TW396158B - Compound having 5-HT4 receptor antagonist activity, process for preparation the same and its use - Google Patents

Description

Ministry of Economic Affairs, Central Bureau of Standards, Zhenggong Consumer Cooperative Co., Ltd. No. 83〗 07151 Patent Application Chinese Description Animal Correction Page (Sept. 86) A7 B7 _ 5. Description of the Invention (丨 You \ The present invention is based on a Novel pharmacologically active compound, its preparation method and its use as a pharmaceutical. European Patent-A-42 9984 (UiUsshin Flour Milling Co., Ltd., Nishin Flour Mill Co., Ltd.) mentions having a 5-HT3 receptor antagonist The active indole derivatives. European Journal of Pharaacology 146 (1988), 187-188, and Naunyn-SchBiedeberg's Arch. Pharmacol. ( 1989) 340: 403-410, mentioning a non-traditional serotonin receptor * now named 5-HU receptor, and a serotonin 5_HT3 receptor inhibitor, as ICS 205-930, as a receptor W0 91/16045 (Sin it. HKline and French Laboratories Limited) mentions the use of 5-HT4 receptor antagonists in the heart to treat anterior chamber irregularities and Stroke 0 European Patent A-501 322 (Glaxo Limited (MGlaxo Group Limited) mentions that the indole derivative has 5-HT4 antagonist activity. W0 93/1 8036 SmithKline Beecham pic mentions that it has a 5-HT4 receptor antagonist activity or is a pharmacological agent. An acceptable salt has the following formula:

This paper size applies to China National Standard (CNS) A4 (210X297 mm) ----------- Ί ------ IT ------ 0 (Please read the (Notes on this page) The Ministry of Economic Affairs Central Government Standards Bureau Zhengong Consumer Cooperative Co., Ltd. Printed No. 83〗 07151 Patent Application Chinese Description Animal Correction Page (Sept. 86) A7 B7 _ V. Description of Invention (丨 补 尤 \ 本The invention relates to a novel compound with pharmacological activity, its preparation method and its use as a pharmaceutical. European Patent-A-42 9984 (UiUsshin Flour Milling Co., Ltd.) -Indole derivative of HT3 receptor antagonist activity. European Journal of Pharaacology 146 (1988), 187-188 and Naunyn-SchBiedeberg's Arch. Pharmacol.) (1989) 340: 403-410, referring to a non-traditional serotonin receptor * now named 5-HU receptor, and a 5_HT3 receptor anti-orange agent with ICS 205-930, Acts as an antagonist of this receptor. W0 91/16045 (Smithland and the French Restricted Plant) (Sin it. HKline and F (rench Laboratories Limited) mentions the use of 5-HT4 receptor antagonists of the heart to treat anterior chamber rhythms and strokes 0 European Patent A-501 322 (MGlaxo Group Limited) mentions that indole derivatives have 5-HT4 antagonist activity. WO 93/1 8036 SmithKline Beecham pic mentions that it has a 5-HT4 receptor antagonist activity, or a pharmaceutically acceptable salt thereof, whose formula is as follows:

This paper size applies to China National Standard (CNS) A4 (210X297 mm) ----------- Ί ------ IT ------ 0 (Please read the Note on this page) Patent Application No. 831071 5 丨 Chinese Correction Sheet (Sept. 86) A7 B7 V. Description of the Invention (> 〇 where supplementary Ά X is 0, S, SO, S02 'CHa, CH or HR (where R is hydrogen or C1-e complex); A is a saturated or unsaturated polymethylene chain of 2-4 carbon atoms; R1 and 卩 2 are nitrogen or Cl-β 焼; R3 Is hydrogen, halogen, Ci-e alkyl, amine, nitro or alkoxy; R4 is hydrogen, halogen, Ci-e alkyl or "_βalkoxy; Υ is 0 or ΝΗ; Z is times -Formula (a) * (b) or (c):-(CH2) n (ch2). 'Rs (a) ---- ----- III --- I--order (please read the back first) (Please note this item before filling out this page) (CH2) p-(〇w-

--N R7 CH2) m // (b) Printed by the Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs ~ r9 (C) where 1 is 1, 2, 3, or 4; n2 is 0, 1, 2, 3, 4, or 3, 4 or 5; Yes 2 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) No. 831071 5 Chinese Patent Application Correction Sheet (Sept. 86) A7 B7 V. Description of the invention (≫ 〇 where the supplementary Ά X is 0, S, SO, S02 'CHa, CH or HR (where R is hydrogen or C1-e complex); A is a saturated or unsaturated polyatom of 2-4 carbon atoms Methyl chain; R 1 and 卩 2 are nitrogen or Cl-β 焼; R 3 is hydrogen, halogen, Ci-e alkyl, amine, nitro or alkoxy; R 4 is hydrogen, halogen, Ci- e alkyl or "_βalkoxy; Υ is 0 or ΝΗ; Z is a sub-formula (a) * (b) or (c):-(CH2) n (ch2). 'Rs (a) --- ------ III --- I--Order (Please read the note on the back before filling this page) (CH2) p-(〇w-

--N R7 CH2) m // (b) Printed by the Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs ~ r9 (C) where 1 is 1, 2, 3, or 4; n2 is 0, 1, 2, 3, 4, or 3, 4 or 5; Yes 2 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) No. 83107151 Patent Application Chinese Description Revised Sheet (Sept. 86) A7 ^ Β7 V. Description of the invention ( 7) (b) ί, M can correspond to the double-ring partial exploration α or call. Compounds of formula (I) can be prepared by using Z in cooperation with the indole moiety. The appropriate method is referred to V〇93 / 18036, the main body of which is incorporated herein for reference. 0 ---------- install -----; --tT ------ line (please read first Note on the back " 3 ^ Write this page) Printed by DuPont Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs 10-This paper size applies to China National Standard (CNS) Α4 size (210 × 297 mm)

A7 Λ 'Description of the invention (3) q ^ 〇, 1, 2, or 3; port is 0: I or 2; m is 0, 1 or 2 >

