TWI298022B - Pharmaceutical compositions for the prophylaxis or treatment of atrial remodeling or atrial fibrillation - Google Patents

Description

1298022 A7 ______B7 V. INSTRUCTIONS (II) The present invention relates to the use of certain compounds for the treatment or prevention of certain cardiovascular diseases such as atrial reconstitution, and the use of a particular dose and/or dose of the compound for treatment or The use of preventing atrial fibrillation. 5 Introduction Atrial fibrillation (AF) is the most commonly encountered arrhythmia in a clinical setting. It is a major hazard of embolic stroke and is accompanied by an increase in the risk of death. AF (the symptoms can include atrial palpitations, etc.) is a disease caused by a trigger, such as: atrial ectopic beating (irregular heart in mega) or 10 atrial tachycardia (irregular beating), and The interaction of the matrix, such as: the heterogeneity of the interstitial space or the conduction blockage of the anatomical location. Fibrillation consists of a stimulating wavefront passing through a continuous circular path around the atrium. Once stimulated, the atrial organization spends some time to revert to its state of being able to be stabbed again. This time is called, and the time of retreat (refraOtory peri〇d), (AERp=atrial has 15 effective days Shoujian). Therefore, if the stubborn time is greater than the stimulus wavefront cycle through 360. The time, the wavefront encounters non-irritating, obsessive "substance, and fibrillation will stop, the heart returns to the sinus rhythm. Otherwise, the Af wave proceeds, and then enters", and continues atrial fibrosis Quivering, sometimes almost endless. Patients with paroxysmal AF usually develop chronic (continuous or permanent) af. When 20 is interdependent with the above initiators and substrates, the contributing factors are attributed to the progression and persistence of the disease. Promoters known as atrial remodeling are caused by changes in various structural, cellular, electrophysiological, and neuronal mediators that occur after the AF phenomenon. Antiarrhythmic drugs usually work in part by increasing the time of atrial stagnation and/or reducing the atrial, conduction speed (condllction vel〇clty), or both of these paper sizes for the Chinese National Standard (CNS). A4 size (210X297 mm) —--------- (Please read the note on the back and fill out this page) Customs Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1298022 A7 ______ _B7_ V. Invention Description ( 3>) The force increases the atrial wavelength, and thus reduces the number of re-entry waves, and alleviates/reduces AF. Studies in AF patients have shown that structural/tissue changes occur in the atrium that tends to have AF, but the structure The relationship between reconstruction and chronic arrhythmia is not fully understood. The change is mainly related to adaptation (cell morphology digestion of cardiomyocytes) and maladaptation (cell degeneration with alternative fibrillation). Quivering means, for example, an increase in connective tissue. Atrial expansion and/or enlargement can also occur. These structural changes are general, not often, during prolonged continuous AF. Observed. (See: Thijssen vl et al., CaWv still c· 10 h/ 2000-month_February; 9(1): 17-28; and Janes mj, five (10) ·/1997 May; 18 Suppl C: C12-8 On the other hand, in one study, in the context of persistent atrial fibrillation, important left atrial and left atrial episodic organ function and tissue reconstruction (eg, expansion) were found to be one or The outcome of two-month persistent atrial fibrillation, while the class I5 appears to be a period of heparin anticoagulant experience experienced by patients prior to selective cardioversion (Weigiler MJ et al., November 1999) 82(5): 555-8). Atrial reconstruction is a method of producing mechanical and cellular changes (structural/tissue changes) in the atria and/or electrophysiological (electrical) changes in the atria, usually The results of AF development, although atrial reconstruction is not always the result of atrial fibrillation, that is, it is not an inevitable result, especially in paroxysmal AF patients (see: Thijssen VL et al., Card/vaw corpse) Ίί/ζο/ 2000 — Month-February; 9(1): 17-28; Tse HF and Lau CP C//« 五又/? 尸/2少57〇/ 1998 May; 25(5): 293-302; Lau CP and Tse HF, C7/m heart/7 corpse // 3^/0/ 1998 May; 25(4): 293-302; Lau CP and Tse 4 This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) l·--.------- (Read first Precautions on the back of the page, please fill out this page) Order d Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1298022 15 A7 V. Invention Description (+) HF et al. 'Clin Exp Pharamacol Physiol,\99Ί 12V 24(12). 981 7 . I. and Janes MJ // Jean 々·/ 1997 May; 18 Suppl d12*"8, atrial fibrillation and atrial reconstruction to review). These changes generally tend to be sustained AF. The structural/organizational changes have been as described above. Electrophysiological (electrical) atrial reconstruction referred to herein includes or means: a) changes in atrial attentive time (AERp) or atrial obstruction (especially reduction); b) changes in the rate of adaptation of the time of attachment ( For example, the general rate of adaptation disappears such that the rate of withdrawal of the heart rate is not as prolonged as expected; and/or c) changes in the action potential (eg, shortening of the period, changes in morphology, etc.). Preferably, electrophysiological (electrical) atrial reconstruction means a change in atrial remnant time (AERP) or atrial obstruction (especially reduction). Remotely, electrical atrial reconstruction may also include changes in atrial conduction velocity and/or changes in dispersion (especially increase), such as: dispersion of the pull 7 . "Dispersion, is the difference in the size of one or more electrical phenomena, such as: the time between the tissue close to the region (for example: AERP). In humans and pigs, ' 5-HT4 receptors are present in the atria. (see for example: aj

Kaumann et al., Naunyn, Schmiedeberg, s Arch Pharmacol (1990).

324:619-622 ; A.J. Kaunmann et al Br J

Pharmac〇l (1990) 100: 879-855). The subclass of 5-HT4 receptor (5_HT4a) has recently been identified as specific for human atrial and porcine atrium (〇. Blondel et al., FEBS Letters, 412, 1997, pp. 465-474). This 5-HT4A receptor is not present in the ventricles. For a general name for the 5-HT receptor, see: D· Hoyer,

Neu ropha rmac ο l ogy, 1997, 36(4/5), 419 〇 WO 91/16045 (SmithKline Beecham) reveals that cardiac 5-HT4 receptor antagonists can be used to treat arrhythmia and reduce the incidence of stroke. This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public meals) --I I--------------------II (please read the notes on the back first) Fill in this page again) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 20 1298022 A7 B7 V. Invention Description (iT) WO 93/1 8036 (SmithKline Beecham) reveals a large number of condensed p-inducing compounds, as 5-HT4 In vivo antagonists, including: Ν-[(], butyl-4-hexahydropyridyl)methyl]-3,4-dihydro-2H-[1,3;K, Example 3 on pages 17-18 Plow [3,2-a]吲哚-10-carboamine (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, particularly irritating intestinal disorders. WO 93/18036 also states in general terms in general terms on pages 6-7: "Specific cardiac 5-HT4 receptor antagonists, which avoid atrial fibrillation and other 5-HT-related arrhythmia, are also expected to be reduced The occurrence of a stroke." See also US 5,852,014, EP 0 884 319 10 A2, LM Gaster et al, X Med CT^m·, 1995, 38, 4760-4763 and Drugs of the Future, \99Ί, 22(\2) for SB 20Ί266, ::1325-1332, its high selectivity to the 5-HT4 receptor is over the 5-HT receptor. (The potency and selectivity of SB207266 is also shown by the 5-HT4 receptor antagonist, and the selectivity test results are presented later in this patent application). For an improved synthesis of 15 SB 207266, see WO 98/07728, WO 98/11067, WO 00/03983, and WO 00/03984. The structure of SB 207266 is as follows: First read the back of the note and fill in this page. I I I I I Department of Economics, Intellectual Property Bureau, Staff, Consumers, Co-operatives, Printing

20 Other 5-HT4 antagonists are disclosed in w〇94/27965 (Syntex) and this paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1298022 A7 B7 Ministry of Economic Affairs Intellectual Property Office staff consumption Co-operative printing 5, invention description (6) One of these compounds: RS 100302 (R〇che), its name is n_(2-(4_(3-ammonyl-7-chloro-2,3-dihydro- 1,4-benzodioxanyloxypropyl)hexahydropyridinyl-ethyl)-methanesulfonylguanamine is recommended to be effective in treating atrial fibrillation and atrial fibrillation in porcine models. (Μ·μ·Rahme et al., C/rc·"/Add/(10), 1999, 100 (19), 2010-2017). Other 5-HT4 antagonists are disclosed in rd Clark et al., 10,000/.oorg C7/c, 1994, 4(20), 2481-4; Clark, supra, 1995, 5(18), 2119-2122 (eg: RS100235). 'WO 93/05038 (SmithKline 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-aminochloro-1,4-benzene And after the end of the _5-reposted acid (1-butyl-4-hexahydroindole) methyl ester. For the hydrochloride salt of this compound (sb 204070-A) see L. M. Gaster et al., J. Med C//em. 1993, 36, 4121-4123. Other 5-HT4 antagonists disclosed in WO 93/05038 include SB 207710 [8-amino-7-iodo-1,4-benzodioxan-5-carboxylic acid (1-butyl-4- Hexahydropyridyl)methyl ester] and its hydrochloride as shown in Example 52; and SB 205800 [N-(Bubutyl-4-hexahydropyridinyl)methyl-8-amino-7-chloro -1,4-benzodioxan-5-formamide, as shown in Example 14. The structure of SB 204070, SB 207710 and SB 205800 is as follows: 10 15 20

(Please read the notes on the back and fill out this page.) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1298022 A7 B7 V. Invention Description (γ) SB 204070 SB 207710 SB 205800 Rev. 5 Other SmithKline Beecliam publications of the HT4 antagonist include WO 93/16072, WO 94/10174, WO 94/27987, WO 5 95/04737 ° GR 1 13808, which is named 1-methyl-1H_吲哚-3 -carboxylic acid (1-(2-((methylsulfonyl))amino)ethyl)-4-hexahydropyridyl)methyl ester or [1-(2-[(methylsulfonyl)]amino] Ethyl)-4-hexahydropyridyl]methyl-methyl-1H-indole-3-carboxylate, another potent and selective 5-HT4 antagonist from Glaxo 10 Wellcome. GR 125487 Is 5-fluoro-2-methoxy-1H-,-3-carboxylic acid [1-[2-[(methyl sulphate)amino]ethyl]-4-hexahydropyridine methyl ester, Another potent and selective 5-ΗΤ4 antagonist: its pKi at the 5-ΗΤ4Α and 5-ΗΤ3Α receptors = 10.0 and <6.5 respectively. For GR 113808 and GR 125487, see: Grossman et al., Br 1994, 111, 332; EP 15 501322 A1 and EP 501322 B1. For GR 1138 08 See Example 1 of EP 501322 B1, and for the examples of GR 125487 and its hydrochloride, methanesulfonate and maleate, see Examples 12, 21 and 22 of EP 501322 B1. Chemical structures of GR 113808 and GR 125487 as follows:

