CN1017901B

CN1017901B - Process for the preparation of antipsychotic fused-ring pyridnylpiperazine derivatives

Info

Publication number: CN1017901B
Application number: CN86103071A
Authority: CN
Inventors: 詹姆斯·斯蒂瓦特·纽; 约瑟夫·P·伊维克
Original assignee: Bristol Myers Co
Current assignee: Bristol Myers Co
Priority date: 1985-05-06
Filing date: 1986-05-05
Publication date: 1992-08-19
Also published as: GB2174703B; AU593244B2; HU195509B; FI85484B; DK165745C; DE3615180C2; JPH0753728B2; HUT43848A; GR861149B; IT1208607B; NL8601146A; ES8900253A1; ATA121486A; SE8602061D0; GB2174703A; ES8801250A1; AU5679586A; LU86421A1; FI85484C; ES554659A0

Abstract

Disubstituted 1,4-piperazinyl derivatives are disclosed wherein one substituent is a bicyclic fused-ring furo-, pyrrolo-, cyclopentadieno-, or thieno-pyridine heterocyclic system and the second substituent is an alkylene chain attached to cyclic imide heterocycles, such as azaspiro[4.5]decanediones, dialkylglutarimides, thiazolidinediones, succinimides, and morpholine-2,6-diones; or a benzylic carbinol moiety. These compounds have potent antipsychotic and serotonin antagonist activities. 4-[4-[4-(4-Furo[3,2-c]pyridinyl)-1-piperazinyl]butyl]-3,5-morpholinedione is an example of a typical embodiment having selective antipsychotic activity.

Description

Process for the preparation of antipsychotic fused-ring pyridnylpiperazine derivatives

Put it briefly of heterocyclic carbon compound and their preparation and the application of the present invention system about having medicine and biological action characteristics.Specifically, the present invention system is about 1,4-disubstituted piperazine derivative, one of them substituting group be contain furans-, the pyrroles-, cyclopentadiene-and thiophene-and the dicyclo class fused heterocyclic systems of pyridine ring system, another substituting group is an alkylidene chain, butylidene chain preferably, its end has cyclic imide ring or benzylalcohol group.The example of these end group types is described as follows:

A large amount of relevant technology appearred in past 15 years, wherein a lot of research institutions from Bristol Myers company.The respective compound relevant with the central nervous system effect represented with following general structural formula (1):

Wherein alk is the alkylidene chain that connects piperazine ring and cyclin imide group, and B has the optional substituent heterocycle of selecting.

Wu etc. are at United States Patent (USP) 3,717,634 and 3,907,801 and his relevant paper (J.Med.Chem. of delivering, 15,447-479(1972)), introduced various azaspiros (the 4.5)-last of the ten Heavenly stems two ketone antipsychotic compound, wherein B represents various monocyclic heterocycles such as pyridine, pyrimidine or triazine, they all have selectable substituting group.

Temple, yevich and Lobeck be at United States Patent (USP) 4,305, report in 944, and azaspiro (4.5) ketone in the last of the ten Heavenly stems two has the compound of stable effect, and wherein B is 3-cyanopyridine-2-base or 3-Methoxy Pyridine-2-base.

Temple, yevich and Lobeck be at United States Patent (USP) 4,361, reported the dialkyl group glutarimide compound with stable effect in 565, and wherein B is 3-cyanopyridine-2-base, has another selectable substituting group on its pyridine ring.

Temple and yeager be at United States Patent (USP) 4,367, reported thiazolidinediones and volution thiazolidinediones antipsychotic drug in 335 and 4,456,756, and wherein B is the 2-pyridine ring, replaces on the ring or not, perhaps has a cyano group substituting group.

Temple and yevich be at United States Patent (USP) 4,411, and the antipsychotic compound of report has various cyclin imide groups and benzylalcohol group in 901 and 4,452,799, and wherein B is benzisothiazole or benzoisoxazole ring system.

Should also be noted that following pending application patent.Sequence number (SN) 531 on September 12nd, 83 at U. S. application, 519, and in the now licensed application, New and Yevich disclose succimide and the phthalimide derivatives with antipsycholic action, and the proposition claim, wherein B is the 2-pyrimidine ring.These compounds have angst resistance effect.

