CN101007794B - N,N'-disubstituted piperazine derivative, and its preparation method and medicinal composition and uses - Google Patents
N,N'-disubstituted piperazine derivative, and its preparation method and medicinal composition and uses Download PDFInfo
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- CN101007794B CN101007794B CN2006100236772A CN200610023677A CN101007794B CN 101007794 B CN101007794 B CN 101007794B CN 2006100236772 A CN2006100236772 A CN 2006100236772A CN 200610023677 A CN200610023677 A CN 200610023677A CN 101007794 B CN101007794 B CN 101007794B
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Abstract
The invention relates to field of medical design, medical chemistry and pharmaceutics. The invention intends to find out molecule that can activate or prevent potassium ion channel activity by employing computer on the basis of crystal three-dimensional structure of potassium ion channel, then derivatives sifted compound and provides N, N'- disubstituted piperazine derivatives and its salt accepted by pharmacy. The construction formula of said derivatives is expressed in following graph. The invention also relates to the method for preparing said derivatives and its salt and their application. Said compound can be used as activating agent or preventing agent for potassium ion channel, and the potassium ion can be selectively shifted in or out cell by activating or preventing the activity of potassium ion channel. The compound mentioned in this invention can be used to treat and/ or prevent cranial vascular disease relevant to physiological pathological and pharmacologia of cardiovascular system effectively.
Description
Technical field
The present invention relates to medicinal design, pharmaceutical chemistry and field of pharmacology, more specifically, the present invention is based on the screening of potassium-channel crystal three-dimensional structure utilization computer virtual, so that seek can be exciting or suppress the active molecule of potassium-channel, and the compound molecule that is filtered out derived, thereby provide and have the N that potassium-channel suppresses active novelty, N '-disubstituted piperazine derivative, the invention still further relates to N, the preparation method of N '-disubstituted piperazine derivative and pharmaceutical composition thereof and purposes.
Background technology
Potassium-channel is a kind of special membranin, is present in all cells, and potassium ion is had highly selective and high-permeability.Potassium-channel has participated in many important cell functions, but as control the electric current excitability of cell and excitement/reply coupling etc., by such mode, the current-mode of the neural and heart of potassium-channel regulation and control, release neurotransmitters, the secretion of control Muscle contraction and hormone; In non-electric current excitability cell, potassium-channel then embodies its physiological function by regulating and control single pass conducting path.Compare with the ionic channel of other type, the hypotype number of potassium-channel is numerous.If potassium-channel transgenation, can cause the generation of some cardiovascular and cerebrovascular diseases and nervous system disorders, as uneven, the long QT syndromes of the rhythm of the heart (long QTsyndrome), ataxia (episodic Ataxia), muscular dystrophy (myotonicmuscular dystrophy) and epilepsy (epilepsy) etc. in short-term.Different types such as that potassium-channel can be further divided into is that voltage relies on, aglucon (or acceptor) is that rely on, the ATP sensitivity, calcium-activated and sodium activated.Only the potassium-channel of voltage dependence has just cloned tens kinds of hypotypes.The potassium-channel structure of all the other types is unclear fully as yet.They all have confidential relation with cardiovascular systems physiology, pathology and pharmacology.
Potassium ion (K
+) passage can be along with the variation of membrane potential, perhaps along with the activation of negatively charged ion and/or ligand optionally K
+Move into or emigrated cells.K
+The main effect of passage is to keep resting membrane electric potential; Another effect is to make action potential multipole in the sensitive cells.Potassium-channel has been represented dissimilar ionophorous proteins, and to have illustrated several toxin now mainly be by blocking one or more special K
+Passage works.Heart cell is with K
+The remarkable diversity of passage different subtype is a feature.In action potential process, can open the K of several types because of the depolarization of film
+Passage, the ionic current summation of these different passage deliveries can cause the multipole of film and reach resting potential.In case the film depolarization, the instantaneous export-oriented K of one of these channel type
+Passage can produce one ionic current (I of (at the 1-10 millisecond) startup fast
10), (10-200 millisecond) decline (inactivation) rapidly then.I
10Initial multipole to heart action potential plays the most significant effect, and can be blocked by several non-specific medicinal compounds such as aminopyridines and Tedisamil-III class anti-arrhythmic agents.Retardance I
10Cause the prolongation of heart action potential.It is believed that prolonging the heart action potential time-histories is to suppress reactivity atrium and the not normal a kind of mechanism of ventricle heart body again.Present available III class antiarrhythmic compounds, wherein majority can be called quick type delayed rectification K by retardance
+A kind of independent K of passage
+The passage hypotype works.
On amino acid sequence level, the homology between the different subfamilies is about 40%, the homology between the same subfamily about 70%.The Kv passage forms the ion porose area by four α subunits, and each α subunit is made up of the C end and the N end that diaphragm breaks (S1-S6) and cell is interior and extracellular length is different of striding of six sections high conservatives.S4 segment and valtage-gated sodium-ion channel have higher homology, and it has hydrophilic and lipophilic character simultaneously, and per three residues just have a positively charged amino acid, are the valtage-gated activated chief components of potassium-channel.It is relevant with voltage dependent form inactivation that end group amino acid is considered to.Connection between S5 and S6 segment deeply to film, participates in forming the ion porose area, is called as H5 district or porose area in potassium-channel.The porose area structure is a high conservative in the potassium ion selective passage, and particularly to be taken as be the potassium ion selective characteristic sequence to sequence (T/SXXTXGY (F) G).After removing G or Y ion selectivity there is very big influence, can completely loses as the selectivity of Shaker passage.The residue of 2 pairs of Shaker passages such as Heginbotham porose area suddenlys change one by one, and finding has 4 residues very crucial, and they are respectively TVGG, lay respectively at 1,5,6 and 8 of characteristic sequence, and the sudden change of these residues can cause passage to lose selectivity.