20 GR 113808 GR 125487 This paper size is applicable to China National Standard (CNS) Α4 specification (210Χ297 mm) (Please read the note on the back and fill out this page) 1298022 A7 ____ _ B7__ V. Invention description (g) GR 13 8897 is named [1-[2-[(methylsulfonyl)amino]ethyl]-4-hexahydropyridinyl]methyl [2-(3-methyl-1,2,4- Π-diazolyl)phenyl]carbamate, another potent and selective 5-ΗΤ4 antagonist from Glaxo Wellcome: its 5-HT4A and Hongda HT3a receptors are 2 〇〇 and 5 < 5.0. For examples of GR138897, see Examples 1 and 3 of WO 93/20071 and claims 8-10, and US 5,618,827, EP 0 640 081 B1 and (Z)-2-butene diester and methanesulfonate see WO Examples 2 and 4 of 93/20071 and items 9-10 of the patent application. The chemical structure of GR138897 is as follows: Η (f \ (Please read the notes on the back and fill out this page)

Ch3 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 10 GR138897 1_^-353433 Its name is 1-(1-methylethyl)-]^-(2-(4-((三环(3.3.1.1) 癸-1-yl-l-amino)amino)-1-hexanitrogen ratio °-based) ethyl sit-3-carbamide, or mercaptoethyl)-indole-(2-(4-(tricyclic) ·3·1 ·1) superscript (3,7)癸-1 -ylamino)amino)-1 -hexahydro 0 to sigma)ethyl)-1Η-$丨嗤-3 -methylglycine Amine, or ι_(ι_methyl-1Sethylethyl)-N-(2-(4-((tricyclo(3·3.1·13,7)癸-1-ylcarbonyl))amino)H_hexahydrogen ratio σ定)ethyl)-1 Η- 0 induces sali-3-carbamamine, a potent selective 5-54 antagonist developed by Eli Lilly, see: Cohen ML et al., Development Research, 43: 193-199 j April 1988 (including LY 353433 active oxidative metabolites LY-343031 and LY-343032) The paper size applies to the Chinese National Standard (cns) A4 specification (21〇Χ297 mm) 1298022 A7 B7 Economy Ministry of Intellectual Property, Staff Consumer Cooperatives, Printing 5, Inventions (^) Show), Cohen Mh et al., J. Pharmacology cmd Experimental 277:97-104, 1996, April See also: EP 732333 A1. Ideal for a new compound or a new compound of the class, which can be used for atrial reconstruction therapy (eg treatment or prevention). 5 rapid atrial rate, especially chronic fast atrial The pace (or chronic atrial rhythm in animal experiment settings) is a condition in which central room reconstruction (especially electrical reconstruction) occurs, and the central house effective time (AERp) is reduced. Electrical reconstruction has been shown to play an important role in accelerating AF. Now we have found that 5_ΗΤ4 receptor antagonists (inhibitors), 10 special 疋 SB 207266 can at least partially reverse this in the atrial effective duration (AERP) The reduction, ie, can increase AERp. Therefore, it is expected that the -5-HT4 receptor antagonist like sb / 207266 will alleviate atrial reconstruction and / or protect the atrium from reconstruction, it will be electrically reconstructed. Therefore, according to A first aspect of the present invention is to provide a use of a 5_ΗΤ4 receptor antagonist for the manufacture of a medicament for preventing or treating atrial reconstruction, for example: in a mammal, such as a human. The mammal in need thereof (for example: a human) to provide a method for treating or preventing atrial reconstruction, comprising administering to the mammal an effective amount of an anti-5_ΗΤ4 receptor binding agent. The present invention also provides a 5? ητ4 receptor antagonist for preventing or treating atrial remodeling, for example, in a mammal such as a human. Preferably, the present invention involves pre-expansion of the $ flat-top defense or treatment of electrophysiological (electrical) cardiac reconstruction, as described above. In all its aspects, the present invention applies the Chinese National Standard (CNS) A4 specification (21〇χ^^ ----- by the atrial fibrillation 15 20 _^_ 10 10 s. ----ttF—I (please read the note on the back and then fill out this page) Order the Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1298022 A7 B7 V. Invention Description (9) Sexual tremor is possible atrial reconstruction, for example : Atrial reconstruction made possible by recurrent atrial fibrillation. In all aspects of the invention, the mammal being treated (eg, human) is a patient with atrial fibrillation or suspected, especially persistent Or patients with permanent atrial fibrillation [eg, long-term (eg, >15 years or >5 years) patients] long-term (eg, >1 year or &gt; 5 years) patients with persistent or permanent atrial fibrillation Most likely to have problems with atrial remodeling, as described above. Preferably or additionally, in all aspects of the invention, a therapeutic/prophylactic agent/method/5-HT4 receptor antagonist (eg, SB 207266 or its medicinal Can accept 10 salts) for suppression Symptom recurrence of atrial fibrillation in patients with continuous or permanent AF (preferably permanent AF). "Paroxysmal AF" includes or means an AF phenomenon with an average period of <48 hours of phenomenon Persistent AF can be stopped automatically or a 5-HT4 antagonist and/or other antiarrhythmic drugs can be converted into general sinus rhythm 15 (NSR). The main part of paroxysmal AF is individual AF, which does not. Potential cardiovascular disease and no atrial reconstruction. If it does not stop quickly, persistent AF will turn into permanent AF. "Continuous AF", for example: symptomatic permanent AF, usually longer than persistent AF Time, and includes or means an AF phenomenon of an average period of 248 hours and &lt; 1 year, such as a symptomatic phenomenon, or more preferably an average period of &lt;48 hours and &lt; 6 months. Permanent AF usually does not stop automatically and often requires an electrical or pharmacological cardioversion to convert to NSR. Atrial electrical remodeling usually occurs and occurs in left atrial dilatation and left ventricular dysfunction. 25 "Permanent AF" includes or Meaning the level of individual phenomena This duration is longer than the sheet -11- applies Shen Guoguo scale of Standards (CNS) A4 size (210 X 297 mm) 90358A- contact

1298022 A7 B7 V. INSTRUCTIONS (AF phenomenon of 11 AFZ, for example: &gt; 1 year or &gt; 5 years of _, or permanent _ α It usually does not respond to the electrical conversion method, and with complete electrical reconstruction Related, and usually accompanied by ongoing CV disease (local anemia, cardiomyopathy, and/or southern blood pressure, etc.) / 5 Preferably, the present invention involves preventing or treating atrial reconstruction that is possible by rapid atrial rate (eg, experimental chronic atrial rhythm.) The mammal being treated (eg, I human) can be a patient with a rapid atrial rate or a suspected patient, eg, an abnormally rapid atrial rate. User, the 5_HT4 receptor Antagonists may include any of those referred to in the introduction. Thus, for example, a 5-HT4 receptor antagonist agent for use in the present invention may be included in any patent application scope of any of the patent publications referred to in the introduction. Any compound covered (eg, the scope of the patent application item!) is disclosed as

5-HT4 receptor antagonists (for example: WO 93/1 8036: WO 93/05038, WO 93/16072, WO 94/10174, WO 94/27987, WO 95/04737, WO 15 93/20071, EP 501322 B1, WO 94/27965 and/or EP 732333 A1), and/or any 5-HT4 receptor antagonist, for example, which may be specifically exemplified in any patent or journal publication referred to in the introduction, disclosed as 5-11 4 receptor antagonists. Other 5-HT4 receptor antagonists can be found using the 5_ht4 antagonist test detailed below. A pharmaceutically acceptable salt of a 5-HT4 receptor antagonist 20 (for example, a HCl salt), a solvate, a hydrate, a complex and/or a prodrug and the like are included in the 5-HT4 receptor. Antagonists, in the definition of categories. Suitable pharmaceutically acceptable salts are apparent to those skilled in the art and include, for example, acid addition salts with inorganic acids and organic acids such as hydrochloric acid, hydrogen acid, sulfuric acid, Acid or acid; the organic acid such as: succinic acid, paper size applicable to China National Standard (CNS) Μ specifications (210X297 mm) I-------t! (Please read the back of the note first) Matters to fill out this page) Order Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed 1298022 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed A7 B7 V. Invention Description (o-butyric acid, acetic acid, fumaric acid, lemon Acid, tartaric acid, benzoic acid, p-toluene tocopheric acid, methicillin or naphthoic acid. The 5-HT4 receptor antagonist is preferably an antagonist of the 5-HT4A receptor, for example at 0. Blondel Identified by FEBS Letters, 412, 1997, 465-474. Preferably, the 5-HT4 receptor antagonist is a 5-HT4 receptor antagonist of the heart, meaning those present in the human atrium. An antagonist of the 5-HT4 receptor, preferably meant to be substantially only present in the human heart Antagonists of those 5-HT4 receptors in the atrium (see, for example, Kaumann et al. Naunyn-Schmiedeberg's 10 Arch Pharmacol (1990), 342: 619-622; AJ Kaumann et al. Br - 丨. J Pharmacol ( 1990) 100: 879-885), 0. Blondel et al., FEBS Letters, 412" 1997, pp. 465-474. The 5-HT4A receptor is such a receptor. Preferably, 5-HT4 (or 5) -HT4A) Receptor antagonists are selective 15 5-HT4 (or 5-HT4A) receptor antagonists. Such antagonists may, for example, bind to and/or inhibit 5-HT4 (or 5-HT4A) receptors. 10 times stronger than any other 5-HT receptor, preferably at least 25 times, more preferably at least 1 〇〇. This selectivity can be measured by known tests. See, for example, D Hoyer, (3)/〇 π, 1997, 36(4/5), 419 and references cited therein for the nomenclature of 5-11 butyl receptors. 20 Preferably, 5-HT4 (or 5-HT4A) receptor antagonists are disclosed in w 〇93/1 8036 (including examples) and/or compounds in the scope of the patent application. For example, according to claim 1 of WO 93/18036, the 5-HT4 receptor antagonist may comprise a compound of formula (1) or Its medicine Acceptable salts: 13 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------------------t!--- --- (Please read the note on the back and fill out this page) 1298022 A7 B7

V. Description of the invention ((3)) (1)

X is 0, S, SO, S02, CH2, CH or NR, where R is hydrogen or C alkyl! 5 A is a polymethylene chain of 2 to 4 carbon atoms which are saturated or unsaturated; R and R 2 are hydrogen or an alkyl group;

