吸入(5%用於引發,續以0.5至1.5% 用於技術準備)的麻醉引發前,將迷你豬(Charles River, France)禁食並預先用藥(2毫克/公斤的氯甲笨基苯并二氮蕈 ί同2 1 - 8 + 1 5宅克/公斤的氯胺明,肌肉内)。長期麻醉以靜脈 30 本紙張尺度適用中國國豕標準(CNS)A4規格(210 X 297公釐) 200425914Please read the precautions in the back first · Written copy · Page I-I 1 IIII Order II -2H-[〖, 3] 噚 工 [3,2-a], Indole jo-methanamine-Use The synthesis method described in the introduction. Example 1-Test results of atrial fibrillation / atrial reconstruction with SB 207266 on the 5-HT-induced arrhythmia anesthetized Yucatan minipig model, the anti-arrhythmic efficacy of SB 207266 (0.3 and 10 mg / Kg, intravenous injection) was assessed for the initiation of AF. As shown in Figure 1, prior to af initiation, the animal became sensitive with a rapid atrial rhythm of 3 hours (200 millisecond cycle length), with local application of 5-MT (4 mg / hour) to the atrial simulation site. Heart 28 This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200425914 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention () Effective construction time of the house (Baguang) and AF priming is measured during the modal rhythm. In the two groups of vehicle and drug therapy, rapid atrial rhythm and 5_H D = dressing f EARP & 11.6 soil reduction of 2.6 to 90.0 ± 2 "milliseconds, in the application of vehicle or fun Before—see the black diamond (♦) in Figure 1 and the left-handed 'long 彳' picture in Figure 2. A small decrease in aerp is seen when g 5-H D is added without atrial rhythm-see white diamonds (◊) in Figure 1. As shown in the right-hand side lengths in Figures 2 and 3, the prodrug AF initiation (eight [occurrence%)) caused by 10 consecutive abrupt rhythms (2 second bursts with a period of 20 seconds) is Stable and reproducible 10 (76 ± 8, 69 ± 7, 73 ± 4%, n = 7 in the vehicle group of FIG. 2). As shown in Figure 3, 'Application of SB-207266 after atrial rhythm and 5-HT application' resulted in an increase in AERP-dependent doses at ο ″ and ίο mg / kg (compared to ρ < 0.01) medium Material) from 90.1 ± 2 · 7 to 102.3 ± 2.7 and Π0.0 ± 3.6 ms. At the same time, in the absence of drugs, Af priming decreased from 64 ± 6% to 46 ± 11 and 30 ± 9% at 15 ° and 1.0 mg / kg (ρ <0.01), respectively. These results suggest that SB-207266 is effective in preventing or treating atrial reconstruction or AF caused by rapid atrial rhythm, with prolonged selective atrial abscess (AERP length). 20 Example 2-More detailed test results of atrial fibrillation / atrial reconstruction using SB-207266 The following describes the experimental steps, results, discussions, and conclusions produced in Example 1 above in more detail. Refer to Figures 1-3 and Figure 4 again. This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 public love) Γ Read the notes on the back before filling in this page) Binding ----- Hua 200425914 @ Λ7 ___B7 _______ 5. Description of the invention ()例 2-Materials and test system # 存. The following technical equipment was used for this study: (Please read the notes on the back before filling this page) • Anesthesia Evaporator: Boyle International 2, Medishield, Harlow, England 〇5 Artificial Respiratory Pump: Model 613, Harvard, South Natick, MA, USA 〇 Heated Sorrel Chestnut: Model TP-420, Gaymar Industries, NY, US A. • Blood gas analyzer: ABL 500, Radiometer, Copenhagen NV, Denmark 〇 10 • Pressure converter: Model P23 ID, Gould Electronics, Cleveland, OH, USA. ^ Pleasure injection: B Braun Melsungen AG, Germany • Electrophysiological stimulator: S8800 stimulator and SIU-5 stimulator separation unit, Grass Instrument Co., Quincy, MA, USA. 15 • Chart Paper Recorder: TA-5000 Multiple Recorder, Gould Electonics. Digital recorder: DTR 1800 Biologic, Claix, France. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. Male Yacatan mini-pigs (weighing 2-17 kg) were obtained from Charles Rivei (Saint-Aubin les Elboeuf, France) and adapted to the environment by rest for 2 weeks before the experiment. 20 乔 翁 的 手 街 孝 #. In 25% 02 and 75% NA mixtures, mini-pigs (Charles) were primed before inhalation with an isoflurane inhaler (5% for initiation, followed by 0.5 to 1.5% for technical preparation). River, France) fasting and pre-medication (2 mg / kg chlorobenzylbenzodiazepine with 2 1-8 + 1 5 g / kg ketamine, intramuscular). Long-term anesthesia with veins 30 paper size applicable to China National Standard (CNS) A4 (210 X 297 mm) 200425914
五、發明說明(·) ^射輸入五(二乙基丙二基醯脲鈉(12毫克/公斤/小時)來維 =:機械式的通風口(Harvard泵613)在左胸廓切開期間被用 “疋ί、人工呼吸,以保持心房血液氣體及pH在正常限制产 、^ 刀析儀)。流體填充的導官被置於股骨動脈及靜脈 5 別測量動脈壓力(P23 ID轉換器)及藥物施用。心電圖之 導泉11 ΠΙ及心口的導線被安置用來監視標準ECG參數。 兩對包極被掛在左心房壁,用於後續刺激⑻刺激器及 SIU-5單元)並且用來測量心電圖。 10 15V. Description of the invention (·) ^ Radiation input penta (sodium diethylpropionyl sulfonium urea (12 mg / kg / hour) Levi == mechanical vent (Harvard pump 613) is used during left thoracotomy "疋 、, artificial respiration to keep the atrial blood gas and pH at normal limit production, anatomical analyzer). The fluid-filled guide is placed in the femoral artery and vein 5 Do not measure arterial pressure (P23 ID converter) and drugs The guide wire of the ECG 11 and the heart mouth were placed to monitor standard ECG parameters. Two pairs of envelops were hung on the left atrium wall for subsequent stimulation of the ⑻stimulator and SIU-5 unit) and used to measure the ECG 10 15