Rs is hydrogen, CK2 alkyl, aralkyl or RB * (CH2) = -R1〇 (where Z is 2 or 3 M and R10 is selected from cyano, hydroxy, Ci-e alkoxy, phenoxy (ΜΟΚχ-βalkyl., COCeH5, -CONRuRu, NRnCORn, 50 02 «1? 111? 12 or" 115021? 12, where Rn and R12 are hydrogen or Ci-e alkyl; and Re, R7 and R8 are Independent hydrogen or Ci-e alkyl; M and Rs are hydrogen or Ci-io alkyl; or a compound of formula (I), in which the C0-Y coupler is replaced by a heterocyclic organism Substituted; has the activity of a 5-HT4 receptor antagonist. Examples of alkyl or alkyl-containing groups include Ci, C2, C3, C4, Cs, Ce, c7, cs, ce, c10, Cn, or c12 branches , Straight, or cyclic alkyl. Ci-4 alkyl includes methyl, ethyl, n-, and isopropyl, n-, iso-, secondary-, and trifluorene-butane. Naphthenes The groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Aryl includes phenyl and naphthyl, and may be optionally selected from one or more of halogen 'he alkyl and Ci-e alkoxy substitution. Halogens include fluorine, molybdenum, bromine and iodine. One containing Y in formula (I) A suitable biological isotope of amidine or ester coupling is given by the formula (d):

-6- This paper size applies to China National Standards (CNS) A4 specifications (210X297 mm) See ----- 1T ----- 1 ^ r / i .. > (Please read the note on the back first Please fill in this page again) Central Bureau of Standards of the Ministry of Economic Affairs :) 1 Industrial and Consumer Cooperatives printed No. 83107151 Patent Application A7 Chinese Manual Revised Page (September 86) B7 Five Central Government Procurement Bureau of the Ministry of Economics printed the shelling consumer cooperative Preparation and description of the invention (/ rJ) (Please read the precautions on the reverse side before filling out this page) Treating isohexidine (30.1 g) with anhydrous potassium carbonate (64.9 g, 0.47 mole) A stirred solution of 0.23 moles) and benzyl bromide (27.9¾ liters * 0.23 moles) in ethanol (250 ml) and heated for 3 hours. Allow the mixture to cool, simmer, and concentrate the filtrate in the sky. The remaining oil was dissolved in chloroform (200 mL) and washed with water (1 x 150 mL). Dry (Na2S04) and concentrate in vacuo to leave a yellow solid (41.0 g). This solid was fully trickled with osmium pentoxide (38.3 g, 0.27 mol), then gently stirred and heated under nitrogen, 180 C for 2.5 hours. The reaction mixture was cooled and then treated with water (300 ml). When the solid mass dissolves, add 1 (2 (: 03) alkalization solution in solid form and extract with ethyl acetate (2 x 250 milliliters). Dry (Na2S04) combined extract and vacuum-shrink to leave a Brown oil body (35.3 g). The oil was decanted into anhydrous ether (250 ml) and lithium aluminum hydride (10.1 g, 0.26 mol) was added dropwise to ether (150 ml) over a period of 30 minutes under nitrogen at 0 t: M. Suspension. When the addition is complete, warm the mixture to room temperature and stir for 1.5 hours. Cool again to 0 and carefully add water (10 ml) * 10% HaOH solution (15 liters) and water (2 5 ml). K silicon thin earth is used to mix the mixture and vacuum shrinkage. K leaves a brown oily body, which after steaming in vacuum can produce a title compound (27.8 g, 67%) as a colorless oily body at 0.2 5mm Hg • Boiling point 1061: 〇 NMR (CDCla). Δ: 7.20-7.37 (b, 5H), 3.48 (s, 2H), 2.85-2.95 (, 2H), 2.55 (d, 2H), 1.87-2.00 U.2H), 1.60-1.75 (·, 2Η), 1. 10-1. 40 (·, 5H). . Sharp? · -20 This paper size is in accordance with Chinese Standard (CNS) A4 (210X297 mm). Printed by the Central Standards Bureau of the Ministry of Economic Affairs and Labor Cooperatives. A7 B7 V. Description of the invention (4) Where the dotted ring represents 5 -members One or two double bonds at any position in the ring; H, J, and I represent oxygen, sulfur, nitrogen, or carbon, respectively, but at least one of Η, J, and I is not carbon; U represents nitrogen or carbon. Suitable examples of (d) are X, Y and Z described in European Patent-A-328200 (Merck Sharp & Dohme Ltd.), such as a fluoradiazole moiety. X is usually 0. A values include -CH2- (CH2) r-CH2- (where r is 0, 1 or 2); -CH2-CH = CH-; -C (CH3) = CH- or when X is CH or N * A But K is-(CH2) 2-CH = or -CH = CH-CH =. Other examples of A are the same as those described later. 1? 1 and 1? 2 are often hydrogen or 1? 1 and 1? 2 are bis-dimethyl. r is always 1. R3 is preferably hydrogen. 1-4 is preferably hydrogen or halogen (for example, fluorine). Y is preferably 0 or NH. When Z is a sub-formula (a) and the nitrogen heterocycle is attached to a nitrogen atom, η1 is preferably 2, 3 or 4, and if the nitrogen heterocycle is attached to a carbon atom, η1 is preferably 1. For example, when q is 2 o'clock and 4th position. When the order Z is-the formula (b) * η2 is preferably such that the number of carbon atoms of the ester or amidine coupling is between 2 and 4 carbon atoms. Appropriate values of P and ra include p = m = l; p = 0-ra = l * p = l > in = 2 > p = 2 > m = 1 ° -7- Wood paper dimensions are applicable to Chinese national standards ( CNS) Α4 specification (210X297 mm) ^ 1¾ .------ ir ----- ▲ (Please read the precautions on the back before filling out this page) Article 831071 51¾ Chinese Manual of Patent Application Amendment Page (86 September 2007) A7 B7 396158 V. Description of the Invention (〆) ί

