TW407160B - Tricyclic indazole derivative compounds, processes for the preparation thereof and pharmaceutical compositions comprising the compounds - Google Patents

Abstract

Compound of general formula (I) in which: R1 represents a hydrogen atom, a halogen or a C1-4 alkoxy, methyl, hydroxyl or amino group, R2 and R3, which may be identical or different, represent a hydrogen atom, a C1-4 alkyl group, a phenyl or a benzyl, X represent an oxygen atom or an -NH- or -N(C1-4 alkyl)-group, and A is a group of formula B or C.

Description

407160 A7 B7

V. Description of the invention (The present invention relates to the preparation and treatment of Benxixin, especially as an inhibitor of the 5-HTV5-HT4 receptor. ”, European Patent Application No. 0,350,130 (11) Compound: αΐ) In particular, the following derivatives: Heart (endo_8 • methyl_8 • azabicyclo [3 21] octyl-3, -7,8-dihydro-6Η-pyrazole 幷 [4 , 5, ^] · Pyridin-2-carboxamidamine, N (inner_9-methyl-9-azabicyclo) -78 • dihydro-6ηpyridine and lin-2-amine 'Ν_π azabicyclodioctyl-3-octyl) -7,8-dihydro-611-pyrazolo [4,5,1 heptamidine-2-carboxamidine hydrochloride and 7,8 -Dihydro-6Η-pyrazole 幷 [4,5,1-ij] pyridinium_ 2 _carboxylic acid_ Ν (end_ 8 _ methyl-8-azabicyclo [3,2,1] octane-3 -Based esters. This application describes these compounds as potent 5-HT receptor inhibitors, but more specifically as 5-HT3 subtype receptor inhibitors-Bezold-Jadsh ^ The trial has established the nature of the 5-HT3 subtype receptor and in the central nervous system ("neuronal 5-HT). However, it does not mention that these compounds are on the 5-HT receptor subtype 'like 5-HT4 Related activities In addition, 'the 5-HT3 receptor inhibitor is well known and has special properties such as antiemetic, especially when anticancer drugs with high vomiting properties are used. These compounds' such as (setron ) Family of compounds, such as (〇ndansetr〇n) or (Granisetron) 0 -4 paper music scale across the state SS family 榡 榡 (('NS) Λ4 size (2IOX 297 public 漦)) -------- 1T ------. Come, J * < (Please read the notes on the back before filling out this page} '-407160 A7 V. Description of Invention (B7

According to the present invention, it has been observed that the material has a mixed activity of 5 brown 3 and synaptic-equal balance. These equal compounds have the same affinity for the 5-jHT3 and 5-HT4 receptors, that is, their 5_ΗΤ3 / 5_ΗΤ4 affinity ratio is about 15 to 5 ', and' 5f 3 is better. This novel And unexpected pharmacological properties can be allergic to viscera. Intestinal spasm ’is the main symptom of intestinal dysfunction (brain), which produces potent time depression. In addition, the compound exhibits special anti-secretory activity on the intestine, and has strong anti-diarrheal properties in the absence of the colon as a buffer zone. According to the present invention, the benzamidine derivative of the general formula (1) is as follows: 0jx-A R. (I) where: Ri is a hydrogen atom 'halogen or alkoxy, methyl, hydroxyl or amine, R2 And I may be the same or different, and are a hydrogen atom, a Cw alkyl group, a phenyl group, or a fluorenyl group, X is an oxygen atom, and A is a formula B or c A * (CH2) n ··· -、 玎 ------ ^ '* ·-(Please read the notes on the back before filling this page) · · _

Ν 'B

C Ν-(CH2) n (CH2) m -5- Wood paper scale suitable for Sichuan 1¾¾ house standard 々 (rNS) Λ4 specification (2iO'x297 public acid) «07160 ΑΊ _______ Β7 V. Description of invention u) '--- -Where: γ is a nitrogen atom or a methylene group, R4 is a hydrogen atom, (^ _4 or a benzyl group, η is equal to 0 or 1, and m is equal to 0 or 1. In the application: _C, 4 is a The main chain 'may contain from 1 to 4 carbon atoms, such as methylethyl, propyl' isopropyl, butyl, tetrabutyl or tertiary butyl 'or feoxy-words respectively A straight or branched carbon chain with a school or alkoxy group, and -halogen is an iodine, bromine, gas or fluorine atom. The compound of general formula (I) contains one or more asymmetric carbon atoms, which can Isomers or non-specular isomers' and mixtures thereof, including racemic mixtures, exist in the form of the _ part of the present invention. The compounds of general formula (I) can be in the form of free radical or pharmacologically acceptable acid addition salts Existence is part of the present invention. Preferred compounds according to the present invention wherein: R 2 and R 3 may be the same or different, are hydrogen atoms, c " alkyl, especially fluorenyl. Other preferred compounds are A of formula C, and more preferred compounds of A are formula C and X is an oxygen atom. The latter compounds preferably have η equal to 0 and 0. The compounds of the present invention can be prepared by the following scheme. I) Compounds can be prepared according to Scheme 1 from compounds of formula (II), wherein R, R 2 and R3 are as defined for compounds of formula (I) and W is a halogen, especially a gas atom, and compounds of formula (III), where X And A are as defined for the compound of formula (I), and the reaction is prepared __ __ -6- Mu Zhile scale valve in this state 1¾ family standard (('NS) (210X 297 ^^) ~ " " >..-(Please read the notes on the back before filling this page) '-· ， A7 B7 0 407160 V. Description of the invention (4)' 一 ~ '一 " This reaction can be performed in advance by using the butyl lithium in tetrahydropyran to form the relative alkoxide. When X is an amine, whether NH or N-Cw alkyl, the reaction can be performed at "It is also soluble" in the presence of a base such as trichloromethane or dichloromethane. In the presence of a base such as triethylamine, these esterification or amination reactions are well known to those skilled in the art. The temperature range is between -0 ° c and + 50 ° c. Process 1 o

X-A

A pack-,-(Please read the notes on the back before filling out this page) R ‘(II) (ill) 〇〇 ^ R. (丨)’ R.

1T starting materials are commercially available and are known in the literature or can be prepared by those skilled in the art using standard methods. Q This' list is a compound HXA compound of formula (III) where n = 0 and X is an oxygen atom or an NH group And A is Formula B and is commercially available. Compound of formula (111) h_x_a Compound 'where n = 1 and X is an oxygen atom or an NH group and a is formula b, has been described in the Journal of Medical Chemistry (7.1 ^ (1 _ (: 1 ^ 111.), (1991), 34 The compound of formula (III) is HXA compound, wherein n = 1, X is NH group and A is formula B and Y is nitrogen atom, which is described in French Patent Application No. 2,735,475. Compound of formula (III) -X-A compounds, where A is formula c, are also described in the literature 'for example, the following publication: Journal of the American Chemical Society (J Am. Chem. -7-Paper scale) , NS > Λ4 specification (2 丨 0 · × 297mm) line 407160 a? ---- —_ B7 V. Description of the invention (5)

Soc), (1958) '80' 4677: Tet. Lett. (1996) '37' 3977 and DE Patent Application No. 3,322,574 and European Patent Application No. 081, 054. The compound of formula (11) described in Scheme 1, wherein w is an ammonia atom and Ri, R2 and h are as defined for the compound of formula (I), can be obtained from the compound of formula (χιπ) according to a method well known to the artist, It can be obtained by thixosulfite, thionyl chloride, or grass gas activation of the acid from benzyl acid. 〇

Compounds of formula (XIII) can be prepared according to the method generally described in Scheme 2, starting with derivatives of compounds of formula (IV), where R ,, r 2 and R 3 are as defined for compounds of formula (). Process 2

According to this scheme, the compound of formula (IV) can be boron trifluoride and acetonitrile in J. Am. Chem. Because of the standard cold (('N'S) Λ4 specification (210 × 297 male)) "# 部 屮 央 lf ^^ u 3ί,; ^ " :: ν7ί, 0

