CN1092421A - Medicine - Google Patents

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Publication number
CN1092421A
CN1092421A CN 93114856 CN93114856A CN1092421A CN 1092421 A CN1092421 A CN 1092421A CN 93114856 CN93114856 CN 93114856 CN 93114856 A CN93114856 A CN 93114856A CN 1092421 A CN1092421 A CN 1092421A
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Prior art keywords
hydrogen
alkyl
amino
halogen
butyl
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CN 93114856
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Chinese (zh)
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L·M·加斯特
K·R·穆尔霍兰
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Priority claimed from GB929221482A external-priority patent/GB9221482D0/en
Priority claimed from GB929223137A external-priority patent/GB9223137D0/en
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Abstract

Formula (I) compound, its Chinese style (I) is made up of formula (I-1) to (I-4), and pharmaceutically acceptable salt, and the purposes of formula (I) compound or its drug acceptable salt and its are as treatment gastrointestinal illness, the application of the medicine of cardiovascular disorder and CNS disease.

Description

Medicine
The invention relates to new compound, its preparation method and as the purposes of medicine with pharmacologically active.
European Journal of Pharmacology 146(1988), 187-188 and Naunyn-Schmiedeberg ' s Arch.Pharmacol.(1989) 340:403-410 described a kind of non-classical serotonine acceptor, is denoted as 5-HT now 4Acceptor has been described simultaneously and also can be used as 5-HT 3The ICS205-930 of receptor antagonist can be used as the antagonist of this receptor.WO 91/16045(Smithkline and French Laboratories Limited) heart 5-HT has been described 4The application of receptor antagonist in treatment room irregular pulse and shock.
EP-A-501322(Glaxo Group Limited) described and had 5-HT 4The indole derivatives of antagonistic activity.
WO 93/02677, and WO 93/03725, and WO 93/05038, WO 93/05040 and PCT/GB93/00506(Smithkline Beecham plc) described and had 5-HT 4The compound of receptor antagonist activity.
EP-A-234872(Adria Laboratories Inc.) and EP-A-493041(Erabomont Inc.) the benzo bicyclic carboxamides described.
EP-A-339950(Rorer International Overseas Inc.) described as 5-HT 3The diphenylene-oxide methane amide of receptor antagonist.WO 92/09284 has described as 5-HT 3The preparation method of many rings ether ring based compound of receptor antagonist.
Have been found that now some new compounds also have 5-HT 4The receptor antagonist characteristic.
Used in this specification sheets, " treatment " comprises suitable prevention.
Therefore, the invention provides the formula I compound, wherein formula I comprises formula (I-1) to (I-4), and its pharmaceutically acceptable salt and formula I compound or its pharmaceutically acceptable salt have 5-HT in preparation 4Purposes in the receptor antagonist activity medicine:
Figure 931148561_IMG8
Wherein
X is O or S;
R 1Be hydrogen, amino, halogen, C 1-6Alkyl, hydroxyl or C 1-6Alkoxyl group;
R 2Be hydrogen, halogen, C 1-6Alkyl, C 1-6Alkoxyl group, nitro, amino or C 1-6Alkylthio;
R 3Be hydrogen, halogen, C 1-6Alkyl, C 1-6Alkoxyl group or amino;
R 4Be hydrogen or C 1-6Alkyl;
Figure 931148561_IMG9
Wherein
X is O or S;
A represents a singly-bound ,-CH 2-or CO or A be (CH 2) a-E-(CH 2) b wherein one of a and b be 0 and another is 0 or 1, and E is O, S or NH;
R 1Be hydrogen, amino, halogen, C 1-6Alkyl, hydroxyl or C 1-6Alkoxyl group;
R 2Be hydrogen, halogen, C 1-6Alkyl, C 1-6Alkoxyl group, nitro, amino or C 1-6Alkylthio;
R 3Be hydrogen, halogen, C 1-6Alkyl, C 1-6Alkoxyl group or amino;
R 4Be hydrogen or C 1-6Alkyl;
Wherein
X is O or S;
A represents a singly-bound ,-CH 2-or CO, or A is (CH 2) a-E-(CH 2) b, wherein one of a and b are 0 and another is 0 and another is 0 or 1, and E is O, S or NH;
F and g are hydrogen or form a key together;
R 1Be hydrogen, amino, halogen, C 1-6Alkyl, hydroxyl or C 1-6Alkoxyl group;
R 2Be hydrogen, halogen, C 1-6Alkyl, C 1-6Alkoxyl group, nitro, amino or C 1-6Alkylthio;
R 3Be hydrogen, halogen, C 1-6Alkyl, C 1-6Alkoxyl group or amino;
R 4Be hydrogen or C 1-6Alkyl;
Figure 931148561_IMG11
Wherein
X is O or S;
R 1Be hydrogen, amino, halogen, C 1-6Alkyl, hydroxyl or C 1-6Alkoxyl group;
R 2Be hydrogen, halogen, C 1-6Alkyl, C 1-6Alkoxyl group, nitro, amino or C 1-6Alkylthio;
R 3Be hydrogen, halogen, C 1-6Alkyl, C 1-6Alkoxyl group or amino;
R 4' and R 4" be respectively hydrogen or C 1-6Alkyl;
Comprise in (I-4) in formula (I-1):
Y is O or NH;
Z is inferior formula (a), (b) or (c)
Figure 931148561_IMG12
Wherein
n 1Be 0,1,2,3 or 4; n 2Be 0,1,2,3 or 4;
n 3Be 2,3,4 or 5;
Q is 0,1,2, or 3; P is 0,1 or 2; M is 0,1 or 2;
R 5Be hydrogen, C 1-12Alkyl, aralkyl or R 5Be (CH 2) z-R 10Wherein z is 2 or 3 and R 10Be selected from cyano group, hydroxyl, C 1-6Alkoxyl group, phenoxy group, C(O) C 1-6Alkyl, CO-C 6H 5,-CONR 11R 12, NR 11COR 12, SO 2NR 11R 12Or NR 11SO 2R 12, R wherein 11And R 12Be hydrogen or C 1-6Alkyl; With
R 6, R 7And R 8Be respectively hydrogen or C 1-6Alkyl; With
R 9Be hydrogen or C 1-10Alkyl;
Or the formula I compound, wherein the CO-Y connection is substituted by the heterocycle bioisoster.
Suitable alkyl or the example that contains alkyl group comprise C 1, C 2, C 3, C 4, C 5, C 6, C 7, C 8, C 9, C 10, C 11Or C 12Side chain, straight chain or cyclic alkyl.C 1-4Alkyl comprises methyl, ethyl, just-and different-propyl group, just-, different-, secondary-and tert-butyl.Cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.
Aryl comprises can be by one or more halogens that are selected from, C 1-6Alkyl and C 1-6Phenyl and naphthyl that the substituting group of alkoxyl group replaces arbitrarily.
Halogen comprises fluorine, chlorine, bromine and iodine.
In formula (I-1):
R 1Preferred hydrogen or amino.
R 2Preferred hydrogen or halogen.
