CN1022485C - Aromatic 2-aminoalkyl-1, 2-benzoisothiazol-3(2H) one-1, 1-dioxide derivatives - Google Patents
Aromatic 2-aminoalkyl-1, 2-benzoisothiazol-3(2H) one-1, 1-dioxide derivatives Download PDFInfo
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- CN1022485C CN1022485C CN 90108782 CN90108782A CN1022485C CN 1022485 C CN1022485 C CN 1022485C CN 90108782 CN90108782 CN 90108782 CN 90108782 A CN90108782 A CN 90108782A CN 1022485 C CN1022485 C CN 1022485C
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- dioxide
- benzisothiazole
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
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- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention relates to aromatic 2-aminoalkyl derivatives of 1,2-benzoisothiazol-3(2H)one-1,1-dioxides, processes for the preparation of same, and to their use as anxiolytic and antihypertensive agents.
Description
The present invention relates to some aromatics 2-aminoalkyl-1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide derivative and they are as the purposes of anxiety medicament and antihypertensive agents.
Anxiety is defined as the worried of some future event or worries.Most of people are even not every people can cause that some anxiety disorder agonizes because of being subjected to certain stimulation once in a while.Sensations such as anxiety that some people then may be caused by daily life pressure or fear are crushed, and make one or two people become the member that society loses throughput.Preferred base therapy method in view of indivedual consultation of doctors groups propose proved already, was carrying out the therapeutive while, and using chemotherapeutic agents is the useful householder method of treatment anxiety disorder, thereby can make the serious one or two people that the torment ability of resuming production that is subjected to.
The benzene phenodiazine
Compounds is the current medicament that is selected as the treatment anxiety.Especially zeisin, stable and oxazepam are common drugs.This compounds has great possibility to be abused, particularly in the patient who treats.In addition, benzene phenodiazine
Usually have undesirable sedative effect, and draw together as ethanol with other cartridge bag and to have deleterious interaction.
The applicant has now found that the aromatics 2-aminoalkyl-1 that a class is new, the ketone-1 of 2-benzisothiazole-3(2H), and 1-dioxide anxiety medicament, this medicament does not have the benzene phenodiazine usually
The undesirable action of class.When pointed according to the present invention when using compound disclosed herein, can alleviate as symptom such as excessive fear, worry, uneasiness, anxiety, stress situation, neurotic depression and be of value to and alleviate some Personality disorder.In addition, compound of the present invention is effective antihypertensive agents, and this medicament has the effect that brings high blood pressure down to the patient of need medication.
The present invention relates to have a class aromatics 2-aminoalkyl-1 of following general formula, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide derivative and its medicinal acid addition salt.
N is 2 to 5 integer; A and B respectively are oxygen, sulphur or NR ' (R ' represent hydrogen or methyl); R
1Be hydrogen, hydroxyl or methoxyl group; R
2Be hydrogen or methyl.
The invention also discloses the preparation method of these compounds and they purposes as anxiety and antihypertensive agents.
" medicinal acid addition salt " used herein speech is meant any non-toxic organic or the inorganic acid addition salt of the basic cpd of application formula I representative.The representative examples of mineral pigments of the acceptable acid addition salts that forms comprises hydrochloric acid, hydrogen bromine salt, sulfuric acid and phosphoric acid and acid metal-salt such as Sodium phosphate dibasic and sal enixum.The organic acid that forms acceptable acid addition salts comprises monobasic, binary and tribasic carboxylic acid, this sour example is just like acetate, oxyacetic acid, lactic acid, pyruvic acid, propanedioic acid, Succinic Acid, pentanedioic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, xitix, toxilic acid, hydroxymaleic acid, phenylformic acid, P-hydroxybenzoic acid, phenylacetic acid, styracin, Whitfield's ointment, 2-phenoxy benzoic acid and sulfonic acid such as methylsulfonic acid or 2-ethylenehydrinsulfonic acid.Can form monobasic or binary acid salt, and this class salt exists with hydration or anhydrous basically form.Usually, the acid salt of these compounds is water-soluble and the crystalline material of various hydrophilic organic solvents.In addition, compare with their free alkali form, this salt has high melt point usually, and its chemical stability is stronger.