April in 1998,3 people such as Doyle delivered the crystalline structure of first ion selectivity passage on Science, and the resolving power of this crystalline structure is 3.2
, the potassium-channel of bacterium Streptomyceslividans is desired in the source.KcsA only has two sections to stride membrane structure, linked to each other by porose area, but the Kir passage that its amino acid sequence homology compares (equally also be two sections and stride membrane structure) will more approaching valtage-gated potassium channel, and in the porose area scope, the sequence of KcsA is almost identical with the Kv passage.Crystalline structure shows that the KcsA passage is the tetramer, four identical α subunits are symmetrically distributed around the center porose area, and each subunit is striden film α spiral (S1 and S2) by about 30 amino acid whose porose area segments " trourelle (turret) " outer with stretching out film with two sections and coupled together.The shape of passage resembles an inverted taper shape.The TVGYG residue forms a narrow selectivity pan, and a diameter about 10 is arranged below pan
The hole, the main chain carbonyl points to the hole, side chain is away from porose area, promptly the moment of dipole of spiral concentrates on here.Aqueous porose area passage is about 18
, the ionic channel porose area always is about 45
Stephen in 2005 etc. have delivered the crystalline structure of the potassium-channel of mammals voltage dependent form Shaker family on Science, the resolving power of this crystalline structure is 2.9
This structure comprises the complete β subunit of striding fenestra district and VS position, voltage-sensitive district, intermediary T1 zone and participation redox reaction.But the selective filter of these crystalline structure collar extensions zone amino-acid residue is a high conservative.This may for adopting the active effectively molecule of computer virtual screening potassium-channel to provide.
The present invention selects potassium-channel as target, the means of utilization area of computer aided medicinal design are carried out virtual screening to the compound in the commercial ACD that can buy (http://www.mdl.com/) storehouse,, activity higher to giving a mark compound preferably carried out chemosynthesis and derived, and biological activity test.Biological activity test proves that we obtain compound potassium-channel is had the good restraining activity.The ACD storehouse is the abbreviation of Available Chemicals Directory, means the present pharmaceutical chemicals dictionary that can buy.There is close getting in touch in MDL company and nearly thousand tame pharmaceutical chemicals companies in the world, and bring in constant renewal in database, and grasp recent product of each pharmaceutical chemicals company and situations such as price and packing by network.Up to the present, the ACD storehouse has comprised nearly 1,300, the information of 0,000,000 compounds, each compound all has physico-chemical property data commonly used, structure, price, packing, manufacturer and contact method (address, phone, fax or e-mail etc.) (http://www.mdl.com/products/pdfs/acd_ds.pdf), so ACD is the information source that each research institution, drugmaker seek, order raw material.
Summary of the invention
The objective of the invention is based on the screening of potassium-channel crystal three-dimensional structure utilization computer virtual, so that seek can be exciting or suppress the active molecule of potassium-channel, has the N that potassium-channel suppresses active novelty thereby provide, N '-disubstituted piperazine derivative.
Another object of the present invention provides N, the preparation method of N '-disubstituted piperazine derivative.
Another purpose of the present invention provides a kind of can effectively the treatment or the pharmaceutical composition that comprises above-claimed cpd of prevention and closely-related cardiovascular system diseases of potassium-channel and related complication thereof.
A further object of the present invention provides above-claimed cpd and the purposes of pharmaceutical composition aspect the medicine of preparation treatment or prevention and closely-related cardiovascular system diseases of potassium-channel and related complication thereof.
The present invention is based on the screening of potassium-channel crystal three-dimensional structure utilization computer virtual, to seek the having active effectively molecule of potassium-channel.In April, 1998 Doyle to have delivered first source on Science be the crystalline structure of the ion selectivity passage of bacterium Streptomyces lividans.The present inventor utilizes the crystalline structure of potassium-channel, and toxin and potassium-channel action site information such as quaternary ammonium ion (QA), 4-quinolylamine and scorpion venom, snake venom, melittin, two reactive sites of potassium-channel have been chosen, utilization molecular docking program DOCK4.0 has carried out the three-dimensional data base search respectively to it, to seek possible retarding agent.The small molecules three-dimensional structure database that the inventor searches is an ACD-3D small molecules database, and 250,000 compounds are arranged approximately.Because also there is certain difficulty at present in the technology of the novel potassium-channel inhibitor of high flux screening, the effect of virtual screening is just remarkable especially.Use this method, the inventor carries out virtual screening, ordering marking to the ACD database, has selected 22 potential parts.The electricity Physiological Analysis shows wherein have 6 compounds that the inhibition activity of height is arranged, and the 300-1000 that its inhibition activity is TEA (triethylammonium tetrakis) doubly.The bioanalysis result shows that these compounds are I
KThe specific inhibition agent.N wherein, N '-disubstituted piperazine compounds is to I
KAnd I
ARestraining effect is in various degree all arranged, its IC
50As shown in table 2.Wherein, 1-benzyl-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine suppresses the selectivity height in the extracellular, to I
KSuppress to be I
A16.3 times of (IC
50Ratio is 16.3).The inventor derives to 1-benzyl-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine, to obtain the exciting or active better series derivates of inhibition to potassium-channel.