R 3Preferred hydrogen or halogen.
R 4Hydrogen normally.
In formula (I-2):
R 1Preferred hydrogen or amino.
R 2Preferred hydrogen or halogen.
R 3Preferred hydrogen or halogen.
R 4Hydrogen normally.
In formula (I-3):
R 1Preferred hydrogen or amino.
R 2Preferred hydrogen or halogen.
R 3Preferred hydrogen or halogen.
R 4Hydrogen normally.
In formula (I-4):
R 1Preferred hydrogen or amino.
R 2Preferred hydrogen or halogen.
R 3Preferred hydrogen or halogen.
R 4' and R 4" hydrogen normally.
Containing the acid amides of Y or the suitable bioisoster of ester connection portion in the formula I is formula (d):
Figure 931148561_IMG13
Wherein
The representative of dotted line ring is at any locational one or two pair key of 5 yuan of rings; H, J and I represent oxygen respectively, sulphur, nitrogen or carbon, condition is H, at least one is not a carbon among J and the I; U represents nitrogen or carbon.
(d) suitable example such as EP-A-328200(Merck Sharp ﹠amp; Dohme Ltd.) in to X, the description of Y and Z, Li such as oxadiazole part,
Y is preferably O or NH.
When Z is inferior formula (a), and when nitrogen heterocyclic is connected on the nitrogen-atoms, n 1Be preferably 2,3 or 4, and be connected on the carbon atom as the 4-position and when q is 2 n when nitrogen heterocyclic 1Be preferably 1.
When Z is inferior formula (b), n 2Preferably and the carbonatoms between ester or acid amides connection portion be the situation of 2 to 4 carbon atoms.
The suitable value of p and m comprises p=m=1; P=0, m=1, p=1, m=2, p=2, m=1.
When Z is inferior formula (c), n 3Preferred 2,3 or 4.
R 8And R 9All be preferably alkyl, particularly R 8And R 9One of be C 4Or higher alkyl.
The concrete structure of significant especially Z is as follows:
The present invention also provides has side chain (ⅰ), (ⅱ), and (ⅲ), (ⅳ), (ⅴ), (ⅵ) or new formula I compound (ⅶ).Further, (ⅰ), (ⅱ) or the piperidine ring (ⅲ) can be by the displacement of pyrrolidyl or azelidinyl, and/or (ⅰ) or the N-substituting group (ⅱ) by C 3Or higher alkyl or substituted by the benzyl that can replace arbitrarily.
In addition, formula (ⅰ) or (ⅱ) in the N-substituting group can be by as defined (CH in the formula I 2) nR 4Substitute and with respect to the specific embodiment among the EP-A-501322.
The pharmaceutically acceptable salt of formula I compound comprises and conventional acid example hydrochloric acid, Hydrogen bromide, boric acid, phosphoric acid, sulfuric acid and pharmaceutically acceptable organic acid such as acetate, tartrate, toxilic acid, citric acid, succsinic acid, phenylformic acid, xitix, methylsulfonic acid, α-Tong Wuersuan, the formed acid salt of α-Phosphoric acid glycerol esters and Cori ester.
The quaternary ammonium derivative that the example of pharmaceutically acceptable salt comprises the formula I compound is as by R wherein xBe C 1-6Alkyl, phenyl-C 1-6Alkyl or C 5-7Cycloalkyl and T is the compound R corresponding to the acid anion group xThe quaternised compound of-T.R xSuitable example comprises methyl, ethyl and just-and different-propyl group; And benzyl and styroyl.The suitable example of T comprises halogenide such as bromide, muriate and iodide.
The example of pharmaceutically acceptable salt also comprises inner salt such as N-oxide compound.
The formula I compound, its pharmaceutically acceptable salt (comprising quaternary ammonium derivative and N-oxide compound) also can form pharmaceutically acceptable solvate, as hydrate.Mention the formula I compound or its salt anyplace, all comprise its solvate.
Wherein CO-Y is that the formula I compound of ester or acid amides connection portion can be by preparing Z part and the conventional coupling of appropriate acid.Suitable method such as GB 2125398A(Sandoz Limited), GB 1593146A, EP-A-36269, EP-A-289170 and WO 92/05174(Beecham Groupp.l.c.) described in.When CO-Y is replaced by the heterocycle bioisoster, suitable method such as EP-A-328200(Merck Sharp ﹠amp; Dohme Limited) described in.Also can be) with reference to EP-A-501322(Glaxo Group Limited.
The present invention also comprises the method for the formula I compound that preparation is new, and this method comprises suitable acid derivative and suitable alcohol or amine reaction.A kind of method comprises that with aromatic substituent wherein be needed substituting group in the final formula I compound, maybe can be converted into substituent acid derivative required in the final formula I compound and contain alcohol or the acid amides reaction that Z maybe can change into the group of Z, after this if desired, change into phenylformic acid substituting group and/or Z, and can at random form pharmaceutically acceptable salt.
The appropriate method of the conversion between aromatic substituent comprises that hydrochlorinate becomes chlorine, and nitroreduction is amino, dehydrohalogenation such as debromination.Yet any processing treatment is carried out before ester or acid amides coupling usually.
The appropriate method that contains the conversion between the Z part comprises by replacing and/or going protection that the N-substituting group is carried out conventional processing, perhaps needs 2-in final compound, when 3-or 4-substituted piperidine base, and can be with suitable pyridinyl derivatives reduction.
The compounds of this invention is 5-HT 4Therefore receptor antagonist can believe that it can be used for treatment or prevention gastrointestinal illness, cardiovascular disorder and CNS disease usually.
The compounds of this invention is to treatment irritable bowel syndrome (IBS), and particularly IBS diarrhoea is very useful, and promptly these compounds are blocked the ability that 5-HT stimulates intestinal motility by activating enteric nervous unit.In animal IBS model, this ability is easy to measure by the reduction of defecation rate.The treatment of the The compounds of this invention pair urinary incontinence relevant with IBS is also very useful.
They also can be used for other gastrointestinal illness as with last intestinal motility diseases associated and can be used as antiemetic.Especially, they can be used for treatment nauseating and gastroesophageal reflux disease and dyspeptic stomach syndromes.Antiemetic is active to be measured with known cytotoxic agent/radiation induced vomiting animal model.
Can prevent auricular fibrillation and other room relevant ARR specificity heart 5-HT with 5-HT 4Receptor antagonist also can reduce the generation (referring to A.J.Kaumann 1990, Naumyn-Schmiedeberg ' s Arch.Pharmacol.342, the suitable animal test method of 619-622) of shock.
The anxiety activity probably by hippocampus have an effect (Dumuis etc. 1988, Mol Pharmacol., 34,880-887), this activity available standards animal model, social interaction test and X-maze test illustrate.
The migraineur usually is in anxiety and nervous state, the latter can advance headache generation (Sachs, 1985, Migraine, Pan Books, London).Also observe in 48 hours of migraine, the ring-type AMP concentration in the celiolymph raise significantly (Welch etc., 1976, Headache 16,160-167).Can believe that migraine comprises that the forerunner reaches the ring AMP concentration and the 5-HT of relevant rising mutually 4The stimulation of acceptor is relevant, so 5-HT 4The use of antagonist is of value to alleviates migrainous generation.