請 先 閲 讀 背 面 之 注 意 事 Η|裝 頁I \ 經濟部智慧財產局員工消費合作社印製 20 實例2-實驗步驟 心#盒·鱗的邊咸農廣。左心房附屬器官以快速心房節律 (3小時内200毫秒周期長度)敏感化而產生組織之起始電重 建[A· Goette 等人,丨996, C/rcw/如⑽,94, 2968-2974]。然後 5呢溶液(2小時内4毫克/小時,在心房節律結束之前30分 鐘開始)被局部地制,II著使用置於接近刺激電極的纖維貼 片。在易感狀態期間及恆定之局部塗敷5-HT之後,基線心 房執抝性及AF引發性被測量。 .嘗立逻岈龙。心房有效執抝時間(AERp)使用如前述[A. Bnl,B. G_ 等人,乂户細以以 276, 637_646] 之白用單一頜外刺激技術來測量。簡言之,短於靜脈竇 性節律之基本周期長度的8個刺激系列,續以單一過早額外 騎(4毫秒,丨.5倍起點電流),以漸次之較短偶合間隔從心 房即律引發’直到沒有獲得心房反應。A£Rp &表不能在組 織中引發傳播反應的最長偶合間隔。在AERp測量之後,心 31 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公爱) I 訂 # 200425914 經濟部智慧財產局員工消費合作社印製 五、發明說明(- 房纖料顫動(AF)異狀開始。AF被引發,續以2秒突發刺激 勺匕房即基本周期長度為20毫秒周期長度、2毫秒期間, 兩倍於心臟舒張基線)在易受傷窗期(AERp+]〇亳秒)導入。 AF被定義為在心電圖中測量到至少}秒的不規則電活性。 矸宏設診及齋#。在評估動物之可再現基線反應之後, 迷你豬被無規騎指定來獲得經消毒的^水(媒介物組, P7)或漸增劑量之SB_207266(〇 3及1〇毫克/公斤,ny),在 測疋AERP及後續之AF刺激前的15分鐘,在超過1〇分鐘 的時間内以靜脈注射。SB-2〇7266溶解於經消毒的蒸餾水中 並且每天被製備成足量的給與藥物溶液。用媒介物治療代表 蒸餾水的體積類似用於藥物溶液的體積(1 〇毫升)。每劑的 SB-207266以45分鐘的間隔被施用,以容許動物從先前的突 發節律刺激中回復。指出該方法之主要時間點的簡要流程在 圖1及4中呈現。 之▲裘虞肩的穿佐。對每一個AF刺激而言, 在藥物的施藥(a寺間點1 5分鐘)及離心(1 500 X g,;[ 〇分鐘、4 C下)結束之後,5分鐘的血液樣本被收集於EDTA(6%)中。 該血漿樣本被儲存在-80°C做後續分析。在媒介物組中不收集 血漿樣本。在豬的此5毫微克/毫升的分析方法中,SB-207266 的血漿濃度測定是以LC/MS/MS與LLQ來進行。 實例2-資料處理及分析 廣/#及診禀。所有的參數在圖紙多用紀錄器(TA-5000)上 監測,並且在整個方法(DTR 1 800)中進行數位化記錄。當測 請 先 閱 讀 背 之 注 意 事 項 再 填 寫 本 頁 裝 10 15 20 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公爱)Please read the notes on the back of the book first. Page I \ Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 Example 2-Experimental steps Left atrial appendages are sensitized with rapid atrial rhythm (200 millisecond cycle length in 3 hours) to generate initial electrical reconstruction of tissue [A · Goette et al., 996, C / rcw / Rugao, 94, 2968-2974] . Then the 5? Solution (4 mg / h in 2 hours, which started 30 minutes before the end of the atrial rhythm) was made locally, and a fiber patch placed near the stimulation electrode was used. Baseline atrial adherence and AF priming were measured during the susceptible state and after constant local application of 5-HT. . Try Liluo Xiaolong. The atrial effective hold time (AERp) was measured using the single extramaxillary stimulation technique described in [A. Bnl, B. G. et al., 276, 637_646]. In short, 8 stimulation series shorter than the basic cycle length of sinus rhythm, continued with a single premature extra ride (4 milliseconds, 丨. 5 times the starting current), with rhythm from the atrium at successively shorter coupling intervals Raise 'until no atrial response is obtained. A £ Rp & indicates the longest coupling interval that cannot trigger a propagation response in the tissue. After the AERp measurement, the paper size of the paper is applicable to the Chinese National Standard (CNS) A4 (210 X 297). Order # 200425914 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. (AF) abnormality begins. AF is triggered, followed by a 2-second burst stimulation. The basic cycle length is 20 milliseconds, and the period of 2 milliseconds is twice the baseline of diastole. In the vulnerable window period (AERp +) 〇 亳 second) import. AF is defined as irregular electrical activity measured in the electrocardiogram for at least} seconds.矸 宏 Setup and Zhai #. After assessing the animal's reproducible baseline response, the mini-pigs were randomly assigned to obtain sterilized water (vehicle group, P7) or increasing doses of SB_207266 (03 and 10 mg / kg, ny), 15 minutes before the measurement of AERP and subsequent AF stimulation, intravenous injection was performed for more than 10 minutes. SB-2〇7266 is dissolved in sterilized distilled water and prepared into a sufficient amount of a drug administration solution every day. Treatment with vehicle represents a volume of distilled water similar to that used for drug solutions (10 ml). Each dose of SB-207266 was administered at 45 minute intervals to allow animals to recover from previous burst rhythm stimulation. A brief process that indicates the main time points of the method is presented in Figures 1 and 4. ▲ Qiu Yu's shoulder wear. For each AF stimulus, a 5-minute blood sample was collected at the end of the drug application (15 minutes at a temple) and centrifugation (1,500 X g; [0 minutes, 4 ° C]). EDTA (6%). The plasma samples were stored at -80 ° C for subsequent analysis. No plasma samples were collected in the vehicle group. In this 5 ng / ml analysis method for pigs, the plasma concentration of SB-207266 was determined using LC / MS / MS and LLQ. Example 2-Data processing and analysis All parameters are monitored on the drawing multi-purpose recorder (TA-5000) and digitally recorded throughout the method (DTR 1 800). When you are testing, please read the memorandum items on the back and fill in this page. 10 15 20 This paper size is applicable to China National Standard (CNS) A4 (210 X 297).
I I I I I訂 • I I # 200425914 經濟部智慧財產局員工消費合作社印製 Α7 Β7 五、發明說明Γ .) 量時’心臟速率從ECG計算並且平均心房血壓從脈搏麗力來 計算。經修正之QT根據巴賽特(Bazzet,s)s[QTc=QT(毫 秒)/RR(秒1/2)]來測定。AF引發性以從10個連續突發獲得之 反應百分比來表示’並且在10個突發刺激順利期間所記錄的 5 AF現象平均時間,是以秒表示。 巍診分#。該值以平均土SEM來表示。比較是使用變數 分析(ANOVA)、續以紐曼-庫斯(Newman-Keuls)試驗做多重逐 對比較而進行的。對突發刺激反應的AF引發性使用庫斯卡-瓦利斯(Kruskal-Wallis)排行總和試驗來分析。所有的統計是 10使用統計5.1釋出套裝軟體(StatSoft,Inc.,Tulsa,〇K,USA) 來進行。 實例2-結果 在迷你赭上的5 - HT引發心房纖維性顫動。良化辕式今, 15在局部塗敷5-HT之前進行為期3小時之快速心房節律的進 行為必要的,以在心房組織上產生足夠的電子重建,來方便 對突發刺激反應之AF發生。為此目的,研究不同干預的影 響-包含單獨的快速心房節律、單獨的5-HT、及節律與5-HT 兩者組合-對AERP的改變。在快速心房節律(200毫秒基本周 20 期長度)3小時之後,AERP被大大地從11 〇·7±4·6毫秒減少到 93.6±3.6毫秒(η=7 ; ρ<0.01)。單獨給予5-ΗΤ做為局部施用3 小時不會大大地改變AERP(104.0±6.5毫秒相對於控制組的 1 1 〇.2±1.9毫秒,n二6)。在快速心房節律之後5-HT的施用不會 導致AERP的再大大減少,其為91.8土3.3毫秒(與節律單獨的 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) ------------装-------訂------ !!# (請先閲讀背面之注意事項再填寫本頁) 200425914 A7 B7 @ 五、發明說明(·) 93.6±3,6毫秒比較)。見圖!之圖示及在圖2之左手邊長條圖。 (請先閱讀背面之注意事項再填寫本頁) 如在圖2之右手邊長條圖中所顯示的,在被加以快速心 房節律及同時施用5-HT的豬身上,在媒介物治療組中所進 行料續AF刺激㈣AF穩定及可再現的引發性(從十個突 5發節律中有71土5%的正面反應,而範圍是在5個刺激中有69 至·74〇/。)。所測量之對突發節律反應的Αρ ;見象平均時間為 2=0.5秒(範圍為! .2至6 7秒)’並且在連續af刺激期間為 穩定的,如下表1所示。 經濟部智慧財產局員工消費合作社印製 SB-207266在5-HT引發之AF上的影響、故盔消秦的綠 10身上靜脈注射漸增劑量之SB-207266(0,3及L0亳克/公斤), 引發AERP依賴劑量地從前藥值9〇±3亳秒分別增加到^^及 1.〇毫克/公斤(P<0.01相對於媒介物)的1〇2土3及11〇±4亳种 在施用1.0毫克/公斤SB-207266之後,由快速心房節律毛力:上。 5-H丁施用所導致之AERp的減少被完全恢復(見圖3左手透 15長條圖時,AF弓1發性之劑量相關的減少被觀察到,^ 在〇.3耄克/公斤(p=〇.139相對於媒介物)下,從治療前 64±6%減少到46±11%,及在毫克/公斤({3<〇〇1)下減少到 30±9%(見圖3右手邊長條圖)。af現象的平均時間是稍微作 值付注意地從樂物治療前的i 9±〇 4秒,減少到在〇·3毫 20公斤SB·207266施用之後(Ρ<〇.〇5相對於媒介物)的丨二〇: 秒。在較高劑量下觀察到AF平均時間無進一步的 : 下表1所示。 如 的▲袭瀵彦。在每—次SB_2〇7266藥劑鈇 之後5分鐘所收集的血漿樣本中,測量sb_2〇7266的噗 34 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐)' -----__ 200425914 在媒介物治療及SB-207266治療之動物之間的比較 A7 _ B7__ 五、發明說明()I I I I I order • I I # 200425914 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Α7 Β7 V. Description of the invention Γ.) The heart rate is calculated from the ECG and the average atrial blood pressure is calculated from the pulse force. The corrected QT is measured according to Bazzet, s) [QTc = QT (milliseconds) / RR (seconds 1/2)]. AF initiation is expressed as a percentage of response obtained from 10 consecutive bursts' and the average time of 5 AF phenomena recorded during the smooth burst of 10 bursts is expressed in seconds.