The invention provides and have the novel N that following structural formula I represents, N '-disubstituted piperazine derivative or its pharmacy acceptable salt:
Wherein:
The integer of n=0-1;
R
1And R
2Saturated or unsaturated alkyl, C3-C7 cyclic hydrocarbon radical, benzyl, aromatic base or the 5-7 unit heterocyclic radical of representing hydrogen, halogen, C1-C6 straight or branched independently of one another;
Described halogen is fluorine, chlorine, bromine or iodine;
Described aromatic base can be phenyl, substituted-phenyl, naphthyl or xenyl; Wherein said substituted-phenyl can comprise 1～4 substituting group, and this substituting group can be selected among halogen, C1-C6 straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C4 alkoxyl group, sulfydryl and the C1-C4 acyl group;
The first heterocyclic radical of described 5-7 can contain 1-3 heteroatoms that is selected from oxygen, sulphur or nitrogen; and/or by the phenyl among the structural formula I and close, and/or contain one or more substituting groups that are selected from halogen, C1-C6 straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C4 alkoxyl group, sulfydryl, C1-C4 acyl group and aromatic base.
N provided by the invention, N '-disubstituted piperazine derivative pharmacy acceptable salt, can enumerate particularly with organic acid such as propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate or citric acid or acidic amino acids such as aspartic acid, L-glutamic acid and form behind the esters again the salt that forms with mineral alkali, as sodium, potassium, calcium, aluminium salt and ammonium salt; Or the salt that forms with organic bases, as methylamine salt, ethylamine salt, ethanolamine salt etc.; Or form the salt of mineral acids such as hydrochloric acid behind the esters, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid with basic aminoacidss such as Methionin, arginine, ornithine, or with organic acid salt such as formic acid, acetate, picric acid, methylsulfonic acid, ethyl sulfonic acid.
The N of structural formula I of the present invention, a preferred embodiment of N '-disubstituted piperazine derivative or its pharmacy acceptable salt is 1-substituted benzyl-4-(2-(4-replacement-benzenesulfonyl)-ethyl)-piperazine compounds or its pharmacy acceptable salt:
Wherein, n=1;
R
1Be hydrogen or fluorine;
R
2Definition as mentioned above.
The N of structural formula I of the present invention, another preferred embodiment of N '-disubstituted piperazine derivative or its pharmacy acceptable salt is 1-substituted benzyl-4-(2-(4-replacement-benzenesulfonyl)-ethyl)-piperazine compounds or its pharmacy acceptable salt:
Wherein, n=1;
R
1Definition as mentioned above;
R
2Be hydrogen or chlorine.
The N of structural formula I of the present invention; another preferred embodiment of N '-disubstituted piperazine derivative or its pharmacy acceptable salt is 1-(benzo [1,3] dioxolane-5-methylene radical)-4-(2-(4-replacement-benzenesulfonyl)-ethyl)-piperazine compounds or its pharmacy acceptable salt:
Wherein, n=1;
R
1Be [1, the 3] dioxolane that closes with benzo;
R
2Definition as mentioned above.
The N of structural formula I of the present invention, the 4th preferred embodiment of N '-disubstituted piperazine derivative or its pharmacy acceptable salt is 1-substituted-phenyl-4-(2-(4-replacement-benzenesulfonyl)-ethyl)-piperazine compounds or its pharmacy acceptable salt:
Wherein, n=0;
R
1And R
2Definition as mentioned above.
The invention provides the N of structural formula I, the preparation method of N '-disubstituted piperazine derivative, this method steps is as follows:
(1) in organic solvent, under the effect of alkali, the compound of piperazine mono-hydrochloric salts and structural formula a reacts, and obtains the compound of structural formula b;
Wherein said organic solvent is tetrahydrofuran (THF), ether, dimethyl formamide, glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methyl alcohol or ethyl acetate; Described alkali is organic bases or mineral alkali, and wherein organic bases is pyridine, triethylamine, 4-dimethylamino pyridine (DMAP) or diisopropylethylamine, and mineral alkali is yellow soda ash, salt of wormwood, sodium hydroxide or potassium hydroxide; R
1Definition as mentioned above; X is Cl or Br.
(2) compound of structural formula c and acetate 2-chloroethene ester react the compound of structural formula d;
(3) compound of structural formula d gets the compound of structural formula e through hydrolysis, chlorination;
(4) compound of the compound of the structural formula b that obtains of above-mentioned steps (1) and the structural formula e that step (3) obtains reaction obtains the N that structural formula I of the present invention represents, N '-disubstituted piperazine derivative after the separation.
In preparation method provided by the present invention, employed raw material piperazine mono-hydrochloric salts can get di hydrochloride piperazine by piperazine and excess chlorination H-H reaction, again with the piperazine of equivalent react the piperazine mono-hydrochloric salts; The halogenide of structural formula a can commercially obtain.
Advantage such as N provided by the invention, the preparation method of N '-disubstituted piperazine derivative have that reaction conditions gentleness, abundant raw material are easy to get, operation and aftertreatment are simple.
N of the present invention, N '-disubstituted piperazine derivative pharmacy acceptable salt can adopt pharmaceutically conventional salifying method to prepare.
N of the present invention, N '-disubstituted piperazine derivative at computer virtual screening and potassium-channel in conjunction with experiment, by activation/inhibition channel activity, can treat and prevent closely-related cardiovascular system diseases of potassium-channel and related complication thereof effectively, for example hypertension, coronary disease illness, myocardial infarction and other cardiovascular and cerebrovascular diseases.At N, on the interactional model of N '-disubstituted piperazine derivative and potassium-channel, observe all compounds 10
-7-10
-5In the M concentration range this model all there is effect.
N of the present invention, N '-disubstituted piperazine derivative toxicity is very low.
Pharmaceutical composition of the present invention contains the N of the said structure formula I that treats significant quantity, N '-disubstituted piperazine derivative or its pharmacy acceptable salt, and contain one or more pharmaceutically acceptable carriers.