407160 V. Description of the invention (6 SOC_) (1980) 100 1357, the conditions described in the treatment can be obtained formula (v) compound 4 'where RR2 and Rs are as defined for the compound of formula ⑴, followed by the acid medium {胬 Under the conditions familiar to this artist (Jerry March, Advanced Organic Chemistry, published by John Wiley & Sons, third edition, P.572) N-nitrosation with sodium nitrile to obtain a compound of formula (v 丨). Compounds of formula (v 丨) can then be processed under conditions known as Knöevenagd reactions (advanced organic chemistry in Jerema District, published by John Weili and its children's publishers) , Third Edition, pp. 835_84), the compound of formula (νπ) 'where R〗 R 2 and R 3 are as defined for the compound of formula ([). The N-nitrosating functional group of the compound of formula (νπ) can be used in the presence of acetic acid, reduced with zinc powder, and immediately cyclized to obtain the compound of formula (VIII) 'wherein R !, 112 and R3 are the same as those of the compound of formula (1) definition. Finally, the compound of formula (IX) can be prepared by oxidizing the compound of formula (VIII) in the presence of ozone, or treated with sodium periodate or osmium tetroxide to obtain the compound of formula (IX). The compound can then be oxidized with silver nitrate in the presence of potassium peroxide to produce a compound of formula (XIII), where R!, R 2 and R are as defined for a compound of formula (I). Alternatively, a compound of formula (XIII), wherein Ri, R2 and R3, as defined for a compound of formula (I), can be prepared according to the general preparation method described in Scheme 3. Process 3 ΝΗ (IV)

〇 The size of this paper is Hongzhou Zhongli prison family standard ((, NS), Λ4 size (210X297 public dream ·) (Please read the precautions on the back before filling this page)-° 407160 A7 B7 V. Description of the invention (7 " The Ministry of Governance decides the standard and Π 7, eliminates the combination: ;;: " 印 1 ;. 10 Ο

Rp (χΙΟ R2R3 (XIII) According to this scheme, a compound of formula (X) can be prepared by reacting a derivative of formula (IV) with 2-cyanofuran and trichloride under the conditions interpolated by the above-mentioned 菅 沢.) The compound of formula (XII) can be obtained by nitrosating the compound of formula (X), and then reducing the obtained compound of formula (XI) with zinc and cyclizing the intermediate. Finally, the compound of formula (XII) is acetonitrile and benzene and Oxidation of a mixture of acetone (cliem Abs.) 55, p 16518, 1961 with a mixture of potassium permanganate and potassium carbonate yields compounds of formula (XIII) in which R1, R + R3 are the same as those of compounds of formula (1) Definition. Compounds of formula (IV) can be prepared by methods known to those skilled in the art. For example, compounds of formula (IV), in which R 2 and R 3 are hydrogen atoms, can be phase-inverted by 2 amine phenol derivative gas, acetamidine gas. (X Huang et al., Synthesis, (1984) 10 85〗), prepared by reduction reaction with lithium aluminum hydride or boron complex, usually in an ether solution such as tetrahydrofuran or ether Similarly, the compound of formula (IV), whose center and / or center is cM alkyl, phenyl 'or fluorenyl, can be directly obtained from 2 -Nitrobenzene derivatives were prepared by reacting acetophenone or 2 · gas- or 2-bromoacetophenone with Raney nickd in ethanol (Melloni et al. 'J Het. Chem (, (1983) 20 259). The following "Examples illustrate suitable methods and techniques for preparing this invention, but are not a limitation of the present invention. Microanalysis and NMR * IR spectroscopy have determined that the size of the compound wood paper is suitable for / 1; : ¾¾1¾: standard 4 (('NS) A4 ^ iT (7lOX 297 ^ i " --------- installation ------ order ------ spring,.-. (Please first Read the notes on the reverse side and fill in this page) · · · · A7 B7 407160 V. Structure of the invention description (8). Example 1 for preparing compound of formula (I): 7,8-dihydropyrazolium [1, 5 , 4-This] [1,4] Benzene-fluorene-carboxylic acid-endo-8-fluorenyl-8-azabicyclo [3.2.1] octyl-3-yl ester hydrochloride will be 2.5 g (0.0122 Moore) of 7,8-dihydropyrazolo [i, 5,4-de] [l, 4] phenylpyrene, 1 to 2 -chicanic acid, 2.5 ml of sulforium chloride and a few drops of dimethylformyl 80 ml of 1,2-digasethane mixture of amine was heated to 80 ° C for 1 hour and 30 minutes. The solvent was evaporated completely under reduced pressure to obtain the acid gaseous substance, which can be used in subsequent steps without purification. 10 ml (0.02 mol) of 2 mol concentration of secondary butyl lithium pentyl lake was added dropwise to a content of 2.75 g (0.0195 mol) of 8 · methyl_8-azabicyclo [3 21 ] Siu-Yan-3-Yeast 1000 liters of tetrahydrofuran solution. After the mixture was stirred at 0 t for 30 minutes, 20 ¾ liters of 1,2-gas ethyl acetate solution of the acid gaseous substance (00122 mol) obtained above was added dropwise. The mixture was stirred at room temperature for 18 hours. The reaction was poured into water in an ice bath, and the product was extracted with chloroform. The organic layer was washed with water until the acid and alkali were neutral, dried and the solvent was rashed. The product was purified on silica gel by chromatographic analysis and washed out with a mixture of aerosol and methane to obtain 2.77 g of the product, which is a free radical type. Add the lice ether sap to the free radical of the product 'and then grind it with the ether and methane mixture' to obtain its hydrochloride. Marriage point = 292C (decomposed). N- (exo-8_methyl · 8_azabicyclo [3 2oct_3_kib dihydropyrazolidine [1,5,4-also J [l, 4] benzene humeng _ 2 _ Carboxylamidine hydrochloride 11-SS family standard in the old Chinese standard ((, NS) A ^ iT7i〇x2W public jacket, 1r ^,---(Please read the precautions on the back before (Fill in this page) --.- Ministry 4 \ Standard Bureau f-: λ, ί] Seal 407 60 A7 B7 t centric 1} Λ Η; Yu Heil V. Description of the invention (9 / 0.363 g (0.0178 mol) 7,8_dihydroepine, 5,4 pure 14] Benzene gas -2-carboxylic acid, 0.19 ml (0.0021 mol) grass gas and a few drops of dimethylformamide t 15¾ liters of the tetrahydrofuran mixture was stirred at room temperature for 1 hour. The solvent was completely evaporated under reduced pressure to obtain the acid gaseous product, which was used in subsequent steps without purification. The acidic gaseous product obtained above (0.0021 mo 5 ml of tetrahydrofuran was added dropwise to a solution of 15 ml of tetrahydrofuran containing 0.620 g (0.0044 mol) of 3- lactamine and 0.26 ml of triethylamine (0.015 mol). The mixture was stirred at room temperature for 5 hours. The reaction was poured into a saturated sodium bicarbonate solution In the process, the product was extracted with aerosol, the organic layer was washed with water, dried and the solvent was evaporated. The product was purified by chromatographic separation on Maoxijiao, a mixture of aerosol, methylbenzene and water-soluble ammonia (95.5: 0.5) After washing out, 20 g of product can be obtained, which is a free radical type. Hydrogen ether solution is added to the free radical of the product and then triturated with ethane to obtain the hydrochloride salt. Melting point> 270 ° C. The same Method to prepare trans_ (inner_ 8 _methyl_ 8 _ azabicyclo [3 2 oct-3-yl) -7,8-dihydropyrazole, benzohumen, 2 _carboxamide Amine hydrochloride. Melting point> 280 ° C. Complex ± L1: N- (endo-9-methyl-9-azabicyclo [3.3.1] non-3-yl) -7,8-dihydroane Jun 弁 [1,5,4-Zhao] [1,4] Benzene _-2-carboxamide '. Amine hydrochloride consists of 0.68 g (2.94 moles) of 7,8-dihydropyrazolidine [l, 5,4-de] [l, 4] benzyl-2-carboxylic acid 'and -9-methyl-9-aza-12 wood pulp within 90-90 g (0.0059 mol) The standard uses four standard valves in the valve (d'S) Λ4 specification (2IOX 297 gong) --------- batch of clothes ----- 1T ------ quan- ·-. ( (Please read the notes on the back before filling out this page) · · *-40 7160 A7 B7 V. Description of the invention (1〇) Bicyclic [3.3 · 1] non-3 -ylamine, starting with the repair process described in Example 2 after purification on gem gel by f-chromatographic analysis. It was washed out with a mixture of aerosol, methane and water-soluble ammonia (90: 10: 0.1) to obtain 0 350 g of the product, which is a free radical type. The hydrogen solution is added to the free radicals of the product in chloroform, and the solvent is evaporated, so that a crystal of a mixture of ethyl acetate and chloroform can be obtained. Melting point = 270-272 ° C (decomposed). : Ν-ί [8 · (phenylhydrazone) -8-azabicyclo [3.2.1] octan-3_yl] methyl] -7,8-dihydropyrazolidine [1,5,4-also ] [1,4] Phenylpyrene · "Jin-2-Epiridamine amine hydrochloride from 0.460 g (0.0023 mole) of 7,8-dihydro p ratio [1,5,4-this] [1,4] Benzene sulfonium-2-carboxylic acid, and 0.570 g (0.0025 mole) of 8 · (phenylfluorenyl)> 8-azabicyclo [3.2 · 1] octane-3 -methylamine Initially, the conditions described in Example 2 were used to treat 'after purification on silica gel by chromatographic analysis, and washed out with a mixture of chloroform and methane (9 .. 1), to obtain the product 0120 g, as a free radical Type. The hydrochloride salt can be obtained by adding hydrochloroether solution to the free radical of the product and grinding it with ethyl alcohol. Melting point > 255 ° C. F rolling 5 .: 7,8-dihydro P specific vomiting Benzo, 5,4-this] [1,4] benzohum-2 -carboxylic acid-endo-9_ (benzyl) -9-azabicyclo [3.3.1] non-3-yl ester 0.38 g (0.0014 mol) of 7,8-dihydro? Ratio. Jun and [1,5,4-^^ [1,4.] Benzene humen-2-carboxylic acid, and 0.300 g (0 00122 Mol) within the benzoazabicyclo [3.3.1] nonane_3_ol, treated with the conditions described in Example i After purification on silica gel by chromatographic analysis, aerobic, methane and water-soluble -13- wood paper music scale Shizhou τMin K1 糸 standard 1 (CNS) Λ4 specifications (2 丨 Ox 297 public expense ---- ----- Install ------ Order ------ j. ·-. (Please read the precautions on the back before filling this page) --- 『A7 B7

