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

Abstract

The present invention relates to a pharmaceutical composition being a tablet for human oral administration, comprising N-[(1-nbutyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxa mide (SB 207266) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable solid carrier, wherein the SB 207266 or the salt thereof is present in the tablet in at least 5.0 mg per 250 mg of tablet weight (measured as the free base), wherein the tablet is the result of a granulation process, and wherein the composition includes dicalcium phosphate. Preferably, the composition is substantially as follows, provided that the dose of the SB-207266 in the composition can be increased: SB-207266 5.0 mg Microcrystalline cellulose 50.0 mg Hydroxypropylmethylcellulose (HPMC) 12.5 mg Sodium starch glycollate 12.5 mg Dicalcium phosphate 167.5 mg Magnesium stearate 2.5 mg Tablet weight 250 mg.

Description

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

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;

And [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-

J 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 ·

This 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

CH3

GR 125487 NHS02Me (Please read the notes on the back before filling this page)

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____ 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: 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 [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

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 &gt; 15 years or &gt; 5 years) patients]. Long-term (e.g. &gt; 1 year or &gt; 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 &lt; 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 () '&quot;' _ Seeing Elephants' Example: &gt; 丨 year or &gt; 5 year period, or Shuijiu period. &quot; ^ 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) 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 ------------ 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) This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) 200425914

A7 ----— V. Description of the invention () 10 of which (CH2) n3—

(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 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

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 &gt; &297; 297mm) (Please read the notes on the back before filling in this page)

200425914 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 &gt; 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 / &gt; 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

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 &lt; 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: · &quot; about 7〇-7 :) kg, each

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 &quot; 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 Read the precautions on the back and re-install the page III Order # 200425914 © A7 B7 10 15 r &lt; ·· 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.

During 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

Please 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 &lt; 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

V. 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

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 &amp; 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 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 &lt; 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 &lt; 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 &lt; 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 &lt; 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 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 &lt; 0.05 ^ P &lt; 0.05 ρ &lt; 0.05 ρ &lt; 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 &lt; 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 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 &gt; 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 &gt; 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 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 &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 αΐ &lt; 5.52 d2 5.63 d3 5.53 GABA &gt; 5.00 BDZ &gt; 5.00 Hi 5.40 opiate K (pK〇> 6 crane tablet μ (pK〇)> 6 opiate δ (ρΚ 丨) &gt; 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 _: &gt; -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 &quot; (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)