Rs is hydrogen, halo, C _6 alkyl, amine, nitro or Cw alkoxy; R4 is hydrogen, halo, C1 -6 alkyl or C1 _6 :): oxy; Y is 0 or NH ; 10 Z is a subtype (a), (b) or (c): (CH2)q ------------------I ^------- -- (Please read the notes on the back and fill out this page), r5 Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Cooperatives (4) -(CH2)n2~ R7(CH2)m (b) 14 This paper scale applies to Chinese national standards. (CNS) A4 size (210 X 297 mm) 1298022 A7 ___B7 __ V. Invention description (1 bucket) One (CH2)n3—N (R6 R9 (Ο (please read the back note first and then fill in this page) Η1 is 1, 2, 3 or 4; n2 is 1, 2, 3 or 4; n3 is 2, 3, 4 or 5; q is 0, 1, 2 or 3; p is 0, l or 2; m is 0, l or 2; 5 Rs is _, C _12 alkyl, aralkyl or r5 is (CH2)z-Ri〇, wherein ζ is 2 or 3, and R!o is selected from cyano and hydroxy 'Cw alkoxy, phenoxy, (:(〇)0:&quot; alkyl, COC6H5, -CONRnR12, NRnCORu, S02NRnR12 or NRnS02R2, wherein Rn and Rl2 are hydrogen or Cl_6 alkyl; and i〇R6 , R? and independent hydrogen or C〗 _6 And R9 is hydrogen or a Cl-10 alkyl group; or a compound of formula (I) wherein (:0_丫 linkage is replaced by a heterocyclic organism isostere. wherein the co-γ linkage is replaced by a heterocyclic organism isostere The bioisosteres may be as disclosed in WO 93/18036, page 3, lines 11-25. However, it is preferred that the bioisosteres are absent; that is, preferably Y is Ο or NH. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the consumer consortium. Preferably, X is 〇. Preferably, A is _((::112)3_. Preferably, R and K are independently halogen or methyl. Preferably, Rs is hydrogen and R4 is hydrogen or a halogen group. (Comparative: Patent Application No. 2-5 of WO 93/1 8036). An aryl group (for example, when Rs is an aralkyl group) includes a phenyl group. And a naphthyl group, optionally substituted with 20: or more substituents selected from the group consisting of halo, alkyl and Cw alkoxy. When I is aralkyl, this may include an optionally substituted benzyl group, For example, the benzene ring is substituted by one or more substituents selected from the group consisting of a halogen group, a Cw alkyl group, and a Cw alkyl group. (Comparative: WO 93/18036 Patent Application No. 9 15 Applying the standard of Zhongguanjia (CNS) A4 size (10) X 297 mm)----- 1298022 A7 B7 V. Invention description () and page 3, lines 6-7). Cars are good, Z is secondary (a). In the secondary formula, it is a carbon atom attached to an azo ring. Preferably, ηι is ν, preferably q=3, such that the secondary -(CH2)nj -R5 formula (a) comprises a six-membered azo ring, ie: z is preferably (CH2)nl Attached to the position of the argon ring. Still more preferably, z is 4-6 hexamethylmethyl and I is N-substituted (ie: Z is

Wherein Z is 4_hexahydropyridinyl fluorenyl, N-substituted with R5, preferably the N-substituted Rs is C24C3 or greater alkyl (ie: C2_I2 alkyl or c:^2 alkyl, Or alternatively a substituted benzyl group; or an n-substituted R5 is substituted with (CH2)nR4 as defined in the formula (1) of EP-A-501322, and is related to a specific example of EP-A-501322. Good place, z is (^(正·丁N-ηβιι

Methyl-4-pyridinyl)methyl, ie: ^, . (Comparative · 93/1 8036 patent application scope! and 7_9 and page 4 6~ W〇 page 10). Preferably, in the present invention, the 5-HT4 receptor antagonist comprises a compound selected from the group consisting of: (a) an example as described in WO 93/18036; [to 46] One, (b) one of the examples 1 to 54 as described in WO 93/05038, (c) one of the compounds described in claim 6 or 20 of WO 93/20071, or 15 or less To 38 16 This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) (please read the notes on the back and fill out this page)

1298022 Α7 Β7 Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives, Printing 5, Inventions (丨t) (d) One of the compounds described in EP 501322 B1, Patent Application No. 9 or Examples 1 to 2, is free Test form or its pharmaceutically acceptable salt. Alternatively, in the present invention, the 5-HT4 receptor antagonist may comprise a compound selected from the group consisting of: (a) one of the compounds described in Examples 1 to 15 as described in WO 94/27965, or RS 100235 Or RS100302, or (b) exemplified by Examples 1 to 38 as described in EP 732333 A1, in the form of the free base or a pharmaceutically acceptable salt thereof. In the present invention, it is particularly preferred that the 5-HT4 receptor antagonist comprises: (i) N-[(l^butyl-4-hexahydropyridinyl)methyl]-3,4-dihydro-2H -[1,3] mouth and other tillage [3,2-a]吲哚-1〇_carbamamine (SB 207266); (ii) N-(2-(4-(3-(8_ Amino)_ 7_ gas group 2,3_dihydro-1,4-benzodioxan-5-yl)-3-oxopropyl)hexahydropyridin-1-yl)ethyl)-methanesulfonyl decylamine (rs 15 100302); (iii) methyl-1H-indole-3-carboxylic acid (1-(2-((methylsulfonyl)))))))))) Or methylethyl)-Ν-(2·(4-((tricyclo)(3.3.1.1)癸-1-ylcarbonyl)amino)-1-hexahydropyridyl)ethyl)-1Η-carbazole -3 -Procarbamide (LY-353433); 20 is 1-(1-methylethyl)-indole-(2-(4-((tricyclo)(3.3.1.13,7)癸-1)) Alkyl)-1-aminohydropyridyl)ethyl)-1 - oxazole-3-carboxamide; or a pharmaceutically acceptable salt thereof. Additionally, it is preferred that the 5-ΗΤ4 receptor antagonist comprises: (ν) 8-amino-7-chloro-1,4-benzobisindole-5-rebel (1_butyl-hexahydro) (Please read the notes on the back and fill out this page.) The paper size applies to the Chinese National Standard (CNS) Α4 specification (210Χ297 mm) 1298022 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau System V. Invention Description (||) An oxime ester (SB 204070) or a pharmaceutically acceptable salt thereof, for example, a hydrochloride thereof; (vi) 8-amino-7-iodo-1,4-benzodioxan-5-carboxylate Acid (1-butylhexahydropyridyl) decyl ester (SB 207710) or a pharmaceutically acceptable salt thereof, for example, 5· its hydrochloride; (vii) N-(l-butyl-4-hexa Hydropyridyl)methyl-8-amino-7-chloro-i,4-benzodioxanecarbamide (SB 205800) or a pharmaceutically acceptable salt thereof; (viii) [l-[ 2-[(Methanesulfonyl)amino]ethyl]-enhexahydropyridinyl]methyl|lip [2 (3-methyl-1,2,4-disoxadiazol-5-yl)benzene a urethane (GR 138897) or a pharmaceutically acceptable salt thereof, for example: (ζ) 2 -butene diester or decane decanoate; or (ix) 5- Methyl-2-methoxylΗ-indolecarboxylic acid [(methylsulfonyl)amino]ethyl]-ren hexahydropyridine methyl ester (GR 125487) or its pharmaceutically acceptable &quot;&quot; · Its hydrochloride, a hospital salt, or maleate. More preferred antagonists include: (1) SB 207266, (V) SB 204070, (vi) SB 207710, (V11) SB 2 〇 58 〇〇 and (iv) qing mm; or a pharmaceutically acceptable salt thereof. Take 5 4 4 fork body antagonists for N-K1, butyl-4-hexahydro hydrazine bite), 3,4-dihydro-2 Η Η, 3] $ well and [3, 2_ small引口朵" or Jianku m In addition to the atrial. Diseases other than fibrillation 疋 about reducing the atrial effective time (AERP) and / or do not want 18 10 15 20 -— —— 】 8 degrees tearing 1298022 A7 B7 five , invention description ((g) 10 15 Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperatives, printing 20, atrial changes, the second point of view of the invention is also needed for mammals (such as: humans) A method of treating or preventing a disease or condition other than atrial fibrillation, with a reduction in atrial effective time (AERp) and/or unwanted atrial changes, including the administration of an effective amount to the mammal 5 - HT4 receptor antagonist. The second aspect of the invention also provides a 5-HT4 receptor antagonist for use in diseases or health conditions other than atrial fibrillation, with respect to reducing atrial effective duration (AERP) And/or unwanted atrial changes. The third aspect of the present invention provides 5-H &amp;Receptor antagonists in the manufacture of pharmaceutical agents for increasing atrial effective duration of arrest (AERP) and/or for effectively altering a patient suffering from the disease or condition or a mammal suspected of being a patient (eg, human) In addition to atrial fibrillation, atrial shackles, which are desired. @X月's second point of view is also in mammals that need it (such as humans to provide - atrial effective (four) time (AERp) and / or effectively change the disease or health of the patient or the coffee, including the pair::::::: Effectively injured 1 5-HT4 receptor antagonist. Also provided by the third viewpoint of = Ming 5 · ΗΤ4 receptor antagonist, plus atrial effective (4) (A) (AERP) and / or effectively change the health of the patient or suspected patient of the mammal (such as atrial fibrillation outside the atrial _, which increases Or change is ^ heart solid view from the 5_HT4f body antagonist μ manufacturing (please read the back of the note and then fill out this page) Order 19 1298022 A7 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 20, invention description ((? Use on the back to prevent Treatment of the heart layer loose, 'the law (such as: chronic atrial rhythm) or 11 in the atrial fibrillation, forget about the disease or health status, and atrial rhythm (for example: chronic atrial Rhythm). Preferably, in the first, third and fourth views of the first and third of the present invention, the disease or condition is in addition to arrhythmia. Preferably, The second and fortune of the present invention, m (four) green is a disease or health condition of the heart (10)", and/or a disease or health condition of a mammal such as a human being. In order to use the 5-HT4 receptor, it is generally formulated into a pharmaceutical composition according to standard pharmaceutical practice and L. The /5-ΗΤ4 receptor antagonist can be administered conventionally in any route conventionally used for pharmaceutical administration, for example, parenteral, oral, topical or inhalation. The inhibitor can be prepared for self-administration, and the step according to f is also combined with a standard pharmaceutical carrier. Inhibitors can also be administered in combination with known second therapeutically active compounds, = conventional dosages. These steps may involve mixing, granulating, and compressing or dissolving the material to the appropriate desired formulation. It is to be understood that the form and characteristics of the pharmaceutically acceptable carrier are specified by the amount of active ingredient to be combined with, the route of application, and other well-known variables. The carrier must be, is acceptable, and is compatible with the other materials of the formulation and is not deleterious to the recipient. The carrier on the Xile can be, for example, a solid or a liquid. Examples of solid carriers are lactose, white clay, sucrose, talc, gelatin, amaranth, pectin, arbor gum, magnesium stearate, stearic acid and the like. Exemplary liquid carriers are syrup, peanut oil, olive oil, water, and the like. Similarly, the carrier or diluent may include time delay materials well known in the art, such as: glyceryl monostearate or reading back Si. Fill out this page 20 This paper scale applies to the Chinese National Standard (CNS) A4. Specifications (210 X 297 mm) 1298022 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed V. Inventions (&gt;0) Glyceryl distearate alone or mixed with wax. A wide variety of pharmaceutical forms are available. Thus, if a solid carrier is used, the preparation may be in the form of a powder or lozenge in a hard capsule, or a throat or a sputum. The serving size of the solid carrier can vary widely, but a preferred enthalpy is from about 25 gram to about gram. When a liquid carrier is used, the preparation may be a syrup, an emulsifier, a soft capsule, or a sterilized injectable liquid such as an ampoule or a nonaqueous liquid suspension. The inhibitor is preferably administered parenterally, i.e., intravenously, muscle smear, subcutaneous injection, intranasal, intrarectal, intravaginal or intraperitoneal administration. Intravenous forms of parenteral administration are generally preferred. The appropriate dosage for this administration can be prepared by conventional techniques. The inhibitor can also be administered orally. Suitable dosage forms for administration thereto can be prepared by conventional techniques. Inhibitors can also be administered by inhalation, i.e., intranasal and oral inhalation. Suitable dosage forms for administration, such as spray formulations, can be prepared by conventional techniques. Inhibitors can also be administered topically, that is, non-systemically. This includes the application of the exterior of the inhibitor to the epidermis or oral cavity, and the infusion of the compound into the ear, eyes and nose such that the compound does not substantially enter the bloodstream. For all methods disclosed herein, for example, SB 207266 or an inhibitor of a pharmaceutically acceptable salt thereof, the daily oral dose intake is preferably from about 〇·1 to about 80 gram/kg of total body weight. It is preferably from about 2 to 3 mg/kg, more preferably from about 0.5 to about 15 mg/kg. Daily parenteral (eg intravenous) dose intake is preferably from about 0·〗 to about 80 mg/kg of total weight, compared to 15 20 21 paper scale applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Read the back Φ note and fill out this page 1298022 A7 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 20, invention description (孓|) Good is from about 0.2 to about 30 亳 / / 八匕古々 Hair/kg, and more preferably from about 0.5 to 1 hair, the daily dose of the mother's day is preferably from milligrams, one to four times a day, and the hair is up to 15 ingestion is better every day from about 〇〇〗 ^ 1 pg/kg to approx. 1 mg/kg. To practice the above preferred dosage range and based on the in vivo results of your pig experiment described above, the first dose of sputum was set at 0.3 and 1.0 mg/kg 207266 intravenously, right, effective treatment of atrial fibrillation, the following A dosage range of preferably 1 for the prevention or treatment of atrial fibrillation includes administration of SB 207266 or a pharmaceutically acceptable class thereof. Oral or parenteral (eg intravenous) for each dose: 〇··mg/kg to 】·〇mg/kg of total weight (eg illusion to ^ in kg), more preferably from about 〇·2 to 】 〇 mg / kg (for example: 〇 2 to 】 (home gram / kg is still better from 0.3 to 1 〇 mg / kg, and the best is from " to 1.0 $ gram / kg (for example: 〇 5 to! 〇 MG/kg), especially on ritual animals, such as humans. For humans, for example, weighing about MW kg, daily oral or parenteral (eg intravenous) dose intake is G.3 i ΐ·〇 Mg, kg / kg, corresponding to about (21_22 5) to (7〇_75) mg per day; about 2 kg to 1.0 pg / kg, corresponding to daily from (about Μ·] To (7〇_75) 克克力〇.5 gram/kg to 】.0 mg/kg, corresponding to from (about 35-37.5) to (7〇·75) mg per day. Oral or non-human X The preferred per sputum for gastrointestinal (eg, intravenous) administration is 5-2 gram (especially 20 mg), 50 mg, and 80 mg. ^ I is determined as the weight of SB 207266 free test, making For SB 207266 salts, the weight of any acid added to the free base is excluded.