Some subclass compound that belongs in the scope of the invention is listed below:
2-[ω-[(2,3)-dihydro-1,4-benzo dioxane-2-yl) methylamino-] alkyl]-1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide
2-[ω-[(2,3-dihydro-1,4-benzo oxygen thia oneself-the 3-yl) methylamino-] alkyl]-1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide
2-[ω-[(2,3-dihydro-1,4-benzo dithia hexamethylene-2-yl) methylamino-] alkyl]-1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide
2-[ω-[(2,3-dihydro-1,4-benzoxazine-3-yl) methylamino-] alkyl]-1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide
2-[ω-[(2,3-dihydroquinazoline-2-yl) methylamino-] alkyl]-1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide
2-[ω-[(2,3-dihydro-naphtho [1,2-b] [1,4] dioxane-2-yl) methylamino-]-alkyl]-1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide
(compound of these subclass can be substituted in the two or three-digit of dioxane.）
（1f）
2-[ω-[replace (indol-3-yl) ethylamino] alkyl]-1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide
2-[ω-[(replacement) 1,2,3,4-tetrahydrochysene-β-Ka Lin] alkyl]-1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide
2-[ω-[(replacement) 1,2,3,4-tetralin-2-amino] alkyl]-1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide
The compound that the preferred subclass of the present invention is made up of formula (1h), the alkane chain is endways by (replacement)-1,2,3 in the formula, and 4-tetrahydrochysene-β-Ka Lin ring system replaces.
The present invention more preferably subclass is and the relevant compound of formula (1f), in the formula alkyl chain endways by 2,3-dihydro-naphtho [1,2-b] [1,4]-dioxane-2-base or-the 3-base system replaces.
The most preferred subclass of the present invention is and the relevant compound of formula (1a), in the formula alkyl chain endways by 2,3-dihydro-1,4-benzo dioxane-2-base system replaces.
Above-mentioned alkylidene group-(CH
2)
n-can think to be isolated in the cross structure in the heterocycle system at two ends.Its symbol n represents 2 to 5 integer as mentioned above.Those n are that 2 to 4 alkylidene group is a preferred group of the present invention.
The aromatics 2-aminoalkyl-1 of formula I, the ketone-1 of 2-benzisothiazole-3(2H), the 1-dioxide derivative can be with the similar approach preparation of the skilled professional's known standard technology in present technique field.Therefore, compound of the present invention can be by with the nucleophilic amine of suitable formula (2) and the N-alkyl-1 of formula (3), the ketone-1 of 2-benzisothiazole-3(2H), and the Substrate of 1-dioxide carries out condensation and prepares,
In the formula, x and n define suc as formula (1), and the suitable leavings group of symbol (L) representative is as chlorine, iodine, mesylate and tosylate.
The most handy nucleophilic reagent near equimolar amount of this nucleophilic condensation reaction (2) and Substrate (3) carry out, reaction times is depended on the specific reactants of use, be about 1 to 24 hour, the scope of temperature of reaction is about 25 ℃ to 140 ℃, reacts in the scope that is preferably in 60 ℃ to 125 ℃ and carries out.
In addition, reaction is preferably in uncle's organic bases such as alkyl amine or pyridine, or carries out under the existence of mineral alkali such as salt of wormwood.
Because employed reactant is typical crystalline material, preferably use solvent.Suitable solvent comprises any nonreactive solvent, preferably has boiling spread and be those solvents of 60 ℃ to 150 ℃.Therefore, spendable suitable solvent such as sherwood oil; Chlorinated hydrocarbon such as tetracol phenixin, ethylene chloride, methylene dichloride or chloroform; Chlorinating aromatic compounds is as 1,2,4-trichlorobenzene or orthodichlorobenzene; Dithiocarbonic anhydride; Ether solvent such as diethyl ether, tetrahydrofuran (THF) or Dui diox; Aromatic solvent such as benzene, toluene or dimethylbenzene; Or alcoholic solvent such as ethanol.Most preferred solvent is those solvents of known promotion nucleophilic reaction, as methyl-sulphoxide and dimethyl formamide.