(100 ml) and a glacial acetic acid (4 ml) suspension for 18 hours. The mixture was quenched and the filtrate was concentrated in vacuo. The main product is solid and can be eliminated. This material was shaken with the residue of concentrated potassium carbonate solution (50 ml), aerosol (50 ml) and mash. After passing through the mixture, the chloroform layer was separated and dried (Na2SO4), and concentrated in vacuo to obtain a title compound (1.52 g, 100%) as a white solid. Recrystallized from chloroform / 60-80 gasoline, melting point 139-1411C ° 1 Η Ν Η R (CDC 1 3) δ-8.32 (d, lH), 7.03-7.30 (β, 3Η), 6.53 (t, lH), 4.48 (t., 2H), 4.05 (t, 2H), 3.30 (t, 2H), 3.02-3.15 (m, 2H), 2.52-2.70 (b, 2H), 2.27-2.40 (m, 2H), 1.65 -1.90 -------- »—!-• -install-- (Please read the note on the back of the page and then this page) Printed by the Central Standard of the Ministry of Economic Affairs of the Zhengong Consumer Cooperative (π, 4Η), 1.10-1.30 (b, 2H). 5-HT4 receptor antagonist activity 1) guinea pig colon Using a male guinea pig weighing 250-400 g, a longitudinal intestinal plexus preparation having a length of about 3 cm was obtained from the lateral colon area. They were weighed 0.5 g and suspended in a separate tissue bath containing Krebs' solution * 37 spoons were maintained while being pumped with 0 2 containing 5% C02. The Krebs solution also contained aethiothepin 10_7M and granisetron 10-βΜ Μ in all experiments to block 5-ΗΤι, 5-HT · »and 5-HT3 receptors. effect. After 30 seconds of contact and 15 minutes of dose cycle, a simple 5-HT concentration response curve can be constructed, and the 5-HT concentrate can be selected to make the muscle large -23-This paper uses the Chinese national standard ( CNS) A4 specification (210X297 mm) Ordered by the central ministry of the Ministry of Economic Affairs and printed by the Industrial and Consumer Cooperatives A7 B7 V. Description of the invention (5) When Z is a sub-formula (c), n3 is preferably 2, 3 or 4 . Both Chi 8 and Re are preferably alkyl groups, and in particular, one of R8 and Re is "or larger" alkyl groups. The specific values of Z are particularly as follows:

(vii) The compound of formula (I) includes a side chain (i), (ii), (iii), (iv), (v), (vi) or (vii). In the further bidding, (i), (ii) or (iii) this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -------- / 1¾ ------ tr ----- '0 (Please read the precautions on' t before filling out this page) Page 33107151¾ Revised page of the Chinese manual for the patent application (September 86) A7 B7 396158 Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs Printing 5. Description of the invention (> |) — / .; j The maximum yield of about 40-70% ii (about 10-eM). This group was then administered alternately every 15 minutes to the 5-HT concentrate and a nicotinic glucoside stimulant, DMPP, of approximately the same potency. After receiving the 5-MT and DMPP mineral reaction, a hypothetical 5-HT / receptor antagonist was gradually added to the bath. The effect of this compound can then be detected by reducing the percentage of shrinkage caused by 5-HT or DMPP. From this data, the pICso value can be obtained, which is defined as the antagonist's -log concentration which reduces contraction by 50%. A compound that reduces 5-HT response instead of DMPP response is believed to be a 5-HTa receptor antagonist. Of this compound? 1 (: 50 is 9.65 ± 0.20 (»\ = 4). 2) The rat esophagus is in accordance with Bax ter et al., Naunyn-Scheie-deberg's Arch Paraacol.) 343, 439-446 (1991). The intramuscular smooth muscle tube of this muscle was isolated and embedded in 37 spoons of isotonic oxygenated (95% 〇2 / 5% Co2) Tyrodes solution. All experiments were pretreated with H-methyl-N-2-propynyl benzylamine (Bajlin * pargyiine) in the presence of cocaine (30 μM) (100 WM, washed off after 15 minutes). 5-HT relaxation response can be obtained after pre-shrinking of the esophagus by carbachol (3w.H). -24-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) --------,-h—one pack-- (Please read the precautions on the back first and write this page) Order Printed on A7 B7 by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (6) The hexahydropyridine ring may be replaced by tetrahydropyrrolyl or -nitrotetrafluorenyl, and / or in (i) or (Π The N-substituent may be substituted by a C3 or larger alkyl group or a suitable benzyl group. In another example, the N-substituent in formula (i) or (H) may be defined by formula (I) or related to a specific example of European Patent-A-50 1322 (CH2) „R4 The pharmaceutically acceptable salts of compounds of formula (I) include the acid addition salts of conventional acids such as hydrogen chloride, hydrogen bromide, boric acid, phosphoric acid, sulfuric acid, and pharmaceutically acceptable sulfonium. Acids, such as acetic acid, tartaric acid, maleic acid, citric acid, succinic acid, benzoic acid, anti-increasing acid, methanesulfonic acid, α-ketoglutarate, α-glyceryl phosphate, and glucose-1-phosphate. Examples of acceptable salts include quaternary derivatives of compounds of formula (I), such as compounds quaternized by compound Rx-T (wherein R is Cl-e complex, phenyl-Cl-beta alkyl, or Cb-7 cycloalkenyl * T is an anion that corresponds to an acid) Suitable examples of «include methyl, ethyl and n- and iso-propyl; benzyl and phenethyl. Suitable examples of T Includes dental compounds such as chloride, bromide, and iodide. Examples of scientifically acceptable salts also include oral salts such as N-oxides. Compounds of formula (I) , Its pharmaceutically acceptable amidines (including quaternary derivatives and N-oxides) can also form pharmaceutically acceptable solvates, such as hydrates, including any of the formulas (I) mentioned in the text It is also necessary to understand the (CHZ) 2 part of the compound of formula (I) (where z is -9- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ^- -----IT-----_.it / 1-(Please read the notes on the back before filling in this page) Chinese Patent Application No. 83107151 Patent Application Revised Page (Sept. 86) Α7 ^ Β7 V. Description of the invention (7) (b) ί, M can correspond to the bicyclic moiety to explore the α or zhao. Compounds of formula (I) can be prepared by the cooperation between Z and the indole moiety. The method is referred to V〇93 / 18036, the main body of which is incorporated herein for reference. 0 ---------- install ------; --tT ------ line (please read the back (Notes again 3) (written on this page) Printed by Shellfish Consumer Cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs 10-This paper size applies to Chinese National Standards (CNS) A4 specifications (210 × 297 mm) 5. Description of the invention (8) A7 B7 Examples of Compounds in the Ministry of Economic Affairs of the People's Republic of China "Ri R2 Γ R3 R4 XY z E1 Η Η 1 Η Η 0 0 (i) E2 Η Η 1 Η Η 0 0 ( vi) E3 Η Η 1 Η Η 0 NH (i) E4 Η Η 1 Η Η 0 0 (iii) E5 Η Η 1 Η Η 0 NH (Hi) E6 Η Η 0 Η Η 0 0 (i) E7 (CH3) 2 1 Η Η 0 0 (i) E8 Η Η 1 Η Η S 0 (i) E9 Η Η 2 Η Η 0 0 (i) E10 Η Η 1 Η ch2 0 (i) E11 Η Η 0 Η ch2 0 ii) E12 Η Η 2 Η ch2 0 (i) E13 Η Η 0 Η ch2 NH (i) E14 Η Η 0 Η Η 0 NH (i) E15 Η Η 1 Η Η 0 0 Bzppm E16 Η Η 1 Η Η Η so 0 (i) -1 1- -------! (| ^ ------, order ----- ▲ (Please read the precautions on the back before filling this page) The paper size Applicable to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 printed by the Ministry of Economic Affairs Central Standards Bureau M Industrial Consumer Cooperative Fifth, description of invention (9) Examples of compounds of formula (I) (continued)