(Please read the precautions on the back and fill out this page) _装• ϋ n ϋ —^--------- 1298022 A7 V. Inventive Note (51) Therefore, the fifth aspect of the present invention provides N_ [(1_n-Butyl-'hexahydropyridine)methyl]3,4-monohydro-2Η-[1,3]η.井和[3,2-a]吲哚_;[ 〇_甲甲甲胺 (SB 2^07266) or its pharmaceutically acceptable salt for use in the manufacture of a medicament for the treatment or prevention of a mammal The atrial fibrillation of the upper (eg, human), by daily oral or parenteral dose intake of the = milk animal is from the total weight of about 〇 〗 〖 gram to about 1 〇 〇 〇 SB 2 〇 7266 or its salts (measured as free base). The fifth aspect of the invention also provides a method of treating or preventing atrial fibrillation in a mammal in need thereof, comprising administering to the mammal a daily dose of oral or parenteral dose uptake of the total weight per kilogram of the mammal. 0.1 mg•0 g of Ν-[(1/butyl I hexahydropyridyl)methyl b 3,4_ dihydro[,3]cortino[3,2-a]吲哚-ίο·甲Indoleamine (SB 2〇 7266) or a pharmaceutically acceptable salt thereof (measured as the free base). ......, _ also mention ^ N-[(1_n-butyl I hexahydropyridinyl)methyl]-3,4-dihydrocatch [I 号 啡 并 [3,2-aHh 秦 甲 甲(SB 2〇 7266) or its medicinal=continuous salt' is used to treat or prevent heart-to-heart tremors in mammals (eg, humans) by administering daily oral or parenteral agents to mammals: Take the total weight of about ... mg to ** Q mg of sb2 〇 7266 or its salts (measured as free base). In all viewpoints (first to fifth) of the intestines, the best intake per oral or monthly system is from about 〇 mg to about 0 0 per kg of total weight! SB 207266 or The salt 'better is from about 0. 2 mg / kg 0 5 bristles / Λ, still better 〇 · 3 to h 〇 mg / kg, for example, about 〇. 5 gram / kg to 〗. 〇mg/kg Please read the back note and fill out this page to install IIIII book 15 20 1298022 A7 V. Invention description (丄^) (Please read the note on the back and fill in this page) ▲More preferably in the invention In all of the views, the daily dose of human is taken b. Oral or parenteral (preferably orally) is 2 mg, 5 mg, 8 mg of SB 207266 or a salt thereof (measured as the free base). The daily dose may be administered per day with a single dose of f, or may be administered at the same or different times of the sputum 5^ two or more smaller doses, which together produce the particular sputum agent. The sixth aspect provides N_[(1/butyl-'hexahydropyridinyl)methyl b 3,4-dihydro-2H-[1,3H. The use of wells [3,2_small 哚_1〇_carbamamine (SB 207266) or its pharmaceutically acceptable salts for the manufacture of medicaments for the treatment or prevention of atrial fibrillation in humans SB 207266 or a salt thereof (measured as a free test) is administered to humans for oral or parenteral (preferably oral) doses of 2 mg, 5 mg or 8 g per human. Also provided to a human in need thereof is a method for treating or preventing atrial fibrillation comprising administering to a human a daily oral or parenteral dose of 2 〇 15 mg, 5 mg or 80 mg of SB 207266 or Salts (measured as free base). Printed by the Ministry of Economic Affairs' Intellectual Property Office Staff Consumer Cooperative also provides SB 207266 or its pharmaceutically acceptable salts for the treatment or prevention of atrial fibrillation in humans by administering daily oral or parenteral doses to humans 20 Mg, 50 mg or 80 mg of SB 2 〇 7266 or its 2 〇 salt (measured as free base). In all aspects of the invention, it is preferred that a 5-HT4 receptor antagonist (eg, SB 207266 or a pharmaceutically acceptable salt thereof) is used in/for symptomatic atrial fibrillation (AF), And/or administration of a patient with persistent or permanent (preferably permanent) AF. 24 The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ' --- 1298022 A7

V. Description of invention (external) 10 15 Employees of the Intellectual Property Office of the Ministry of Economic Affairs 20 _ 20 gram 50 gram and/or 8 gram of human oral dose and about 2 gram/A kg to 1·0 gram/kg The daily dose is designed to minimize the cardiovascular and/or other side effects of the administration of 207266. Preferably, 'in all aspects of the invention, the agent/therapeutic or prophylactic method/5-HT4 receptor antagonist (eg, SB 2〇 7266 or a pharmaceutically acceptable salt thereof) is used for continuous or Inhibition of recurrence of atrial fibrillation symptoms in patients with permanent AF (preferably permanent af). The method of inhibiting the occurrence of d-fibrillation (IV) in a permanent disease using SB 2〇 7266 is described in detail in Example 3 which follows. For ffl/administration of SB 207266, it is generally desirable to achieve a more rapid complete therapeutic response. In order to achieve this, it is believed that SB 207266 or its salts can be initially used at higher loading doses (e.g., oral doses) to achieve therapeutic concentrations more quickly. - It has been found that the steady state plasma concentration of SB 207266 is reached in about 5 days after the daily dose, which is consistent with the removal of half-life T1/2 by about 2 〇 24 hours. It is believed that this long-term concentration of stable state is not ideal, because patients with atrial fibrillation/reconstruction, but have converted (cardiac conversion) into general sinus rhythm and continue to AF, are more likely to be converted in the heart. Then af will happen again soon. I believe that the cumulative degree of oral administration of one dose on the next day is about 丨·5 times. Therefore, the application of SB 207266 for the younger brother to apply a dose of about 1.5 times a day, will certainly create a stable stable plasma concentration, a treatment of Af after heart conversion