Other influential CNS disease comprises schizophrenia, the sick and Huntingdon chorea of Parkinson.
The present invention also provides the pharmaceutical composition that contains formula I compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
Such composition prepares and is suitable for usually in the intestines as oral by mixing, in the nose or rectum, perhaps administered parenterally, and can be tablet therefore, capsule, oral liquid, pulvis, granula, lozenge, structure pulvis again, nasal spray, suppository, but forms such as injectable and primer solution or suspension.The preferred oral administration composition is because they are convenient for common use.
Tablet for oral use and capsule exist with unitary dose usually, and contain conventional excipients such as tackiness agent, weighting agent, and thinner becomes tablet, lubricant, disintegrating agent, tinting material, seasonings and wetting agent.Tablet can come dressing by means known in the art such as enteric coating.
Used suitable weighting agent comprises Mierocrystalline cellulose, mannitol, lactose and other analogue.Suitable disintegrants comprises starch, polyvinylpyrrolidone and starch derivative such as Explotab.Examples of suitable lubricants comprises as Magnesium Stearate.
Suitable pharmaceutically acceptable wetting agent comprises sodium lauryl sulphate, oral liquid can be for example water or oil suspension, solution, emulsion, the form of syrup or elixir is perhaps for reverting to the desciccate form existence of liquid with water or other appropriate excipients restructural before using.This liquid preparation can contain conventional additive such as suspension agent, as Sorbitol Powder, and syrup, methylcellulose gum, gelatin, Natvosol, carboxymethyl cellulose, the edible fat of aluminum stearate colloid or hydrogenation, emulsifying agent such as Yelkin TTS, sorbitan monooleate or gum arabic; Non-water figuration body (can comprise edible oil) is Prunus amygdalus oil for example, fractionated coconut oil, grease such as glycerine, propylene glycol or alcoholic acid ester; Sanitas such as methyl or propyl para-hydroxybenzoate or Sorbic Acid, and can contain conventional seasoning or tinting material if desired.
Oral liquid is water or oil suspension normally, solution, and emulsion, the form of syrup or elixir is perhaps for reconstituting the desciccate form existence of liquid with water or other vehicle before using.This liquid preparation can contain conventional additive such as suspension agent, emulsifying agent, non-water vehicle (can contain edible oil), sanitas and seasoning or tinting material.
Oral compositions can be by conventional mixing, and filling or method in blocks prepare.Married operation repeatedly can make active agent be distributed in fully in the composition that has used a large amount of weighting agents.Certainly, this operation is this area routine.
For administered parenterally, can be made into the liquid unit doses form that contains The compounds of this invention and aseptic vehicle.According to the character of vehicle and enriched material, compound both can be suspended also can be dissolved, and the solution that parenteral is used prepares by compound dissolution is filled in suitable phial and the ampoule behind sterilization vehicle and filtration sterilization and seals usually.Beneficially also can be with assistant agent such as local anesthetic, sanitas and buffer reagent are dissolved in the vehicle.In order to improve stability, after being packed into phial, freezing the removing with vacuum of composition can be anhydrated.
Parenteral prepares by method same as described above basically with suspension, sterilizes by oxyethane except compound being suspended in but not being dissolved in the vehicle and before in being suspended in aseptic vehicle.Beneficially tensio-active agent or wetting agent are included in the composition, can promote the uniformly distributing of The compounds of this invention.
Treatment or prevention Mammals such as humans allergic's bowel syndrome have been the present invention further provides, maldigestion, room irregular pulse and shock, anxiety and/or migrainous method, this method comprise formula I compound or its pharmaceutically acceptable salt of using significant quantity.
The significant quantity for the treatment of disease noted earlier depends on the relative potency of The compounds of this invention, needs character and the degree and the mammiferous body weight of the disease of treatment.In any case, contain 0.05 to 1000mg usually as 0.5 to 500mg The compounds of this invention in the unitary dose that 70Kg grows up.Unitary dose can be used one or many every day, for example every day 2,3 or 4 times, and more commonly one day 1 to 3 time, promptly at about 0.0001 to 50mg/Kg/ day, more generally in 0.0002 to 25mg/Kg/ day scope.
Do not demonstrate deleterious toxicology reaction in the above in the dosage range of mentioning.
The present invention also provides formula I compound or its pharmacy acceptable salt purposes as the active treatment thing, especially for treatment irritable bowel syndrome, gastroesophageal reflux disease, maldigestion, room arrhythmia and shock, anxiety and/or migraine.
The following example has illustrated the preparation of formula I compound, and following illustrative examples is the preparation about intermediate.Formula (I-1) compound and intermediate are prepared among the 2-1 etc. at embodiment and illustrative examples 1-1, and formula (I-2) compound is prepared among the 2-2 etc. at embodiment and illustrative examples 1-2, and the preparation of formula (I-3) to (I-4) compound is similar above-mentioned.
Should be appreciated that wherein Y is that the preparation of any compound of O is the respective compound of NH provides as Y wherein.
Preferred compound is corresponding to any compound prepared among the embodiment, but the compound that an amino substituting group is arranged and a chlorine substituent is arranged in the 5-position comprising the 4-position at phenylformic acid parent nucleus described in the formula (I-1) to (I-4).
The intermediate of illustrative examples 1-1(embodiment 1-1)
A) 4-acetylaminohydroxyphenylarsonic acid 3-allyl group-5-chloro-2 hydroxybenzoic acid methyl esters
Under agitation with 4-acetylaminohydroxyphenylarsonic acid 5-methyl chloro salicylate (EP-A-0339950), (17.0g, 0.070mol), allyl bromide 98 (6.32ml, 0.073mol), acetone (350ml) and salt of wormwood (19.35g, 0.140mol) mixture heating up reflux, after 23 hours, reaction mixture is cooled off, filter, and filtrate evaporated under reduced pressure and vacuum-drying are obtained light brown solid.This solid is dissolved in 1 again, in the 2-dichlorobenzene (300ml) and under agitation reflux.Behind the 24h reaction mixture is cooled off reduction vaporization.Then gained semi-solid brown residue is obtained yellow solid shape title compound (8.24g, 42%) with silica gel chromatography purifying (2: 1 pentanes: EtOAc → EtOAc makes eluent).
1H NMR（200MHz，CDCl 3）δ：
11.10（s，1H），7.81（s，1H），7.04（s，1H），5.88（m，1H），5.00（m，2H），3.95（s，3H），3.45（d，2H），2.25（s，3H）.