Ri R2 Γ «3 r4 X Υ ζ E17 Η Η Δ Η Η CH 0 ⑴ E18 Η Η Γ Η Η CH 0 (i) E19 Η Η 1 Η Η S ΝΗ (i) E20 Η Η 1 Η Η Ο ΝΗ Bzppm E21 Η Η 1 Η ο-ΝΗ ppm E22 Η Η 1 Η Η 0 ΝΗ nC6H] 3ppm- E23 Η Η 1 Η Η 0 ΝΗ (ii) E24 Η Η 1 Η Η 0 ΝΗ Etppm E25 Η Η 1 Η Η 0 ΝΗMeS 〇2aEippm E26 Η Η 1 Η Η 0 ΝΗ (vi) E27 Η Η 1 8-F Η 0 0 (i) E28 Η Η 1 8-F Η 0 ΝΗ (i) E29 Η Η 1 Η Η NMe 0 (i) --- ^ ------ 1T ----- (Please read the notes on the back before filling in this page) This paper size applies to China National Standard (CNS) A4 (210X297 mm) Central Standard of the Ministry of Economic Affairs Advise Nugong Consumer Cooperatives to print A7 B7 V. Description of invention (w) Examples of compounds of formula (I) (continued)

Ri «2 r« 3 R4 X Υ ζ Ε30 ― π-Η Η S 0 ⑴ Ε31 Η Η 0 Η Η S 0 (i) Ε32 ― ύ — Η Η S 0 (i) Ε33 ― Λ Η. Η Ν 0 (i) Ε34 Η Η 0 Η Η S ΝΗ (i) Ε35 ― ― Η S ΝΗ (i) Ε36 Η Η .1 Η Η ΝΗ 0 ⑴ Ε37 Η Η 0 Η Η 0 0 (vi) Ε38 Η 2 Η Η 0 ΝΗ (i) Ε39 H Η Γ Η Η NG G (i) Ε40 Η Η 0 Η Η S 0 (vi) -13- ---------—— 装 ------ Order- ----- 线 '# ίι \ · (Please read the precautions on the back before filling in this page) The paper size is applicable to the Chinese National Standard (CNS) Α4 specification (210 × 297 mm) Central Ministry of Economic Affairs,- A7 B7 printed by the Bureau of Industrial and Consumer Cooperatives V. Description of the invention (11) Examples of compounds of formula (I) (continued)