Note

Order

The results of the preliminary population medical dynamics model printed by the consumer cooperatives are shown in Figure 5, which shows the simulated SB 207266 plasma concentration versus time for two ingestions (Day! Day 2) 25 paper scales applicable to Chinese national standards (CNS) A4 size (210 X 297 mm) 1298022 10 15 A7 V. Invention description gram, continued 8 days a day, 8 〇 mg, for 8 days, once a day, the simulation in Figure 5 indicates the maintenance of 15 times load ingestion Dose gross health status is more rapid in 24 hours, thus reducing the maximum plasma concentration of 5 207266 for each _ telemetry monitoring period, while at the same time within 10% target steady state. The patient was discharged from the hospital earlier and was treated with the convenience of the patient. ', Jia Jiashi For these reasons, the preferred SB _66 or its medicinally acceptable dose is about 12 on the first day. A daily maintenance dose of up to about 2 times; U5 to, 丨. 75 times, for example, about 15 times), and a daily maintenance dose is administered on subsequent days in a hurry. :,, therefore, in all aspects of the present invention, the application of the agent, method or charge 鸠6 or its salts is 'about the loading dose on the first day, to about 2. G times the daily maintenance charm, The SB 20 coffee or its (iv) daily dose is then administered on subsequent days. Preferably, the loading dose is a daily maintenance dose of from about a to about 1.75 times, more preferably a parental maintenance dose of 虻社α and 1 soil ^ i·5 times. The maternal daily maintenance dose includes daily oral or parenteral doses or dose intake as defined in the fifth and/or six views of the present month. Two excellent oral groups 20 for oral administration of 2G7266 for human use are as follows: This paper scale applies to China __Standard (CNS) A4 specifications (10) 297 297 public ------------ Pack--- ---丨丨定-----II fPlease read the notes on the back and fill out this page.) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 26 1298022 Five A7 -- R7 Invention Description (4?) &quot; ~'~----- SB-207266 5.0 mg SB-207266 5·〇 mg microcrystalline cellulose 3〇·〇 mg microcrystalline cellulose mannitol 112·0 mg HPMC 30·0 mg stearic acid Mg 3 ·0 mg Temple Powder Glycol #3 Dicalcium Phosphate U.5 mg mg Tablets Weight 150 mg Stearic Acid Mg 167·5 mg 2. 5 mg 25 g HPMO Hydroxypropyl Methyl Cellulose Second ( The dosage of the composition on the right hand side can be easily increased to the result that the second composition of the gram is a micronization process. All publications include, but are not limited to, patents and patent applications, which are hereby incorporated by reference in their entirety, the disclosures of which are hereby incorporated by reference. The present invention is described with reference to the following examples, which are intended to be illustrative only and not to limit the scope of the invention. Some examples are illustrated by the illustrations, in which Figure 1 shows that the 5-HT4 antagonist is reconstituted in the atrial fibrillation chamber | atrial rhythm; the method is an anesthetized mini-pig with an atrial simulated electrode, and is shown on 2 pigs. The outline of the procedure used to experimentally generate 5-HT-induced atrial fibrillation and the method of printing by the Intellectual Property Agency's Employees' Consumer Cooperatives, 15 and according to Examples 1 and 2, treated with 5_HT4 antagonist (S: 207266) Figure 2 is titled "5-HT4 antagonist in atrial fibrillation/atrial remodeling atrial rhythm; vehicle treatment group (n=7),", showing changes in atrial ERP and triggered by rapid atrial rhythm and 5-HT / The resulting paper size of atrial fibrillation applies to China National Standard (CNS) A4 specifications (2) G χ 公 爱 〉 〉 27 27 27 27 27 27 27 27 27 27 27 27 27 12 12 12 12 12 12 V. INSTRUCTIONS (1) Health's 7 mini-pigs in the vehicle treatment group; Figure 3 is titled "5-HT4 antagonist in atrial fibrillation/atrial remodeling/atrial rhythm; SB 207260 treatment group (11= 7),,, show the change of atrial ERP And 5 cases of atrial fibrillation caused by rapid atrial rhythm and 5_HT, 7 small pigs in the SB 207266 treatment group; Figure 4 shows atrial fibrillation and atrial remodeling induced by 5_ht on mini-pigs Method of different presentation versions of the process profile, as described in Example 2; and Figure 5 shows two ingestions (12 mg on day 1 and 80 mg per day on day 7 for 7 days, 80 per day for 8 days) mM) simulated SB_2〇 7266 plasma) □ _ plotted against time. Example SB 207266 - Ν-[(1' butyl-4-hexahydropyridyl)methyl]-3,4-dihydro 15 ―211&quot;^1,3] 噚耕和[3,2-a]吲哚-10-carbamamine - was prepared using the synthetic methods described in the introduction. Example 1 - Test results of atrial fibrillation/atrial reconstruction with SB 207266 20 Anti-arrhythmia effect of SB 207266 on a 5-HT-induced arrhythmia anesthesia Yucatail mini-pig model (0.3 and 1.0 mg/kg, Intravenous injection was evaluated for the triggering of AF. As shown in Figure 1, the animals became sensitive with a rapid atrial rhythm of 3 hours (200 msec cycle length) prior to AF initiation, with a partial application of 5-HT (4 mg/hr) in the atrial simulated position. Heart 28 This standard is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) &quot; I !^__w (please read the note on the back and then fill out this page) 1298022 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Invention Description (d) Room Effective Execution Time (AERP) and AF Initiation Ampoule simulations and sudden electronic rhythms are measured during the period. In the two groups of media and music therapy, rapid atrial rhythm and application caused a reduction in EARP from iiuuj to 9〇〇±2” milliseconds, as shown in Figure 1 before media 5 or drug application. The black diamond (♦) and the left-hand strip in Figure 2. When 5-HT was added without atrial rhythm, a small reduction in AERp was seen - see the white diamond (◊) in Figure 1. As shown in the right-hand bar graphs in Figures 2 and 3, the prodrug AF priming (eight 1: occurrence %) caused by 10 consecutive abrupt rhythms (2 sec burst of 2 〇 millisecond period length) is It is stable and can be regenerated (76 ± 8, 69 ± 7, 4%, n = 7 in the vehicle group of Figure 2). As shown in Figure 3, administration of SB-207266 after atrial rhythm and 5-HT application resulted in an increase in the dependent dose of AERP. at 〇·3 and 1〇 mg/kg, respectively (cf. p&lt;0.01 vehicle) ) From 9〇1 soil 2.7 to 1〇2·3±2 7 and 11 0·0±3·6. Pen seconds. At the same time, AF priming was reduced in the absence of drugs, respectively, from 64·3 15 and 】·0 mg/kg (Ρ&lt;0·〇Ό from 64±6% to 46±11 and 30% soil 9%. SB-207266 has an effective property in preventing or treating atrial reconstruction or AF caused by rapid atrial rhythm, accompanied by a prolonged selective atrial shot 7 (AERP length). 20 Example using SB-207266 for more detailed experimental atrial fibers Test results of sexual fibrillation/atrial reconstruction The following is a more detailed description of the experimental steps and results produced in the above example. The results are discussed in time. Again, see Figure 1-3 and Figure 4 again. ---装---II---订·-------- &lt;Please read the notes on the back and fill out this page.) This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) — 1298022 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (1) Example 2 - Materials and test system #存. The following technical equipment was used for this study: • Anesthesia evaporator: Boyle International 2, Medishield, Harlow, England 〇 5 • Artificial respiration: Model 613, Harvard, South Natick, MA, USA. • Heated water pump: Model TP-420, Gaymar Industries, NY, USA. • Blood gas analyzer: ABL 500, Radiometer, Copenhagen NV, Denmark 〇 10 • Pressure transducer: Model P23 LD, Gould Electronics, Cleveland, OH, USA. • Drug 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 Recorder, Gould Electonics. • Digital tape recorder: DTR 1800 Biologic, Claix, France. Participate in Le. Male Yacatan mini pigs (12-17 kg weight) were obtained from Charles River (Saint-Aubin les Elboeuf, France) and maintained for 2 weeks of rest conditioning prior to the experiment. 20 参#的手.准涝. In 25% 02 and 75% N20 mixtures, mini pigs (Charles) before inhalation with isoflurane inhalation (5% for initiation, continued with 0.5 to 1.5% for technical preparation) River, France) fasted and premedicated (2 mg/kg chlorotolyl benzodiazepine 21-8 + 15 mg/kg amiodarone, intramuscular). Long-term anesthesia with veins 30 -------------------tr---------Aw (please read the notes on the back and fill out this page) The scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1298022 A7 V Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing ___B7 V. Invention description (0&gt;G) Injection input five (diethyl propylene Maintained with sodium carbendazim (12 mg/kg/hr). Mechanical vents (Harvard Pump 613) were used to provide artificial respiration during left thoracic incision to maintain atrial blood gas and pH within normal limits (ABL 500 analyzer). Fluid-filled catheters were placed in the femoral artery and veins, 5 to measure arterial pressure (P23 ID converter) and drug administration, respectively. Electrocardiogram leads II, III and core leads were placed to monitor standard ECG. Parameters: Two pairs of electrodes were hung on the left atrium wall for subsequent stimulation (S8800 stimulator and SIU-5 unit) and used to measure the electrocardiogram. 10 Example 2 - Experimental procedure Heart beta, iron, edge, annihilation 4 Left atrial appendage with rapid atrial rhythm (200 ms period length within 3 hours) Sensitization produces the initial electrical reconstruction of the tissue [A· Goette et al., 1996, C/rci//a&quot; (10), 94, 2968-2974]. Then, 5-HT solution (4 mg/hr in 2 hours) , starting at 3 minutes and 15 minutes before the end of the atrial rhythm) was used locally, by using a fiber patch placed close to the stimulating electrode. After the susceptibility state and constant local application of 5-HT, the baseline atrial administration Spasticity and AF priming were measured. Acupuncture Atrial Effective Time (AERp) was used as described above [A. Bril, B. Gout et al., J. 276, 637-646] 20 using a single additional stimulus Technique to measure. In short, 20% of the series of stimulations that are shorter than the basic period of the sinus rhythm, followed by a single premature extra stimulus (4 milliseconds, 1.5 times the starting current), gradually shorter The coupling interval is initiated from the atrial rhythm until the atrial response is not obtained. AERP represents the longest coupling interval that does not elicit a propagating response in the tissue. After the AERp measurement, the heart 31 ------- - I - I i 111111 11-- ----WAW i Jing Xian read the back of the note and then fill out this page, &gt; This paper size is suitable China National Standard (CNS) A4 specification (210 X 297 mm) 1298022 A7 V. Description of invention (3|) Atrial fibrillation (AF) abnormality begins. AF is triggered, followed by atrial rhythm of sudden stimulation for 2 seconds (The basic period length is 20 mm period length, 2 ms period, twice the diastolic baseline) and is introduced during the vulnerable window period (AERP+] 0 ms). AF is defined as the measurement of irregular electrical activity of at least sec in an electrocardiogram. 