B) methyl benzoate 4-acetylaminohydroxyphenylarsonic acid 5-chloro-2-hydroxyl-3-(2-oxoethyl)
With product (8.23g a), 0.029mol) be dissolved in acetone (300ml) and the water (60ml), (6.79g, 0.058mol) (1.82ml 0.0029mol) handles and at room temperature stirs and spend the night the usefulness 4%wt that continues perosmic anhydride soluble in water with N-methylmorpholine-N-oxide compound.Behind the 21h, add 10% sodium sulfite solution (100ml) and mixture is stirred 1/2h, afterwards reduction vaporization acetone.Then reaction mixture is distributed in EtOAc and the water.Then also will full organic layer drying (Na also with EtOAc extraction (2 *) with water layer 2SO 4) and reduction vaporization, obtain pale solid, with its vacuum-drying.Then solid is dissolved in again and also under agitation uses sodium periodate (9.41g, water 0.044mol) (60ml) solution-treated in the methyl alcohol (250ml).Then mixture is at room temperature stirred and spend the night.Vacuum is removed methyl alcohol afterwards.Then resistates is distributed in EtOAc and the water.Use the EtOAc aqueous layer extracted then, with the organic layer drying (Na that merges 2SO 4) and reduction vaporization obtain dun oil.Should obtain brown spumescence title compound (5.90g, 71%) with silica gel chromatography purifying (EtOAc makes eluent) by oil then.
1H NMR（200MHz，CD 3OD）δ：
8.00（s，1H），4.92（t，1H），4.10（s，3H），3.12（d，2H），2.33（s，3H）
C) 2-acetoxyl group-7-methoxycarbonyl-5-chloro-4-diacetylamino-2, the 3-Dihydrobenzofuranes
With b) product (5.90g 0.021mol) is dissolved in diacetyl oxide (55ml) and pyridine (55ml) mixture, adds some 4-Dimethylamino pyridine crystal, and spends the night stirring under the mixture room temperature.Behind the 20h, reaction mixture is distributed in EtOAc and the water.Then water layer is extracted with EtOAc, with the organic layer drying (Na that merges 2SO 4) and reduction vaporization obtain brown oil, with its vacuum-drying.Should obtain light brown oily title compound (2.87g, 37%) with silica gel chromatography purifying (2: 1 pentanes: EtOAc makes eluent) by oil then.
1H NMR（250MHz，CDCl 3），δ：
8.00（s，1H），7.00（dd，1H），3.92（s，3H），3.38（dd，1H），3.00（dd，1H），2.32（s，3H），2.28（s，3H），2.10（s，3H）.
D) 7-methoxycarbonyl-5-chloro-4-diacetylamino benzo [b] furans
Stir down c) product (2.87g 7.77mmol) is dissolved in the trifluoroacetic acid (50ml) and reflux.Behind the 1h, with reaction mixture cooling and reduction vaporization.Resistates is distributed in NaHCO 3In the aqueous solution and the methylene dichloride.Then with water layer dichloromethane extraction (2 *).And with the organic layer drying (Na that merges 2SO 4), reduction vaporization obtains brown oil, with it with silica gel chromatography purifying (1: 1 gasoline: the diethyl ether eluent) obtain light yellow oily title compound (0.765g, 32%).
1H NMR（250MHz，CDCl 3），δ：
8.10（s，1H），7.81（d，1H），6.70（d，1H），4.10（s，3H），2.30（s，6H）.
The intermediate of illustrative examples 2-1(embodiment 2-1)
A) (2-carboxyl thiophenyl) acetate
(34.5g, (10.0g, (7.56g 64.9mmol) handles water 64.9mmol) (200ml) solution thiosalicylic acid 0.32mol) with the sodium chloroacetate in water-soluble (100ml) will to contain yellow soda ash.Be heated backflow (2 hours), cooling also is acidified to PH2 with dense HCl.Material filtration collection and vacuum-drying that crystallization is gone out obtain orange powder shape title compound (12.5g, 91%).
1H NMR（250MHz，CD 3SOCD 3）δ：
13.10-12.85（bs，2H），7.90（d，1H），7.50（t，1H），7.35（d，1H），7.20（t，1H），3.80（s，2H）
B) thioindoxyl-7-carboxylic acid
With (2-carboxyl thiophenyl) acetate (6.5g, 30.66mmol) reflux 1 hour in thionyl chloride (45ml), cooling, vacuum-evaporation and with resistates and methylbenzene azeotropic.Resistates is dissolved in 1 again, and also use aluminum chloride in the 2-dichlorobenzene (8.0ml) (8.18g 61.3mmol) handles in batches.Be heated to 45-50 ℃ (1 hour).Be alkalescence with ice and sodium-hydroxide treatment to mixture then.Divide water-yielding stratum, use extracted with diethyl ether, be acidified to PH1 and placement with dense HCl then.Filter the precipitation and the vacuum-drying of collecting formation and obtain red powder shape title compound (2.45g, 41%).
1H NMR（250MHz;CD 3SOCD 3）δ：
8.05-7.95（m，2H），7.50（t，1H），6.55（s，1H）
C) thionaphthene-7-carboxylic acid
With thioindoxyl-7-carboxylic acid (0.3g, 1.55mmol) Glacial acetic acid (5ml) solution handle and be heated backflow (18h) with zinc amalgam (making) by zinc bits (1.14g), cooling, by diatomite filtration and filtrate vacuum-evaporation is obtained the title compound and 2 of red solid, 3-dihydrobenzo thiophene-7-carboxylic acid (1: 1) (0.152g, 55%).
1H NMR（250MHz，CD 3SOCD 3）δ：
8.15（d，1H），8.05（d，1H），7.85（d，1H），7.50（t，2H）
Embodiment 1-1[R 1=NH 2, R 2=Cl, R 3=H, R 4=H, X=O, Y=NH, Z=(i)]
(1-butyl-4-piperidino methyl)-4-amino-5-chloro-benzo [b] furans-6-methane amide
(0.765g 2.47mmol) is dissolved in 10% sodium hydroxide (15ml) and ethanol (15ml) mixture with the product of illustrative examples 1.Then with the reaction mixture reflux.Behind the 23h, reaction mixture is cooled off.Reduction vaporization is removed ethanol and aqueous residue is acidified to PH2 with dense HCl then.The gained gray solid is leached and vacuum-drying.Then solid suspension is also under agitation used 1 at acetonitrile (10ml) with DMF(10ml) in the mixture, (0.440g 2.71mmol) handles the 1-carbonyl dimidazoles.Behind the 20h, with reaction mixture reduction vaporization and vacuum-drying.Then thick imidazoles thing is suspended in anhydrous THF(20ml) in, add be in anhydrous THF(5ml) in N-butyl-4-piperidinylmethylamine (0.461g, 2.71mmol) (WO 93/05038).Under argon gas, mixture heating up is refluxed then.Behind the 4h, with reaction mixture cooling and reduction vaporization.Resistates is distributed among EtOAc and the 10%NaOH.Water layer is extracted with EtOAc, and with the organic layer drying (Na that merges 2SO 4), reduction vaporization obtains brown solid, and it is obtained white foam shape title compound (0.425g, 46%) with silica gel chromatography purifying (20%MeOH/EtOAc makes eluent).M.p.t 88-89 ℃ (from CH 2Cl 2The crystallization of/60-80 sherwood oil)
1H NMR（200MHz，CDCl 3），δ：
8.04（s，1H），7.64（d，1H），7.35（brt，1H），6.81（d，1H），4.71（s，2H），3.43（t，2H），2.97（d，2H），2.33（t，3H），2.05-1.60（m，5H），1.55-1.20（m，5H），0.91（t，3H）.