Ri «2 r R3 R4 X Υ Ε41 Η Η 0 Η Η S ΝΗ (vi) Ε42 — — Η Η S 0 (vi) Ε43 — — Η Η S ΝΗ (vi) Ε44 Η Η 1 Η Η S 0 < vi) Ε45 — Γ — Η Η ΝΗ ΝΗ ⑴- ΈΑ6 Η Η 1 Η Η Ν ΝΗ (i) Δ-ARiR2is- (CH2) 2-CH- Bz -benzylΓ-ΑKK] ^ 2 ^ -ΓΉ = € Η -(: Η = ppm-4-hexaW-pyridine 棊 π-AR ^ 215-0 (^ 3) = ^-aEt-aminoethyl vertebrate-ARjR2 is-CH = CH-Λ-from two is -C ( CH3) = CH-C (CH3) = -14- This paper size applies to Chinese National Standard (CNS) Α4 size (210 × 297 mm) I ------ ir ----- * m (Please read the back first Please note this page before filling in this page) ♦ 1 Printed by the Central Ministry of Economic Affairs n,-^ M Industrial and Consumer Cooperatives A7 _ _B7_ V. Description of the Invention (12) The present invention is a compound of formula (I), where "is 3-phenoxypropyl, such as the compound of formula (IA), especially a compound similar to the aforementioned E3 (where phenoxypropyl replaces the n-butyl |? 5 substituent). The compound of the present invention is 5-HT4 Receptor antagonists, idle messages are often used to treat or prevent gastrointestinal, cardiovascular, and central nervous system diseases.翮 Treatment of intestinal allergies (IBS) * Especially diarrhea of IBS, that is, these compounds block the ability of 5-HT to stimulate the intestinal motility by activating intestinal neurons. The animal's horizontal form of IBS can be very convenient Measured by a reduction in the rate of defecation. They can also potentially be used to treat urinary incontinence often associated with IBS. — They can also potentially be used in other gastrointestinal disorders such as antiemetics related to upper bowel movements In detail, they may be used to treat gastric-esophageal reflux and indigestive nausea and stomach symptoms. The activity of antiemetics is known from known cytotoxic agents / radiation-induced vomiting animals Model. Cardiac SS-specific 5-HT4 receptor antagonists can prevent atrial fibrillation and atrial arrhythmias associated with 5-HT and may reduce the incidence of stroke (A. J. Coman (A. J Kauraann), Naouy η-Schmiedeberg structural pharmacology (N aumy η-Schmiedeberg · s A "ch. P ha" mac ο 1.) 3 4 2, 619-622, appropriate animal experimental methods ）. Depressive activity may be through hippocampal S3 (Dumu is) et al. 1988, Mol Pharmacol. 34, 880-887). This activity can be demonstrated using standard animal model social interaction tests and X-maze tests. Victims of migraine are usually under anxiety and emotional stress before the headache. This paper applies the Chinese National Standard (CNS) A4 specification (2 丨 0 > < 297 mm) »1 ^ ------. 玎- ----- ^ yf ». · Karma (Please read the precautions on the back before filling out this page) Printed by the Central Standard Ministry of Economic Affairs and Consumer Cooperatives of the Ministry of Economic Affairs A7 B7 V. Description of the invention (13) (S Sachs), 1985 'Migraine, Pain Book, London). The amount of cyclic AMP in cerebrospinal fluid increased continuously within 48 hours of migraine (Welch et al., 1976' Headaches 16, 160-167). Infrared migraine, including the prodromal phase and the increase of saccate AMP, are related to the stimulation of 5-HT4 receptors. Therefore, administration of 5-HT4 antagonists has the potential to relieve migraines. Others Diseases of the central nervous system include schizophrenia, Parkinson's disease, and Huntington's disease. The present invention also refers to a pharmacological compound that includes a compound of formula (IA), or a pharmaceutically acceptable Salts and a pharmaceutically acceptable carrier. These compounds are made from mixtures and are usually suitable For enteral, such as oral, canonical or rectal, or parenteral administration, it can be made into lozenges, capsules, oral liquids, powders, granules, sugar-coated tablets, reconstitutable powders, crotch sprays Children's, suppositories, injectable, impregnable solutions or suspensions. K Oral compositions are preferred because they are more convenient for general use. Oral lozenges and capsules are usually M unit doses and contain excipients known in the past such as a combination Agents, fillers, diluents, lozenges, lubricants, disintegrating agents, colorants, flavoring agents, and maize wetting agents. Lozenges can be applied using the methods known in the art « For example, use an enteric coating. Suitable fillers include stigmatonin, glucosamine, lactose and other similar substances. Suitable excipients include starch, polyvinylpyrrolidine and starch derivatives such as starch. Sodium glycylate. Suitable lubricants include magnesium stearate. Suitable pharmaceutically acceptable humectants include sodium dodecyl sulfate. -16- This paper is dimensioned to the Chinese National Standard (CNS) A4 (210 × 297) Mm) -------- ---- -. 玎 ----- · line. -JSI (Please read the note on the back ^ before filling this page) The Central Ministry of Economic Affairs advises only the consumer cooperative to print A7 __B7 V. Description of the invention (l4) Eye Liquids can be prepared in the following forms, such as: • Aqueous or oily suspensions, aqueous solutions, emulsions, syrups, or elixirs, or a dry product that can be reconstituted before use with water or other suitable excipients. Preparation of these liquids Ordinary additives such as suspending agents (such as sorbase, syrup, methyldivinin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate or hydrogenated food fat, emulsifiers such as Lecithin, sorbitan monooleate or gum arabic); non-aqueous excipients (may be edible oil) such as almond oil, fractionated coconut oil, oil esters (such as glycerides, propylene glycol or ethanol ); Examples of preservatives are methyl or propyl parabens or sorbic acid, and if necessary, previously known flavor inserts or colorants are added. Oral solutions are usually in the form of aqueous or oily suspensions, aqueous solutions, emulsions, syrups, or elixirs. They can also be a dry substance, which can be reconstituted with water or other suitable excipients before use. These liquids can be prepared using conventional additives such as suspending agents, emulsifiers, non-aqueous excipients (which can be edible oils), preservatives M, and flavoring or coloring agents. Oral compositions are usually prepared by mixing, filling or making lozenges. Repeated agitation can make the active agent evenly distributed in a large amount of filler of the sister compound. This approach is of course a known skill. Preparation of parenteral tinctures (liquid unit dose forms). Contains a compound of the present invention and a sterile vehicle. Depending on the vehicle and concentration • This compound can be made into suspension or dissolved. A parenteral aqueous solution is normally prepared by dissolving the compound in an excipient, filtering and disinfecting it, filling it into an appropriate vial or ampoule, and sealing it. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents are also dissolved in the vehicle. For the increase -17- This paper size applies to the Chinese National Twin (CNS) Α4 size (210X297 mm)--^ ----------- ▲ / 7 ^ .: (Please read the note on the back first Please fill in this page again) The Central Standard of the Ministry of Economic Affairs advises the Workers Cooperative Cooperative to print A7 _____B7_ V. Description of the Invention (l5) With stability, this sister compound can be frozen after being poured into a medicine bottle and removing water in a vacuum. stand up. Generally, parenteral suspensions are prepared by the same method, except that the compound is suspended instead of dissolved in the vehicle, and M is poisoned by ethylene oxide in heavy smoke, and then resuspended in sterile vehicle. in. More advantageously, the composition contains a surfactant or wetting agent, and the ribs are uniformly distributed in the compound of the present invention. The present invention further provides a method for treating or preventing intestinal allergies, indigestion, atrial irregularity and stroke, anxiety in mammals (such as humans), and / or migraine, comprising administering an effective amount of formula (IA) The compound is also a pharmaceutically acceptable salt thereof. The effective amount for treating a disease previously described herein depends on the relevant efficacy of the compound of the invention, the nature and severity of the disease, and the weight of the mammal. However, for a 70 kg adult, a unit dose of the compound of the present invention normally requires 0.05 to 1 000 mg, such as 0.5 to 500 mg. A unit dose can be administered one or more times a day, such as two, three, or four times a day, more commonly one to three times a day, ranging from 0.0001 to 50 mg / kg / day per day, and 0.0002 to 25 are common. G / kg / day. No harmful toxicity is clearly stated in the above dosage range. The present invention also provides a compound of formula (IA) or a pharmaceutically acceptable salt thereof, which is used as an active therapeutic substance, particularly for treating intestinal allergies, gastric-esophageal reflux disease, indigestion, atrial Irregularities and strokes, anxiety and / or migraines. -18- This paper size applies Chinese National Standard (CNS) A4 specification (210X297mm) — 1 see ------, 玎 ----- (Please read the precautions on the back before filling this page) Economy The Ministry of Standards and Staff Bureau of the People's Republic of China printed A7 ____B7 V. Description of the Invention (16) The following examples illustrate the preparation of compounds of formula (IA), and the following descriptions focus on the preparation of intermediates. ^ Μ_ N-[(l- (3 " • phenoxypropyl) -4-hexaoxazidinyl) methyl] 3,4-dihydro_2Η- [1,3]-? 