巍 Diagnostic 分 #. This value is expressed as an average soil SEM. Comparisons were made using multiple analysis of variables (ANOVA), followed by Newman-Keuls tests, for multiple pairwise comparisons. AF priming to sudden stimulus responses was analyzed using the Kruskal-Wallis ranking sum test. All statistics were performed using the statistical release 5.1 software package (StatSoft, Inc., Tulsa, OK, USA). Example 2-Results 5-HT on the mini-condyle caused atrial fibrillation. For the benign sacrifice, 15 a 3-hour rapid atrial rhythm is necessary before topical application of 5-HT to generate sufficient electronic reconstruction on the atrial tissue to facilitate the occurrence of AF in response to sudden stimulation . To this end, the effects of different interventions—including separate rapid atrial rhythms, 5-HT alone, and a combination of both rhythm and 5-HT—are studied for changes to AERP. After 3 hours of rapid atrial rhythm (200 milliseconds of basic cycle 20 periods), AERP was greatly reduced from 110.7 ± 4.6 ms to 93.6 ± 3.6 ms (η = 7; ρ < 0.01). Administration of 5-ΗΤ alone as a topical application for 3 hours did not significantly change the AERP (104.0 ± 6.5 milliseconds versus 1 1 0.2 ± 1.9 milliseconds of the control group, n = 6). The application of 5-HT after rapid atrial rhythm does not cause a significant reduction in AERP, which is 91.8 to 3.3 milliseconds (this paper size is separate from the rhythm and applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm)- ----------- Install ------- Order ------ !! # (Please read the notes on the back before filling this page) 200425914 A7 B7 @ 五 、 Explanation of the invention (·) 93.6 ± 3, 6 ms comparison). See picture! The diagram and the bar graph on the left-hand side of Figure 2. (Please read the precautions on the back before filling this page) As shown in the bar graph on the right-hand side of Figure 2, on pigs that have been treated with rapid atrial rhythm and given 5-HT at the same time, in the vehicle treatment group Continuing AF stimuli were carried out. AF was stable and reproducible priming (71 to 5% positive responses from ten bursts of 5 rhythms, and the range was 69 to · 74% in 5 stimuli.). The measured Aρ of the sudden rhythm response; the average time of the image is 2 = 0.5 seconds (range: .2 to 67 seconds) 'and is stable during continuous af stimulation, as shown in Table 1 below. The impact of SB-207266 printed on 5-HT-induced AF by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, and the increasing dose of SB-207266 (0,3 and L0 g / Kg), causing the AERP-dependent dose to increase from the prodrug value of 90 ± 3 sec to ^^ and 1.0 mg / kg (P < 0.01 vs. vehicle) of 10 ± 3 and 11 ± 4 分别, respectively. After applying 1.0 mg / kg of SB-207266, this species was determined by rapid atrial rhythm hair power: up. The reduction in AERp caused by 5-H D administration was completely restored (see Figure 3, left-hand penetrating 15 bar graph, a dose-related reduction in AF arch 1 primary dose was observed, ^ 0.3 g / kg ( p = 0.139 vs. vehicle), from 64 ± 6% to 46 ± 11% before treatment, and to 30 ± 9% at mg / kg ({3 < 0.001) (see Figure 3 Bar graph on the right-hand side). The average time of the af phenomenon is slightly changed from i 9 ± 〇4 seconds before the treatment of the animal to the reduction of 0.3 mm 20 kg after SB · 207266 administration (P < 〇 .05 relative to the vehicle): 20: seconds. At the higher doses, no further average AF time was observed: shown in Table 1 below. As shown by ▲ 瀵 瀵 彦. In each SB_2〇7266 agent In the plasma sample collected 5 minutes later, 噗 34 of sb_2〇7266 was measured. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) '-----__ 200425914 Comparison between SB-207266 treated animals A7 _ B7__ V. Description of the invention ()
I 度。SB-207266的血漿濃度在0.3耄克/公斤sb-207266下被 觀察為137.7 土15.2愛微克/堂升(n=6)並且達到562 3土40 1毫 微克/毫升(n=5)。 5表】由快速心房節律及5在迷你豬上所導致之現象 的平均時間 (10 媒介物 毫升藥 劑) 丄 SB-207266 (愛克/公斤,靜脈注射) 控制 媒介 媒介 前藥 0.3 1.0 AF時間(秒) 2.5土0. 5. 2.9±0. 8 2.1±0. 3 1.9±〇. 4 1.1±0·2 1·1±0·4 P值對 媒介物 前藥 NS NS NS ρ<0.05 ^Ρ<0.05 ρ<0.05 ρ<0.05 NS:不明顯 10 實例2-Μ拾 本研九的結不:綠示.5 - ΗΤ與快速心房節律比較,顯示對 .AERP最小的影響。在山羊中,已經顯示快速心房節律引發 AERP的時間立刻減少(生理速率適當作用)並且此減少進一 步隨時間觀察[M.C.E.F. WUffels 等人,C,rci//如⑽,ι997, %, 15 j7 1 0~3720]。我們的結杲提供確定快速心房節律是足以獲得 AERP的穩定減少。另外,我們的結果顯示%Ητ單獨或在快 速心房節律存在下的5-ΗΤ施用少量地改變AERp。此建 議:5-HT不直接牽涉到電生理機構而導致Αρ,但是可能在 AF上扮演相當的促進角色。 35 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) -----------裝--- (請先閱讀背面之注意事項再填寫本頁) 訂--- 經濟部智慧財產局員工消費合作社印製 200425914 η A7 B7 五、發明説明 (請先閲讀背面之注意事項再填寫本頁) 雖然5-HT對AERP及AF的發生引發最小的影響,5-ΗΤ\ 受體结抗劑S Β -207 266的施用避免/抑制(或反轉)AERP的減 少,並且以劑量依賴的方式保護免於AF引發性。這些結果 顯示與藥物的血漿濃度相關。這些結果建議:5-HT4受體的抑 5 制’例如:以施用S B - 2 0 7 2 6 6,出現會導致心房纖維性顫動的 結果° 實例2-結論 SB-207266已顯示大大地反轉由組合快速心房節律及局 10 部施用5-HT所導致的AERP減少,並且大大地減少AF現象 的發生。這些結果建議:SB-207266及5-HT4受“拮抗劑通常 會在減少/治療心房纖維性顫動上有效,與心房ERP之回復 (增加)相關的特色為在5-HT及心房節律存在下所觀察到的 心房電重建的反轉。 15 在實例2(及也在實例1)中所述之SB-207266的結果出現 來說明治療或預防心房重建及/或心律不整-如:心房纖維性顫 動-的新穎方法,是籍著施用/使用5-HT4受體拮抗劑,如在 此所述的任何化合物。 經濟部智慧財產局員工消費合作社印製 20 實例3-使用口服施用SB-207266來治療或預防人類心房纖維 十生顫動及/或心房重建的方法 使用SB-207266或其鹽類來治療或預防心房重建及/或心 房纖維性顫動的目前較佳方法現在詳述。 此方法敘述對有症狀持續性心房纖維性顫動(AF)之病患 36 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ 297公釐) 200425914 A7 經濟部智慧財產局員工消費合作社印製 五、發明說明() 施用SB-207266或其鹽類(此後稱為,,SB 2〇72 一 ϋ )。目的是抑 k些有m AF之病患的心房纖維性顫動症狀再發生。 小時及<6個月的期間有症狀持續性AF而需要:律轉 變法(例如:DC心律轉變法)的病患為適當的。持續性八^ = 症狀可包括例如:心悸等。較佳地病患具有: •在開始治療之前有治療性抗凝血劑(例如:肝素週; *在缺乏治療性抗凝血劑d週時,其具有經食管的回 聲心動描記法(TEE),對凝血為不反應(negative),並 且接受靜脈注射肝素,直到PTT為穩定並且在治療範 圍内。 民于、了暑脈/主射肝素之外’較佳地是在此治療性凝血劑之 後或在TEE之後,接受SB 207266病患。 SB 2072 66(例如:為游離鹼,但更佳是sb 207266-A的豐 酸鹽)通常施用的曰口服劑量為20亳克、50毫克或80毫克 uid(以游離驗測量)。然而,在施用SB 207266的第1天,通 常施用單一口服負載劑量為1.5倍(1.5x)之分配的每日維持 治療劑量。因此較佳地,單一口服負載劑量在第1天是給予 3〇毫克、75毫克或120毫克,續以在後續天數的20亳克、 5〇毫克或80毫克的每曰劑量。 在弟一天施用口服SB 207266負載劑量為l.5x的兩小時 之後,仍有心房纖維性顫動(及/或藥理上不心律轉變)的病患 較佳地進行直流電(DC)心律轉變法。可續以下列單或雙相 的心律轉變法規則系統。 