40716C V. Description of the invention (11) The helium mixture (97: 3: 0.3) was washed out to obtain the product of 0,240 g, which is a free radical type. . Melting point is about 60 ° C. ~ '1 6: 4 · fluoro-7,8 · dihydropyrazolo [l, 5,4-dsj [l, 4] benzyl beer_2_carboxylic acid · end_8-methyl-8-nitrogen Heterobicyclo [3.2.1] octyl-3-yl ester hydrochloride is made from 1.2 g (0.0054 mol) of 4-fluoro-7,8-dihydropyridine] [1,4 ] Exhaust Jinjin-2-within 1.22 grams (0.00864 moles) of _ 8 • Methylazabicyclo 〖3.2_1] Nonan-3-ol, start with the conditions described in Mi Mi, After purification on silica gel by chromatographic analysis, 103 g of the product obtained was washed out with a mixture of chloroform and methane (95: 5), which was a free radical type. Hydrogen ether; Valley liquid was added to the free radical of the product, and after grinding with diethyl ether, the hydrochloride was obtained. Melting point = 280 ° C (decomposition). ~ -Fluorene- · 4-fluoro-8-methyl-7,8-dihydropyrazolo [1,5,4-this] [1,4] benzohumen-2-carboxylic acid-endo-8 _Methylazabicyclo [3 2 丨] octyl 3-yl ester hydrochloride by 0.250 g (0.00! Μmol)幷 幷 Π, 5,4-this] [1,4] Phenorin-2-carboxylic acid and 0.237 g (0.00168 mole) within 8-fluorenyl-8-azabicyclo [3_2 丨] The alkane-3 alcohol was started and treated under the conditions described in Example 1. After purification on silica gel by chromatographic analysis, it was washed out with a mixture of aeroform and methane (9: i) to obtain 26 g of product. It is a free radical type. The hydrochloride solution is added to the free radicals of the product, and the hydrochloride is obtained after grinding with diethyl ether and formazan. Alkane point = 296 ° C (decomposed). ^ 1τ ------ car----(Please read the notes on the back before filling in this 5)-Part A t * it quasi _τ elimination f: 合 ίί • J; 14 paper standard delivery State standard 家 ((, N, S) 8 4 specifications (2 丨 0 乂) 97 ounces) 40716 (" YE Department-blowing #r; v- ^ u J 消 论 合 ^ " 印-, .Dong, description of the invention (12 bis. 7,7-monomethyl_78_dihydropyrazole hydrazone [154 benzamidine carboxylic acid-endo_ 8 -methyl_ 8 • azabicyclo [3 2 3-yl ester hydrochloride consists of 0.23 g (0.00099 mol) of 7, 'dimethyl-78 dihydropyrazolidine I, 5,4 • blood] Π, 4] benzene 弁 啰 ° well -2-carboxylic acid and 0.225 g (0.0016 mol) within _8_methyl_8_azabicyclo [3.2.1] nonane-3-ol, as described in Example 1 After being purified on silica gel by chromatographic analysis, it was washed out with a gas :: methane mixture (9: 丨) to obtain the product 03 g. As a free radical, a hydrogen ether solution was added to the free radical of the product. After diethyl ether and methane are ground together, the hydrochloride salt can be obtained. Where the melting point = 173 ° C (decomposition). Once on L2_. 3-Ga-7,8-dihydropyrazolium benzamidine-carboxylic acid- Endo-8_methyl'S-aza Cyclo [3.2.1] oct-3-yl ester hydrochloride-3-qi_78 · dihydrotonne 幷 [154 姻 Benzene 幷 humeng-2- Carboxylic acid and within 0 226 grams (0016 mol) _ 8 _ methylazabicyclo [3_2 · 1] nonane · 3 _ alcohol, treated with the conditions described in Example IX, in Israel After the layer analysis was purified on mineral gum, the 'available product 0305 g was obtained with a mixture of aeroform and methane (9: 1), which is a free radical type. Hydrochloroether solution was added to the free radical of the product. After grinding with diethyl ether and methane, the hydrochloride can be obtained. Melting point: > 30〇3C. Example 1 color: 7,8-dihydropyrazolidine [1,5,4-Zhao] [1,4 ] Benzene "No. 11 Well 7_carboxyselection_ 1 -azabicyclo [2.2.2] octyl-3 -yl ester ethylenedisulfonium salt 0.550 g (0.00269 mole) of 7,8-dihydropyrazolium 4] -15- This paper is suitable for ^] Medium: Standard (('NS) M specifications (21〇: < 297 mm) Packing-(Please read the precautions on the back before filling this page) * 1Τ spring "? &Quot; ίΓΙcentral 桠 ίν-, " θ η 40716 (α7 ----- Β7) V. Description of the invention (13) Benzophenone-2-carboxylic acid, 0.28 ml 0.00323 mole) of oxalyl acyl gas and a few drops of dimethyl amine enjoin Yue 10 ml tetrahydrofuran stirred at room temperature dial Shu hours. Evaporate the solvent completely under reduced pressure to obtain the acid gaseous compound, which can be used in the post-painting step without purification. 1.5 ml (0.00378 mol > of 2.5 mol concentration of secondary butyl lithium panthane) was added dropwise to a 10 ml solution of tetrahydrofuran containing 0.485 g (0.00432 mol) of + phenyl ring. The mixture was prepared in (TC After stirring for 30 minutes, it was added dropwise to a 10 ml tetrahydrofuran solution of the acid chloride (0.00269 mole) obtained above. The remote mixture was stirred at room temperature for 20 hours. The reaction was poured into an ice bath. In water, the product was extracted with aerosol. The organic layer was washed with water until the acid cyanine was neutral, dried, and the solvent was evaporated. The product was purified on silica gel using chromatographic analysis, and a mixture of aerosol, formazan and water-soluble ammonia was used. (95: 5: 0.5) Wash out to obtain 0280 g of product, which is a free radical type. Add twice the amount of oxalic acid in ethanol and methanol mixture to the free radical of the product to obtain the glycol diester. Melting point = 221-222 ° C. Complex 丄 L · (1-azabicyclo [2.2 · 2] octyl _ group) _ * 7,8_dihydro p-pyrazolium [l, 5,4-4e _] [l ， 4] Phenylhydrazone-2-carboxamidamine hydrochloride; Pyrene is composed of 0.460 g (0.00225 mole) of 7,8_dihydropyrazolo [15,4 marry [14] 2-carboxylic acid 0.630 g (0.003 moles) of (s) _ aminopyridinium ring, treated with the conditions described in Example 2, after purification on silica gel by chromatographic analysis, followed by aerosol, methane and water solubility Ammonia mixture (90: 10: 1) was washed out to obtain 0.280 g of the product, which is a free radical type a —----------------- ~ 16-wood paper The scale is facing the Chinese family home standard Chinese (('NS) (210X 297 ^^) --------- install -------- order ------ "-..