2-a] D3 丨 night-10-sormine [χ = 〇, A = (CH2) 3 '(R 1 1 R z * R 3 * R a = Ηί Y — NH * Z = 4 ~ hexa nitrogen% Sialylmethyl, RB = 3-phenoxypropyl] H- (4-hexahydropyridylmethyl) 3,4-dihydro-2H- [1,3] treated with 3-phenoxypropyl bromide [3,2-a] indole-10-carboxamide (D2) (250 mg, 0.80 mmol) and triethylamine (0.2 5 · ml, 1.8 mmol) in acetonitrile (15 ml) and A stirred solution of a mixture of Ν, Ν-dimethylformaldehyde (10 ml), and the solution was heated at reflux for 48 hours. After the mixture was allowed to cool, it was shrunk in vacuo and the residue was dissolved in ethyl acetate (25 ml), and water ( (20 ml). The solution was dried under vacuum with (MgS04), and the residue was purified by silica gel with 0 to 20% methanol / ethyl acetate. The title compound was a pink solid, which was then triturated with ether (44 mg), melting point 120-1261. XH HMR (CDCla) δ 8.30 (d, lH), 7.07-7.37 (m, 5H), 6.96 (t, lH), 6.88 (d, 2 H), 6.64 (t, lH), 4.57 (t, 2H), 4.13 (t, 2H), 4.30 (t, 2H). 3.22-3.43 (m.4H), 2. 78-3.00 (m.2H) , 2.13-2. 5 7 (m, 6 H), 1.5 9-2. 0 3 (m, 5 H). (Benzyl-4-hexahydropyridyl) methylamine (Dl) Applicable to this paper size China National Standard (CNS) A4 specification (210X297 mm) -------------- IT ----- ▲ (Please read the precautions on the back before filling this page) No. 83107151 Patent application A7 Chinese manual revision page (September 86) B7 Five printed and invention description (/ rJ) by the Central Government Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative (Please read the precautions on the back before filling in this page) Use without water Potassium carbonate (64.9 g, 0.47 moles) treated with isohexocota * ide (30.1 g, 0.23 moles) and benzyl bromide (27.9¾ liters * 0.23 moles) in ethanol (250 ml The solution was stirred and heated for 3 hours. The mixture was allowed to cool, then simmered, and the filtrate was concentrated in the sky. The remaining oil was dissolved in chloroform (200 ml) and washed with water (1 x 150 ml). Dry (Na2S04) and concentrate in vacuo to leave a yellow solid (41.0 g). This solid was fully trickled with osmium pentoxide (38.3 g, 0.27 mol), then gently stirred and heated under nitrogen, 180 C for 2.5 hours. The reaction mixture was cooled and then treated with water (300 ml). When the solid mass dissolves, add 1 (2 (: 03) alkalization solution in solid form and extract with ethyl acetate (2 x 250 milliliters). Dry (Na2S04) combined extract and vacuum-shrink to leave a Brown oil body (35.3 g). The oil was decanted into anhydrous ether (250 ml) and lithium aluminum hydride (10.1 g, 0.26 mol) was added dropwise to ether (150 ml) over a period of 30 minutes under nitrogen at 0 t: M. Suspension. When the addition is complete, warm the mixture to room temperature and stir for 1.5 hours. Cool again to 0 and carefully add water (10 ml) * 10% HaOH solution (15 liters) and water (2 5 ml). K silicon thin earth is used to mix the mixture and vacuum shrinkage. K leaves a brown oily body, which after steaming in vacuum can produce a title compound (27.8 g, 67%) as a colorless oily body at 0.2 5mm Hg • Boiling point 1061: 〇 NMR (CDCla). Δ: 7.20-7.37 (b, 5H), 3.48 (s, 2H), 2.85-2.95 (, 2H), 2.55 (d, 2H), 1.87-2.00 U.2H), 1.60-1.75 (·, 2Η), 1. 10-1. 40 (·, 5H). . Sharp? · -20 This paper size is in accordance with Chinese Standard (CNS) A4 (210X297 mm) Printed by the SC Industrial Consumption Cooperative of the Central Bureau of Accreditation of the Ministry of Economic Affairs A7 B7 V. Description of the invention (18) a) N-[(l -Benzyl-4-hexahydropyridyl) methyl] indole-3-carboxamide in nitrogen, vermidoline-3-carboxylic acid (15 g, 0.093 moles) in dichloromethane (250 ml) Topping solution • Add grass-fed chlorine (8.7ml, 〇 (() _ ear)) and anhydrous dimethylmethosamine (6 drops). After 2 hours, the residual acid chloride (0.093 mol) was detected in metform and redissolved in dichloromethane (100 ml). After 5 υ, N-Π-benzyl- A stirred solution of 4-hexakismopentyl) methylamine (D1, 16.4 g, 0.093 mol) and triethylamine (15.5 ml, 0.11 mol) in dichloromethane (50 ml). After stirring overnight at the temperature of the altar, the reaction mixture was rinsed with 10% "2 (: 03) and the organic phase was dried (Na2S04). The solvent was evaporated under reduced pressure, and the remaining solid was recrystallized from ethyl acetate, To give the title compound as a white solid (17.5 g, 60%). X \\ HMR (CDCla) d: 9.90 (s.lH), 7.85-7.95 (m, 1H), 7.64 (d, lH ), 7. 1 5-7. 43 (m.8H), 6.17 (t, 1H), 3.48 (s, 2H), 3.37 (t, 2H), 2.83 -2.98 (πι, 2Η), 1. 8 7 -2.08 (m, 2H), 1.54-1.82 (m, 3H), 1.23-1.50 (m, 2H). B) N- [U-benzyl-4-hexahydropyridyl) methyl Base] 3,4-: S-2H-, 3] -Hui Geng and [3, 2-a] indole-1 0 -carboxamide at room temperature with 3-bromo-propionase (10.1 ml, 0.11 mole) and N-chlorosuccinimide (8.7 g, 0.065 mole) treated with benzyl-4-hexahydropyridinyl) methyl] indole-3-carboxamide (17.5 g, 0.050 mole) ) Stir in suspension (250ml) and add it to get a transparent -21 in 15 minutes-This paper size is applicable to China National Standards (CNS) A4 specifications (210X297 mm) C1 Notes on the back of the reading (Fill in this page again) A7 B7 printed by the Central Industry Bureau of the Ministry of Economic Affairs of the Industrial and Commercial Cooperatives. 5. Description of the invention (19) Bright solution. After 1 hour, the color of the mixed solution changed from pale yellow to dark orange, and the temperature rose to 3 8 t: After another 1 hour, treat the mixed solution M 10% NaHC03 solution, and separate the imitated layer. Dry yellow (Na2S04) and vacuum condensation can leave a yellow oil body. * It is used on silicone 3% formic acid / chloroform dissolution and chromatographic analysis. The intermediate 2- (3-bromopropoxy) indole was dissolved in propionamidine (400 ml), K anhydrous potassium carbonate (11 g, 0.08 mole) Work up and soak at room temperature for 20 hours. After vacuum shrinking the reaction mixture, treat the residue with water (200 ml) and extract with chloroform (2 x 250 ml). Combine the extracts in dry (Ma2SO4) and vacuum Concentration. Analysis on a silica gel with 5% formic acid / aqueous dissolution and color milling analysis> A pale yellow oily compound (3.1 g, 15%) can be obtained. It can be converted into its oxalate And recrystallized from acetone to obtain a white solid with a melting point of 1 69-170¾. Free radical: -M HMR (CDCU) δ · 8.32 (d, lH), 7.05-7.38 (m, 8H), 6.53 (t, lH), 4.50 (t, 2H), 4.08 (t, 2H), 3.48 (s, 2H), 3.31 (t, 2H) , 2.83-2.97 (m, 2H), 2.27-2.4 1 (m, 2H), 1.54- 2.06 (m, 5H), 1.25-1.45 (m, 2H). c) N- (4-hexahydropyridylmethyl) > 3,4-dihydro-2H [1,3] plow and [3,2-a] indole-10-carboxamide at 45t :, atmospheric pressure K10% MC (0.8g) hydrogenated N-[(l-benzyl-4-hexahydropyridyl) methyl] 3,4-dihydro-2H- [1,3] a] Indodol-10-carboxamidate oxalate (2.25 g, 0.0046 mol) in ethanol This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) --------- ----- ir ----- '0 if. (ίΜ Read the notes on the back and fill in this page again) Article 831071 51¾ Revised page of Chinese specification of patent application (Sept. 86) A7 B7 396158 V. Description of the invention (〆) ί