The product of formula (1) can utilize the known proper method of these professional those of skill in the art to separate, and for example, with reaction mixture solids removed by filtration material, then filtrate is evaporated to reclaim active ingredient.The compound of formula (1) can and utilize its picric acid or the method for oxalic acid mixture is further purified by recrystallization or generation.
The nucleophilic primary amine of indication is commercially available or the compound described in the literature in the formula (2).In other words, the primary amine of representing by symbol X (R in the formula
2Be hydrogen) can easily prepare by reducing corresponding cyano derivative, for example, X represents the compound of following formula group in the formula (2)
(in the formula A and B such as following formula (1) definition)
Can prepare by the method for the corresponding cyano derivative shown in the reduction following formula (4).
This reduction reaction can utilize all ingredients to carry out, and for example, uses hydrogen and catalytic metal such as palladium carbon, Raney nickel, platinum, rhodium, ruthenium or platinum oxide etc. to carry out catalytic reduction reaction.In addition, also can utilize suitable reagent such as diborane, sodium borohydride, utilize lithium, sodium, potassium, calcium, zinc, magnesium, tin or iron at liquid ammonia or lower molecular weight aliphatic amide or sodium, aluminium or zinc amalgam, zinc, tin or iron in hydroxylic solvent or the dissolving metal reduction reaction in the presence of inorganic acid aqueous solution, carried out, or lithium aluminum hydride.
X represents the nucleophilic reagent of following groups in the formula (2)
Can prepare by corresponding cyano compound and 1 to 2 equimolar lithium aluminum hydride are reacted in suitable solvent, preferably use 1.5 lithium aluminum hydrides such as mole such as grade.Reaction times is about 30 minutes to 24 hours.According to specific reactant, solvent and the temperature used, the time of employing preferably is about 1 to 5 hour.Suitable temperature range is-78 ℃ to 60 ℃, preferably is about 20 ℃.The suitable solvent comprises ether solvent such as ether, tetrahydrofuran (THF) (THF), Dui diox, 1,2-glycol dimethyl ether (DME), diglyme, or aromatic solvent such as benzene, toluene or dimethylbenzene.
Usually X represents following formula group (R in the formula (2)
2Be other group that dehydrogenation is outer) nucleophilic secondary amine
Can by with corresponding primary amines and suitable alkyl fontanel, benzene methanesulfonic acid alkyl ester or methylsulfonic acid alkyl ester in appropriate solvent such as acetonitrile, in the presence of at least one equivalent or excessive organic or inorganic alkali such as salt of wormwood, directly carry out alkylated reaction and prepare.
Many cyano derivatives of formula (4) are compound known.On the other hand, these compounds can be by similar approach preparation as described below.For example, the identical instances of application of aforementioned is used following formula (5) compound (A and B are as defined above in the formula)
With 2-bromine or preferably 2-chloroacrylonitrile reaction.Say roughly, for vinyl cyanide and 2 or how equimolar alkali such as salt of wormwood, in appropriate solvent, mix with formula (5) compound of equimolar amount and fontanel.Range of reaction temperature is 0 ℃ of boiling point to reaction mixture, and reaction time range is about 1 to 24 hour.The suitable solvent of using comprises dimethyl formamide; Methyl-sulphoxide; Acetone; Chlorinated hydrocarbon such as tetracol phenixin, chloroform or methylene dichloride; Ether solvents such as diethyl ether, tetrahydrofuran (THF) (THF) or diglyme; Aromatic solvent such as benzene, toluene or dimethylbenzene; Or alcoholic solvent such as methyl alcohol or ethanol.