-(Please first Read the notes on the back and fill in this page)-~ _-^ ------- V. Description of the invention (14) " Add hydrogen ether solution to the free radical of the product, and diethyl ether—after the research and production The hydrochloride can be obtained. Melting point = 266-268 ° C. In the same way, (Ej-K- (1-azabicyclo [2 2 2] octyl-% group) -7,8- Dihydropyrazole hydrazone [1,5,4_location jn, 4] benzopyridin-2 · Carboxamidate ethanedioate. Melting point = 191-193Ό. U 12: 7,8_dihydropyrazole幷 n, 5,4-i £] [l, 4] benzene 幷 hum, well_2_carboxylic acid_i · azabicyclo [2.2.2] octyl-3_yl methyl ester hydrochloride by 0.600 g ( 0.00294 mol) of 7,8-dihydro blowing [1,5,4-this] [ι 4] Benzene humeng-2 -carboxylic acid And 0.665 g (0_0072 moles) of __azabicyclo [2.2.2] nonane-3 -methanol were treated with the conditions described in Example 1, after purification on silica gel by chromatography, and A mixture of chloroform, methane and water-soluble ammonia (95: 5: 0.5) was washed out to obtain 0.58 g of the product, which is a free radical type. A hydrogen ether solution was added to the free radical of the product, and it was burned with ether and methyl chloride— After grinding, the hydrochloride can be obtained. Melting point = 26TC = Example 13: (ΚΗϋ)-(1,4-diazabicyclo [2.2.2] oct-3-ylmethyl) _ 7 8_ dihydropyrazolium [l, 5,4-4gj [l, 4] Benzamidine-2-carboxamidine hydrochloride (2 :)) is composed of 0.204 g (0.001 mol) of 7,8-dihydro p ratio [1,5,4-4ej [i 4] Benzene humen-2-carboxylic acid, and 0_25 grams (0.0018 moles) of (Magic_trans_Xiakou diazabicyclo [2_2.2] nonane-2-methylamine starting with Conditional treatment in Example 2 'After purification on silica gel by chromatographic analysis, 1K was present (~ CNS) (210X 297 ^) in aerosol, nail, pit, and -17-wood paper scale iM]. ^ ~~ '--- 一 ~-I-I— n I— I nn I— I-1 n I-T _ HI I n _______ K. u ^ », -u > ---. (Please read first Note on the back, please fill in this page again) '-· V. Description of the invention (15 Α (νη6 [A7 B7 line " · " central if " ^ p' η Water-soluble ammonia mixture (90: 10: 0.1) Wash out 075 g of the product can be obtained, which is a free radical type. Hydrochloroether solution is added to the free radical of the product, and after grinding with ethyl alcohol, the dihydrochloride can be obtained. Melting point> 250 ° C (decomposition ). Preparation Interstitial formula (XIII) compound is here again! 14: 7,8_dihydropyrazole 幷 n, 5,4-dsj [l, 4] Benzene saccharine_ 2 -Chinic acid 14.1. (3,4-Di Hydrogen-2H-M-Benzamidine-5-yl) fluoro_2-ylmethane ketone 200ml (0.2 Molar) of boron trinitride solution (丨 Molar concentration of heptane) within 1 hour ' Nitrogen pressure was slowly added to maintain the temperature between 0 and 5. Between 5 g (0.11 mole) of 3,4-dihydro-2E-1,4-phenylxanthine, 200 ml of 12 · digas ethane solution The mixture was heated to reflux for hr 30 minutes, and then cooled. 20 ml (0.22 mol) of 20 ml of fluorofluoronitrile and 20 ml of 1,2 dioxane were added over 20 minutes. The reaction mixture was refluxed for 3 hours and then left overnight at room temperature. To hydrolyze the formed imine intermediate, the reaction was cooled in an ice bath, and then 500 ml of 3 mol hydrochloric acid was added, and the temperature was maintained at 5 to 8 c. The mixture was then heated to reflux for 45 minutes. 3 The mixture was cooled again, and then the mixture was basified by adding 30% strength sodium hydroxide to acid and alkali. The product was extracted with methane and the organic layer was saturated with sodium carbonate. Aqueous solution And dried, the solvent evaporated Chromatography .2 under reduced pressure was purified on silica, eluted with two methane gas. The product may be the end product from hexane to give reply i i 7 grams. Melting point = 6 3 ° C. In the same way, _7_fluoro_ (34_dihydro_2ε_μ can be obtained. • Stupid hum, please read the precautions before reading, then fill in% Ben 1 binding spring-18- wood paper 仏 scale; tH, Oka 1¾ family standard 7 (^ NS) A4 specifications (210X 297 males 5. Fifth, description of the invention (16) 40716C a7 B7 邙 central it bei-T-f: He V \ Yin Geng-5-Ji) Fur-2-Ji Methane; Melting point = 102 ° C. -2,2-Dimethyl- (3,4-dihydro-211,4-benzylbenzyl_5_yl) Bite_2.Methylformaldehyde · 14.2. 2 -Cranyl (4-nitroso-3,4-dihydro "2H_M_benzenesakizaki_ 5 · yl) pinenone 4_33 g (0.063 mol) of sodium nitrite is dissolved in 60 ml of water , Quickly add to a solution of 400 ml of digas methane cooled to (TC 11.7 g (0.051 mole) of 3 4_dihydrophenylpyridinium p-5 -yl) succin-2-yl methanone. Then A solution of 5.2 g of concentrated sulfurous acid and 60 ml of water was slowly added over 1 hour, and the concentration was maintained between 0 and 5 。. The concentration of the product was returned to room temperature and stirred for 1 hour. The product was extracted with dichloromethane, The organic layer was washed with water, dried over sodium sulfate and the solvent was evaporated to dryness. Chromatographic analysis was purified on silica gel and washed with dichloromethane. 12.3 g of product was obtained. Melting point = 135 ° C. In the same way '-7_bromo_ (4_nitroso3, 4_DihydroΜ-benzene # humeng-5 -yl) furan-2-ylhexanone: melting point = 25 7 ° C; _2,2-dimethyl- (4-nitroso-7-bromo- 3,4-dihydro-2ϋ- 1,4-benzyl pent — 5 -yl) Bite-2-yl methyl sulphate §1 ^; Melting point = 130T: 14_3 · 2-fur-2-yl-7, 8-Dihydropyrazolium [15,4_this] _ [Μ] Ben and aeroponically add 12.5 grams (0.19 moles) of zinc powder in portions to 12 3 grams (〇407477 moles) -19- wood Paper scale home icon ((,%) 8 4 pit grid (2ί0 > < 297 Gong 筇 (read the precautions on the back before filling in this page)) .-VJr