5 兮斋# ° After assessing the reproducible baseline response of the animal, 猪 your pig is randomly referred to $ to obtain sterilized steamed water (vehicle group, n=7) or increasing dose of SB_207266 (〇3 And 1 〇 mg/kg, administered intravenously for more than 1 minute in 15 minutes prior to the determination of AERP and subsequent AF stimulation. SB-207266 was dissolved in sterile distilled water for 1 week and prepared daily as a foot. The amount of the drug solution is given. The volume treated with the vehicle represents the volume of the distilled water similar to the volume used for the drug solution (swell). Each dose of SB-207266 is applied at 45 minute intervals to allow the animal to be from the previous The response to the sudden rhythm stimulus is indicated. The brief flow of the main time points of the method is presented in Figures 1 and 4. The 55-2072M's shame attacked Guangyan's #live. For each af stimulus, in the drug After the application (time point 15 minutes) and centrifugation (1500 X g, 10 minutes, 4 C), the 5 minute blood sample was collected in EDTA (6%). Read the back Φ Note and fill in page 15 Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption Society Print 20 This plasma sample was stored at -80 ° C for subsequent analysis. Plasma samples were not collected in the vehicle group. In this 5 ng / ml assay for pigs, the plasma concentration of SB-207266 was determined. Performed by LC/MS/MS and LLQ. Example 2 - Data Processing and Analysis Source # and. All parameters were monitored on the Drawing Multi-Use Recorder (TA-5000) and digitized in the entire method (DTR 1800). Record. When measuring 32 paper scales apply Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1298022 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description in the day ~ dirty rate from ECG calculation And the average atrial blood pressure comes from the pulse pressure. The QT of the ten,, and the work is determined according to the Bazzet (s) formula [qTc = qT(m)/RR(#)]. The AF trigger is from 1〇. The percentage of reactions obtained in consecutive bursts is expressed, and the average time of 5 AF phenomena recorded during the 10 bursts of stimuli is expressed in seconds. 巍妒分#. This value is expressed as mean soil SEM. Use variable tool analysis (ANOVA), continue to Newman _ The Newman_Keuls test was performed in multiple pairs-by-pair comparisons. The AF-priming for sudden stimulus responses was analyzed using the Kruskal-Wallis ranking sum test. All statistics were 1 using statistics. 5.1 Release the set software (StatS〇ft, Inc., Tulsa, 〇K, USA). 'Example 2 - Results 5-HT on mini-pigs trigger atrial fibrillation.辕 久久, 15 is necessary to perform a 3-hour rapid atrial rhythm 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 stimuli. To this end, the effects of different interventions - including separate fast atrial rhythm, 5-HT alone, and a combination of rhythm and 5-HT - were studied for changes in AERP. After 3 hours of rapid atrial rhythm (2 〇〇 milliseconds of basic circumference 20), AERP was greatly reduced from 110·7±4.6 亳 seconds to 93·6±3·6 milliseconds (η=7; ρ&lt;0· 01). Administration of 5-guanidine alone for 3 hours did not significantly alter AERP (104.0 ± 6.5 milliseconds relative to the control group of 11 〇 · 2 ± 1 · 9 ms, n = 6). The application of 5-HT after rapid atrial rhythm does not result in a further reduction in AERP, which is 91.8 ± 3 · 3 milliseconds (with 节 丨丨丨 丨丨丨 丨 丨 丨 单独 丨丨丨·丨丨丨丨丨丨丨· (Please read the note on the back and fill out this page.) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm). 1298022 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 V. Invention Description (23) 93.6 Soil 3·6 millisecond comparison). See the illustration of the figure and the bar graph on the left hand side of Figure 2. As shown in the right hand bar graph of Figure 2, continuous AF stimulation in the vehicle treatment group showed stable and reproducible AF in pigs that were subjected to rapid atrial rhythm and simultaneous administration of 5-HT. Initiation (7 out of ten out of 5 rhythms ± 5% positive response, and range from 69 to 74% of 5 stimuli). The average time of the af phenomenon measured for sudden rhythm response was 2·5 ± 0.5 hours (range ι·2 to 6.7 seconds) and was stable during continuous AF stimulation as shown in Table 1 below. Show. The effect of SB-207266 on 5-HT induced AF. In the Wei 10 body of 屯经消I, an increasing dose of SB-207266 (0.3 and 1·〇亳g/kg) was injected intravenously, and the AERP-dependent dose was increased from the prodrug value of 9 3 3 ms to 〇·3 and 1 respectively. • 1 〇 2 ± 3 and 〖 10 ± 4 亳 seconds of 〇 mg / kg (ρ &lt; 0:01 vs. vehicle). After administration of 1.0 kg/kg SB-207266, the reduction in AERP caused by rapid atrial rhythm plus 5-HT administration was completely restored (see Figure 3 on the left hand side of the 15 bar graph). At the same time, dose-related reductions in AF-priming were observed to decrease from 64 ± 6% before treatment to 46 ± 11% at 〇 3 mg / kg (ρ = 〇 · ΐ 39 versus vehicle), And reduce it to 〇0±9% under ι·〇mg/kg (ρ&lt;〇〇1) (see the right-hand bar graph in Figure 3). The mean time of the AF phenomenon was slightly but notably reduced from 1.9 ± 0.4 seconds before drug treatment to 11 ± after 施用 3 mg / 20 kg SB-207266 (ρ &lt; 〇 · 05 vs. vehicle) 〇 4 seconds. No further reduction in AF mean time was observed at higher doses, as shown in Table 1 below. i | Hey! . In the plasma samples collected 5 minutes after the end of each SB-207266 drug, the circulating concentration of SB-207266 is measured. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). I---I ------------------------------------------------------------------------------- , invention description. The plasma concentration of SB-207266 was observed to be 137·7±15·2 ng/ml (n=6) at 0.3 g/kg SB_207266 and reached 562.3 soil 40.1 ng/home liter (11=5). 5 Table] Comparison of the mean time of AF caused by rapid atrial rhythm and 5-HT in mini-pigs. Comparison of vehicle-treated and SB-207266-treated animals (10 ml of drug) SB-207266 (mg /kg, IV) Control vehicle media prodrug 0.3 1.0 AF time (seconds) 2.5±0. 5. 2.9±0. 8 2.1±〇. 3 1.9±0· 4 1.1±0.2 1.1±0.4 P value for vehicle Prodrug: NS NS NS ρ&lt;0·05 ρ&lt;0·05 ρ&lt;0·05 ρ&lt;0.05 NS: not obvious 1〇Example 2-drum^ The results of this study show that 5-HT is compared with fast atrial rhythm, Shows the minimal impact on AERP. In goats, it has been shown that the rapid atrial rhythm triggers a short time for AERP (physiological rate is appropriate) and this reduction is further observed over time [MCEF· Wijffels et al., C7rc*i//plus/(10), 1997, 96, 15 37 1 〇-3720]. Our results provide a deterministic rapid atrial rhythm that is sufficient to achieve a steady reduction in AERP. In addition, our results show that 5_HT alone or in the presence of rapid atrial rhythm 5_H administration significantly changes AERP. This suggestion: 5-HT does not directly involve electrophysiological institutions leading to AF, but may play a considerable facilitating role in AF. This paper size is applicable to the National Standard (CNS) A4 specification (21〇x 297 public). II MM MB aas βΗΚ · MM μ· I mm One-ojfl I -1 I ϋ _1 I (Please read the notes on the back first) Fill in this page again) 1298022 A7 B7__ V. Description of the invention (in (please read the notes on the back and fill out this page) Although 5-HT has the least effect on the occurrence of AERP and AF, 5-HL receptor antagonist SB The administration of -207266 avoids/inhibits (or reverses) the reduction of AERP and protects against AF priming in a dose-dependent manner. These results are shown to correlate with the plasma concentration of the drug. These results suggest: 5-HT4 receptor inhibition For example, with the administration of SB-207266, there is a result that can cause atrial fibrillation. Example 2 - Conclusion SB-207266 has been shown to greatly reverse the AERP reduction caused by combined rapid atrial rhythm and local administration of 5-HT. And greatly reduce the occurrence of AF. These results suggest that SB-207266 and 5-HT4 by ▲ antagonists are usually effective in reducing / treatment of atrial fibrillation, and the characteristics associated with atrial ERP response (increased) is At 5-HT and atrium The reversal of atrial electrical reconstruction observed in the presence of the law. 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 arrhythmia - eg, atrial fibrils A novel method of sexual fibrillation is by administering/using a 5-HT4 receptor antagonist, such as any of the compounds described herein. Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printing 20 Example 3_Using Oral Administration SB-207266 Methods for treating or preventing atrial fibrillation and/or atrial remodeling in humans. The current preferred method of treating or preventing atrial remodeling and/or atrial fibrillation using SB-207266 or a salt thereof is now described in detail. Patients with symptomatic persistent atrial fibrillation (AF) 36 This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1298022 A7 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed V. Invention Description (Application SB-207266 or its salts (hereinafter referred to as "SB 2〇 7266,"). The aim is to inhibit the recurrence of atrial fibrillation symptoms in patients with persistent AF. Lt; a patient who has symptom persistence af during 6 months and who needs a cardioversion method (for example, DC heart rhythm conversion method) is appropriate. Symptoms of persistent af may include, for example, palpitations, etc. Preferably, the patient has : At the beginning of treatment, there is a therapeutic anticoagulant (eg heparin) > 3 weeks · In the absence of therapeutic anticoagulant &gt; 3 weeks, it has transesophageal echocardiography (tee), right Coagulation is negative and receives intravenous heparin until the PTT is stable and within the therapeutic range. In addition to intravenous heparin, it is preferred to receive a patient with SB 207266 after this therapeutic coagulant or after TEE. SB 207266 (e.g., the free base, but more preferably the hydrochloride salt of SB 207266-A) is usually administered at a dose of 20 mg, 50 mg or 80 mg uid (measured as the free base). However, on the first day of administration of SB 207266, a single oral dose of 1.5 times (1.5 χ) of the administered dose per maintenance was usually administered. Preferably, however, a single oral loading dose is administered on the first day at 30 mg, 75 mg or 120 gram, followed by a dose of 20 mg, 50 mg or 80 mg per sputum on subsequent days. After two hours of oral administration of SB 207266 at a loading dose of 1.5 hr on the first day, patients with atrial fibrillation (and/or pharmacologically no arrhythmia) are preferably subjected to direct current (DC) rhythm conversion. The following single or biphasic heart rhythm transformation rule system can be continued. 15 20 Single-phase 37 paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 public) (Please read the note on the back and fill out this page) Two-phase 1298022 A7 B7 V. Invention description (4 )