The medicine that compound of the present invention and pharmaceutical composition can be used for preparing treatment or prevent to be regulated by potassium-channel the cardiovascular and cerebrovascular diseases that causes.
Compound provided by the present invention and medicinal compositions can be various ways, as tablet, capsule, pulvis, syrup, solution shape, suspension or aerosol etc., and may reside in suitable solid or liquid support or the diluent and the suitable disinfector injecting or instil of being used for.This pharmaceutical composition can also further comprise odorant agent, flavouring agent etc.
Its ideal ratio of pharmaceutical composition provided by the present invention is, formula I compound accounts for gross weight than 65%～99.5% as activeconstituents, rest part compares 0.5-35% for accounting for gross weight, or 1-20% more preferably, or be preferably pharmaceutically acceptable carrier, diluent or solution or the salts solution of 1-10%.
The various formulations of pharmaceutical composition of the present invention can be according to conventional preparation method's preparation of pharmaceutical field.
Compound of the present invention and pharmaceutical composition can comprise humans and animals to the clinical use of Mammals, can through port, the route of administration of nose, skin, lung or gi tract etc.Most preferably be oral.Best preferred per daily dose is the 0.01-200mg/kg body weight, disposable taking, or 0.01-100mg/kg body weight part vic.Which kind of instructions of taking that don't work, individual's optimal dose should be decided according to concrete treatment.Generally be from low dose, increase dosage gradually until find optimal dosage.
Description of drawings
Fig. 1 is preceding 300 compounds that bound energy is less, and wherein, A is these 300 bound energy that compound calculates by DOCK 4.0 of expression; B represents the bound energy (BE that 300 compounds calculate with DOCK
1) bound energy (BE that calculates with Sybyl
2).
Fig. 2 illustrates that born of the same parents use 1-benzyl-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine (Ia) that Hippocampal Neurons is influenced outward.
Fig. 3 illustrates and uses the effect of 1-benzyl-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine (Ia) to Hippocampal Neurons delayed rectification potassium-channel in the born of the same parents.
Embodiment
In following embodiment, will further illustrate the present invention.These embodiment only are used to illustrate the present invention, but do not limit the present invention in any way.All parameters among the embodiment and remaining explanation unless otherwise indicated, all are the explanation foundation with the quality.
Embodiment 1
The computer virtual screening:
In April, 1998, Doyle delivered the crystalline structure of first ion selectivity passage on Science, and the source is the potassium-channel of bacterium Streptomyces lividans.Utilize the crystalline structure of potassium channel, and toxin and potassium channel action site information such as quaternary ammonium ion (QA), 4-quinolylamine and scorpion venom, snake venom, melittin, two reactive sites of potassium-channel have been chosen, utilization molecular docking program DOCK4.0 has carried out the three-dimensional data base search respectively to it, to seek possible retarding agent.The small molecules three-dimensional structure database of being searched is an ACD-3D small molecules database, and 250,000 compounds are arranged approximately.
Experimental technique:
(1) micromolecular compound structure treatment
The small molecules three-dimensional structure is used for before the molecular docking, also must be through a series of Data Format Transform.At first the three-dimensional structure in the database is exported with the MDL/RDF form, then corresponding RDF file conversion is become the MDL/SDF form, at last the SDF file conversion is become SYBYL/MOL2 data layout (DOCK4.0 has attached the program that the MDL/SDF file conversion is become the SYBYL/MOL2 form).With SPL program among the molecular simulation software SYBYL small molecules database MOL2 is carried out hydrogenation, adds the processing of electric charge at last, what electric charge adopted is the Gasteiger-Marsili electric charge.
(2) macromolecular structure is handled
Check that whether residue lacks, deletes part and all water moleculess in the acceptor molecule, adds perhydro and Kollman_All type electric charge to molecule.
(3) description of avtive spot
Consider the potassium channel inhibitors action site, with around the TEA binding site Tyr82 8
Amino-acid residue in the scope is defined as collar extension active pocket zone; Utilize the AutoMS program to calculate the molecular surface at activity of potassium channels position another binding pocket of TEA, utilize the sphgen program to produce the shape ball collection of describing avtive spot then, the matching speed of small molecules and macromole reactive site when the molecular docking program utilizes these ball collection to accelerate butt joint.
(4) computing grid file
Utilize the Grid program to calculate the grid file of interior electrostatic interaction of box and model ylid bloom action energy.
(5) molecular docking
Utilize DOCK4.0 to carry out the three-dimensional data base search 250,000 compounds in the ACD storehouse are carried out scalping, the parameter that adopts is (10,10), in the butt joint result, select 5000 best molecules then, adopt parameter (25,25) these molecules are carried out more careful search, selection at last wherein 300 bigger molecules of bound energy is further analyzed.
(6) docking structure is handled
Utilize the Docking module among the SYBYL that the result of DOCK4.0 is optimized, keep macromolecular structure motionless in the optimizing process.Be calculated as follows the bound energy of mixture at last:
E
binding＝E
R-L-E
R-E
L
E wherein
R-LBe the energy of mixture, E
RBe the energy of acceptor, E
LIt is the energy of part.Calculate and adopt the Tripos field of force, the GASTHUCK electric charge is optimized to energy gradient RMS less than 0.5kcal/mol
Experimental result:
300 compounds choosing and the interaction force of potassium-channel, the bound energy that calculates by DOCK is from-38.33 to-22.76kcal/mol, the bound energy that calculates by Sybyl from-178.85 to-72.15kcal/mol (as shown in Figure 1, Fig. 1 is preceding 300 compounds that bound energy is less, wherein, A is the bound energy (■: total bound energy that these 300 compounds of expression calculate by DOCK 4.0; ●: model ylid bloom action; ▲: electrostatic force); B represents the bound energy (BE that 300 compounds calculate with DOCK
1) bound energy (BE that calculates with Sybyl
2) (▲: compound 1-6; ■: compound 7-22; ◆: compound 23-300.)), the two data have very big consistence.And also considered simultaneously form fit, form parameters such as the potential of H key and quasi-medicated property with potassium-channel, selected 22 compounds wherein (to be numbered: 01-22) be further analyzed.Calculate the free energy that combines of 22 compounds and potassium-channel by AutoDock3.0.The various bonding attributes of 22 compounds are as shown in table 1.