Λ rM _ 40716Cb7___ V. Description of the invention (17) of (4-nitroso-3,4_dihydro_ m_ M_benzoxen-5—_yl) furan_ 2 -ylmethyl roasting net 0ml ice Acetic acid and 500 ml of methanol solution. This addition reaction continued for 20 minutes and the temperature of the reactant increased by 25, c. The mixture was allowed to cool to 'filtration of zinc' and the filtrate was concentrated under reduced pressure. The remaining acetic acid was removed by azeotropic distillation with toluene. The product was extracted with 300 ml of ethyl acetate and the organic layer was 170 ml of 1 equivalent mole of hydrochloric acid, 170 ml of 5% sodium nitrate '170 ml of 2 equivalent mole of sodium hydride (twice) and Washed with water. The organic layer was dried and the solvent was evaporated under reduced pressure. The product was purified on hard gum by chromatographic analysis and washed out with a cyclohexane: ethyl acetate mixture (3: 1). 8.7 g of product was obtained. Melting point = 115 ° C. In the same way, it can be obtained The following compounds: -4 -Fluoro-2-cre-2-yl-7,8-dihydropyrazolium [H4 也]-[ι, 4] Benzene 17: Melting point = 122 ° C; -4- Methyl-2 -bite-2 -yl_ 7,8-dihydroblow-up [1,5,4-4e _]-[l, 4] Benzazine 3; Melting point = 72 ° C: -7, 7-dimethyl-2-cre-2-yl_7,8_dihydropyrazolidine [15 4_such as-[ι, 4] benzene # 11 tillage: melting point = 112 ° C; -4 -bromo -2-fur-2-yl- 7,8-dihydropyrazole benzobenzozine ° well: Melting point = 14 (TC. — — — — — — — — — I ^ I — II, 1T..- (Read the precautions on the back before you fill out this page) ------------- 20- 5. Description of the invention (18 40716 (A7 B7 屮-火 if- 准 ifi 1 [· Aιί 14.4 .7,8-Dihydropyrazolium [15 4_ 此] _ [14] Benben Geng-2-carboxylic acid 4r 16 g (0 · 10 mol) of hyaluronic acid was added and cooled to about $. Pyridine contains 4 g (0.0177 mol) of 2 · fur-2-yl-78-dihydropyrazolium [15,4 [1,4] benzophenone and 2.44 g (0.01 6 mol) of potassium carbonate in 50 ml of acetonitrile nitrile solution; the temperature of the reaction mixture must not exceed 30 ° C. The mixture was left to stand at 15 C for 1 hour, and 6 ml of osmic acid was added within 1 hour. Then add 12 ml of sodium bisulfate, and then add 8 ml of formic acid to bring the acid and alkali to about 4. The precipitate was filtered off and washed with acetonitrile. The mash was concentrated under reduced pressure and the residue was dissolved in water and concentrated with hydrochloric acid. After acidification until the acid and base are i, the solid is filtered off, washed with water and dried. 13 g of product can be obtained. Melting point = 24 (TC. In the same way, the following compounds can be prepared: -4 -fluoro-7, 8-dihydroρ ratio 唆 幷 [l, 5,4-4e _]-[l, 4] Stupid. No. _ 2 _ Chinic acid melting point = 265Ό; -4, methyl-7,8-dihydropyridine Azole # [1,5,4- ^ £]-[1,4] Benzene moth-acid: melting point = 220 ° C: -7,7-dimethyl-7,8-dihydropyrazole Prionine_2 • Chinic acid: Melting point = 248 ° C. ΙΙΙΣ: 7,8-dihydropyrazole wells [1,5,4-erythrobenzoin_ 2 _carboxylic acid 15.1.1- (3, 4-Dihydro-2 per-M-phenylxanthine phen-5-yl) ethanolone 100 ml (0 ·〗 mol) of a tri-gas boron solution (1 mol concentration of Alkanes) Slowly add the temperature under the pressure of nitrogen within 1 hour to maintain the temperature between 0 and 5 > However, please read the notes on the back before filling in this page) • Loading Ding.-= 0 to 21 post Standard rule, 1¾ drunk standard cold (rNS) M appears (210x297 cm)