10 15 20 電擊數 單相的 37 }紙張尺錢射_家標準(CNS)A4規格(21〇 X 297公釐) (請先閱讀背面之注意事項再填寫本頁) 200425914I degrees. The plasma concentration of SB-207266 at 0.3 μg / kg sb-207266 was observed to be 137.7 ± 15.2 μg / Dil (n = 6) and reached 562 ± 40 1 μg / mL (n = 5). Table 5] The average time of the phenomenon caused by rapid atrial rhythm and 5 on mini-pigs (10 vehicle ml of medicine) 丄 SB-207266 (Ag / kg, intravenous injection) Control medium prodrug 0.3 1.0 AF time ( Seconds) 2.5 soil 0.5. 2.9 ± 0. 8 2.1 ± 0. 3 1.9 ± 0. 4 1.1 ± 0 · 2 1 · 1 ± 0 · 4 P value vs. vehicle prodrug NS NS NS ρ < 0.05 ^ P < 0.05 ρ < 0.05 ρ < 0.05 NS: Not obvious 10 Example 2-M The results of Jiu Jiu Jiu: Green indicates .5-ΗΤ compared with rapid atrial rhythm, showing minimal effect on .AERP. In goats, it has been shown that the time for rapid Atrial Rhythm to trigger AERP is immediately reduced (a proper effect of physiological rate) and this decrease is further observed over time [MCEF WUffels et al., C, rci // Rugao, 997,%, 15 j7 1 0 ~ 3720]. Our scabs provide confirmation that rapid atrial rhythm is sufficient to obtain a stable reduction in AERP. In addition, our results show that% Ητ alone or in the presence of fast atrial rhythms of 5-ΗΤ administration slightly alters AERp. This suggestion: 5-HT is not directly involved in the electrophysiological mechanism and causes Αρ, but may play a considerable promoting role in AF. 35 This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) ----------- install --- (Please read the precautions on the back before filling this page) Order- -Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, 200425914 η A7 B7 V. Description of the invention (please read the notes on the back before filling this page) Although 5-HT has the smallest impact on the occurrence of AERP and AF, The administration of HT \ receptor antagonist S B -207 266 avoids / inhibits (or reverses) the reduction of AERP and protects it from AF-priming in a dose-dependent manner. These results appear to be related to the plasma concentration of the drug. These results suggest that the 5-HT4 receptor is inhibited by, for example, SB-2 0 7 2 6 6 and results in atrial fibrillation will occur. Example 2-Conclusion SB-207266 has been shown to significantly reverse The combination of rapid atrial rhythm and 5-HT administration of 5-HT resulted in a reduction in AERP and greatly reduced the occurrence of AF. These results suggest that SB-207266 and 5-HT4 suffer from "antagonists that are generally effective in reducing / treating atrial fibrillation. The characteristics associated with the recovery (increasing) of atrial ERP are characterized by 5-HT and atrial rhythm Observed reversal of atrial electrical reconstruction. 15 The results of SB-207266 described in Example 2 (and also in Example 1) appear to illustrate the treatment or prevention of atrial reconstruction and / or arrhythmias-such as atrial fibrillation -A novel method for the administration / use of 5-HT4 receptor antagonists, such as any of the compounds described herein. Printed by the Consumer Cooperatives of the Intellectual Property Office of the Ministry of Economic Affairs 20 Example 3-Treatment with oral administration of SB-207266 Or methods for preventing atrial fibrillation and / or atrial reconstruction in humans. The presently preferred method of using SB-207266 or its salts to treat or prevent atrial remodeling and / or atrial fibrillation is now described in detail. Patients with Symptoms of Persistent Atrial Fibrillation (AF) 36 This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 200425914 A7 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Description of the invention () Administration of SB-207266 or its salts (hereinafter referred to as, SB 2072). The purpose is to suppress the recurrence of atrial fibrillation symptoms in patients with m AF. Hours and < Six-month period of symptomatic persistent AF is needed: patients with a rhythm change method (eg: DC heart rhythm change method) are appropriate. Persistent eighth = symptoms may include, for example, palpitations, etc. Preferably disease The patient has: • a therapeutic anticoagulant (eg, heparin week) before starting treatment; * in the absence of therapeutic anticoagulant d week, it has transesophageal echocardiography (TEE), Non-negative, and receive intravenous heparin until PTT is stable and within the therapeutic range. It is preferred that after the summer vein / main heparin 'is after this therapeutic coagulant or after TEE Patients receiving SB 207266. SB 2072 66 (eg, free base, but more preferably sb 207266-A salt) is usually administered at an oral dose of 20 mg, 50 mg, or 80 mg uid (as free (Experimental measurement). However, on the first day of SB 207266 administration, usually A single oral loading dose of 1.5 times (1.5x) the assigned daily maintenance therapy dose is administered. Therefore, preferably, a single oral loading dose is 30 mg, 75 mg, or 120 mg on day 1 and continued on subsequent days Daily doses of 20 g, 50 mg, or 80 mg. Two hours after oral administration of a SB 207266 loading dose of 1.5x a day, there is still atrial fibrillation (and / or pharmacological arrhythmia) ) Patients preferably undergo a direct current (DC) rhythm shift. It can be continued with the following single or biphasic heart rate change rule system. 10 15 20 Number of electric shocks Single-phase 37} Paper rule money shot_Home Standard (CNS) A4 size (21〇 X 297 mm) (Please read the precautions on the back before filling this page) 200425914