Yevich and Lobeck on December 18th, 1984 in the application of the sequence number (SN) 583,309 of U. S. application, reported a series of 1-fluorophenyl carbonic acyl radicals with antipsycholic action-, alcohol radical-, ketal-, propyl group-4-(2-pyrimidyl) bridged piperazine derivatives.

At last, New, Yevich and Lobeck be the sequence number (SN) 691 at U. S. application on January 16th, 1985, in 952 the application, a series of antipsychotic compound are disclosed, they contain multiple cyclic imide group, and wherein B is single the replacement or disubstituted pyridine ring system, and has proposed claim.

In general, the compound that acts on the psychosis system listed above is relevant with compound of the present invention, but according to the difference of group B in the structural formula 1, still they can be come from the structure difference.See that fundamentally the compound in the above-listed technology, B be the monocycle aromatic heterocycle normally, only bicyclic system example is the condensed benzheterocycle, i.e. benzisothiazole or benzoisoxazole ring system.According to this point, above-claimed cpd and compound of the present invention difference can be come.In the present invention, B comprises different classes of annelated heterocycles, promptly furans-, the pyrroles-, cyclopentadiene-, or thienopyridine ring system.The compounds of this invention also can come with the compound difference in the above-listed technology according to antipsycholic action characteristic and side effect on pharmacology.In this respect, compound of the present invention has selectivity antipsychotic (psychosis) effect to medmain.Marvellous especially is, they are low to the avidity of Dopamine Receptors, and this is just in time opposite with antipsychotic drug in the above-mentioned prior art.In this respect, compound of the present invention on pharmacology with atypical standard psychosis leoponex (2) similarity in a measure.As for (2) please referring to the Merck index, the 10th edition (1983), the 344th page and listed reference.

Obviously, leoponex belongs to the dibenzo diaza

The class antipsychotic drug, it structurally with the few of relation of series of compounds of the present invention.And compound of the present invention can not cause the outer syndrome of deleterious cone, and the antipsychotics that uses at present usually produces this harmful side effect after taking for a long time.And being selected from each serial compound of the present invention proves through animal model, can reverse and take the numb disease that standard psychosis trifluoperazine causes.

The topmost aspect of the present invention is to be the bridged piperazine derivatives of feature about what have psychosis (antipsychotic) effect with structural formula I compound and pharmaceutically-acceptable acid addition thereof

In the structural formula I, the following group of Z representative.

For group (a), R ³And R ⁴Respectively be selected from hydrogen, contain the alkyl of 1～4 carbon atom, perhaps R ³And R ⁴Be taken as the alkylidene chain that contains 3～6 carbon atoms together.For group (b), R ⁵And R ⁶Respectively be selected from hydrogen, contain the alkyl of 1～4 carbon atom, the phenyl (A is a hydrogen or halogen atom) that A replaces, perhaps R ⁵And R ⁶Be taken as the butylidene chain together; W can be the S(sulphur atom) or CH ₂(methylene radical).For group (C), V is oxygen or sulphur atom.For group (d), G is selected from hydrogen, contains the alkyl of 1～4 carbon atom, contains the alkoxy or halogen of 1～4 carbon atom, and m equals 1～4, and U is C=0 or SO ₂In addition, in the structural formula I: n=2～4, but must be when Z equals (e), n=3; R ¹Be selected from hydrogen, contain the alkyl of 1～4 carbon atom; Perhaps X or Y respectively are selected from CH ₂, O, S, or NR ⁷, but must with always equal one of among Y or the X=CH-is a condition; R ²Be selected from hydrogen, contain the alkyl of 1～4 carbon atom, contain the alkoxyl group of 1～4 carbon atom, contain the alkylthio of 1～4 carbon atom, halogen and hydroxyl; R ⁷Be hydrogen or the alkyl that contains 1～4 carbon atom.C _1～4Regulation also can use term " rudimentary " expression.

The type of compounds of preferentially selecting for use comprises structural formula I compound, and wherein Z can be: group (a); Group (b), R ⁵And R ⁶As the butylidene chain, W is a sulphur atom together; Group (c), wherein V is a Sauerstoffatom; Group (e).To these types of preferentially selecting for use, Y or Sauerstoffatom or sulphur atom, X be methyne (=CH-); N=4, unless when Z equals (e) n=3; R ²Be hydrogen.