When symbol A and the different atom of B representative, will obtain mix products.Available the known common method of professional those of skill in the art is as more easily separating and purifying mixture with silica gel chromatography or fractional recrystallization.In addition, the R in formula (1) compound
1Or R
2When substituting group is hydroxyl, must its hydroxyl of protection before carrying out above-mentioned 2-bromine or the condensation reaction of 2-chloroacrylonitrile.Suitable protecting group comprises phenmethyl or methyl, and these blocking groups are removed subsequently, with the corresponding nucleophilic amine of production (2) expression.The removal of this protecting group can be adopted any suitable technical known method, as the catalytic reduction of phenmethyl, handles as Hydrogen bromide with acid, or handles with boron tribromide.
The compound of formula (3) comes down to the N-alkyl derivative of saccharin.Leavings group (L) in formula (3) compound can be represented any the known group of professional those of skill in the art, as benzene methanesulfonic acid ester (OTS) or methanesulfonates (OMS), iodide, bromide or muriate or hydroxyl.L represents bromide or the iodide can be in suitable solvent in formula (3) Substrate, handles corresponding two fontanels with the sodium salt of the saccharin of monovalent and prepares for the method for alkane, and the treatment time is about 1 hour, and temperature is about 100 ℃.Shown in following reaction formula:
Symbol Hal represents chlorine, bromine or iodine in the following formula.
The suitable solvent comprises dimethyl formamide; Dimethyl sulfoxide (DMSO); Acetone; Aromatic solvent such as benzene, toluene or dimethylbenzene; Or ether solvents such as diethyl ether, tetrahydrofuran (THF) or 1, the 2-glycol dimethyl ether.
The compound of formula (1) has useful anxiety and antihypertensive properties.5-HT is adopted in its anxiety performance suggestion
1A(serotonin
1A) extracorporeal receptor is in conjunction with research.See Middlemiss etc., Eur.J.Pharmacol., 90,151-3(1983) and Glaser etc., and Arch.Pharmacol., 329,211-215(1985).The antihypertensive effect of compound described herein can be according to Fozard, J.Cardiovascular Pharm., 4, method 829-838(1982) is measured with two kinds of methods of rat of the rat of anesthetized normotensive and/or clear-headed trouble spontaneously hypertensive.
But compound per os of the present invention, subcutaneous, intravenously, intramuscular, intraperitoneal or rectal administration.Best route of administration is oral.The dosage of compound can be any significant quantity, and will be different with the anxiety severity of patient, administering mode and required treatment.May need repetition to give compound every day, and will be with patient's situation and administering mode and different.
With regard to oral, the anxiety of formula (1) compound and the scope of hypertension significant quantity can be patient body weight every day 0.005 to 10mg/kg, are preferably patient body weight every day 0.05 to 5mg/kg.The preferred anxiety dosage of formula (1a) compound is about 0.1mg/kg patient body weight every day.The composition of unit dosage can contain 1 to 50mg active ingredient, but medication every day one or many.
With regard to parenterai administration, the anxiety of formula (1) compound and the scope of hypertension significant quantity are about patient body weight every day 0.005 to 10mg/kg, preferably are about patient body weight every day 0.05 to 5mg/kg.The non-enteron aisle composition of unit dosage can contain 0.1mg to 10mg active ingredient, but medication every day one or many.
Oral compound can be made into solid or liquid preparation, as capsule, pill, tablet, lozenge, melt, pulvis, solution, suspension or emulsion.Usually the solid dosage unit that adopts comprises capsule or tablet.Capsule can be common gelatin, wherein contains vehicle such as tensio-active agent, lubricant and inert filler such as lactose, sucrose and W-Gum in addition.In addition, the compound of formula (1) can be used tablet matrix such as lactose, sucrose and W-Gum and tackiness agent such as kordofan gum, W-Gum or gelatin commonly used, disintegrating agent such as yam starch or alginic acid and lubricant such as stearic acid or hard acid magnesium mix, thereby are pressed into tablet.