Embodiment 2-1[R 1=H, R 2=H, R 3=H, R 4=H, X=S, Y=O, Z=(i)]
(1-butyl-4-piperidino methyl) thionaphthene-7-carboxylicesters
With thionaphthene-7-carboxylic acid and 2, (0.262g 1.46mmol) is dissolved in the dry DMF (5ml) 1: 1 mixture of 3-dihydrobenzene thiophene-7-carboxylic acid and with 1, (0.161g 1.61mmol) handles the 1-carbonyl dimidazoles.Mixture is stirred (72 hours).Under Ar gas, lithium methide (1.18ml 1.5MEt will be used also in N-butyl-4-piperidyl methyl alcohol (WO 93/05038) (0.275g 1.61mmol) is dissolved in anhydrous THF(10ml) 2O solution 1.77mmol) is handled, and stirs then 15 minutes.It is also stirred (72 hours) with imidazoles thing solution-treated.Vacuum-evaporation also is distributed in H 2Among the O/EtOAc.Tell organic layer, use Na 2SO 4Dry also filtration, vacuum-evaporation filtrate obtains orange oil then.Should oil by fast silica gel chromatogram method purifying and use CHCl 3→ 3%MeOH/CHCl 3Wash-out obtains brown oil, and it is obtained limpid gluey title compound (0.009g, 2%) by the HPLC separation and purification.
1H-NMR（250MHz，CDCl 3）δ：
8.15（d，1H），8.05（d，1H），7.60（d，1H），7.30（d，1H），7.05（t，1H），4.30（d，2H），3.05-2.95（m，2H），2.35（t，2H），2.00-1.75（m，5H），1.60-1.25（m，6H），0.90（t，3H）.
Embodiment 3-1[R 1=H, R 2=Cl, R 3=H, R 4=H, X=O, Y=O, Z=(i)]
(1-butyl-4-piperidino methyl) 5-chlorobenzene is [b] furans-7-carboxylicesters also
With 5-chlorobenzene [b] furans-7-carboxylic acid [US patent 4888353 also; 33f] (0.5g, 2.54mmol) be suspended in the thionyl chloride (20ml) and reflux (30 minutes) until limpid.Again be dissolved in anhydrous THF(10ml with the solution for vacuum evaporation and with resistates) in.(2.05ml 1.5M diethyl ether solution 3.08mmol) is handled with also using lithium methide in N-butyl-4-piperidyl methyl alcohol (WO 93/05038) (0.479g 2.80mmol) is dissolved in anhydrous THF(5ml) under Ar gas.Mixture is stirred (15 minutes) and drip above-mentioned acyl chloride solution processing.With this solution stirring (18 hours), vacuum-evaporation and with resistates by fast silica gel chromatogram method purifying, use CHCl 3→ 5%EtOH/CHCl 3Obtain light yellow oil/solid as eluent.This material is developed with pentane.Be chilled to-78 ℃ and also filter the solid of collecting formation, vacuum-drying obtains light yellow solid shape title compound (0.11g, 13%), mp=39-40 ℃.
1H NMR（CDCl 3，250MHz）δ：
7.90（d，1H），7.80（dd，2H），6.80（d，1H），4.30（d，2H），3.05（d，2H），2.40（t，2H），2.10-1.80（m，5H），1.65-1.25（m，6H），0.95（t，3H）
Embodiment 4-1[R 1=H, R 2=Cl, R 3=H, R 4=H, X=O, Y=NH, Z=(i)]
(1-butyl-4-piperidino methyl)-5-chlorobenzene is [b] furans-7-methane amide also
With the 5-chlorobenzene also [b] furans-7-carboxylic acid [US patent 4888353,33f] (0.18g, 0.92mmol) be suspended in the thionyl chloride (2ml) and reflux (30 minutes) to limpid.Mixture is cooled off, vacuum-evaporation and with resistates and methylbenzene azeotropic, resistates is dissolved in anhydrous THF(4ml again) in and with triethylamine (0.13ml, 0.92mmol) and N-butyl-4-piperidinylmethylamine (WO 93/05038) (0.171g 1.01mmol) handles.Solution is at room temperature stirred (1 hour), vacuum-evaporation also is distributed in H 2O/CHCl 3In.With organic phase Na 2SO 4Drying is filtered and vacuum-evaporation obtains yellow oil.Should oil with fast silica gel chromatogram method purifying, use CHCl 3→ 2%MeOH/CHCl 3Obtain light yellow oily title compound (0.3g, 94%) as eluent and be translated into oxalate, mp=109-110 ℃.
1H NMR(250MHz, CDCl 3) (free alkali) δ:
8.10（d，1H），7.75（d，1H），7.70（d，1H），7.55-7.45（m，1H），6.85（d，1H），3.45（t，2H），3.00（d，2H），2.35（t，2H），2.05-1.65（m，5H），1.55-1.25（m，6H），0.90（t，3H）.
The intermediate of illustrative examples 1-2(embodiment 1-2)
Dibenzofuran-4-carboxylic acid
Will nBuLi(9.7ml, 1.36M hexane solution) hexane (30ml) solution is handled with N,N,N (2.0ml), adds dibenzofuran (2g) then.At room temperature continue to stir to spend the night.Mixture is poured on solid-state CO 2Go up and dilute with water.Layering is acidified to water layer PH2 and uses dichloromethane extraction with 5N HCl.With organic phase drying (Na 2SO 4), filtration and vacuum concentration obtain the title compound (1.60g) of pale solid.
1H NMR250MHz（d 6-DMSO）
δ13.34（bs，1H），8.42（d，1H），8.21（d，1H），8.04（d，1H），7.80（d，1H），7.36-7.52（m，3H）.
Embodiment 1-2[R 1=H, R 2=H, R 3=H, R 4=H, X=O, A are singly-bounds, Y=O, Z=(i)]
1-butyl piperidine-4-base dibenzofuran-4-carboxylate salts acidulants
Add 1 in acetonitrile (50ml) solution of dibenzofuran-4-carboxylic acid (1.00g), 1-carbonyl dimidazoles (763mg) at room temperature continues to stir 2h.The vacuum concentration solvent obtains thick imidazoles thing.
Under 0 ℃, lithium methide (3.13ml, 1.5M diethyl ether solution) is added drop-wise to the anhydrous THF(15ml of 1-butyl-4-hydroxymethyl piperidine (808mg)) in the solution.Under 0 ℃ and nitrogen, continue to stir 30 minutes.Anhydrous THF(20ml with thick imidazoles thing) solution is added in the reaction mixture and at room temperature continues to stir and spends the night.Add entry (2ml) and vacuum concentration solvent.Resistates is distributed in chloroform and the water.With organic phase drying (Na 2SO 4), filter and concentrating under reduced pressure.Resistates through the silicon-dioxide chromatographic separation, is obtained clean ester with chloroform and ethanol as eluent.Close the HCl processing with ether and obtain solid state title compound (1.00g).