The compound that has two class overrides to select for use.For Y wherein is a compounds of Sauerstoffatom, Z or (a), or (c), wherein V is a Sauerstoffatom, or (e).For Y wherein is a compounds of sulphur atom, Z or (a), perhaps (b), or (e).

Pharmaceutically receptible acid salt of the present invention, the negatively charged ion that is meant this salt does not produce obvious influence for the toxicity or the pharmacological action of this medicine, therefore, these salts on pharmacology with the alkali equivalence of structural formula I compound.These salts are preferred usually for medical.In some cases, they have the physical properties that makes medicine be suitable for pharmaceutical formulation more.This class character may be solubleness, does not have water absorbability, with the relevant compressibility of preparation tablet, with the compatibility of other composition that is used for preparation jointly.The routine fashion of these salts is that the base of structural formula I is mixed with a kind of selected acid, preferably by the solution state contact, uses excessive inert solvent commonly used, for example ether, phenylethyl alcohol, ethyl acetate, acetonitrile and water.Any other standard method preparation of professional's available of being familiar with this technology that this salt also can describe in detail with this paper and any.Some organic acid examples that adopt are toxilic acids, acetate, tartrate, propionic acid, FUMARIC ACID TECH GRADE, isethionic acid, Succinic Acid, palmitinic acid, cyclohexane sulfamic acid, carboxylic acids such as trimethylacetic acid, useful mineral acid can be haloid acid, hydrochloric acid for example, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, phosphoric acid or the like.

Will understand that also the present invention can think and comprise relevant any stereoisomer, for example, when Z contains asymmetric carbon; When being (e), when being (b), Z also may exist as Z.Application understands that the whole bag of tricks that the professional of this gate technique is familiar with can finish the separation of single steric isomer.

Compound of the present invention is the useful medicine with antipsycholic action.In this respect, they show the effect of selectivity central nervous system effect, particularly antipsychotic (psychosis) medicine under nontoxic dosage.As other known antipsychotics, compound with structural formula I in body and external standard pharmacological test system produce certain reaction when studying, and we know that the acute of these pilot systems and people and alleviating of chronic mental illness symptom have close getting in touch.

For The compounds of this invention antipsycholic action and specificity are carried out subclass, adopted the methodological technology of external central nervous system receptor binding.Some compound (being commonly referred to aglucon) is determined, can preferential bonding cerebral tissue in special high-affinity position, thereby can inquire into the intensity of psychotolytic activity and side effect.Radiolabeled aglucon can be regarded the yardstick that a kind of compound produces corresponding central nervous system function in vivo or causes side effect as to the inhibition of the special high-affinity position bonding of this class.In our test, adopted this principle, for example, measure tritium-labeled Spiropitan (( ³H) inhibition of bonding SPiperone), this method representation go out tangible Dopamine Receptors bonding activity, (referring to Burt etc., Molecular Pharmacology, 12,800(1976); Science, 196,326(1977); Crease etc., Science, 192,481(1976).

Some important bonding tests of adopting are listed in the following table 1.

Table 1

The receptor binding test

The single-minded bonding medicine of aglucon that the receptor site of test number imagination uses

252A Dopamine HCL/volution piperazine ( ³H) volution D(+)-butaclamol

Pyridine ketone/psychosis piperidone

Medicine

252B α ₁( ³H) WB-phentolamine

4101

252E 1 type serotonin ( ³H) 5-HT 5-HT

（5-HT ₁）

252I 2 type serotonins ( ³H) volution D-lysergic acid diethylamide

(5-HT ₂) piperidone

Reference:

252A-lists the front.

252B-Crews etc., Science, 202: 322,1978, Rosenblatt etc., Brain Res., 160: 186,1979.

U ' Prichard etc., Science, 199: 197,1978; Molec.Pharmacol, 13: 454,1977.

252E-Bennett and Snyder，Molec.Pharmacol.，12∶373，1976。

252I-Peroutka and Snyder，Molec.Pharmacol，16∶687，1979。

Prove that from above-mentioned bonding test gained data compounds category of the present invention is waited until low avidity during Dopamine Receptors is had, and to serotonin S ₁And S ₂The avidity of acceptor is much bigger.These bonding performances make The compounds of this invention be different from the compound of above-cited prior art, and the effective antipsychotic drug that is using at present clinically.About this point, some pharmacological propertieses that compound of the present invention has and atypical psychosis leoponex (a kind of dibenzo diaza

Compound) identical.As if The compounds of this invention lacks dopaminergic bonding avidity, produce the outer side effect of undesirable cone with minimizing and be inclined to relevant.Used most of antipsychotics usually produces this class side effect.