The compound of administration can be made into the solution or the suspension of injection dosage in the non-intestines, is about to the compound adding and contains or do not contain in the medicinal diluent of pharmaceutical carrier.Suitable diluent or carrier comprises liquid such as water or oil, adds or do not add other tensio-active agent or other medicinal auxiliary.In fact the example that can be used for various oil of the present invention has oil, animal oil, and vegetables oil, or the oil in synthetic source, for example, peanut oil, soya-bean oil, and mineral oil.In general, preferred liquid vehicle, particularly injection liquid have the aqueous solution, ethanol and dibasic alcohol such as the propylene glycol or the polyoxyethylene glycol of water, salt solution, glucose and relevant sugar.
The preparation of the typical compound of the actual use of the following example explanation the present invention, but this does not limit the present invention.
The embodiment I
2-[4-[(2,3-dihydro-1,4-benzo dioxane-2-yl) methylamino-] butyl]-1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide
The N-(4-brombutyl) saccharin
Will be in 80ml N, the saccharin in the dinethylformamide (DMF) (9.35g, 50m M) adds 55% sodium hydride, and (2.18g is 50mM) in the dry DMF of 20ml.After 15 minutes, add 1 rapidly, (25ml 200mM), stirs down mixture was heated 1 hour at 100 ℃ the 4-dibromobutane.With reaction mixture cooling, filtration, boil off DMF.Crude product is dissolved in methylene dichloride and filtration, drying and evaporating solns, obtains yellow oil, with silica gel chromatography (CH
2Cl
2/ MeoH, 98/2) purify after, obtain 13.4g(84%) colorless oil.Behind the heavy crystalline substance, the acquisition fusing point is 72 ℃ a N-(4-brombutyl to this oily matter from Virahol) saccharin.
NMR CDCl/TMS 60MHz 8.20-7.85（m，4HAr），4.00-3.30（m，4H），2.40-180（m，4H）。
2-[4-[(2,3-dihydro-1,4-benzo dioxane-2-yl) methylamino-] butyl]-1, the ketone-1 of 2-benzisothiazole-3(2H), the 1-dioxide hydrochloride
With 2-aminomethyl-benzo dioxane [1,4] (0.965g, 5.48mM), salt of wormwood (3g) and the N-(4-brombutyl that as above makes)-saccharin is at N, dinethylformamide (DMF, mix 10ml), mixture is spent the night 100 ℃ of stirrings, and cooling filters and is evaporated to dried.Residue is dissolved in ethyl acetate, washes and use the alkene hcl acidifying with water.Separate the oil that obtains with ether, 5%HCl water washing, this oil is dissolved in methyl alcohol, dry and be evaporated to driedly, obtain 1, the yellow solid that 3g is thick.This material is changed into free alkali and carry out flash chromatography on silica gel separation (CH
2CO
2/ Me OH97/3), obtain the 0.91g required compound.Hydrochloride is recrystallization from Virahol/ethyl acetate solution, obtains fusing point and be 210 ℃ title compound.
Basically by identical step, but use the N-(2-bromotrifluoromethane) the above-mentioned N-(4-brombutyl of saccharin replacement) saccharin, the acquisition compound is 2-[2-[(2,3-dihydro-1,4-benzo dioxane-2-yl)-and methylamino-] ethyl]-1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide, its fusing point are 181 ℃.
The embodiment II
2-[4-(2-[1,2,3,4]-and tetrahydrochysene-β-Ka Lin base) butyl]-1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide
Basically press the same steps as of embodiment I, but replace 2-aminomethyl-benzo dioxane [1,4], make title compound and as crystal of hydrochloride, its fusing point is 272 ℃ with [1,2,3,4]-tetrahydrochysene-β-Ka Lin.
The embodiment III
2-[4-[8-methoxyl group-1,2,3,4-tetralin-2-amino] butyl]-1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide
Basically press the same steps as of embodiment I, but replace 2-aminomethyl benzo dioxane [1,4], make title compound and as crystal of hydrochloride, its fusing point is 233 ℃ with 8-methoxyl group-2-amino-1,2,3,4-tetralin.