ίο 15 經濟部智慧財產局員工消費合作社印製 20 若病患在使 成正常的靜脈竇性節律(nsr),醫生可在:;不反轉 处吾推π 4卜i W生j在其考慮下以不同的 月匕 丁 V的嘗試。成功的心律_鐵、、i: # Μ & μ 持Μ小時。 佯牦义法被疋我為NSR維 接著成功的D C心律轉變法失Μ ς; p > 4 ςβ 9η7,„ 手铒义法為NSR之後,對病患施用 可—天—次地連續6個月(舉例l·或較短或較長的 』門自動反轉成正常靜脈竇性節律(NSR)的那些病电也可 接受一天一次的sb 2〇7266(例如%個月。在此每日治^期間 有AF再發生經驗的病患可以Dc心律轉變_靜脈賽性節 律,並且可繼續接受SB-207266。 較佳地病患在整個SB 207266施用期間必須繼續抗凝血 的治療(例如:肝素)。 因此最佳的方法如下: 症狀持續性AF,在M8小時及<6個月的期間,治療性抗凝 血23週 或 對凝血+靜脈注射肝素的tee(-) 施用SB-207266(負載劑量) DC心律轉變法(若必要) 38 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 裝--------訂i n ·ϋ n n en fli I # i請先閱讀背面之注意事項再填寫本頁) 200425914 Α7 Β7 五、發明說明( 繼續每日的SB-207266 -較佳地也用肝素,例如:6個月 “症狀性再發生的”AF包括或意 甘π —… ~主7 ’内患一股為心悸至 其他症狀的現象。可由ecg( 牛捸☆ % V線的ECG)紀錄進一 7遷立’頭不心房纖維性顫動的證櫨 μ 據或在現象紀錄裝置」 斤5己錄的律動帶,並且可視情況由醫生檢閱。 經濟部智慧財產局員工消費合作社印製 對s-ht4 $體括抗劑活性及SB 2〇7266活性的測試 1)天竺鼠結腸 此動物模式敘述於Wardle KA及Sanger Gj(1993) Br. Pharmacol; 110 1 593-1599。 使用重量250-400公克的雄性天竺鼠。縱向地肌肉腸> 層之胸邛以下的準備約3公分長,從末梢結腸區域獲得。 些以0.5克負載懸浮於包含克伯斯(Krebs)溶液、以〇2中 )% c〇2冒泡的分離組織浴中,並且維持在37t:T。在所: 的貫驗中,克伯斯(Krebs)溶液也包含甲硫西平(methi〇thepi 10莫耳;辰度、葛蘭尼斯酮(gramsetron) 1 〇-6莫耳濃度,以) 20礙5'HTi、5-HT2及5-HT3受體的影響。 在以5-HT建構簡單的濃度反應曲線之後,使用3〇秒— 觸時間及1 5分鐘的劑量周期,5_ht濃度的選擇是獲得肌j 的收縮最多約40-70%(約1(Γ()莫耳濃度)。然後該組織每] 刀釦以此5-ΗΤ濃度來投藥。在一些實驗中,此組織被另〕 10 15 39 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注意事項再填寫本頁) -裝--------訂--- 200425914 A7 〇 ___Β7 _ 五、發明說明() 以約相等有效濃度的尼古丁受體刺激物-二甲基苯基哌嗜 (DMPP)-濃度來投藥。在獲得對5_HT(及適當DMPP a寺)一致 的反應之後’然後添加增加的推定5_HT4受體拮抗劑的濃度 到浸冷之;谷液中。然後以5-HT或以DMPP引起收縮之百分 5比減少來測定此化合物的效果。由此資料中,pIC5G值被測 疋’被疋我為減少收、纟话5 0 %之括抗劑_ 10g濃度。減少對5 _ht、 但非對DMPP之反應的化合物被相信作用為受體拮抗 劑。 S B 2 0 7 2 6 6具有特別良好的活性。 10 在5-HT]、5-HT2及5-HT3受體拮抗劑存在下,5-HT產生 單相膽驗能為媒介的收縮’其特徵在於pECw為 90±0·06(η=14)。增加 SB- 207266-A(SB 207266 的 HC1 鹽類) 濃度(1(Τ1(Μ(Τ8莫耳濃度,11=6)產生5_HT曲線平行向右的移 動,對隶大反應歷影響。視pA2為ι〇·4土0.1,斜率與一無書 15大差別。在車父咼7農度(3χ 1 〇-8莫耳濃度及之上)時,對5-ϋ丁的 最大反應以依賴濃度的方式被減少。SB- 207266-Α的此結果 不是由於局部麻醉的作用,或在膽鹼能受體的直接拮抗作 用’因為WMPP引起的收縮(一種尼古丁受體拮抗劑,其引 起乙盤基膽素釋出及因此之毒菌鹼受體媒介的收縮)甚至在 20南濃度(1Q〇莫耳濃度)之化合物下未被影響。 SB- 207266-A也被測試對抗由5-HT4受體部分拮抗劑 BIMU 1引發之收縮。在這些實驗中,sB- 207266-A減少對 BIMU 1的最大反應,而不導致在濃度反應曲線上之前述向 右移動。 本紙張尺度適用中國國家標準(CNS)A4規格(21〇 x 297公釐) -----------裝---------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 200425914 A7 v B7 五、發明説明() 以SB- 20726 6-A觀察到之明顯不可超越的活性,不是由 於5-HT4受體之不可逆阻礙,因為SB_ 2〇7266_A的拮抗效果 (請先閱讀背面之注意事項再填寫本頁) 可在沖刷時反轉。在最高濃度(其減少5七丁引起的最大收縮) 時,對5-HT的反應在90分鐘内回復。此型態與可逆的拮抗 5 劑一致。 2)小豬的心房 化合物的自動跳動篩選在小豬心房上被測試 [Namiyn-Schmiedeberg^s Arch Pharmacol,324:619- 622]。 當與5-HT單獨之控制曲線比較時,SB_ 2〇7266-Α(1〇_7 l〇莫耳濃度)移動該曲線到右邊,而在最大反應上有明顯的減 少。估計之SB- 207266-Α (SB 207266的鹽酸鹽)估計的 pKh(-logI0Kb)為 1〇·ι(η=2)。 3)老鼠的食道 經濟部智慧財產局員工消f合作社印製 老鼠食道timica肌肉黏膜根據 Baxter等人 ]5 Naunyn-Schmiedeberg^s Arch Pharmacol.?343, 349-446(1991) 來建立。内部平滑肌管的肌肉黏膜被分離並且在37。〇下被固 疋在經氧化(96%〇2/5%C〇2)之泰羅德(Tyr〇des)溶液中,做等 體積張力記錄。所有的實驗在巴吉林(pargyHne)前處理準備 (1 00微莫耳濃度、1 5分鐘,續以沖刷)中進行,並且是在古 20柯驗(30微莫耳濃度)的存在下。對5-HT的緩和劑反應在以 碳酸膽鹼(3微莫耳濃度)前收縮食道組織之後獲得。 在碳酿膽鹼收縮準備時,5-HT產生依賴濃度的緩和, pEC5。為8.1±〇·〇3(η二18)。對照於天竺鼠結腸的模式,其中 5-ΗΤ4受體有神經座落,在此之受體是座落在平滑肌上。在 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 經濟部智慧財產局員工消費合作社印製 200425914 A7 B7 五、發明說明() 老鼠食道的準備上,依賴SB-207266-A濃度是作用為不可超 越的拮抗劑,並減少由5-HT引起之最大反應。因為 S B - 2 0 7 2 6 6 - A抑制最大反應’其不可能測量可靠的p A〗估計。 然而’以表低有效SB-207266-A濃度所得的貢料與pA?2lO.O 5 —致。以SB-207266-A做為5-HT4受體拮抗劑的高選擇性觀 點而言(見前述天竺鼠所分離之結腸的資料及後續的輻射配 體鍵結選擇性分析),可能的是:明顯不可超越的拮抗是由於 來自受體之化合物的緩慢分解。此發生是因為在老鼠食道上 的低5-HT4受體反轉及SB-207266-A相對於5-HT本身之對 10 5-HT4受體的高親和力。 4)對小豬海馬趾5-HT4受體的鍵結 SB-207266-A對小豬海馬趾5-HT4受體的親和力從125I-標不之5-HT4受體结抗劍SB-2077 1 0的抑制來測量[Brown AM, Young TJ? Patch TL? Cheung CW, Kaumann AJ, Gaster 15 LM 及 King FD (1 993),Br J Pharmocol; 1 1 0,1 OP]。此輕射配 體對小豬海馬趾薄膜具有高親和力(KD = 86±11兆分之一莫耳 農度’ Bmax= 16±3毫兆分之一莫耳/毫克(11=4)),同時在 5-HT!a、5-HTic 及 5-HT2 受體時 SB-207710 的 pKi 為 6 或更 低。另外,5-HT3-選擇性配體葛蘭尼斯酮(granisetron)抑制 20 I;1251]-SB-207710鍵結於海馬趾piQ低於5,指出在此準備上 輻射配體對5-HT3受體之可忽視的鍵結。在此系統中,5-HT 以中度親和力鍵結於5-HT4受體(pi為6.6±0.1(n = 9))。 SB-207266-A抑制125l·標示之SB-2077 10的鍵結,ΡΙ^值為 9·4 8±0.06(η = 3),該值是稍微低於pA2/pKB估計值,是由在其 42 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) ----------------- (請先閱讀背面之注意事項寫本頁) 訂: 線 200425914ίο 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 If the patient is making a normal sinus rhythm (nsr), the doctor can: at the non-reversal point, I will push π 4 i 生 生 生 生 生 生 生 在Let's try with different moon dagger D. Successful Heart Rhythm_Iron, i: # Μ & μ Holds M hours. The righteous method was taken for the NSR dimension, and the successful DC heart rhythm conversion method was lost. P; p > 4 ςβ 9η7, „After the manual righteous method is NSR, the patient can be administered 6 consecutive days—days—seconds. Months (for example, those with shorter or longer gates that automatically reverse to normal sinus rhythm (NSR) can also accept sb 207266 once per day (eg,% months. Here daily Patients with AF recurrence experience during treatment can have Dc heart rhythm change_venous rhythm and can continue to receive SB-207266. Preferably, patients must continue anticoagulant therapy throughout the administration of SB 207266 (for example: Heparin). Therefore the best method is as follows: Symptoms of persistent AF, during the period of M8 hours and <6 months, therapeutic anticoagulation for 23 weeks or tee (-) for coagulation + intravenous heparin SB-207266 (Loading Dose) DC Heart Rhythm Transformation Method (if necessary) 38 This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) Packing -------- Order in · ϋ nn en fli I # i Please read the notes on the back before filling out this page) 200425914 Α7 Β7 V. Description of the invention (continued daily SB-207266-Heparin is also preferred, for example: 6-month "symptomatic recurrence" AF includes or intentionally π-... ~ main 7 'symptoms of heart palpitations to other symptoms. Can be ecg (Bud 捸 ☆% V-line ECG) Recording of the 7th 'Erecting of the atrial fibrillation of the head's micro-mu or according to the phenomenon recording device "5 kg recorded rhythmic bands, and can be reviewed by a doctor if necessary. Ministry of Economic Affairs Testing of s-ht4 $ body anti-agent activity and SB 207266 activity printed by the Intellectual Property Bureau employee cooperatives 1) Guinea pig colon This animal model is described in Wardle KA and Sanger Gj (1993) Br. Pharmacol; 110 1 593 -1599. Use male guinea pigs weighing 250-400 grams. Longitudinal muscle intestine > layer of chest sacral preparations about 3 cm long, obtained from the peripheral colon area. These are suspended in a 0.5 gram load containing Krebs (Krebs ) Solution, separated tissue bath bubbling at 0.02% CO2, and maintained at 37t: T. In the test, the Krebs solution also contains methiothepine (methiothepi 10 mol; chendo, gramsetron 1 -10-6 mol concentration, to 20) 5'HTi, 5-HT2 and 5-HT3 receptors. After constructing a simple concentration-response curve with 5-HT, using a 30 second-touch time and a 15-minute dose cycle, the choice of 5-ht concentration is to obtain a maximum contraction of muscle j of about 40-70% (about 1 (Γ ( ) Moore concentration). Then the tissue was administered at this 5-ΗΤ concentration. In some experiments, this tissue was treated separately.] 