To α ₁The bonding action of acceptor (test 252B) shows that compound of the present invention may have the sedative effect composition, and this effect usually is an ideal to the mental patient who treats some hypotype.

Following in vivo test system is used for classification and difference antipsychotics and nonspecific central nervous system down traditionally, and is used to measure the size as numb this class side effect tendency.

Table 2

The used in vivo test of evaluation structure formula I compound

1, the size of the stable effect of escape conditional reflex (CAR)-medicine is measured the fugue reaction of electroshock by reducing the fasting big white mouse of training.Referring to: Albert, Pharmaeologist, 4,152(1962); Wu etc., J.Med.Chem., 12,876～881(1969).

2, suppress the evaluation assessment of stereotypy-blocking-up big white mouse dopaminergic activity that apomorphine (APO) brings out, measure by the behavior integration disease that minimizing dopamine agonist apomorphine causes.Referring to: Janssen etc., Arznei-mittel.Forsch., 17,841(1966).

3, numb-numb with drug-induced big white mouse can be inferred the possibility of the outer syndrome (EPS) of human body generation cone.Referring to: Costall etc., Psychopharmacologia, 34,233-241(1974); Berkson, J.Amer.Statist.Assoc., 48,565-599(1953).

4, numb reverse-measurement medicine is to the size of the numb reverse ability of the big white mouse of bringing out with psychosis.

According to the pharmacology feature of being determined by above these in vivo test, the The compounds of this invention of structural formula I is very promising aspect antipsychotic effectiveness, because their effects in the CAR test are quite strong, and oral ED ₅₀Value is less than 100 milligrams/kg body weight, and they can block the stereotypy that apomorphine brings out effectively.This blocking effect can reflect the effect of dopamine antagonist, therefore can be used as the active method of comparison specificity screening psychosis.Compounds category of the present invention also can think to have the selectivity antipsycholic action, because the dosage that they produce antipsycholic action does not produce numb.It is numb to it should be noted that especially compound of the present invention does not only produce relatively, and some wherein best compounds have the numb ability of the psychosis inductive of reverse, the ED of oral administration apparent in viewly ₅₀Value is less than 20 milligrams/kilogram.When people expect antipsychotics is a class medicine that produces reaction outside the cone as everyone knows, will feel the meaning of compound of the present invention to the numb remarkable effect of bringing out and reversing more so.These undesirable cones are reacted a kind of serious treatment unfavorable factor of representative outward, comprise acute deformability flesh Zhang Buquan, cathisophobia Parkinsonism, tardive dyskinesia.On behalf of the interior biological data of gonosome, some (see below) in table 6.

The discussion that following brief summary is once carried out.The compounds of this invention has antipsycholic action, is particularly suitable for they are used as selectivity antipsychotic (psychosis) medicine, and what ataxia side effect they do not have.Therefore, another feature of the present invention is about improving the method for the mammal mental status, this if desired treatment, it comprises allows these mammal whole bodies take the structural formula I compound of effective dose, perhaps takes and pharmaceutically acceptable its acid salt.

The administering mode of structural formula I compound and dosage standard can the identical mode of reference compound leoponex be carried out, referring to the Merck index, and the 10th edition, (1983), the 344th page, and listed relevant document.Though the dosage of each patient's medication and dosage standard must carefully be regulated, adopt reliable professional judgement, and consider patient's age, body weight and physical appearance, route of administration, the nature and extent of disease, but parenteral mode administration dosage every day is general about to be from 0.05 to 10 milligram/kilogram, preferably 0.1 to 2 milligram/kilogram; Oral dosage approximately is from 1 to 50 milligram/kilogram, preferably 2 to 30 milligrams/kilogram.To some patient, use than low dosage and just can produce enough therapeutic actions, and, then may need bigger dosage other patients.The term that this paper uses " whole body administration " is meant oral, rectum, and the administration of parenteral mode, i.e. intramuscular injection, intravenous injection and subcutaneous injection approach.Usually it will be appreciated that when the administration of a kind of compound oral administration of the present invention, it is a kind of approach preferably, the drug dose that needs is bigger, and produces same effectiveness, and the required drug dose of parenteral mode administration is less.According to the clinical practice of success, the dosage level of taking The compounds of this invention preferably can produce effective antipsychotic (psychosis) effect, and don't causes any deleterious or undesirable side effect.