The embodiment IV
2-[4-[5-methoxyl group-indol-3-yl) ethylamino] butyl] 1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide
Basically press the same steps as of embodiment I, but replace 2-aminomethyl-benzo dioxane [1,4], make title compound and as crystal of hydrochloride, this xln decomposes before fusion with 5-methoxyl group-tryptamine.
1H NMR(free alkali, CDCl+CD
3OD, 360MHz, ppm) 8.4(1H, S), 8.0-7.7(4H, m), 7.2-6.75(4H, m), 3.8(3H, S), 3.8-3.6(2H, m), 3.15(4H, m), 2.9(2H, t), 1.85(4H, m).
The embodiment V
2-[4-[(2,3-dihydro-1,4-benzoxazine-3-yl) methylamino-] butyl]-1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide
Basically press the same steps as of embodiment I, but replace 2-aminomethyl benzo dioxane [1,4], make title compound and as crystal of hydrochloride, its fusing point is 209 ℃ with 2-aminomethyl benzo oxazine.
The embodiment VI
Use 5-HT
1ACombined techniques is to the external test of anxiety performance
5-HT
1ARecognition site radioligand carry out as follows in conjunction with research: the frontal cortex of male normotensive Sprague-Dawley rat is dissected out, freezing in liquid nitrogen, and standby-20 ℃ of storages.Working power Polytron(places 2/3 place of maximum rate, 20 seconds), the tissue of 4-8 rat is merged, in 70 times of volume Tutofusin triss (Tris)-hydrochloride buffer (50mM pH7.7), make homogenate.With homogenate centrifugal (36500 * g, 10 minutes), will be deposited in homogenize again in the damping fluid of equal volume, and repeating this process secondary.For the second time and between centrifugal for the third time, this tissue homogenate was cultivated 10 minutes at 37 ℃.Final precipitation is suspended in the tris buffer that equal volume contains 10 μ M Supirdyl, 5.7mM calcium chloride and 0.1% ascorbic acid.This suspension was cultivated 10 minutes at 37 ℃, was stored in then in the ice until being used in conjunction with measuring.
It is 1ml that tissue homogenate (0.7ml), the tested compound (0.1ml) that radiates ligand (0.1ml) and proper concn and damping fluid are mixed to final volume, and cultivates 15 minutes at 37 ℃.Filter fast to stop cultivating reaction by Whatman GF/B strainer, then (50mM, PH7.0) washing is three times, each 5ml with ice-cooled Tris-Hcl damping fluid.Using Aqrasol-Z, after (NEN) extracting, measuring radioactivity, efficient is 45-50%.With radioligand mark 5-HT
1ARecognition site, its concentration be [
3H]-8-hydroxyl-2-(two-n-propylamine base)-1,2,3,4-tetralin ([
3H]-8-OH-DPAT), 1mM.
Basically by above-mentioned steps, test following compounds, its result is with expression PIC
50(suppressing the denary logarithm value of specificity) in conjunction with 50% test-compound concentration and with the mean value ± S.E.M.(standard error of 3 independent experiments) expression.
The 5-HT of test-compound rat brain cortex
1A/ * increases multiple
Binding affinity
Buspirone 7.52 ± 0.10 1
Embodiment I (A) 9.34 ± 0.03 66
Embodiment II 8.16 ± 0.07 4.4
Embodiment III 8.52 ± 0.14 10
Embodiment V 8.03 ± 0.15 3.2
* test-compound is compared the antilogarithm of difference with buspirone.
As above data are indicated, according to 5HT
1AIn conjunction with research, the effectiveness of test-compound increases by 3 to 60 times than buspirone.
The embodiment VII
The mensuration of antihypertensive properties
With body weight is male normotensive Sprague-Dawley rat (France is provided by Charles River) usefulness vetanarcol (60mg/kg) peritoneal injection of 250-350g, adds the 15mg/kg subcutaneous injection and makes it numb broken.Use Staham sensator (P23 AA type) to be recorded in the blood pressure of arteria carotis communis or femoral artery.Use Beckman cardiotachometer junctor (9757B type) recorded heart rate from electrocardiogram(ECG.Record is presented in the Beckman power registering instrument (R type).Conduit is inserted femoral vein, be used for intravenously administrable.After all operating procedure is finished, intravenous injection heparin 500 units.