If the patient does not revert to normal sinus rhythm (NSR) after using the third shock in one or the above sequence, the physician may make further attempts with different energy at their consideration. A successful heart rhythm transformation is defined as nsr maintenance &gt; 1 hour. Following the successful DC rhythm conversion method for NSR, administration of SB-207266 to the patient can be performed once a day for six consecutive months (for example), or for a shorter or longer period. Those patients who automatically reversed to normal sinus rhythm (NSR) may also receive SB 207266 (for example) 6 months once a day. During this daily treatment period, patients with AF re-existence and sputum test can return to the sinus rhythm with DC rhythm and continue to receive SB-207266. Mildly ill patients must continue treatment with anticoagulation (eg heparin) throughout the administration of SB 207266. (Please read the note on the back and then fill out this page) 5 11 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 20 Therefore, the best method is as follows: Symptom persistence AF, at &gt;48 hours and &lt;6 months During the course of therapeutic anticoagulation for 23 weeks or TEE for coagulation + intravenous heparin (-&gt; I administration SB-207266 (loading dose) DC rhythm conversion method (if necessary) 38 This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 public) 1298022 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed Α7 Β7 V. Invention description (Continue to 曰 曰 - - 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 较佳 , , , , , , , , , , , , , "Recurrence of AF" includes or means a phenomenon in which the patient is generally palpitations or other symptoms. It can be further established by an ECG (eg, 12-wire ECG) record, showing evidence of atrial fibrillation, or in a phenomenon recording device. The rhythm band recorded above, and may be reviewed by a physician as appropriate. 10 Tests for 5-HT4 receptor antagonist activity and SB 207266 activity 1) Guinea pig colon This animal model is described in Wardle KA and Sanger GJ (1993) Br·J Phar Macol; 110 1593-1599 ° Male guinea pigs weighing 250-400 g. Longitudinal muscles of the intestinal muscles 15 layers below the chest are prepared about 3 cm long, obtained from the peripheral colon area. These are suspended in a load of 克·5 g. Krebs solution, in a separate tissue bath bubbling with 5% C〇2 in 〇2, and maintained at 37. Under the 。. In all the tests, the 'Krebs solution also contains Mefluizidium (metlii〇thepin) 1 〇7 molar concentration, granisetron (granisetron) 1 〇 _6 molar concentration, to block the effects of 5-HTi, 5-HT2 and 5-HT3 receptors. After constructing a simple concentration response curve with 5-HT, using a 30 second contact time and a 15 minute dose cycle, the concentration is selected to achieve muscle contraction of up to about 40-70% (about 1 〇·9 molar concentration). The organization then doses the drug at a concentration of 5 ΗΤ every 15 minutes. In some experiments, the tissue is applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) on another paper scale ------ ---f--------tx---------# (Please read the notes on the back and fill out this page) 1298022 A7 B7 V. Explain (2&gt;) to administer the drug at a concentration of approximately equal effective concentration of nicotine receptor stimulant-dimethylphenylpiperazine (DMPP). Consistent response to 5-HT (and appropriate DMPP) Then 'add the increased concentration of the putative 5_HT4 receptor antagonist to the bath solution. The effect of this compound was then determined by a 5-HT or a decrease in the percentage of shrinkage caused by DMPP. In this data, the pIC5 〇 value was determined to be defined as a concentration of antagonist _i〇g that reduced contraction by 50%. Compounds that reduce the response to 5 ht, but not to DMPP, are believed to act as receptor antagonists. SB 207266 has particularly good activity. 10 5-HT produces a single-phase choline-mediated contraction in the presence of 5·ΗΤ, 5-HT2 and 5-HT3 receptor antagonists, characterized by a pEC5Q of 90 ± 0.06 (η = 14). Increasing the concentration of SB-207266-A (HC1 salt of SB 207266) concentration, n=6) produces a parallel movement of the 5-HT curve to the right, with no effect on the maximum response. The apparent ρΑ2 is 10·4±0·1, and the slope is 15 different from the one without weight. At higher concentrations (3χ1 (Γ8 molar concentration and above), the maximum response to 5-ΗΤ is reduced in a concentration-dependent manner. This result of SB-207266-Α is not due to local anesthesia, or in the gallbladder Direct Antagonism of Alkali Receptors 'Because of *DMPP-induced contraction (a nicotine receptor antagonist that causes the release of acetylcholine and the contraction of the cytotoxic receptor mediator) even at 20 high concentrations The concentration of the ear) was not affected. SB-207266-A was also tested against contraction induced by the 5-HT4 receptor partial scavenger BIMU1. In these experiments, SB-207266-A reduced the large-scale reaction to BIMU 1 without causing the aforementioned rightward shift on the concentration response curve. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the back note before filling this page) -------- order i ------- economy Ministry of Intellectual Property Bureau employee consumption cooperative printed 1298022 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (+ 〇) Observed by SB- 207266-A is obviously unsurpassable activity, not due to 5-HT4 The irreversible hindrance of the receptor, because the antagonistic effect of SB_ 2〇 7266_A can be reversed during scouring. At the highest concentration (which reduces the maximum contraction caused by 5-HT), the response to 5-HT returned within 9 minutes. This pattern is consistent with a reversible antagonistic dose of 5 agents. 2) Piglet atrial compound Automated beating screening of compounds was tested on the atrium of piglets [Naunyn-Schmiedeberg, s Arch Pharmacol, 324: 619-622]. When compared to the 5-HT control curve alone, SB_ 2〇 7266-Α (ι〇·7 10 molar concentration) shifts the curve to the right with a significant decrease in maximum response. The estimated SB_207266-A (hydrochloride of SB 207266) estimated pKb(-l〇gu)Kb) is 1〇·1 (η=2). 3) The esophagus of the mouse The mouse meal of the tunica muscle mucosa was established according to Baxter et al. 5 Naunyn-Schmiedeberg^s Arch Pharmacol.? 343? 349-446 (1991). The muscle mucosa of the inner smooth muscle tube is separated and at 37. The underarm was fixed in a oxidized (96% 〇 2/5% C 〇 2) Tyrodes solution for equal volume tension recording. All experiments were performed in a pre-treatment preparation of pargy Hne (100 micromolar concentration, 15 minutes, continued scouring) and in the presence of Gu 20 base (3 〇 micromolar concentration). The buffer response to 5-HT was obtained after contracting the esophageal tissue before the gallium carbonate test (3 micromolar concentration). When carbon was prepared for contraction, 5-HT produced a concentration-dependent relaxation with pECw of 8.1 ± 〇 · 〇 3 (η = ΐ 8). In contrast to the pattern of the guinea pig colon, where the 5-HA receptor has a neural locus, the receptor here is located on the smooth muscle. In l·——·-----9! (Please read the notes on the back and then fill out this page j - order 4 ▼ 1298022 A7 B7 V. Invention description (Brawl) The preparation of the mouse esophagus depends on SB- The 207266-A concentration acts as an unsurpassable antagonist and reduces the maximum response caused by 5-HT. Because SB-207266-A inhibits the maximum response, it is not possible to measure reliable PA2 estimates. However, with the least effective SB- The data obtained from the concentration of 207266-A is consistent with pAplO.O 5 . SB-207266-A is used as a highly selective view of 5-HT4 receptor antagonists (see the above-mentioned information on the colon isolated from guinea pigs and subsequent Radiation ligand binding selectivity analysis), it is possible that the apparently unsurpassable antagonism is due to the slow decomposition of the compound from the receptor. This occurs because of the low 5-HT4 receptor reversal and SB- in the esophagus of mice. 207266-A has a high affinity for 10-HT4 receptor relative to 5-HT itself. 4) Bonding of the hippocampus 5-HT4 receptor in the piglet Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing-T-- -·---------- (Please read the note on the back of this page first) SB-207266-A pair of pigs hippocampus 5-HT4 The affinity of the body is measured from the inhibition of the 125I-labeled 5-HT4 receptor antagonist SB-207710 [Brown AM? Young TJ? Patch TL? Cheung CW? Kaumann AJ? Gaster 15 LM and King FD (1993), Br J Pharmocol; 11 0,1 OP]. This lucky sputum ligand has a high affinity for the piglet hippocampus film (KD=86±11 megahertz molar concentration, Bmax=16±3 megahertz/mg (n=4)), At the same time in the 5-HT1A, 5-HTlc & 5-HT2 receptors SB-207710? & is 6 or lower. In addition, the 5-HT3-selective ligand granisetron inhibits 20 [125I]-SB-207710 linkage to the hippocampus0&amp;; below 5, indicating that the preparation of the radiation ligand to 5-HT3 is A negligible bond. In this system, 5-HT is bonded to the 5-HT4 receptor with moderate affinity (ρΚ^ is 6·6±0·1 (η=9)). SB-207266-A inhibits the bond of 125Ι-labeled SB-207710, the pi value is 9.48±0·06 (η=3), which is slightly lower than the pA2/pKB estimate and is determined by its 42 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1298022 A7 B7 V. The invention describes the antagonisticity of the functional response in his tissue. 5) Selectivity of SB-207266-A (HC1 salt of SB 207266) in vitro SB-207266-A has been evaluated in various non-5-HT4 receptor binding methods. The results are shown in the table below. Functional studies in the stomach base of mice showed: 5 The affinity of the 5-HT2B receptor was 7.47. It is clear that the 5-HT4 receptor has a greater selectivity than other tested receptors. Receptor Bonding Study pKd 5-HT1A &lt;5.00 5-HT1d &lt;5.00 5-HT1e &lt;5.00 5-HT2A 5.89 5-HT2C 5.57 5-HT3 5.94 al &lt;5.52 d2 5.63 d3 5.53 GABA &gt;5.00 BDZ &gt ;5.00 H! 5.40 opiate K (pKi)&gt;6 opiate μ (pK〇&gt;6 opiate δ (pKi)&gt;6 6) 5 HT-induced motility in the dog's stomach pocket (please read first) Precautions on the back I · n ϋ HI^ this page) -- Line · Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed compounds are tested and inhibited in a living manner, the method is described as "BRL24924 dog active stimulation -Stimulation 10 of canine motility by BRL 24924, a new gastric prokinetic agent", Bermudez et al., J. Gastrointestinal Motility, 1990, 2(4), 281-286 先前 Have previously prepared HEIDENHAIN (Heidenhain) a dog with a stomach base that was fasted overnight. The above 5-HT dose range study was also conducted for each dog to confirm that the 43 paper scales are applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1298022 A7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperative Printed V. The minimum static ejection dose caused by the invention, which is an increase in the reproducible gallbladder energy medium in the tension and phase of the stomach contraction, usually 5 or ι μg/kg. For each experiment, 5_HT was administered intravenously at intervals of 3 〇. After the two-in-one reaction, (iv) intravenous injection, or in a second-human sputum 5-HT rain for 15 minutes, each oral capsule was administered. In the monthly r-mai main injection and each oral administration, the sb_2〇7266_a dose-dependent contraction response is antagonistic [ID5〇 for intravenous injection 13 (trust limit is • Η walking / λ kg, for each oral 9 δ (Trust limit 0.7) 28) Micrograms/kg. Furthermore, SB-66_Α has no effect on substrate motility at any dose. There is no consistent or significant effect on 5_ΗΤι, 5_Η丁2 and ML receptor antagonists. /Β: 2〇7266_Α is measured after the intravenous dose. The effect is variable and reversible at lower doses of 1 and 3 μg/kg in summer, at 10 and 100 μg/kg. Under the test, the resistance was maintained longer than the experimental period (285 minutes). 7) Antagonism on the anesthetized piglets In k: the Bayesian test, the antagonistic effect on the tachycardia caused by 5_ΗΤ was evaluated, and the response was $ 5-ΗΤ4 receptor to mediate. All experiments were 2_5 day old pigs where the sacral nerve was removed. The dose of (10) salt of SB_2〇7266-A(10)207266 is given by 〇·〇〇·3 or 1〇μg/kg by intravenous injection, in the form of relying agent $ (11=2 per group) against heartbeat caused by 5-H-butyl Overspeed. At a dose that greatly elicited the 5-HT effect of this 5:HT4 receptor vector (〇·3, !······················· 10 15 20 44 This paper size is fine China's specifications (10) χ 297 public) J——,--------^^丨丨 (please read the back note on this page first) Order: 1298022 A7 B7 Ministry of Economics Property Bureau Staff Consumer Cooperatives Printed V. Invention Description (Dou 4) Tests for the social effects of anti-anxiety agents on the social effects of mice (male, Sprague Dwaleys, Charles River, 250-300 g) with a group of eight Raised in the holding room for 5 days. It was then housed in a small laboratory in a neighboring laboratory for 4 days before the experiment day. In the experiment, mice were administered vehicle, test compound or benzodiazepine anti-anxiety agent, chlordiazepoxide, each time orally, in pairs (11=8-16), from 1 am The beginning of the sputum, the interval of 15 minutes. After 30 minutes, their weight-matched (first encounter) pairs were placed in a social box in a separate chamber. The box is made of white basal 10 perspex, 54 cm x 37 cm x 26 cm, with transparent pespe plexiglass on the front side and no cover. The floor is divided into 24 squares and the box is illuminated brightly [11 5 lux]. Lively social behavior (preparation, smelling, climbing up, down, following, biting, riding, and fighting) is blindly scored with the following 15-minute remote video surveillance, resulting in a total social score. The number of squares that were passed by every 15 rats was also scored and summed. At the end of each test, the box was carefully packed. A total increase in total social dissection was observed with the administration of SB-207266-A (HC1 salt of SB 207266) (0.01, 1, 10 mg/kg). The effect of this effect was somewhat less than the positive control group of chloriazepoxide (CDP; 5 mg/kg per oral) 20, but not very significant. SB-207266-A was not accompanied by any changes in movement during the test and was therefore consistent with anxiolytics. (Please read the notes on the back page first) Binding: This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Claims (1)