Table 1: bound energy (kcal/mol), ordering and the XlogP value of select 22 compounds from 300 candidate compounds:
aBound energy (the BE that uses DOCK to calculate
1) and ordering (R
1)
bBound energy (the BE that uses Sybyl to calculate
2) and ordering (R
2)
cBound energy (the BE that uses AutoDock to calculate
3) and ordering (R
3)
The preparation (Ia) of 1-benzyl-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine
At normal temperatures, feed freshly prepd dry HCl gas to the 200ml three-necked bottle that 8.6g (0.1mol) Piperazine anhydrous that is dissolved in 50ml THF is housed.Under vigorous stirring, reaction 6h removes HCl gas, adds 8.6g (0.1mol) Piperazine anhydrous, behind the normal-temperature reaction 2h, and back flow reaction 6h under the vigorous stirring.Cooling is filtered, and filter cake washs with cold THF.Drying gets piperazine mono-hydrochloric salts white crystal 22.4g (productive rate 92.3%).
4.86g (0.02mol) piperazine mono-hydrochloric salts, 20mlTHF are inserted in the 100ml eggplant-shape bottle.Under 0-5 ℃, drip 2.28g (0.018mol) the benzyl chlorine that is dissolved in 20mlTHF, drip behind the 1h and finish.Normal temperature reaction down spends the night backflow 2h, solvent evaporated.Then, add 30ml water, transfer pH=8-9 with the unsaturated carbonate potassium solution again,, merge organic layer and use MgSO with dichloromethane extraction (20ml * 3)
4Drying is filtered, and gets the faint yellow oily thing of N-benzyl diethylenediamine 2.15g (productive rate 67.9%) after filtrate concentrates.
With acetate 2-chloroethene ester 0.01mol (1.125g) with chlorobenzene-sulfinic acid sodium 0.01mol (1.99g) is joined in the 20ml glycol dimethyl ether, back flow reaction 36 hours, cooling adds 20ml water, extract with methylene dichloride (20ml * 3), merge organic layer and use MgSO
4Drying is filtered, and boils off most of solvent, and silicagel column separates (methylene dichloride: ethyl acetate: sherwood oil=1: 1: 20, volume ratio), gets acetate 2-(4-chloro-benzenesulfonyl) ethyl ester white crystal 1.12g (productive rate 44.4%).
0.01mol (2.52g) acetate 2-(4-chloro-benzenesulfonyl) ethyl ester is joined in 75% ethanol of 20ml, add 20ml 40% sodium hydroxide, refluxed 8 hours.Boil off partial solvent, use methylene dichloride (20ml * 3) to extract then, merge organic layer and use MgSO
4Drying is filtered, and gets 2-(4-chlorobenzene alkylsulfonyl) ethanol grey oily matter: 1.82g (productive rate 82.4%) after filtrate concentrates.
1.0mmol (0.221g) 2-(4-chlorobenzene alkylsulfonyl) ethanol is dissolved in the 5ml methylene dichloride, adds phosphorus pentachloride 0.5 gram, reaction is 2 hours in ice-water bath, and normal-temperature reaction is spent the night.Drip the 10ml frozen water in 1 hour, use methylene dichloride (20ml * 3) to extract organic layer MgSO then
4Drying is filtered, and column chromatography for separation (methylene dichloride: ethyl acetate: sherwood oil=1: 1: 20, volume ratio) gets 1-chloro-4-(2-chloro-ethylsulfonyl)-benzene canescence liquid: 0.21g (productive rate 87.5%).
In the 50ml reaction flask, add 1mmol (0.238g) 1-chloro-4-(2-chloro-ethylsulfonyl)-benzene, 1mmol (0.176g) N-benzyl diethylenediamine, 1.5mmol (0.207g) K
2CO
3, 10mg I
2And 20mlTHF, back flow reaction 3 hours; Stopped reaction boils off solvent then, adds 20ml water, extracts with methylene dichloride (20ml * 3), merges organic layer and uses MgSO
4Drying is filtered, and after filtrate concentrated, silicagel column separated (methylene dichloride: ethyl acetate: sherwood oil=1: 1: 4, volume ratio), got 1-benzyl-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine white crystal 0.312g (productive rate 82.3%).
IR(KBr)：3448，1579，1479cm
-1。
1H?NMR(CDCl
3)：2.62(t，8H)；2.55(t，2H)；3.75(t，2H)；3.84(s，2H)；7.25(m，5H)；7.50(m，2H)；7.83(m，2H)。HRMS(SCI)m/z?calcd?for?M
+，378.1169；found，378.1182。
The preparation of 1-(4-fluorophenyl)-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine (Ib)
Replace the 1-benzyl diethylenediamine with 1-(4-fluorophenyl)-piperazine, press embodiment 2 described operations, all the other desired raw materials, reagent and preparation method obtain target compound 1-(4-fluorophenyl)-4-(2-(4-chloro-benzene sulfuryl)-ethyl)-piperazine with embodiment 2.