200425914 A8 B8 C8 D8 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs; *. Application for patent scope 1. A pharmaceutical composition for oral administration as a lozenge, which contains N-[(l-n-butyl-4 -Hexahydropyridyl) fluorenyl] -3,4 · diargon-2H- [1,3] humphino [3,2-a] indole-10-carboxamide (SB 207266) or its pharmaceutical use Acceptable salts in combination with a pharmaceutically acceptable solid carrier group 5, where SB 207266 or its salts are present in the tablets (measured as free base) at least 5.0 mg per 250 mg of tablet weight, where The lozenge is the result of a micronization process, and the composition contains dicalcium phosphate. 10 2. The composition according to item 1 of the patent application range, wherein the dicalcium phosphate is present in an amount of up to 167.5 mg per 250 mg of the tablet weight. 3. The composition according to item 1 of the scope of patent application, wherein the dicalcium phosphate is present in an amount of about 167.5 mg per 250 mg of the tablet weight. 4. If the composition of the scope of patent application No. 1, it also contains 15-dimensional microcrystalline fiber. 5. If the composition in the scope of patent application No. 2, it also contains microcrystalline cellulose. 6. The composition according to item 4 of the scope of patent application, wherein the microcrystalline cellulose is present in an amount of about 50.0 mg per 250 mg of the tablet weight. 20 7. The composition according to item 5 of the patent application, wherein the microcrystalline cellulose is present in an amount of about 50.0 mg per 250 mg of the tablet weight. 8. If the composition of item 4 of the patent application, it also contains hydroxypropyl methylcellulose (HPMC). 9. If the composition in the scope of patent application No. 5 also contains hydroxypropylmethyl -46-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 93056-claim 200425914 A8 B8 C8 D8 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 6. Scope of patent application Basic cellulose (HPMC). 10. The composition as claimed in claim 8 wherein HPMC is present in an amount of about 12.5 mg per 250 mg of tablet weight. 11. The composition as claimed in claim 9 wherein HPMC is present in an amount of about 12.5 mg per 5 mg of a 250 mg tablet. 12. The composition according to item 4 of the patent application, which comprises starch glycol sodium. 13. The composition according to item 8 of the patent application, which comprises starch glycol sodium. 10 14. The composition according to item 13 of the patent application range, wherein the sodium starch glycolate is present in an amount of about 12.5 mg per 250 mg of the tablet weight. 15. If the composition in the scope of patent application No. 4, it also contains magnesium stearate or stearic acid. 16. If the composition in the scope of patent application No. 4, it also contains 15 magnesium stearate. 17. If the composition in the scope of patent application No. 5 also contains stearic acid. 18. If the composition in the scope of patent application No. 8 also contains magnesium stearate. 20 19. The composition according to item 12 of the patent application scope, which also contains stearic acid. 20. The composition according to item 16 of the application, wherein magnesium stearate is present in an amount of about 2.5 mg per 250 mg of the tablet. 21. For the composition in the scope of patent application No. 17, in which magnesium stearate is -47-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 200425914 A8 B8 C8-------------6. Application scope of patent Existing in an amount of about 2.5 mg per 250 mg of tablet weight. 22. The composition according to item 19 of the scope of patent application, wherein magnesium stearate is present in an amount of about 25 mg per 250 mg of tablet weight. 23. If the composition of the first patent scope is declared, the composition is substantially as shown below 5; the limitation is that the dose of SB-207266 in the composition can be increased: SB-207266 5.0 g of microcrystalline fiber 50.0 mg hydroxypropyl fluorenyl cellulose (HPMC) 12.5 mg sodium starch glycol 12.5 g dicalcium phosphate 167.5 g magnesium stearate 2.5 mg lozenge weight 250 mg. 24. If the composition according to item 23 of the patent application scope, the dosage of SB-207266 in the composition can be increased up to 20 mg. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 25. For example, the composition of the first patent application scope, where n-[(1J butyl_4-hexahydropyridyl) methyl] -3,4-dihydro- 2H- [1,3]. No. [3,2_a] indole-10-amidamine (SB 207266) or its pharmaceutically acceptable salt is the hydrochloride salt of micro SB 207266. 26. The composition according to item 2 of the scope of patent application, in which butyl-hexahydropyridyl) methyl] -3,4-dihydro-2H- [1,3: K geno [3,2_ 4 indole -10- Formamidine (SB 207266) or its pharmaceutically acceptable salt-48-This paper is suitable for the national standard (cns) a4 specification of the rich country (publicly issued) 200425914 A8 B8 C8 ___D8_ It is the hydrochloride salt of SB 207266. 27. The composition according to any one of claims 3 to 22, wherein N-[(l-n-butyl-4-hexahydropyridyl) methyl] -3,4-difluorene-2H- [1,3] Sakamoto and [3,2-a] indole-10-amidamine (SB 207266) or its pharmaceutically acceptable salt is the hydrochloride salt of SB 207266. 28. The composition according to any one of claims 1 to 26, which is used for treating or preventing gastrointestinal, cardiovascular and CNS diseases. 29. The composition according to any one of claims 1 to 26, which is used for treating or preventing cardiovascular disease. 10 30. The composition according to any one of claims 1 to 26, which is used for preventing or treating atrial fibrillation in humans. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper is sized for China National Standard (CNS) A4 (210x297 mm)