1298022 VI. Patent application scope 1. A8 B8 C8 D8 Patent application No. 90119097 with ROC Patent Appln. No. 90119097 Corrected unlined patent application text - Annex (3) --Aniended Claim^ ΐη ------ (Submitted on February 22, 1997) (Submitted on February 22, 2008) F.r&gt;n1 ΎΤΤη Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed JN-[(K-n-butyl I Hexahydropyridyl)indolyl]_3,4_diox_2H_[1,3] is a cultivating [3,2-a]indole-10-carboxamide or a pharmaceutically acceptable salt thereof The use of a medicament for the treatment of electronic (electrophysiological) atrial reconstruction of a mammal, wherein the mammal is a human or mini pig. 2. The use of the first application of the patent scope, in which electrophysiological (electronic) atrial reconstruction includes atrial effective time (AERP) reduction. 3. The use of claim 1 wherein the mammal is a human. 4. The use of claim 2, wherein the mammal is a human. N-[(l-n-butylhexyl 氲 比 淀 )) methyl]_3〆·dihydro_纽·[1,3]&quot; 耕耕和[3,2_a]吲哚-10-甲醯Amine (SB207266) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the prevention or treatment of a non-atrial: blood vessel disease or condition with reduced atrial effective duration (AERP) in a mammal, wherein The mammal is a human or mini pig. Ν-[(1-n-Butyl_4_hexahydropyridinyl)methyl]_3,4-dihydro-2H_[1,3]哼[[3,2_a]吲哚_ι〇-曱醯The use of an amine (SB207266) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for increasing atrial atrial effective duration (AERP) of a cardiovascular disease or condition having or susceptible to non-atrial arrhythmia, wherein The increase or change is desirable, wherein the mammal is a human or mini pig. 25 7. A pharmaceutical composition for human oral administration as a tablet, which contains 10 15 20 4 5. 6· -46 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) 90358B- Pick up 2 book 1298022 (1«-n-butyl hexahydroacridinyl)methyl]·3,4·dihydro-2H_ 'and [3,2 (4), 1G·carbamamine (SB 207266) or its medicine J; % of the salt' is combined with a pharmaceutically acceptable SJ carrier, 5^ (207266 or its salt is present in the tablet at a rate of 5.0 grams per 250 mg of tablet weight (measured as the free base), Wherein the ingot = is the result of a micronization process, and wherein the composition comprises a dish acid gas, such as the composition of claim 7 of the claimed patent range, wherein the perovskite hydrogen per unit is as much as 250 mg per lozenge The amount of 167.5 mg is present. 1〇9. The composition of claim 7 is wherein the hydrogen-filled dance is present in an amount of about 167.5 mg per 250 mg of the tablet. W. The composition of the seventh item, which also comprises microcrystalline cellulose. 11. The composition of claim 8 of the patent application, which also comprises microcrystalline fibrin. 12. The composition of claim 1 of the patent application , wherein the microcrystalline cellulose is present in an amount of about 5 mg per 250 mg of the tablet. Printed by a consumer cooperative 13. The composition of claim n, wherein the microcrystalline cellulose is present in an amount of about 5 〇.〇 mg per 250 mg of the tablet. 20 Μ·If the patent application is 10th The composition of the item, which also comprises hydroxypropyl methylcellulose (HPMC). 15. The composition of claim 4, which also comprises hydroxypropyl methylcellulose (HPMC). The composition of the 14th patent range, wherein jjpMC is -47 - the paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) A8 B8 C8 D8 1298022 VI. The patent application range is 250 mg per tablet weight. An amount of about 12.5 mg is present. 17. The composition of claim 15 wherein the HPMC is present in an amount of about 12.5 mg per 250 mg of the tablet. 18. The composition of claim 10 A composition comprising a starch diol of 5 nanometers. 19. The composition of claim 14 which comprises sodium starch glycol. 20. The composition of claim 19, wherein the sodium starch glycol is per 250 mg of tablet weight about 12.5 The amount of gram is present. 10 21. The composition of claim 10, which also contains magnesium stearate or stearic acid. 22. The composition of claim 10, which also contains stearic acid. 23. The composition of claim 11 also contains 15 towns of stearic acid. 24. The composition of claim 14 of the patent application also contains magnesium stearate. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperatives 25. If the composition of Article 18 of the patent application is applied, it also contains the town of stearic acid. 20. 26. The composition of claim 22, wherein the magnesium stearate is present in an amount of about 2.5 mg per 250 mg of the tablet. 27. The composition of claim 23, wherein the magnesium stearate is present in an amount of about 2.5 mg per 250 mg of the tablet. 28. The composition of claim 25, wherein magnesium stearate is -48 - the paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) A8 B8 C8 D8 1298022 VI. Patent application scope It is present in an amount of about 2.5 mg per 250 mg of tablet weight. 29. The composition of claim 7, wherein the composition is substantially as shown below, but the dose of SB-207266 in the composition can be increased: SB-207266 5.0 gram microcrystalline cellulose 50.0 mg hydroxypropyl Base thiol cellulose (HPMC) 12.5 mg sodium starch glycol 12.5 mg calcium hydrogen phosphate 167.5 mg magnesium stearate 2.5 mg; the weight of the agent is 250 mg. 5 30. The composition of claim 29, wherein the dose of SB-207266 in the composition can be increased by up to 20 mg. 31. The composition of claim 7, wherein N-[(l-n-butyl-4-hexahydropyridinyl)indenyl]-3,4_diargon-2H-[1,3] is Ploughed [3,2-a]indole-10-carbendazim (SB 207266) or its pharmaceutically acceptable salt 10 is the hydrochloride salt of Micro SB 207266. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives 32. For example, the composition of the scope of patent application No. 8 wherein N-[(l-n-butyl-4-hexahydropyridinyl)methyl]-3,4-di Hydrogen-2H-[1,3]indole and [3,2-a]indole-10-carboxamide (SB 207266) or a pharmaceutically acceptable salt thereof is the hydrochloride salt of SB 207266. The composition of any one of clauses 9 to 28, wherein N-[(l-n-butyl-4-hexahydropyridinyl)indenyl]-3,4-dihydrogen -2H-[1,3] 哼耕和[3,2-a]吲哚-10-Methylamine (SB 207266) or its medical-49 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1298022 C8 _D8_ VI. Scope of application The pharmaceutically acceptable salt is the hydrochloride salt of SB 207266. 34. Use of a composition according to any one of claims 7 to 32 for the manufacture of a medicament for the treatment or prevention of gastrointestinal, cardiovascular and CNS diseases. 5 35. Use of a composition according to any one of claims 7 to 32 for the manufacture of a medicament for the treatment or prevention of cardiovascular diseases. 36. Use of a composition according to any one of claims 7 to 32 for the manufacture of a medicament for preventing or treating atrial fibrillation in humans 0 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed on paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 mm)