10 15 39 This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back before filling out this page) -Installation -------- Order --- 200425914 A7 〇 ___ Β7 _ V. Description of the invention () Nicotine at approximately equal effective concentration Receptor stimulant-dimethylphenyl piperazine (DMPP)-concentration to be administered. After obtaining a consistent response to 5_HT (and appropriate DMPP a), then increase the concentration of the putative 5_HT4 receptor antagonist to immersion Cold; in the valley fluid. Then measure the effect of this compound with 5-HT or 5% reduction in shrinkage caused by DMPP. From this data, the pIC5G value was measured. Concentration of 50% of the inhibitor _ 10g. Compounds that reduce the response to 5 ht but not to DMPP are believed to act as Antagonists. SB 2 0 7 2 6 6 has a particularly good activity. 10 In the presence of 5-HT], 5-HT2 and 5-HT3 receptor antagonists, 5-HT produces a single-phase bile energy-tested contraction 'It is characterized by pECw of 90 ± 0 · 06 (η = 14). Increasing the concentration of SB-207266-A (HC1 salt of SB 207266) (1 (Τ1 (Μ (Τ8mol concentration, 11 = 6) produces 5_HT The movement of the curve parallel to the right has an effect on Lida's response calendar. According to pA2 as ι0.4 · 0.1, the slope is significantly different from that of a book without a book. In Chevron 7 farming (3χ 1 〇-8 Molar concentration and (Above), the maximum response to 5-amidine is reduced in a concentration-dependent manner. This result of SB-207266-A is not due to the effects of local anesthesia or direct antagonistic effects on cholinergic receptors' because of WMPP Induced contraction (a nicotine receptor antagonist that causes the release of ethidium choline and therefore the contraction of the muscarinic receptor mediator) is not affected even at 20 min (1 mol) SB-207266-A has also been tested against contraction induced by the 5-HT4 receptor partial antagonist BIMU 1. In these experiments, sB-207266-A reduced the effect on BIMU 1 The maximum response without causing the aforementioned shift to the right on the concentration response curve. This paper size applies the Chinese National Standard (CNS) A4 specification (21 × 297 mm) ----------- pack- -------- Order --------- (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 200425914 A7 v B7 V. Description of the invention ( ) The apparently insurmountable activity observed with SB-20726 6-A is not due to the irreversible obstruction of the 5-HT4 receptor, but because of the antagonistic effect of SB_ 2〇7266_A (please read the precautions on the back before filling this page) Reversed during flushing. At the highest concentration (which reduces the maximum contraction caused by pentamidine), the response to 5-HT recovers within 90 minutes. This pattern is consistent with the 5 reversible antagonists. 2) Piglet's atrium Automated beating screening of compounds was tested on piglet atrium [Namiyn-Schmiedeberg ^ s Arch Pharmacol, 324: 619-622]. When compared with the control curve for 5-HT alone, SB_2077266-A (1_7-10 Molar concentration) shifted the curve to the right, with a significant decrease in maximum response. The estimated SB-207266-A (hydrochloride of SB 207266) has an estimated pKh (-logI0Kb) of 10 · ι (η = 2). 3) Rat's esophagus Printed by the staff of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed by the cooperative. Mouse esophagus timica muscle mucosa was established according to Baxter et al. 5 Naunyn-Schmiedeberg ^ s Arch Pharmacol.? 343, 349-446 (1991). The muscular mucosa of the internal smooth muscle tube was isolated and at 37. It was solidified at 0 ° C in an oxidized (96% 02/5% CO2) Tyrodes solution, and an equal volume tension record was made. All experiments were performed in the preparation of pargyHne (100 micromolar concentration, 15 minutes, continued with scouring), and in the presence of the ancient 20 Ke test (30 micromolar concentration). The moderator response to 5-HT was obtained after contracting the esophageal tissue with choline carbonate (3 micromolar concentration) before. In the preparation of choline choline, 5-HT produces a concentration-dependent relaxation, pEC5. It was 8.1 ± 0.03 (η-2 18). In contrast to the guinea pig colonic pattern, the 5-ΗΤ4 receptor has a neural locus, where the receptor is located on smooth muscle. This paper scale applies Chinese National Standard (CNS) A4 specifications (210X 297 mm) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 200425914 A7 B7 V. Description of the invention () The preparation of rat esophagus depends on SB-207266-A Concentration acts as an insurmountable antagonist and reduces the maximum response caused by 5-HT. Because S B-2 0 7 2 6 6-A inhibits the maximum response, it is impossible to measure a reliable estimate of p A. However, the tribute material obtained at a table with a low effective SB-207266-A concentration is consistent with pA? 2lO.O 5. From the perspective of the high selectivity of SB-207266-A as a 5-HT4 receptor antagonist (see the data of the colon isolated from the guinea pig and the subsequent selective analysis of radiation ligand binding), it is possible that: Insurmountable antagonism is due to the slow breakdown of the compounds from the receptor. This occurs because of the low 5-HT4 receptor inversion in the mouse esophagus and the high affinity of SB-207266-A to 5-HT itself for 10 5-HT4 receptors. 4) Bonding to piglet hippocampal 5-HT4 receptor SB-207266-A has affinity for piglet hippocampal 5-HT4 receptor from 125I-standard 5-HT4 receptor knot anti-sword SB-2077 1 0 [Brown AM, Young TJ? Patch TL? Cheung CW, Kaumann AJ, Gaster 15 LM and King FD (1 993), Br J Pharmocol; 1 1 0, 1 OP]. This light-emitting ligand has a high affinity for piglet hippocampal membranes (KD = 86 ± 11 molons of Mulnon 'Bmax = 16 ± 3 mol / mg (11 = 4)), SB-207710 has a pKi of 6 or lower at the 5-HT! A, 5-HTic, and 5-HT2 receptors. In addition, the 5-HT3-selective ligand granisetron inhibits 20 I; 1251] -SB-207710 binds to the hippocampus piQ below 5, indicating that the preparation of the radiant ligand to 5-HT3 is affected by this preparation. A negligible bond. In this system, 5-HT is bonded to the 5-HT4 receptor with a moderate affinity (pi is 6.6 ± 0.1 (n = 9)). SB-207266-A inhibits the bond of 125l·labeled SB-2077 10. The value of PI ^ is 9 · 4 8 ± 0.06 (η = 3), which is slightly lower than the estimated value of pA2 / pKB. 42 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ----------------- (Please read the precautions on the back first and write this page) Order : Line 200425914