1H NMR250MHz(CDCl 3) (free alkali)
δ：8.12（t，2H），7.98（d，1H），7.68（d，1H），7.50（t，1H），7.34-7.45（m，2H），4.32（d，2H），3.02（d，2H），2.35（t，2H），1.82-2.08（m，5H），1.44-1.63（m，4H），1.26-1.39（m，2H），0.94（t，3H）.
Embodiment 2-2[R 1=H, R 2=H, R 3=H, R 4=H, X=O, A are-CH 2-, Y=O, Z=(i)]
(1-butyl-4-piperidino methyl)-9H-xanthene-4-carboxylicesters
Title compound is prepared by the imidazoles thing by 9H-xanthene-4-carboxylic acid (Can.J.Chem. such as P.Yates, 1975,53,2045) and (1-butyl piperidine-4-yl) lithium methoxide.
Embodiment 3-2[R 1=H, R 2=H, R 3=H, R 4=H, X=O, A be-CO-, Y=O, Z=(i)]
(1-butyl-4-piperidino methyl) 9-oxo-9H-xanthene-4-carboxylicesters
Title compound is prepared by the imidazoles thing by 9-oxo-9H-xanthene-4-carboxylic acid (S.Akagi etc., J.Pharm.Soc.Jpn., 1954,74,610) (R.Anschutz etc., Ber., 1922,55,686) and (1-butyl piperidine-4-yl) lithium methoxide
Embodiment 4-2[R 1=H, R 2=H, R 3=H, R 4=H, X=O, A be-NH-, Y=O, Z=(i)]
(1-butyl-4-piperidino methyl) 10H-phenoxazine-4-carboxylicesters
Title compound is prepared by the imidazoles thing by 10H-phenoxazine-4-carboxylic acid and (1-butyl piperidine-4-yl) lithium methoxide.
Embodiment 5-2[R 1=H, R 2=H, R 3=H, R 4=H, X=O, A are singly-bounds, Y=NH, Z=(i)]
(1-butyl-4-piperidino methyl)-1-amino-2-chlorine dibenzofuran-4-methane amide
Prepare title compound and be translated into oxalate by 1-amino-2-chlorine dibenzofuran-4-carboxylic acid (EP-A-0339950) according to the described method of embodiment 2-3.
m.pt177-178℃
1H NMR(250MHz, CDCl 3), (free alkali) δ:
8.12（s，1H），7.78（d，1H），7.54（d，1H），7.42（m，3H），4.93（s，2H），3.43（t，2H），2.92（d，2H），2.28（t，2H），1.91-1.65（m，5H），1.48-1.35（m，6H），0.87（t，3H）.
Embodiment 6-2[R 1=H, R 2=Cl, R 3=NH 2, R 4=H, X=O, A are singly-bounds, Y=O, Z=(i)]
(1-butyl-4-piperidino methyl) 1-amino-2-chlorine dibenzofuran-4-carboxylicesters
Prepare title compound and be translated into oxalate by 1-amino-2-chlorine dibenzofuran-4-carboxylic acid (EP-A-0339950) according to the described method of embodiment 1-3.
mpt.199-200℃
1H NMR(250MHz, CDCl 3) (free alkali) δ:
8.08（s，1H），7.80（d，1H），7.70（d，1H），7.47（m，2H），5.11（s，2H），4.19（d，2H），3.05（bd，2H），2.39（t，2H），2.12-1.80（m，5H），1.54（m，4H），1.32（m，2H），0.94（t，3H）.
Embodiment 7-2[R 1=H, R 2=Cl, R 3=H, R 4=H, X=O, A are singly-bounds, Y=O, Z=(i)]
(1-butyl-4-piperidino methyl) 2-chlorine dibenzofuran-4-carboxylicesters
Prepare title compound according to the described method of embodiment 3-3 by 2-chlorine dibenzofuran-4-carboxylic acid (EP-A-0339950).
mpt.80-82℃
1H NMR(250MHz), CDCl 3(free alkali) δ:
8.12（d，1H），8.05（d，1H），7.92（d，1H），7.68（d，1H），7.53（t，1H），7.40（t，1H），4.32（d，1H），3.03（d，2H），2.38（t，2H），2.10-1.82（m，5H），1.55（m，4H），1.32（m，2H），0.90（t，3H）.
Embodiment 1-3[R 1=H, R 2=H, R 3=H, R 4=H, X=O, A are singly-bounds, f, and g=H, Y=O, Z=(i)]
(1-butyl-4-piperidino methyl) 1-amino-2-chloro-5a, 6,7,8,9,9a-six hydrogen-oxygens fluorenes-4-carboxylicesters
Under agitation with 1-amino-2-chloro-5a, 6,7,8,9, (0.267g 0.998mmol) is suspended in that (0.178g 1.098mmol) handles in the acetonitrile and with two carbonyl dimidazoles to 9a-six hydrogen-oxygens fluorenes-4-carboxylic acid (EP-A-0339950).Behind the 4h, reaction mixture reduction vaporization and vacuum-drying are obtained the thick imidazoles thing of white solid.Simultaneously, stir and argon gas under, with 1-butyl-4-piperidine carbinols (WO 93/103725) (0.171g, anhydrous THF(8ml 0.998mmol)) solution with being in Et 2(0.665ml 0.998mmol) handles 1.5M lithium methide among the O.0.25h after, slowly add thick imidazoles thing at anhydrous THF(5ml) in suspension.Behind the 24h, with the reaction mixture reduction vaporization and be distributed in EtOAc and water in.With water layer with EtOAc extraction and with the organic layer drying (Na that merges 2SO 4).Reduction vaporization obtains yellow oil, and it is used silica gel chromatography purifying (5%MeOH/CH 2Cl 2Make eluent) obtain light yellow oily title compound (0.082g, 20%), be translated into its oxalate,
m.p.t.105-107℃。
1H NMR(200 MHz, CDCl 3) (free alkali) δ:
7.68（s，1H），4.70（m，1H），4.35（s，2H），4.12（d，2H），3.13（bd，2H），3.00（m，1H），2.55-1.45（m，17H），1.43-1.15（m，4H），0.93（t，3H）.