IR(KBr)：1625cm
-1。
1HNMR(CDCl
3)ppm：2.55(t，4H，)；2.85(t，2H)；2.98(t，4H)；3.35(t，2H)；6.82(m，2H)；6.94(m，2H)；7.54(m，2H)；7.87(m，2H)。HRMS(SCI)m/z?calcd?for?M
+，382.0918；found，382.0922。
The preparation of 1-(2-fluorophenyl)-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine (Ic)
Replace the 1-benzyl diethylenediamine with 1-(2-fluorophenyl)-piperazine, press embodiment 2 described operations, all the other desired raw materials, reagent and preparation method obtain target compound 1-(2-fluorophenyl)-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine with embodiment 2.
1HNMR(CDCl
3)ppm：2.55(t，4H)；2.85(t，2H)；2.98(t，4H)；3.35(t，2H)；6.90(m，2H)；7.02(m，2H)；7.54(m，2H)；7.87(m，2H)。HRMS(SCI)m/zcalcd?for?M+，382.0918；found，382.0925。
The preparation of 1-(benzo [1,3] dioxolane-5-ylmethyl)-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine (Id)
With benzo [1; 3] dioxolane-5-ylmethyl bromo is pressed embodiment 2 described operations for benzyl chlorine, and all the other desired raw materials, reagent and preparation method are with embodiment 2; obtain target compound 1-(benzo [1,3] dioxolane-5-ylmethyl)-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine.
IR(KBr)：1580cm
-1。
1H?NMR(CDCl
3)：2.56(t，8H)；2.85(t，2H)；3.85(t，2H)；3.98(s，2H)；5.88(s，2H)；7.10-7.22(m，3H)；7.50-7.83(m，4H)。HRMS(SCI)m/z?calcd?for?M
+，422.1067；found，422.1067。
The preparation of 1-(diphenyl methyl)-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine (Ie)
For benzyl chlorine, press embodiment 2 described operations with the diphenyl methyl bromo, all the other desired raw materials, reagent and preparation method obtain target compound 1-(diphenyl methyl)-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine with embodiment 2.
IR(KBr)：1625cm
-1。
1H?NMR(CDCl
3)：2.68(t，8H)；2.55(t，2H)；3.75(t，2H)；5.15(s，1H)；7.05-7.14(m，10H)；7.52(m，2H)；7.88(m，2H)。HRMS(SCI)m/z?calcd?for?M
+，454.1482；found，454.1491。
Embodiment 7
The preparation of 1-phenyl-4-(2-benzenesulfonyl-ethyl)-piperazine (If)
Replace chlorobenzene-sulfinic acid sodium with benzene sulfinic acid sodium salt; replace the 1-benzyl diethylenediamine with the 1-phenylpiperazine; press embodiment 2 described operations, all the other desired raw materials, reagent and preparation method obtain target compound 1-phenyl-4-(2-benzenesulfonyl-ethyl)-piperazine with embodiment 2.
IR(KBr)：1605cm
-1。
1HNMR(CDCl
3)ppm：2.55(t，4H，)；2.85(t，2H)；2.98(t，4H)；3.35(t，2H)；6.82-7.14(m，5H)；7.54(m，2H)；7.87(m，2H)。HRMS(SCI)m/z?calcd?for?M
+，364.1012；found，364.1018。
The preparation of 1-(4-luorobenzyl)-4-(2-benzenesulfonyl-ethyl)-piperazine (Ig)
Replace chlorobenzene-sulfinic acid sodium with benzene sulfinic acid sodium salt; replace the 1-benzyl diethylenediamine with 1-(4-luorobenzyl) piperazine; press embodiment 2 described operations, all the other desired raw materials, reagent and preparation method obtain target compound 1-(4-luorobenzyl)-4-(2-benzenesulfonyl-ethyl)-piperazine with embodiment 2.
IR(KBr)：1588cm
-1；
1HNMR(CDCl
3)ppm：2.55(t，4H，)；2.85(t，2H)；2.98(t，4H)；3.35(t，2H)；5.22(s，2H)；6.82(m，2H)；6.94(m，2H)；7.54(m，2H)；7.87(m，2H)；HRMS(SCI)m/z?calcd?for?M
+，396.1075；found，396.1081。
Embodiment 9
The preparation of 1-(2-luorobenzyl)-4-(2-benzenesulfonyl-ethyl)-piperazine (Ih)
Replace chlorobenzene-sulfinic acid sodium with benzene sulfinic acid sodium salt; replace the 1-benzyl diethylenediamine with 1-(2-luorobenzyl) piperazine; press embodiment 2 described operations, all the other desired raw materials, reagent and preparation method obtain target compound 1-(2-luorobenzyl)-4-(2-benzenesulfonyl-ethyl)-piperazine with embodiment 2.
IR(KBr)：1622cm
-1；
1HNMR(CDCl
3)ppm：2.55(t，4H)；2.85(t，2H)；2.98(t，4H)；3.35(t，2H)；5.26(s，2H)；6.90(m，2H)；7.02(m，2H)；7.54(m，2H)；7.87(m，2H)HRMS(SCI)m/z?calcd?for?M
+，396.1075；found，396.1077
1-[2-(benzo [1,3] dioxolane-5-alkylsulfonyl)-ethyl]-preparation of 4-phenyl-Piperazine (Ii)
Replace the 1-benzyl diethylenediamine with the 1-phenylpiperazine; with benzo [1; 3] dioxolane-5--sulfinic acid sodium replaces chlorobenzene-sulfinic acid sodium; press embodiment 2 described operations; all the other desired raw materials, reagent and preparation method are with embodiment 2; obtain target compound 1-[2-(benzo [1,3] dioxolane-5-alkylsulfonyl)-ethyl]-the 4-phenyl-Piperazine.