(100 ml) and a glacial acetic acid (4 ml) suspension for 18 hours. The mixture was quenched and the filtrate was concentrated in vacuo. The main product is solid and can be eliminated. This material was shaken with the residue of concentrated potassium carbonate solution (50 ml), aerosol (50 ml) and mash. After passing through the mixture, the chloroform layer was separated and dried (Na2SO4), and concentrated in vacuo to obtain a title compound (1.52 g, 100%) as a white solid. Recrystallized from chloroform / 60-80 gasoline, melting point 139-1411C ° 1 Η Ν Η R (CDC 1 3) δ-8.32 (d, lH), 7.03-7.30 (β, 3Η), 6.53 (t, lH), 4.48 (t., 2H), 4.05 (t, 2H), 3.30 (t, 2H), 3.02-3.15 (m, 2H), 2.52-2.70 (b, 2H), 2.27-2.40 (m, 2H), 1.65 -1.90 -------- »—!-• -install-- (Please read the note on the back of the page and then this page) Printed by the Central Standard of the Ministry of Economic Affairs of the Zhengong Consumer Cooperative (π, 4Η), 1.10-1.30 (b, 2H). 5-HT4 receptor antagonist activity 1) guinea pig colon Using a male guinea pig weighing 250-400 g, a longitudinal intestinal plexus preparation having a length of about 3 cm was obtained from the lateral colon area. They were weighed 0.5 g and suspended in a separate tissue bath containing Krebs' solution * 37 spoons were maintained while being pumped with 0 2 containing 5% C02. The Krebs solution also contained aethiothepin 10_7M and granisetron 10-βΜ Μ in all experiments to block 5-ΗΤι, 5-HT · »and 5-HT3 receptors. effect. After 30 seconds of contact and 15 minutes of dose cycle, a simple 5-HT concentration response curve can be constructed, and the 5-HT concentrate can be selected to make the muscle large -23-This paper uses the Chinese national standard ( CNS) A4 Specification (210X297 mm) Order No. 33107151¾ Revised Page of Chinese Specification for Patent Application (September 86) A7 B7 396158 Printed by Shellfish Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs 5. Description of Invention (> |) — j. The maximum yield of about 40-70% (about 10-eM). This group was then administered alternately every 15 minutes to the 5-HT concentrate and a nicotinic glucoside stimulant, DMPP, of approximately the same potency. After receiving the 5-MT and DMPP mineral reaction, a hypothetical 5-HT / receptor antagonist was gradually added to the bath. The effect of this compound can then be detected by reducing the percentage of shrinkage caused by 5-HT or DMPP. From this data, the pICso value can be obtained, which is defined as the antagonist's -log concentration which reduces contraction by 50%. A compound that reduces 5-HT response instead of DMPP response is believed to be a 5-HTa receptor antagonist. Of this compound? 1 (: 50 is 9.65 ± 0.20 (»\ = 4). 2) The rat esophagus is in accordance with Bax ter et al., Naunyn-Scheie-deberg's Arch Paraacol.) 343, 439-446 (1991). The intramuscular smooth muscle tube of this muscle was isolated and embedded in 37 spoons of isotonic oxygenated (95% 〇2 / 5% Co2) Tyrodes solution. All experiments were pretreated with H-methyl-N-2-propynyl benzylamine (Bajlin * pargyiine) in the presence of cocaine (30 μM) (100 WM, washed off after 15 minutes). 5-HT relaxation response can be obtained after pre-shrinking of the esophagus by carbachol (3w.H). -24-This paper size is applicable to Chinese National Standard (CNS) A4 (210X297mm) --------,-h—One Pack-(Please read the precautions on the back first and write this page) Order