Embodiment 2-3[R 1=H, R 2=Cl, R 3=NH 2, R 4=H, X=O, A are singly-bounds, and f, g are a key together, Y=NH, Z=(i)]
(1-butyl-4-piperidino methyl) 1-amino-2-chloro-5a, 6,7,8,9,9a-six hydrogen-oxygens fluorenes-4-methane amide
Stir down 1-amino-2-chloro-5a, 6,7,8,9, (0.292g 1.09mmol) is suspended in that (0.186g 1.46mmol) handles in the acetonitrile (20ml) and with two carbonyl dimidazoles to 9a-six hydrogen-oxygens fluorenes-4-carboxylic acid (EP-A-339950).Behind the 20h, reaction mixture reduction vaporization and vacuum-drying are obtained the thick imidazoles thing of white solid.Then the imidazoles thing is dissolved in anhydrous THF(10ml again) in and under Ar gas, add be dissolved in anhydrous THF(2ml) in (1-butyl-4-piperidyl) methylamine (WO 93/05838) (0.204g, 1.201mmol).Then mixture heating up is refluxed.Behind the 8h, with the reaction mixture cooling, and reduction vaporization.Then resistates is distributed in CH 2Cl 2And NaHCO 3In the aqueous solution.Then with water layer CH 2Cl 2Extraction (1 *) is with the organic layer drying (Na that merges 2SO 4), reduction vaporization obtains water white oil, and it is used chromatography purification (10% MeOH/CH 2Cl 2Make eluent) obtain colorless oil title compound (0.161g, 35%), be translated into its oxalate.
m.pt214-215℃
1H NMR(250MHz CDCl 3) (free alkali) δ:
7.82（s，1H），7.54（t，1H），4.72（m，1H），4.29（s，2H），3.32（t，2H），3.03（m，3H），2.32（m，3H），2.12-1.15（m，18H），0.91（t，3H）
Embodiment 3-3[R 1=H, R 2=Cl, R 3=H, R 4=H, X=O, A are singly-bounds, f, and g=H, Y=O, Z=(i)]
(1-butyl-4-piperidino methyl) 2-chloro-cis-5a, 6,7,8,9,9a-six hydrogen-oxygens fluorenes-4-carboxylicesters
Under agitation with 2-chloro-cis-5a, 6,7,8,9,9a-six hydrogen-oxygens fluorenes-4-carboxylic acid (EP-A-0339950), (0.100g 0.396mmol) is suspended in the thionyl chloride (5ml) and reflux.Behind the 1h, reaction mixture cooling and reduction vaporization are obtained shallow brown oil, its vacuum-drying is obtained thick acyl chlorides.Simultaneously, directly (0.272ml 0.436mmol) handles with the 1.6M n-Butyl Lithium with 1-butyl-4-piperidyl methyl alcohol (0.075g, anhydrous THF(3ml 0.436mmol)) solution at argon gas.0.25h after, add the anhydrous THF(5ml of above-mentioned thick acyl chlorides) solution, at room temperature stir the gained mixture and to spend the night.Then with the reaction mixture reduction vaporization and by silica gel chromatography purifying (2%MeOH/CH 2Cl 2Make eluent) obtain colorless oil title compound (0.071g, 44%), be translated into oxalate.
m.pt154-155℃
1H NMR(250MHz, CDCl 3) (free alkali) δ:
7.70（d，1H），7.20（d，1H），4.85（m，1H），4.18（d，2H），3.25（m，1H），3.05（d，2H），2.43（t，2H），2.13-1.70（m，8H），1.65-1.25（m，11H），0.95（t，3H）.
Embodiment 4-3[R 1=H, R 2=Cl, R 3=H, R 4=H, X=O, A are singly-bounds, and f, g are a key together, Y=O, Z=(i)]
(1-butyl-4-piperidino methyl) 2-chloro-6,7,8,9-tetrahydrochysene dibenzofuran-4-carboxylicesters
By 2-chloro-6,7,8,9-tetrahydrochysene dibenzofuran-4-carboxylic acid (EP-A-0339950) preparation title compound also changes into its oxalate according to the described method of embodiment 3-3.
m.pt 188-190℃
1H NMR(200 MHz, CDCl 3) (free alkali) δ:
7.78（d，1H），7.53（d，1H），4.28（d，2H），3.03（d，2H），2.80（t，2H），2.58（t，2H），2.10-1.75（m，9H），1.52-1.25（m，6H），0.90（t，3H）.
Embodiment 1-4[X=O, R 1=H, R 2=Cl, R 3, R 4', R "=H, Y=O, Z=(i)]
10-(1-butyl piperidine-4-ylmethyl) 8-chloro-3,4,5,6-tetrahydrochysene-2, the hot English carboxylicesters of 6-methylene radical-2H-1-Ben Bing Evil
By 8-chloro-3,4,5,6-tetrahydrochysene-2,6-methylene radical-2H-1-benzene and Evil Xin Ying-10-carboxylic acid (R.D.Youssefyeh etc., J.Med.Chem.1992,35,903) and (1-butyl piperidine-4-yl) lithium methoxide prepare title compound by the imidazoles thing.
5-HT 4Receptor antagonist activity
1) guinea pig colon
Use the male guinea pig of heavy 250-400g.Obtain to be about the longitudinal muscle Auerbach's plexus preparation of 3cm from the distal colon district.Its load low suspension at 0.5g is being contained the bulging 5%CO that has 2O 2The chorista of Krebs solution bathe, and above-mentioned tissue bath is remained on 37 ℃.In all tests, Krebs solution also contains 5-HT 1, 5-HT 2And 5-HT 3Acceptor has 10 of blocking effect -7M methiotepin (methiothepin) and 10 -6M granisetron.
After having set up a simple 5-HT concentration response curve, use the administration cycle of 30s duration of contact and 15 minutes, selection can obtain the 5-HT concentration (about 10 of the maximum Muscle contraction of about 40-70% -9M).Organized alternatively administered in per then 15 minutes, the 5-HT of above-mentioned concentration was the nAChR energizer of about equipotent concentration then before this, dimethylphenylpiperazinium (DMPP).After consistent the replying that obtains 5-HT and DMPP, in bathing solution, add the 5-HT of the supposition of rising concentration 4Receptor antagonist.The percentage reduced rate of the contraction that causes with 5-HT or DMPP is measured the effect of this compound then.From these data, can record pIC 50Value, pIC 50Value defined is to reduce by the 50% antagonist concentration of shrinking-log value.Can reduce replying but do not reduce the compound that DMPP replys and being considered for 5-HT of 5-HT 4Receptor antagonist.