40716C A7 B7 Department 屮 4ι if.

yf: A V. Description of the invention (19) (0.0518 moles) 3,4-dihydro-2H-1,4-phenylhydrazone in 75 ml of 1,2-digas ethane solution. The mixture was heated at reflux for 2 hours. Cool and add 5.36 ml (0.102 mol) of acetonitrile in 15 ml of 1,2-digasethane solution over 20 minutes. The reaction mixture is refluxed for 3 hours and then left overnight at room temperature. To hydrolyze the formed imine intermediate, the reaction was cooled in an ice bath, and then 50 ml of 3 mol hydrochloric acid was added, the temperature was maintained between 5 and 8 'and the mixture was heated to reflux for 45 minutes. Cool down again and add 30% k-degree gas emulsification nano-assay. The product was extracted with dichloromethane, and the organic layer was washed with saturated aqueous sodium carbonate solution and dried ', and the solvent was evaporated under reduced pressure. Purified on silica gel by chromatographic analysis, i was washed out with methane. 16 g of an oily product can be obtained:; Epson point = 70% (P = 0.6 mm Hg; 4, 13 kPa). 15 · 2 · 1-(4 -nitroso_ 3,4 _ dihydro !, 4 _ benzene 幷 哜 哜-5 _) acetone j rhyme ^. 39 g (0.034 mol) thorium nitrite dissolved In 30 ml of water, quickly add 4_75 g (0.0268 mol) of (3,4-dihydro-2K-1,4_exhaust 5-17-yl) furan-2-cooled to 0 ° C. A solution of methyl ethyl ketone in 70 ml of digas methane 'is then added with a solution of 2.15 g of concentrated sulfurous acid and 30 ml of water over 1 hour' and the temperature is maintained at 0 to 5. (: Between. The temperature of the product was raised back to room temperature and dried for 1 hour. 1¾ The product was extracted with methane, the organic layer was washed with water, dried over sodium sulfate, and the solvent was evaporated to dryness. The product was analyzed by chromatography Purify on silica gel and wash out with two gas methane. -22- Λ4 grid (210X 297 cm) I m I -1TI ----- I--r ^-.-, (Please read the back (Please note this page and fill in this page again) '--V. Description of the invention (2〇)-4WM- A7 B7 5.5 g of oily product can be obtained. In the same way, the following compounds can be prepared: small desert small methyl ] (4-Nitroso recognizes phenylhydrazone ^ · yl) furan-2-yl ketone; melting point = 101 ° C. 15.3. 2- (2-styryl) · 7,8 _Dihydropyrazole hydrazine [154154_ [14] benzene humeng will dissolve 1 g (0.0268 mol) of sodium hydroxide in 5 ml of water. Within 5 minutes of deduction, add 5 at 0-5 ° C dropwise; 5 grams (00268 mole) of 1 (4-nitroso-3'4-dihydro-2H-1,4-phenylxanthine-5_yl ketanone, 2 84 grams (more Ear) Freshly distilled ice-cold solution of benzoaldehyde and 80 ml of absolute ethanol. Place the reaction mixture at 0-5. (: Stir down After 2 hours, I then added 50 ml of vaporized formazan and too: i / m to search. After adding 200 milliliters of water, the collected organic layer was dried and the solvent was evaporated under reduced pressure. The resulting product 1- (4_nitroso_34_dihydro-2ϋ-1,4-benzoxorphin-5-yl) -3-phenylpropan-2, ene-1-one was dissolved in 70 ml of toluene and 15 ml of acetic acid mixture. Carefully add 6 g (0.009 mol) of zinc powder between temperature 0 and _ 5 = c. Stir the reaction mixture at _ 5 ° C for 1 hour and 30 minutes. Add 200 mL Methanol, the present compound was filtered with Celite, and the filtrate was evaporated under reduced pressure. The product was extracted with digas methane and washed with 1 equivalent mole of hydrochloric acid, 2 equivalent mole of sodium hydride and water. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was purified on silica gel by chromatographic analysis and washed out with a mixture of dioxane: methane (99.8: 0.2). An oily product was obtained 2.7 G. -23 丨, technical support this; 丨] standard of prisoners (rNS) Λ4 specification (21〇χ 297 mm) binding • «> (Please read the note on the back first Please fill in this page again.) A1 A1 The Ministry of Justice, the quasi bureau, BT, and the fifth invention description (21) — " ^ In the same way, the following compounds can be prepared: -4-Fluoro-8 -A 2- (2-styryl) -7,8-dihydropyrazolo [M] benzopyrene: ~ melting point = 98. (:. U'4 7,8-dihydropyrazolo 14] Benzoline_ 2 -carboxylic acid This compound can be obtained according to the following 2 steps: Step A: Pass 2'06 grams of ozone gas stream through 2_ (2_ Stupid vinyl) -7,8-dihydropyrazol and benzophenone farming 100 ml-air methyl roast solution for 1 hour and 15 minutes, and then cooled to -60 ° C. The temperature was then gradually raised to -50 ° F, and a 50 ml solution of digas methane containing 4 32 ml (0.031 mol) of triethylamine was added under a stream of nitrogen. The temperature of the mixture was raised to room temperature and stirred for 18 hours and maintained at the reflux temperature for 3 hours. The product was purified by chromatography on a crushed rubber cylinder and washed out with methane. 0.5 g of product was obtained. Melting point = 145eC. In the same way, the following compounds can be prepared: 4-Fluoro-8-fluorenyl-7,8-dihydropyrazole 幷 [丨 Anal ^^ benzobenzopyrene carboxylic acid; Melting point = 147 ° C . Step B: Dissolve 5 g (0.019 mol) of 2_ (2_styryl) 78_dihydropyrazolo [l, 5,4-de]-[l, 4] phenylhydrazone in 100 ml Diethyl ether and ιιοmL of water, then add 0.1 g (0.0004 mol) of tetroxide and add the mixture to -24-pack, 1T (please read the precautions on the back before filling this page} 40716C B7 V. Description of the invention (22) Stir for 15 minutes. At room temperature, add 7.3 g (0.034 mol) of sodium perforate at room temperature, and stir the mixture for 2 hours. Add 0.1 g of tetroxide, Then 3.6 g (0.0168 mole) of sodium periodate was added in portions, and the mixture was stirred for 2 hours. The mixture was then washed with water. The ether layer was filtered, dried and the solvent was evaporated under reduced pressure. The residue was dried under reduced pressure. Chromatographic analysis was purified on a silica gel cylinder and washed out with dioxane. 1.75 g of product was obtained. In the same way, the following compounds were prepared: • 4-fluoro-7,8-dihydropyrazolidine [ 1,5,4-this]-[Μ] benzopyrene-2 -carboxaldehyde; melting point = 170 ° C; -3 -gas-7,8-dihydropyrazolidine [1.5,4-d &] -[1,4] benzene moaning "well-2 -carboxaldehyde; melting point = 262 ° C. 15.5 7,8-dihydro ρ ratio bite [1,5,4-this]-[1,4] benzene hydrazone 11 well 11-2-Chinic acid will contain 0.64 g (0.00163 mol) A 1 ml aqueous solution of silver nitrate and 0.5 g of water-emulsion solution containing 0.5 g of emulsified and unloaded water were successfully added at room temperature to a 7,8-dihydrogen ratio ratio of 0,3 (0.00163 mol) [1, 5,4-Zhao]-[1,4] benzo <##; Teng 2-carboxy blanket in 10 ml of ethanol solution. The mixture was stirred at room temperature for 22 hours' filtered with Celite and water Wash. The filtrate is dissolved in dichloromethane and the aqueous phase is separated and acidified with acetic acid to an acid hydrazone of 4. The desired product is extracted from the acid mixture with hydrazone'-methane. The organic layer is collected, dried and Evaporate the solvent under reduced pressure. 0.28 g of product can be obtained. Melting point = 23 8 ° C. In the same way, the following compounds can be prepared:-______- 25- Mu Zhile scales sent to Sichuan 1¾ 1¾ family members (CNS) 7 \ 4im (210 X 297 / ^ / ^) --------- Install -------- Order ------- ^-_--(Please read the precautions on the back before (Fill in this page) ·-_ A7

7 B V. Description of the invention (23-4-Fluoro-7,8-dihydropyrazolo [1,5,4-this]-[1,4] benzopyrene-2-carboxylic acid; melting point = 265 ° C; -4 -fluoro-8-methyl-7,8-dihydropyrazolo [l, 5,4-_dd- [l, 4] benzopyridine-2 carboxylic acid; melting point = 242 ° C -3-Ga-7,8-dihydropyrazolidine [1,5,4-Zhao]-[1,4] benzoxorphine-2-carboxylic acid; melting point = 186-187 ° C. The following table Describe the chemical structure and physical properties of the compounds of the invention. Table 0

A

A R. R. (CH2) n

B

C

Number R, r2 R :, R4 XA mn Y Melting point rc) Salt 1 Η Η Η ch3 0 Cc 0 0 _ 292 (d) HC1 2 Η Η Η ch3 NH c 0 0-> 280 HCi 3 Η Η ch3 NH cx 0 0 _ > 270 HC1 4 Η Η Η ch3 NH ce 1 0 _ 270-2 (d) HCI 5 Η Η Η character base 0 cx 0 0 one 127-8 test 6 Η Η Η benzyl 0 ce 1 0-60 絵 · 7 Η Η Η 芊 0 0 0 0 ce 0 0 &> 220 OX. 8 Η Η Η 芊 NH NH c 0 1-> 255 HCI 9 4-F Η Η ch3 0 ce 0 0 280 (d ) HCI 10 4-F 8-CH3 Η ch3 0 ce 0 0-296 (d) HCI 26- Paper guilt scale in use 1¾¾ family standard (('NS) Λ4 grid (210 297)

--------- Installation ------ Order ------ Quan,-'1 (诮 Read the precautions on the back before filling this page) I Η: 、 Invention description (24

A7_4011fiL £ L Number -------- R! R2 r3 R4 XA m η 炫 Dazzle point (° C) Salt 11 4-Br Η Η ch3 0 Ce 0 0 310 (d) HC1 12 Η 7-CH: ' 7-CH3 ch3 0 Ce 0 0-173 (d) HC1 13 '3-C1 Η ch3 0 C 0 0 • > 300 HCI 14] -— 丨. ~ Η Η Η Η 0 ce 0 0 • 15 Η Η Η _ 0 Β 0 ch2 221-2 OX. 16 Η Η Η-ΝΗ Β ο 0 ch2 191-3 ox. 17 Η Η Η _ ΝΗ Β-0 ch2 266-8 I HCI 18 Η Η Η 0 Β • 1 ch2 261 HCI 19 Η Η ΝΗ Β _ 1 ch2 > 280 HCI 20 Η Η Η-ΝΗ Β • 1 N > 250 (d) 2HC1 21 4-CH3 Η Η CHj 0 C 0 0-270 (d) OX. (Please read the precautions on the back before filling this page) -In the "Salt" column, "" ox "stands for ethane diester salt, and" HC1 "stands for hydrochloric acid. In column A '"ce" and "Cx" respectively represent the form in which compound C is inside or outside. In the column of "melting point. C", "d" represents the melting point of decomposition. The compound of formula (I) according to the present invention has undergone pharmacological tests to show its value as a therapeutic main ingredient. These compounds are specifically based on NW Bains (Barnes) et al. Described the method in J_ Pharm. Pharmacol. 40, 548-55 1 (1 988) and studied it in [3H]-(S) -zacopride and mouse cortex 5 -HT3 type serotonin receptor binding inhibitory effect. Male Sprague-Dawley rats (5 mouth ^ §1 ^ -Dawley) (OFA, Iffa Credo) weighing 200 to 250 grams were sacrificed, and their brains were removed. Cut into The block was homogenized with a Polytron® mill at a volume of 25 millimoles in three buffers (position 7.20 s) in a volume of 20 times. The homogenate was centrifuged at 45,000 x g for 20 minutes- 27: The scale meets the standard of Sichuan, and it changes to the standard 7 (('NS) Λ4 specification (2 丨 0 × 297 公 茇 -1Τ-" if · ^, ^ u (), disappearing in conjunction with M .- ;; — 印 " -" Α7 _____ Β7_ 5. Description of the invention (25) (Sorvall centrifuge equipped with an SS34 spinner) and then resuspend the pellet in three times the volume of three buffers Medium, and warmed at 37 ° C and stirred for 10 minutes. Then the suspension was diluted to 20 times the volume with three buffers and centrifuged under the same conditions as above. The obtained pellets were resuspended in 5 times the volume The three buffers were then divided into 5 ml portions and frozen to -80 ° C. On the day of the experiment, they were thawed to 4 ° C and then diluted 1.2 times (25 mM Tris, 150 mM) with Tris-NaCl warming buffer. NaH, pH = 7.4, 22'C). The membrane suspension (100 μl, 1 mg protein) was incubated at 25 ° C for 25 minutes' and at 0.5 nM [3H]-(S) -zacopride (Specific activity: 75-85