Experimental example
Biological activity test:
Experiment title: rat hippocampus CA1 district pyramidal cell's acute isolation and full cell patch pincers record experimental technique: get 5-9 days Spragur-Dawley neonate rats, take out full brain after the sacrificed by decapitation, insert (ACSF in 0 ℃ of artificial cerebrospinal fluid
*), cut the brain slice of thick about 400-500 μ m with vibratome, tell the hippocampus part, move into the outer liquid (ES of the standard cell lines that contains proteaseXIII 1mg/ml
*) in 32 ℃ hatched 8 minutes.Take out the back and wash 2-3 time, hippocampus is changed in the outer liquid that contains trypsin inhibitor 1mg/ml, bovine serum albumin 1mg/ml stop enzymolysis, continue logical oxygen stand for standby use with fresh outer liquid.Under dissecting microscope, isolate the CAI district, adopt the gradually little suction pipe of 3 bores (2-0.5mm) to blow and beat tissue block gently, the supernatant liquor that will contain hippocampal pyramidal cell moves into culture dish, inhales and removes most of suspension and change the outer liquid of new standard cell lines, gets final product opening entry.
Experiment adopts Axopatch 200A amplifier with full cell patch pincers mode record current response, and room temperature is at 21-23 ℃.The eletrode tip internal diameter is 1-2 μ m, in charging behind the liquid impedance be 3-5M Ω.By the control of DigiData1200A A/D translation interface, tranquillization is clamped down on voltage at-50mv to the record of clamping down on voltage instruction and membrane current by pClamp 6.2 softwares, and sample frequency is 10-40KHz, and frequency filtering is 1-10KHz.The series resistance compensation is generally 75～85%, and capacitance compensation is 60～80%; Eliminate leakage current and residual capacitive current by the P/4 method.Have the rat hippocampus CA1 of acute isolation district pyramidal cell and can record two kinds of potassium currents: fast inactivation moment potassium current (I with different dynamic feature
A) and decay postpone outward rectification potassium current (I very slowly
K).Experiment adopts voltage method to separate total potassium current and I
K: clamp down on voltage by-50mv at first hyperpolarization to-110mv, then with the voltage step depolarize of 10mv to+60mv, can write down out I
AAnd I
KThe mixing total current; When after clamping down on the hyperpolarization of voltage, inserting the medium voltage of one-50mv, 50ms at-110mv, the I of decay fast
ABut the composition complete deactivation, this just has been separated to I
KComposition; Total current deducts I
KPromptly obtain I
A 2Used medicine is prepared with the blocking-up sodium channel with the outer liquid that contains 1 μ M TTX.Drug delivery system is the quick dosers of Bio-Logic RSC-100 18 pipes.The average and the standard error of gained data are represented with x ± S.E.M..
Testing compound: Ia-Ii
Experimental result:
(1) as shown in Figure 2, born of the same parents use 1-benzyl-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine that Hippocampal Neurons is influenced outward.Figure A left column graphic presentation I
KAnd I
ASeparation: top primary current figure is total potassium current IT, and the centre is I
K, the below is for to deduct I from IT
KThe gained electric current is I
ARight row figure is respectively IT, the I after the administration
KAnd I
AActivating the employed voltage of IT is: hyperpolarization is to-110mV, and depolarize continues 400ms to+60mV then; Activate I
KVoltage and IT similar, but before depolarize, add an of short duration 50ms-50mV depolarize voltage.Figure B is that 1-benzyl-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine suppresses I
KAnd I
AConcentration-effect curve.I
ABe peak value, and I
KThen be 300ms observed value after the depolarize.(n＝5～12)。
(2) as shown in Figure 3, in born of the same parents, use of the effect of 1-benzyl-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine to Hippocampal Neurons delayed rectification potassium-channel.Ordinate zou is I among the figure
KRelative value, X-coordinate be the compound concentration that uses in the administration time born of the same parents in the born of the same parents outside born of the same parents to I
KInhibition all about 75%.
Show by biological activity test, the N among the embodiment, N '-disubstituted piperazine derivative is to I
KAnd I
ARestraining effect is in various degree all arranged, its IC
50As shown in table 2.Wherein, 1-benzyl-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine suppresses selectivity in the extracellular the highest, to I
KSuppress to be I
A16.3 times of (IC
50Ratio is 16.3).
Table 2:
N is the neurone number of tested person
Claims (12)
1. the N that has following structural formula I, N '-disubstituted piperazine derivative:
Wherein:
The integer of n=0-1;
R
1And R
2Saturated hydrocarbyl, aromatic base or the 5-7 unit heterocyclic radical of representing hydrogen, halogen, C1-C6 straight or branched independently of one another;
Wherein said halogen is fluorine, chlorine, bromine or iodine;
Described aromatic base is phenyl, substituted-phenyl, naphthyl or xenyl, wherein said substituted-phenyl comprises 1～4 substituting group, and this substituting group is selected among halogen, C1-C6 straight or branched alkyl, cyano group, nitro, amino, hydroxyl, trifluoromethyl, carboxyl, C1-C4 alkoxyl group and the C1-C4 acyl group;
Described 5-7 unit heterocyclic radical contains 1-3 heteroatoms that is selected from oxygen, sulphur or nitrogen, and by the phenyl among the structural formula I and close.
2. N according to claim 1, N '-disubstituted piperazine derivative is characterized in that, described N, N '-disubstituted piperazine derivative are 1-substituted benzyl-4-(2-(4-replacement-benzenesulfonyl)-ethyl)-piperazine compounds, wherein, n=1; R
1Be hydrogen or fluorine.