The compounds of this invention has usually and is at least 7 pIC 50

Claims (17)

1, formula I compound, wherein formula I is made up of formula (I-1) to (I-4), and pharmaceutically acceptable salt and formula I compound or its pharmaceutically acceptable salt have 5-HT in preparation 4Application in the receptor antagonist activity medicine:
Figure 931148561_IMG2
Wherein:
X is O or S;
R 1Be hydrogen, amino, halogen, C 1-6Alkyl, hydroxyl or C 1-6Alkoxyl group;
R 2Be hydrogen, halogen, C 1-6Alkyl, C 1-6Alkoxyl group, nitro, amino or C 1-6Alkylthio;
R 3Be hydrogen, halogen, C 1-6Alkyl, C 1-6Alkoxyl group or amino;
R 4Be hydrogen or C 1-6Alkyl;
Figure 931148561_IMG3
Wherein:
X is O or S;
A represents a singly-bound ,-CH 2-or CO or A be (CH 2) a-E-(CH 2) b wherein
One of a and b are 0 and another is 0 or 1, and E is O, S or NH;
R 1Be hydrogen, amino, halogen, C 1-6Alkyl, hydroxyl or C 1-6Alkoxyl group;
R 2Be hydrogen, halogen, C 1-6Alkyl, C 1-6Alkoxyl group, nitro, amino or C 1-6Alkylthio;
R 3Be hydrogen, halogen, C 1-6Alkyl, C 1-6Alkoxyl group or amino;
R 4Be hydrogen or C 1-6Alkyl;
Figure 931148561_IMG4
Wherein:
X is O or S;
A represents a singly-bound ,-CH 2-or CO, or A is (CH 2) a-E-(CH 2) b,
Wherein one of a and b are 0 and another is 0 or 1, and E is O, S or NH;
F and g are hydrogen or are a key together;
R 1Be hydrogen, amino, halogen, C 1-6Alkyl, hydroxyl or C 1-6Alkoxyl group;
R 2Be hydrogen, halogen, C 1-6Alkyl, C 1-6Alkoxyl group, nitro, amino or C 1-6Alkylthio;
R 3Be hydrogen, halogen, C 1-6Alkyl, C 1-6Alkoxyl group or amino;
R 4Be hydrogen or C 1-6Alkyl;
Figure 931148561_IMG5
Wherein
X is O or S;
R 1Be hydrogen, amino, halogen, C 1-6Alkyl, hydroxyl or C 1-6Alkoxyl group;
R 2Be hydrogen, halogen, C 1-6Alkyl, C 1-6Alkoxyl group, nitro, amino or C 1-6Alkylthio;
R 3Be hydrogen, halogen, C 1-6Alkyl, C 1-6Alkoxyl group or amino;
R 4' and R 4" independently be hydrogen or C 1-6Alkyl;
Comprise in (I-4) in formula (I-1):
Y is O or NH;
Z is inferior formula (a), (b) or (c):
Figure 931148561_IMG6
Figure 931148561_IMG7
Wherein
n 1Be 0,1,2,3 or 4; n 2Be 0,1,2,3 or 4;
n 3Be 2,3,4 or 5;
Q is 0,1,2 or 3; P is 0,1 or 2; M is 0,1 or 2;
R 5Be hydrogen, C 1-12Alkyl, aralkyl or R 5Be (CH 2) z-R 10Wherein z is 2 or 3 and R 10Be selected from cyano group, hydroxyl, C 1-6Alkoxyl group, phenoxy group,
C (O) C 1-6Alkyl, CO-C 5H 5,-CONR 11R 12, NR 11COR 12,
SO 2NR 11R 12Or NR 11SO 2R 12, R wherein 11And R 12Be hydrogen or C 1-6Alkyl; With
R 6, R 7And R 8Independent is hydrogen or C 1-6Alkyl; And
R 9Be hydrogen or C 1-10Alkyl;
Or wherein the CO-Y connection portion by the formula of heterocycle Indezole bioisostere replacement (I) compound.
2, according to the compound of claim 1, wherein:
In the formula (I-1):
R 1Be hydrogen or amino, R 2Be hydrogen or halogen, R 3Be hydrogen or halogen, R 4Be hydrogen;
In the formula (I-2):
R 1Be hydrogen or amino, R 2Be hydrogen or halogen, R 3Be hydrogen or halogen, R 4Hydrogen normally;
In the formula (I-3):
R 1Be hydrogen or amino, R 2Be hydrogen or halogen, R 3Be hydrogen or halogen, R 4Be hydrogen;
In the formula (I-4):
R 1Be hydrogen or amino, R 2Be hydrogen or halogen, R 3Be hydrogen or halogen, R 4' and R 4" be hydrogen.
3, according to the compound of claim 1 or 2, wherein the part that is connected with CO-Y-Z is those that are comprised among any embodiment described here.
4, according to arbitrary described compound in the claim 1 to 3, wherein Z is inferior formula (a) and (CH 2) n 1Be connected on the carbon atom of nitrogen heterocyclic.
5, according to the compound of claim 4, wherein Z is the 4-piperidino methyl that N-replaces.
6, according to the compound of claim 5, wherein said N-substituting group is C 2Or more senior alkyl or can any substituted benzyl.
7, (1-butyl-4-piperidino methyl)-4-amino-5-chlorobenzene [b] furans-7-methane amide also,
(1-butyl-4-piperidino methyl) thionaphthene-7-carboxylicesters,
(1-butyl-4-piperidino methyl) 5-chlorobenzene is [b] furans-7-carboxylicesters also, or
(1-butyl-4-piperidino methyl)-5-chlorobenzene is [b] furans-7-methane amide also.
8,1-butyl piperidine-4-ylmethyl dibenzofuran-4-carboxylicesters,
(1-butyl-4-piperidino methyl) 9H-xanthene-4-carboxylicesters,
(1-butyl-4-piperidino methyl) 9-oxo-9H-xanthene-4-carboxylicesters,
(1-butyl-4-piperidino methyl) 10H-phenoxazine-4-carboxylicesters,
(1-butyl-4-piperidino methyl)-1-amino-2-chlorine dibenzofuran-4-methane amide,
(1-butyl-4-piperidino methyl) 1-amino-2-chlorine dibenzofuran-4-carboxylicesters, or
(1-butyl-4-piperidino methyl) 2-chlorine dibenzofuran-4-carboxylicesters.
9, (1-butyl-4-piperidino methyl) 1-amino-2-chloro-5a, 6,7,8,9,9a-six hydrogen-oxygens fluorenes-4-carboxylicesters,
(1-butyl-4-piperidino methyl)-1-amino-2-chloro-5a, 6,7,8,9,9a-six hydrogen-oxygens fluorenes-4-methane amide,
(1-butyl-4-piperidino methyl) 2-chloro-cis-5a, 6,7,8,9,9a-six hydrogen-oxygens fluorenes-4-carboxylicesters, or
(1-butyl-4-piperidino methyl) 2-chloro-6,7,8,9-tetrahydrochysene dibenzofuran-4-carboxylicesters.
10,8-chloro-3,4,5 10-(1-butyl piperidine-4-ylmethyl), 6-tetrahydrochysene-2, the hot English carboxylicesters of 6-methylene radical-2H-1-Ben Bing Evil.
11, according to arbitrary described compound in the claim 7 to 10, be the form of pharmaceutically acceptable salt.
12, according to arbitrary described compound in the claim 7 to 10, wherein Y is NH.
13, a kind of method for preparing the ester or the amide compound (wherein Y is O or NH) of claim 1, this method comprise suitable acid derivative and suitable alcohol or amine reaction.
14, a kind of pharmaceutical composition, it contains arbitrary described compound and pharmaceutically acceptable carrier in the claim 1 to 12.
15, the compound of claim 1 is as the active treatment material.
16, claim 1 compound is used as 5-HT in preparation 4Purposes in the receptor antagonist pharmaceuticals.
17, the purposes of claim 16 be the treatment or the prevention gastrointestinal illness, in cardiovascular disorder and the CNS disease as 5-HT 4Receptor antagonist.
CN 93114856 1992-10-13 1993-10-12 Medicine Pending CN1092421A (en)

Applications Claiming Priority (6)

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GB929221482A GB9221482D0 (en) 1992-10-13 1992-10-13 Pharmaceuticals
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