Q A7 B7 五、發明說明(‘) 他組織中官能性反應的拮抗性所測得。5)SB-207266-A(SB 207266之HC1鹽)在試管中的選擇性 SB-207266-A已經在各種非5#丁4受體鍵結方法中被評 估。結果顯不於下表中。在老鼠胃基底的官能性研究顯示: 5 5-ΗΤ2Β受體的親和力為7 47。清楚地對5_ΗΤ4受體有超過其 他被測試受體幾次方大的選擇性。 受體鍵結研究 pKd 5-HT1A <5.00 5-HT1d <5.00 5-HT1e <5.00 5-HT2A 5.89 5-HT2C 5.57 5-HT3 5.94 αΐ <5.52 d2 5.63 d3 5.53 GABA >5.00 BDZ >5.00 Hi 5.40 鸦片劑K (pK〇>6 鶴片劑μ (pK〇>6 鴉片劑δ (ρΚ丨)>6 6)在狗胃袋中之5· -ΗΤ引發的能動性 化合物以活體中的方法被測試抑制性,該方法被敘述,, 以BRL24924的狗能動性刺激-新的胃前動力劑(Stimulati〇n ----I-----1--1 · 1 I (請先閱讀背面之注意事項^^本頁) •線 經濟部智慧財產局員工消費合作社印製 10 of canine motility by BRL 24924, a new gastiic prokmetic agent)-, Bermudez 等人,J. Gastr〇lntestinal M〇tillty, 1990,2(4),281-286。 有先前準備海德漢(Heidenhain)胃基底的狗,被隔夜禁 良對每隻狗也進行剑述之的5-HT劑量範圍研究,以確 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公楚) 200425914 A7 經濟部智慧財產局員工消費合作社印製 五、發明說明(,) 定引起的最小靜脈注射劑量,該劑量為在緊張度及相型之胃 收縮上可再現之膽驗能媒介的增加,通常為5或1〇微克仏 斤。對每一個實驗而言,5_HT 1乂 3〇分鐘的間隔被靜脈注射 施用。在兩個一致的反應之後’拮抗劑被靜脈注射、或在第 5三次注射5-HT前15分鐘以每次口服的膠囊投藥。 在靜脈注射及每次口服,^_2〇7266_八依^劑量對5七丁 的收縮反應為抬抗的[ID5〇對靜脈注射為(信任限度為 οκό)微克/公斤、對每次口服為96(信任限度〇 7_叫微 斤。再者’抓則—在任何时下對基底的能動性 是無影響的。對5-HT!、5-fTT β ς υτ - 1 5ΗΊΓ2及5_ΗΤ3χ體拮抗劑沒有一致 性或重大的影響。 SB 207266-Α作用期間是在靜脈注射劑量之後被測量。 在較低劑量1及3微房斤時,該料是可變的並且明顯可 逆的,同時在1〇及1〇〇微克/公斤下,拮抗性維持大於實驗 期間(2 8 5分鐘)。 7)在經麻醉之小豬上的拮抗性 在k些貝驗中,_ :>-HT引起之心跳過速的拮抗性被評 估反C疋纟5-HT4叉體來媒介的。所有的實驗是2_5天大 的小緒’其中逑走神經被切除。SB-2〇726"(sb 2〇7266的 HC1鹽)劑量為0.卜〇 3或1〇微克/公斤以靜脈注射給予,以 依賴劑量的方式(每組㈣结抗5·Η 丁引起之心跳過速。在大 大引“匕:)-HT4叉體媒介之5·ΗΤ效果的劑量下(0.3、U微 克/公斤,靜脈注射),在實驗期間之拮抗性回復不完全。 10 15 20 ----------------- (請先閱讀背面之注意事項寫本頁) •線- 44 200425914 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明() 對抗焦慮劑活性之活體測試 對老鼠之社交作用的測試 老鼠(雄性 ’ Sprague Dwaleys,Charles River,250、3〇〇 克) 以一組八隻被豢養於保持室中5天。然後其在實驗日前被單 5獨豢養於鄰近實驗室的小室中4天。在實驗當日,老鼠被成 對地(n=8-1 6)施以媒介物、測試化合物或苯並二氮雜輩抗焦 慮劑、利眠寧(chlordiazepoxide)、每次口服,是從上午1 〇點 開始、1 5分鐘間隔。3 0分鐘之後,其以重量相配的(第—次 相遇)成對被置於分開室的社交作用箱中。該箱是由白色柏司 10 佩有機玻璃(PersPex)所製成,54公分x37公分x26公分,有 透明的柏司佩有機玻璃為前側且無蓋。地板被分成24個正方 形,並且該箱被明亮地照明[115勒克斯(lux)]。活潑的社交行 為(準備 '聞嗅、上下攀爬、跟隨、咬、騎及擊鬥)以下面! 5 分鐘的遙控錄影監視來盲目地評分,產生總社交分數。被每 一支老鼠經過的正方形數目也被評分並加總。在每一個測試 結束之後,該箱被小心地包裝。 在施用 SB-207266-A(SB 207266 的 HC1 鹽)(0.01、1、10 堂克/公斤)觀祭到總社交分數大大地增加。此效應的大小是 有點小於chloriazepoxide (CDP ; 5毫克/公斤、每次口服) 20的正面控制組,但是不是很顯著。SB-207266-A在測試期間 不伴隨著任何移動的變化,並且因此與抗焦慮性一致。 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注意事項ί寫本頁) -裝Q A7 B7 V. Description of the invention (‘) Measured against the antagonism of functional responses in other tissues. 5) Selectivity of SB-207266-A (HC1 salt of SB 207266) in test tubes SB-207266-A has been evaluated in various non-5 # but 4 receptor binding methods. The results are not shown in the table below. A functional study on the gastric basal of the mouse showed that the affinity of the 5-5-TT2B receptor was 7 47. It is clear that the 5_ 大 Τ4 receptor has several selectivities over the other tested receptors. Receptor Bonding Study pKd 5-HT1A < 5.00 5-HT1d < 5.00 5-HT1e < 5.00 5-HT2A 5.89 5-HT2C 5.57 5-HT3 5.94 αΐ < 5.52 d2 5.63 d3 5.53 GABA > 5.00 BDZ > 5.00 Hi 5.40 opiate K (pK〇> 6 crane tablet μ (pK〇)> 6 opiate δ (ρΚ 丨) > 6 6) 5 · -ΗΤ-induced active compound in a dog's stomach pouch to live The method was tested for inhibition, and the method is described to BRL24924 Dog Motility Stimulation-A New Progastric Motive (Stimulati〇n ---- I ----- 1--1 · 1 I (Please Read the notes on the back ^^ this page first) • Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Online Economy 10 of canine motility by BRL 24924, a new gastiic prokmetic agent)-, Bermudez et al., J. Gastrointestinal M〇 tillty, 1990, 2 (4), 281-286. Dogs with previously prepared Heidenhain stomach bases were subjected to overnight 5-HT dose range studies on each dog to confirm Paper size applies to China National Standard (CNS) A4 (210 X 297 Gongchu) 200425914 A7 Employees ’Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs System V. Description of the invention The minimum intravenous dose caused by () is the increase of reproducible energy testing media in tension and phase-type gastric contraction, usually 5 or 10 micrograms. For each experiment, 5-HT was administered intravenously at an interval of 1.30 minutes. After two consistent responses, the 'antagonists were injected intravenously, or 15 minutes before the 5th injection of 5-HT in each oral dose. Capsule administration. In the intravenous injection and each oral administration, the dose of ^ _2〇7266_ 八 依 ^ is the anti-contractive response to the 57-butadiene [ID5〇 for intravenous injection (the limit of trust is οκό) μg / kg, for each The number of times of oral administration is 96 (the limit of trust 〇7_ is called micro-pounds. Furthermore, 'grasping rules — has no effect on the motility of the substrate at any time. For 5-HT !, 5-fTT β ς υτ-1 5ΗΊΓ2 and 5_ΗΤ3χ body Antagonists have no consistent or significant effects. SB 207266-A duration of action is measured after intravenous doses. At lower doses of 1 and 3 μl, the material is variable and significantly reversible, while at the same time At 10 and 100 μg / kg, the antagonistic resistance remains large During the experiment (285 minutes). 7) Antagonism on anesthetized piglets In the shellfish test, the antagonism of _: > -HT induced tachycardia was evaluated against C 疋 纟 5-HT4 prongs. All experiments were small threads 2 to 5 days old in which the vagal nerve was removed. SB-2〇726 " (HC1 salt of SB 2〇7266) was administered at a dose of 0.03 or 10 micrograms / kg by intravenous injection, in a dose-dependent manner (caused by anti-? Cardiac tachycardia. The antagonistic recovery was incomplete during the experiment at a dose that significantly induced the effect of the "Η:)-HT4 prostaglandin medium (0.3, U micrograms / kg, intravenously). 