Claims (1)

Patent No. 83107151 was filed in Chinese for the original patent application scope (September 86) 396158 A8 B8 — C8 -r; D8; (> SL · VI'ψψ \ 1. A compound of formula UA) or a compound thereof Scientifically acceptable salts (ΙΑ) (Please read the notes on the reverse side before filling out this page) X is 0, S_, SO, S02, CH2, CH or NR (where R is hydrogen or C 1-β complex); A is a saturated or unsaturated poly (methylidene) fluorene of 2-4 carbon atoms; R1 and fluorene 2 are ammonia or Ci-efluorenyl; R3 is hydrogen, halogen, Ci-e alkyl, amine, nitro or C, -β alkoxy; line is hydrogen, halogen, Ci-e alkyl or h-β alkoxy Y is 0 or HH; Z is sub-formula (a): (CH2) q-(CH2) n ^ FU (a) where n1 is 1, 2, 3, or 4; this paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) Patent No. 83107151 filed by the Chinese applicants for the original patent scope ( (Sept. 86) 396158 A8 B8 — C8 -r; D8; (> SL · hexa'ψψ \ 1. a compound of formula UA) or a scientifically acceptable salt thereof (ΙΑ) (Please read the notes on the reverse side before filling out this page) X is 0, S_, SO, S02, CH2, CH or NR (where R is hydrogen or C 1-β complex); A is a saturated or unsaturated poly (methylidene) fluorene of 2-4 carbon atoms; R1 and fluorene 2 are ammonia or Ci-efluorenyl; R3 is hydrogen, halogen, Ci-e alkyl, amine, nitro or C, -β alkoxy; line is hydrogen, halogen, Ci-e alkyl or h-β alkoxy Y is 0 or HH; Z is sub-formula (a): (CH2) q-(CH2) n ^ FU (a) where n1 is 1, 2, 3, or 4; this paper size is in accordance with China National Standard (CNS) A4 (210X297 mm) 396158 'Scope of patent application < 1 is 0, 1, 2, or 3; (please read the notes on the back before filling this page) Rs is 3-phenoxypropyl; Re is argon or "-βalkyl; or The compound of formula (IA), in which CO-Y bond Satoshi is replaced by a heterocyclic isosteric compound; it has the activity of a 5-HT4 receptor antagonist. 2. The compound according to item 1 of the patent application, where X is 0. 3 · The compound according to item 1 or 2 of the patent application scope, where A is (CH2) 3- 0 4. The compound according to item 1 or 2 of the patent application scope, among which 1 ^ and 1? 2 Respectively hydrogen or methyl. 5. Compounds according to item 1 or 2 of the scope of patent application, where R3 is oxygen K and R45 S or halogen. 6. · Compounds according to item 1 or 2 of the scope of patent application, where Y is 〇 or NH 〇 7. The compound according to item 1 or 2 of the scope of patent application, in which Z is the formula U) and (CH2) „1 are attached to the carbon atom of the nitrogen heterocyclic ring. δ. Compound according to item 7 of the scope of patent application • where Z is N-substituted 4-hexahydropyridylmethyl. Printed by Shellfish Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs 9. Ν-[(Bu (3-¾oxopropyl) -4-hexahydropyridyl) methyl] 3,4-dihydro-2H- [1, 3] Pyrene and [3,2-a] indiodo-10-carboxamide or a pharmaceutically acceptable peptone. 10. A method for preparing an ester or amine in accordance with item 6 of the patent application, which method includes reversing an appropriate acid derivative with an appropriate alcohol or amine. This paper is in accordance with Chinese national standards (CNS ) A4 specification (210X297 mm) 396158 A8 B8 C8 D8 々, patent application scope 11. A kind of B drug sister compound used as a 5-HT < t receptor antagonist, including according to item 1 or 2 of the scope of patent application Compound * M and a pharmaceutically acceptable carrier. 12. The compound according to item 1 of the scope of patent application, which is a substance using M as an active treatment. 13. A pharmaceutical composition using M as a 5-ΗΤλ receptor antagonist according to item 11 of the scope of the patent application, which is used to treat or prevent bowel disease, cardiovascular disease, and neuropathy disease. (Please note the notes on the back of Mtt before filling out this page.) Order Printed by the Central Standards Bureau of the Ministry of Economic Affairs and printed by the Cooper ’s Consumer Cooperatives.