In the presence of Ci / Mole concentration, in the presence of Amersham, Chalfont (| ^ to Chalfont, United Kingdom), the test compound may be present or absent [in Tris_NaC1 buffer with a final volume of 500 microliters]. After incubation, it was filtered with a Whatman CF / B® filter treated with polyethyleneimine (0.01%) beforehand. 4 ml of tins per test tube-

NaCl buffer was diluted beforehand, and then washed 3 times with 45 ml of Tris_NaC buffer. Dry in the oven. (:, 5 minutes) Cut the filtrate before. The radioactivity retained in the filtrate can be measured by liquid scintillation analysis. Non-specific binding can be determined by 10 μM MDL 72222 (according to the method described by NM Bowens et al.). The concentration of each test compound can be measured by the percentage of inhibition of [3HHs) zacoopnde specific binding, and the concentration of the compound (50%) that inhibits 50% of the specific binding of ⑼b⑻⑽kaxin. Got. The compound IC50 has 値 between 0-5 n Μ and 2 μM, especially i nM and 5 〇 ---- 28-Mufen from Du Shizhong_Household (TnsTm ^ T (" 210X 297 ^ ____ 4〇 ^ i6C B7__ 5. Description of the invention (26) μM, especially between 1 nM and 20 nM. (Please read the notes on the back before filling this page) The compound of the present invention is based on Grossman (Grossman ) Et al. Described the method in Br. J. Pharmacol. (1989) 97 45 1 to study its antagonistic effect on 5-HT3 receptors on descending colon smooth muscle isolated from guinea pigs. Block 5-HT + 5-HT2 receptor (0.1 μM via methylpropylmethyl ergotamine (methysergide) and 5-HT 4 receptor desensitization (10 μΜ 5-methoxy color After serotonin (serotonin) (0-1-100 μM) stimulated the 5ΗΤ3 receptor, the guinea pig descending colon smooth muscle had a concentration-dependent contraction. This contraction was recorded by an isometry. The antagonism of the compound on the 5-ΗΤ3 pseudoclear receptor can be measured by measuring a serotonin curve (non-cumulatively increasing continuous contraction) at a concentration of 1 nM to 0 · Quantitative action / control concentration after 1 minute warming for 30 minutes. The compounds of the present invention can also be described by Br. J. Pharmacol. 109 according to Grossman et al. Method of 618-624 (1993) 'Investigate its affinity to the 5_ ^ 4 receptor of guinea pig striatum, sacrifice guinea pigs weighing 300 to 400 grams (Hartley, Charles' may River), take out his brain. Excited his striatum and at -80 ° C Bingkang 3 On the day of the experiment, Hepes buffer (acid-base 値 = 7 4,20 ° C) and homogenized with a Polycrush mill. The homogenate was centrifuged at 48,000 × g for 10 minutes and the pellet was resuspended and centrifuged under the same conditions. Finally the pellet was resuspended in In Hepes buffer (30 mg of fresh tissue / ml). The membrane is used in its original form. ---. -29 *-Ben .. 乂, >, < , 孓 m ((, Ή A shirt see grid (2 丨 ^ 297 public 荩) V. Description of the invention (π 40Ή Grill Α7 Β7

If; ί- and jj 100 microliters of membrane suspension in the presence of 0, 0 lnM [3H] GRll38〇8 (exclusive store 〖sheng.80-85 (: 1 / ¾mol concentration), the final volume is In 1 ml of Harpers buffer, the final volume is 1 ml of Harpers buffer (50 millimolar concentration, pH 7.4 is 7.4), and it is heated for 120 minutes in the presence and absence of the test compound. After warming, it was filtered with an Itman GF / B filter which had been treated with 0.01% polyethyleneimine, and each tube was washed with 4 ml of a buffer at 0 ° C., and the washing solution was filtered again. It was retained in the filtration The radioactivity of the substance can be measured by liquid scintillation analysis. Non-specific binding can be determined in the presence of 30 μM serotonin. Specific binding represents 90/0 of the total radioactivity of the filtrate. Each kind of treatment The concentration of the measured compound can be measured from the percentage of inhibition of [3H] GR1 13808 specific binding, and the concentration of the compound that inhibits 50% of specific binding (C5G). Compound 1 of the present invention: (1) Between i nM and 2 μM, especially between 50 nM, and more preferably between 1 nM and 20 nM "Finally, the compounds of the invention According to package Fest (Baxter) et al. In

The method in Naunyn Schmied Arch. Pharmacol. (1991), 343, 439 was used to study the effect or inhibitory effect on the binding of the 5-HT4 receptor on the mouse esophagus. Male Sprague_Dawley mice weighing between OO and 450 grams were used. Quickly remove a section of about 1.5 cm from the end of the esophagus, remove the muscle layer, open the inner layer of demucosal mucosa longitudinally, and place it at 32 ° C with oxygenated carbon dioxide (95% 02 and 5% c02). The Krebs-Hense eit solution was separated into an organ trough and connected to a conversion initiator of equal length with a membrane tension of 0.5 g. The shrinkage of the button is from 30 — ^ ϋ JI np ^ i ^ i 1— 1 ^ 1 I. i ______ (Please read the precautions on the back before filling in this page] · 'Order 4071 ^^ A7 B7 V. Description of the Invention (Initiated by carbocholine at 28 0.5 μM, and the contraction is stabilized after r, γ, ^ 5: ¾ minutes), Gan was exposed to increasing cumulative concentration from 0.1 nM to 1 ^ ^. KM <The compound that the poem-testing compound can induce relaxation is defined as a 5-ΗΤ4 agent. Then τ # I 二 can not be released? The compound is released, and the device is exposed to increasing cumulative concentrations from 0+ micromolar concentration In the case of tryptophan which can induce maximum relaxation, then compare the action curve of serotonin in the presence of> test compound with the curve established in the absence of the compound. If the test compound is present, the curve is On the right, the compound is defined as a 5-ΗΤ4 agent. The compound of the compound according to the present invention is "between 5 and 10, preferably between 7 J and 10. For comparison purposes, according to the present invention, examples Compound No. 1 in No. 1 and the closest analogue described in European Patent Application No. 0,350,130 'That is an example IV compounds, according to the method described in the test results are given in f Jing read back of two: Shen intended to do if re-write the soil of this page)

1T &quot; r 屮 it 15 j fi combined with the following table IC 50 micromolar concentration pKb Γ--5-ΗΤ3 5-ΗΪ4 Example 1 2.5 5.2 8.0 Example IV European Patent Application No. 0,35〇, 130 No. 2.3 25.0 7.0 The results of these biological tests show that the compound in European Patent Application No. 0,350,130 does not mention the 'equal activity' of the compounds according to the invention such as 5-ΗΤ_, ': &gt; · Η4 specificity of the serotonin receptor inhibitor . The advantages of this equal activity have been mentioned above.