10 15 20- ---------------- (Please read the notes on the back to write this page first) • Line-44 200425914 Printed by A7 B7, Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs ) Tests on the social effects of mice on in vivo testing of anxiolytic activity (Male 'Sprague Dwaleys, Charles River, 250, 300 g) A group of eight was housed in a holding room for 5 days. Then it was tested in the experiment A few days ago, sheets 5 were kept alone in a cell adjacent to the laboratory for 4 days. On the day of the experiment, mice were administered in pairs (n = 8-1 6) with vehicle, test compound or benzodiazepine anxiolytic agent, Limianning (chlordiazepoxide), taken orally each time, starting at 10:00 am with 15 minute intervals. 3 0 After the clock, they are matched in weight (the first encounter) in a social function box in a separate room. The box is made of white Perth 10 plexiglass (PersPex), 54 cm x 37 cm x 26 Cm, with transparent Perspex plexiglass as the front side and no cover. The floor is divided into 24 squares, and the box is brightly illuminated [115 lux]. Lively social behavior (prepare to 'sniff, climb up and down , Follow, bite, ride and fight) below! 5 minute remote video surveillance to blindly score to generate a total social score. The number of squares passed by each mouse is also scored and added up. At the end of each test After that, the box was carefully packaged. After applying SB-207266-A (HC1 salt of SB 207266) (0.01, 1, 10 donations / kg), the total social score was greatly increased. The magnitude of this effect was a bit Positive control group less than chloriazepoxide (CDP; 5 mg / kg orally) 20, but not very significant. SB-207266-A was not accompanied by any changes in movement during the test and was therefore consistent with anxiety This paper scale applicable Chinese National Standard (CNS) A4 size (210 X 297 mm) (Please read the notes ί write back of this page) - loaded
Claims (1)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0019410A GB0019410D0 (en) | 2000-08-07 | 2000-08-07 | Novel use |
GB0019524A GB0019524D0 (en) | 2000-08-08 | 2000-08-08 | Novel use |
GB0019523A GB0019523D0 (en) | 2000-08-08 | 2000-08-08 | Novel use |
Publications (1)
Publication Number | Publication Date |
---|---|
TW200425914A true TW200425914A (en) | 2004-12-01 |
Family
ID=37515827
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW90119097A TWI298022B (en) | 2000-08-07 | 2001-08-06 | Pharmaceutical compositions for the prophylaxis or treatment of atrial remodeling or atrial fibrillation |
TW93114682A TW200425914A (en) | 2000-08-07 | 2001-08-06 | Pharmaceutical tablet composition comprising n-[(1-nbutyl-4-piperidinyl)methyl]-3,4-dihydro-2h-[1,3]oxazino[3,2-a]indole-10-carboxamide (sb 207266) or a salt thereof |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW90119097A TWI298022B (en) | 2000-08-07 | 2001-08-06 | Pharmaceutical compositions for the prophylaxis or treatment of atrial remodeling or atrial fibrillation |
Country Status (3)
Country | Link |
---|---|
AR (2) | AR030136A1 (en) |
MY (1) | MY138979A (en) |
TW (2) | TWI298022B (en) |
-
2001
- 2001-08-06 TW TW90119097A patent/TWI298022B/en not_active IP Right Cessation
- 2001-08-06 TW TW93114682A patent/TW200425914A/en unknown
- 2001-08-07 AR ARP010103782A patent/AR030136A1/en unknown
- 2001-08-07 MY MYPI20013703 patent/MY138979A/en unknown
-
2004
- 2004-06-16 AR ARP040102089 patent/AR046493A2/en unknown
Also Published As
Publication number | Publication date |
---|---|
AR046493A2 (en) | 2005-12-14 |
TWI298022B (en) | 2008-06-21 |
AR030136A1 (en) | 2003-08-13 |
MY138979A (en) | 2009-08-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20060293309A1 (en) | Method of treating disorders and conditions using peripherally-restricted antagonists and inhibitors | |
EA030093B1 (en) | Capsule formulation of pirfenidone and pharmaceutically acceptable excipients | |
TW200522981A (en) | Immediate-release formulation of acid-labile pharmaceutical compositions | |
JPH0733331B2 (en) | Analgesic and anti-inflammatory compositions comprising diphenhydramines | |
TW201136916A (en) | New uses | |
AU703242B2 (en) | Film coated tablet of paracetamol and domperidone | |
TW200815010A (en) | CGRP antagonists | |
PT1355631E (en) | Oral fast-melt formulation of a cyclooxygenase-2 inhibitor | |
MXPA04012659A (en) | Use of mglur5 antagonists for the treatment of gerd. | |
US20070292498A1 (en) | Combinations of proton pump inhibitors, sleep aids, buffers and pain relievers | |
JPS59501459A (en) | Improved analgesic and anti-inflammatory compositions comprising caffeine and methods of use thereof | |
TW200304384A (en) | Pharmaceutical composition | |
US20080161307A1 (en) | Organic Compounds | |
EA015483B1 (en) | Use of a p38 kinase inhibitor for treating psychiatric disorders | |
US6008222A (en) | Method for oral administration of buspirone and nefazodone | |
CN107530335A (en) | New pharmaceutical use | |
JPH05509293A (en) | Use of 5-HT4 receptor antagonists in the treatment of arrhythmias and seizures | |
JP2011517678A (en) | Use of udenafil and a combination of alfuzosin or oxybutynin for the treatment of overactive bladder | |
JP5925862B2 (en) | Methods and compositions for treating serotonin receptor mediated conditions | |
CN100413539C (en) | The use of 5ht4 receptor antagonists in the prophylaxis or treatment of certain cardiovascular conditions | |
TW200425914A (en) | Pharmaceutical tablet composition comprising n-[(1-nbutyl-4-piperidinyl)methyl]-3,4-dihydro-2h-[1,3]oxazino[3,2-a]indole-10-carboxamide (sb 207266) or a salt thereof | |
WO2021014370A1 (en) | Pharmaceutical composition for use in the treatment and prevention of motion sickness | |
US20050089558A1 (en) | Compositions and methods for the co-formulation and administration of tramadol and propoxyphene | |
CN102512389B (en) | Fexofenadine hydrochloride oral disintegrating drug composition | |
JP5468351B2 (en) | Oral pharmaceutical composition |