3. N according to claim 1, N '-disubstituted piperazine derivative is characterized in that, described N, N '-disubstituted piperazine derivative are 1-substituted benzyl-4-(2-(4-replacement-benzenesulfonyl)-ethyl)-piperazine compounds, wherein, n=1; R
2Be hydrogen or chlorine.
4. N according to claim 1, N '-disubstituted piperazine derivative is characterized in that; described N, N '-disubstituted piperazine derivative are 1-(benzo [1,3] dioxolane-5-methylene radical)-4-(2-(4-replacement-benzenesulfonyl)-ethyl)-piperazine compounds; wherein, n=1, R
1Be [1, the 3] dioxolane that closes with benzo.
5. N according to claim 1, N '-disubstituted piperazine derivative is characterized in that, described N, N '-disubstituted piperazine derivative are 1-substituted-phenyl-4-(2-(4-replacement-benzenesulfonyl)-ethyl)-piperazine compounds, wherein, n=0.
6. N according to claim 1; N '-disubstituted piperazine derivative; it is characterized in that; described N; N '-disubstituted piperazine derivative is selected from 1-benzyl-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine; 1-(4-fluorophenyl)-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine; 1-(2-fluorophenyl)-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine; 1-(benzo [1; 3] dioxolane-5-ylmethyl)-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine; 1-(diphenyl methyl)-4-(2-(4-chloro-benzenesulfonyl)-ethyl)-piperazine; 1-phenyl-4-(2-benzenesulfonyl-ethyl)-piperazine; 1-(4-luorobenzyl)-4-(2-benzenesulfonyl-ethyl)-piperazine; 1-(2-luorobenzyl)-4-(2-benzenesulfonyl-ethyl)-piperazine and 1-[2-(benzo [1,3] dioxolane-5-alkylsulfonyl)-ethyl]-the 4-phenyl-Piperazine among.
7. described N of claim 1, the preparation method of N '-disubstituted piperazine derivative, this method comprises:
(1) in organic solvent, under the effect of alkali, the compound of piperazine mono-hydrochloric salts and structural formula a reacts, and obtains the compound of structural formula b;
Wherein said organic solvent is tetrahydrofuran (THF), ether, dimethyl formamide, glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methyl alcohol or ethyl acetate; Described alkali is organic bases or mineral alkali, and wherein organic bases is pyridine, triethylamine, 4-dimethylamino pyridine or diisopropylethylamine, and mineral alkali is yellow soda ash, salt of wormwood, sodium hydroxide or potassium hydroxide; R
1Definition according to claim 1; X is Cl or Br;
(2) compound of structural formula c and acetate 2-chloroethene ester react the compound of structural formula d, R wherein
2Definition according to claim 1;
(3) compound of structural formula d gets the compound of structural formula e through hydrolysis, chlorination;
(4) compound of the compound of the structural formula b that obtains of above-mentioned steps (1) and the structural formula e that step (3) obtains reaction obtains the N that structural formula I represents, N '-disubstituted piperazine derivative after the separation.
8. one kind has the potassium-channel excitement or suppresses active pharmaceutical composition, it is characterized in that said composition contains the described N of the claim 1 for the treatment of significant quantity, N '-disubstituted piperazine derivative.
9. pharmaceutical composition according to claim 8 is characterized in that, described N, N '-disubstituted piperazine derivative account for 65%～99.5% of this pharmaceutical composition gross weight ratio.
10. according to Claim 8 or 9 described pharmaceutical compositions, it is characterized in that said composition further comprises one or more pharmaceutically acceptable carriers.
11. the described N of claim 1, the purposes of N '-disubstituted piperazine derivative aspect the medicine of preparation treatment or prevention cardiovascular system diseases and related complication thereof.
12. the purposes of the described pharmaceutical composition of claim 8 aspect the medicine of preparation treatment or prevention cardiovascular system diseases and related complication thereof.
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| CN1070399A (en) * | 1991-09-13 | 1993-03-31 | 麦克公司 | The amide derivatives oxytocin antagonist that piperizinylcamphorsuoxytocin replaces |
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| WO2005000822A1 (en) * | 2003-06-27 | 2005-01-06 | Astrazeneca Ab | N-{‘4-substituted piperazine-1-sulfonylmethyl!alkyl}-n-hydroxyfomamide compounds as metalloproteinase inhibitors |
| WO2005023260A1 (en) * | 2003-09-09 | 2005-03-17 | F. Hoffmann-La Roche Ag | 1- (2-amino-benzol) -piperazine derivatives as glycine uptake inhibitors for the treatment of psychoses |
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|---|---|---|---|---|
| CN1070399A (en) * | 1991-09-13 | 1993-03-31 | 麦克公司 | The amide derivatives oxytocin antagonist that piperizinylcamphorsuoxytocin replaces |
| US5474994A (en) * | 1992-05-26 | 1995-12-12 | Recordati S.A., Chemical And Pharmaceutical Company | Bicyclic heterocyclic derivatives having α1 -adrenergic and 5HT1A |
| CN1708489A (en) * | 2002-10-25 | 2005-12-14 | 诺瓦提斯公司 | 1-(4-benzyl-piperazin-1-yl)-3-phenyl-propenone derivatives |
| WO2005000822A1 (en) * | 2003-06-27 | 2005-01-06 | Astrazeneca Ab | N-{‘4-substituted piperazine-1-sulfonylmethyl!alkyl}-n-hydroxyfomamide compounds as metalloproteinase inhibitors |
| WO2005023260A1 (en) * | 2003-09-09 | 2005-03-17 | F. Hoffmann-La Roche Ag | 1- (2-amino-benzol) -piperazine derivatives as glycine uptake inhibitors for the treatment of psychoses |
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