The scale of the paper music i | Use the rate of prisoners in China and Fujian (TnsT -31 ----- △ 4 gauge _ grid (210 / :: 97 public expense V. Description of the invention (29) A7 B7 &quot;, &quot; .ίΓ -ν 央 # 伯 Ans' T. &quot; f ^^ 力 · -32 Therefore, these compounds can be used as preparations of 5_HT ^ 5_H stem tryptamine medicaments. The antagonism, therefore, the compound of formula (1) of the present invention It can be especially used for intestinal dysfunction, as follows, esophageal reflex, intestinal peristalsis disorders, irritating bowel symptoms, visceral sensitivity. Baseline gallbladder fibrosis, mild cancer symptoms; urethral or intestinal disorders, giant society treatment or prevention. —Wannian, due to the affinity of the 5-THT3 receptor of the compound of the present invention, 'can also be used for the treatment and / or prevention of nausea and vomiting, for example, after antitumor treatment or after the administration of anesthetic; esophageal spasm: central nervous system loss ; Such as schizophrenia, 'mania, anxiety, and crying; cognitive disorders, such as Alzheimer's disease such as Alzheimer's or age-related dementia, memory and' king-power deficiency, cerebrovascular defect, [Kinson's Disorders; Psychiatry: Dyskinesia 'Pain, Migraine and Headache; Gastric Alcohol Or drug dependence or withdrawal: gastrointestinal disorders such as indigestion, stomach ulcers, heartburn, flatulence: cardiovascular disorders and respiratory disorders. The compounds of the present invention can be combined with suitable excipients to make any suitable mouth, Or non-I enteric drugs, such as lozenges, coated tablets, capsules, hard capsules, and suspensions or solutions for oral or flooding, can be administered from 0.005 to 5 mg / kg body weight One day ^ &quot; times. This paper is used in the em house standard rate (CNS) ---------- install -------- order ------ ί ,:--· * (Please read the notes on the back before filling this page)-·

Claims (1)

Amendment to the Chinese Patent Application No. 871Π333 (gjg-December-June-Six. Patent Application Range 1. A compound of formula (I): 0 R. (X) where: Ri is hydrogen or 'halogen or methyl chloride Group, hydroxy or amine group, R2 and R3 may be the same or different, are hydrogen atom or C μ alkyl group X is oxygen atom or -N-- or -NCCm alkyl group)-'and A is formula B or C • (CH2 ) n Ν 'B Ν /-(CH2) n (CH2) m. C (锖 Please read the notes on the back first and fill out this page). I Order— · Printed by the Central Consumer Bureau of the Ministry of Economic Affairs, Industrial and Consumer Cooperatives, where: Y is a nitrogen atom or sub- Methyl, R 4 is a hydrogen atom, CM alkyl or fluorenyl, n is equal to 0 or 1, and m is equal to 0 or 1. It is in the form of specular isomers or non-specular isomers, including racemic mixtures' and their addition salts with pharmaceutically acceptable acids. 2. The compound of formula (丨) according to item 1 of the scope of patent application, where the representative formula c is applicable to the National Paper Standard (CNS) A4 (2 丨 0X297 mm) Amendment to the Chinese Patent Application No. 871Π333 (gjg-December-June-Six. Patent Application Range 1. A compound of formula (I): 0 R. (X) where: Ri is hydrogen or 'halogen or methyl chloride Group, hydroxy or amine group, R2 and R3 may be the same or different, are hydrogen atom or C μ alkyl group X is oxygen atom or -N-- or -NCCm alkyl group)-'and A is formula B or C • (CH2 ) n Ν 'B Ν /-(CH2) n (CH2) m. C (锖 Please read the notes on the back first and fill out this page). I Order— · Printed by the Central Consumer Bureau of the Ministry of Economic Affairs, Industrial and Consumer Cooperatives, where: Y is a nitrogen atom or sub- Methyl, R 4 is a hydrogen atom, CM alkyl or fluorenyl, n is equal to 0 or 1, and m is equal to 0 or 1. It is in the form of specular isomers or non-specular isomers, including racemic mixtures' and their addition salts with pharmaceutically acceptable acids. 2. The compound of formula (丨) according to item 1 of the scope of patent application, of which the formula c is applicable to the paper standard "National Standards (CNS) A4" (2 丨 0X297 mm). Cooperative printed 4 (m6 (T driving '--___ D8', patent application ϋ --- one ~ one ~-basic difficulties. 3 · ^ According to the compound of formula 请 in the scope of the first patent claim, its characteristics are Its package-7,8 · dihydropyrazolo [I, 5,4 • red] [M] benzopyrene_2-carboxylic acid_end_8_methyl-8-azabicyclo [3 2 丨 丨Octyl% ester hydrochloride; _ N- (exo_8_methyl_8 azabicyclo [3 2 ^ octyl]. Dioxo-dihydropyrazolo [1,5,4 -this] [丨, 4] Benzo-2 # carboxamidine hydrochloride;. ~ (Inner_9-methyl-9-azabicyclo [3.3.1] non_3_yl) _7 8_dihydro Pyrazolo [1,5,4- such as J [M] benzopyrene_ 2 _carboxamidine hydrochloride; • pyrene-[[8- (benzyl) _8_azabicyclo [3 2 ”] Octyl_3_yl] methyl] _7,8-diazepine P than fluorene Π, 5,4-^] [Μ] benzo" No. 2-Carboxamidate hydrochloride;- 7,8-diargyrenebenzobenzopyrene well-2_carboxylic acid-endo_9_ (benzyl) _9 · azabicyclo [3.3.1] non-3- Ester; -4-fluoro-7,8-dihydropyrazolo [uj · this] [1,4] benzene 幷 啩 2_carboxylic acid_ endo-8 -methyl-8-azabicyclo [ 3.2.1] oct-3-yl ester hydrochloride; -4-form-8-methyl-7,8-dihydro p ratio and "l, 5,4-de] [l, 4] Well p, p-2-carboxylic acid-endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester hydrochloride; -7,7-dimethyl-7,8- Dihydropyrazolo [1,5,4-this] [1,4] benzo-peptide · 2-carboxylic acid-endo-8-methyl-8-azabicyclo [3.2.1] octane-3 -Yl ester hydrochloride. St &gt; -3-Ga-7,8-dihydropyrazolo [1,5,4-this] [1,4] benzoxyl-2-carboxylic acid-endo-8 -Methyl-8-azabicyclo [3.2.1] oct-3-yl ester hydrochloride; This paper size applies to China National Standard (CNS) A4 (210X297 mm) m I, {--.. .... I i ^ in I 一 eJn Λ- (Please read the precautions on the back before filling in this page) VI. Application for a patent 4.40 * 716 ° A8 B8 C8 D8 -7,8-dihydropyridine Zolo [1,5,4-this] [1,4] benzohumin_2 _carboxylic acid_ 丨 · azabicyclo [2.2.2] octane-3-yl ester oxalate; • aza Bicyclo [2.2.2] oct_3_yl) _7,8_dihydropyrazolo [1,5,4-4 &amp;] [1,4] benzo 11 # 11 well-2- Fermented amine amine hydrochloride; _ 7,8-dihydropyrido [1,5,4-4§J [1,4] benzo "No. _ 2 _ rebel acid 丨 _ azabicyclo [2.2 .2] Oct-3-ylmethyl ester hydrochloride: or-(Phenyl-〇1)-(1,4-diazobicyclo [2.2.2] oct-3-ylmethyl group Bite [1,5,4-4g_] [1,4] Pyrazine p-well-2-epiamine hydrochloride (2.1) '. A method for preparing a compound according to item 丨 of the scope of patent application, which is characterized by the compound of formula (II): '〇Aw (II) {Please read the precautions on the back before filling this page) V. 0 Central Ministry of Economic Affairs Printed by the local shellfish consumer cooperative «. Where Ri 'R2 and R3 are as defined in item 1 of the patent scope and the arm is halogen, which reacts with the compound HXA, where X and a are as defined in item i of the patent scope. ^ 5- A pharmaceutical composition as a 5-HT3 / 5-HT4 receptor antagonist, which comprises the compound according to item 丨 of the patent application as the active ingredient II = two or more excipients. Use the national standard (CNS) A4 specification (210X297 mm)