With the compound of embodiment I is 2-[4-[(2,3-dihydro-1,4-benzo dioxane-2-yl) methylamino-] butyl]-1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide salt brine solution subcutaneous administration, its consumption is the 1ml/kg body weight.Observed blood pressure (B.P.) and heart rate (H.R.) change as follows:
Dosage △ BP(mm Hg) △ is HR(time/minute)
25μg/kg -35 -80
500μg/kg -50 -90
In another experiment, directly be measured as the arteriotony and the heart rate of the clear-headed male spontaneously hypertensive rat (France is provided by Charles River) of 250-350g.With the salt brine solution of identical test-compound with the 1ml/kg body weight, subcutaneous (s.c) administration of according to the form below dosage or oral (per os).
Route of administration and dosage △ BP(mmHg) △ HR(time/minute)
100μg/kg s.c. -20 +80
200μg/kg s.c. -65 +100
500μg/kg s.c. -75 +120
1mg/kg per os -25 +100
5mg/kg per os -45 +100
In a word, be subjected under the strip spare, compound 2-[4-[(2,3-dihydro-1,4-benzo dioxane-2-yl) methylamino-] butyl] 1, the ketone-1 of 2-benzisothiazole-3(2H), 1-dioxide reduce blood pressure and the heart rate of anesthesia normal arterial pressure rat effectively, also reduce the blood pressure of clear-headed spontaneous hypertensive rat, and with reflex tachycardia.
Claims (1)
1, preparation following formula 2-[4-(8-methoxyl group-1,2,3,4-tetralin 2-amino) butyl]-1,2-benzisothiazole-3 (2H) ketone-1, the method for 1-dioxide or its pharmaceutical salts,
This method comprises the nucleophilic amine that following formula is represented
With the N-alkyl-1 that following formula is represented, 2-benzisothiazole-3 (2H) ketone-1,2-dioxide
(L is a leavings group in the formula; ) reaction under temperature is 25 ℃ to 140 ℃, last 1 to 24 hour, separate thus obtained required product then.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/836,276 US4748182A (en) | 1986-03-05 | 1986-03-05 | Aromatic 2-aminoalkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxide derivatives and their use as anti-hypertensive and anxiolytic agents |
| US836,276 | 1986-03-05 | ||
| CN87101689A CN1016061B (en) | 1986-03-05 | 1987-03-05 | Process for the preparation of aromatic 2-aminoalkyl-1,2-benzisothiazol-3(2H)one-1,1-dioxide derivatives |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN87101689A Division CN1016061B (en) | 1986-03-05 | 1987-03-05 | Process for the preparation of aromatic 2-aminoalkyl-1,2-benzisothiazol-3(2H)one-1,1-dioxide derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1050872A CN1050872A (en) | 1991-04-24 |
| CN1022485C true CN1022485C (en) | 1993-10-20 |
Family
ID=25742291
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 90108782 Expired - Fee Related CN1022485C (en) | 1986-03-05 | 1987-03-05 | Aromatic 2-aminoalkyl-1, 2-benzoisothiazol-3(2H) one-1, 1-dioxide derivatives |
| CN 90108783 Expired CN1018832B (en) | 1986-03-05 | 1987-03-05 | Aromatic 2-aminoalkyl-1,2-benzoiothiazol-3(2h)one-1, 1-dioxide derivatives |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 90108783 Expired CN1018832B (en) | 1986-03-05 | 1987-03-05 | Aromatic 2-aminoalkyl-1,2-benzoiothiazol-3(2h)one-1, 1-dioxide derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN1022485C (en) |
-
1987
- 1987-03-05 CN CN 90108782 patent/CN1022485C/en not_active Expired - Fee Related
- 1987-03-05 CN CN 90108783 patent/CN1018832B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CN1050872A (en) | 1991-04-24 |
| CN1050874A (en) | 1991-04-24 |
| CN1018832B (en) | 1992-10-28 |
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