In the treatment, compound of the present invention is used with pharmaceutical compositions usually, and composition comprises the structural formula I compound of antipsychotic significant quantity or its pharmaceutically-acceptable acid addition, and pharmaceutically acceptable carrier.The pharmaceutical composition that is used for the treatment of such disease can contain at least one compound of the present invention of a large amount of or trace (for example from 95% to 0.5%), add a kind of pharmaceutical carrier, this carrier comprises one or more solid, semisolid or liquid diluent, weighting agent and nontoxic, inertia and pharmaceutically acceptable prescription auxiliary material.This class pharmaceutical composition is unit form preparation according to dosage preferably, that is to say in fact one mark or the multiple that contains the drug dose that can produce desired therapeutic response as calculated that is predetermined of each dose unit.Dose unit can contain one, two, three, four or more times single dose, or single dose 1/2,1/3, or 1/4.Single dose preferably contains the metapedes of taking medicine to produce the dosage of desired therapeutic action, once use one or several dose unit according to the predetermined dose standard, common full dose, half amount, 1/3 of once taking one day dosage measured or taken medicine once in 1/4, one day, secondary, three times or four times.The medicine that other can also be arranged.Each unitary dose of pharmaceutical composition preferably comprises 1 to 500 milligram effective constituent, makes tablet, lozenge, capsule, pulvis, aqueous suspension, oil suspension, syrup, ingredients, aqueous pharmaceutical usually.Best oral compositions form is tablet or capsule, can contains common vehicle, for example tackiness agent (syrup, gum arabic, gelatin, sorbyl alcohol, west Huang

Glue or polyvinylpyrrolidone), weighting agent (lactose, sucrose, W-Gum, calcium phosphate, sorbyl alcohol or glycine), lubricant (Magnesium Stearate, talcum powder, polyoxyethylene glycol or silica gel), disintegrating agent (as starch) and wetting agent (as sodium lauryl sulphate).Solution or suspension that structural formula I compound and common medicinal medium form can be used for administered parenterally, but as its aqueous solution injection for intravenous, its oil suspension can supply intramuscular injection.Can be used as the desired clarity of having of administered parenterally, stability and this based composition of suitability, its method for making are that the active compound of 0.1% to 10% weight ratio is soluble in water or be dissolved in the medium by multi-hydroxy fat alcohol (as glycerol, propylene glycol, polyoxyethylene glycol or their mixture) formation.Polyoxyethylene glycol is made up of nonvolatile mixture, is generally liquid, and it is water soluble but also dissolve in organic solvent not only, its molecular weight approximately from 200 to 1500.

The compound of structural formula I, wherein Z is made of group among the present invention (a-e), and the preparation method makes piperazine or the alkylation of " imines " intermediate, and its method is similar to the described method of patent of above-mentioned Wu etc. or Temple etc.All methods are included in the reference.These methods also can be merged into a kind of unit method for making for preparing structural formula I compound.This method can appropriate change, so as preparation the present invention includes but other compound of special narration not.Furtherly, changing the formal slightly different same compound of this method generation also obviously is not difficult to accomplish for the people who is familiar with this technology.Introduce some example as special explanation.

The unit method for making

Among the last figure, R ¹, R ², X, in the implication of Y and the front structure formula I to distinguish specified implication the same.Symbol D is the divalence structure relevant with group (a-d), part-structure shown in the face (a '-d ') as follows, and perhaps D is following groups (e '),

In the group (a '-e '), all the implication of symbols is all identical with the specified implication in corresponding position, front.Symbol E can be O among the last figure; N-H; Or N-(CH ₂) n-Q.Symbol " h " is by the front defined, and " Q " refers to suitable substituting group such as chlorine, bromine, iodine, sulfuric ester, phosphoric acid ester, and be right-tosylate, or methanesulfonates.Symbol " J " can be H ₂N-(CH ₂) n-; Q-(CH ₂) n-;

; Or H-.Relation between E and J is

The condition of carrying out condensation among the method A is that reactant is refluxed in anhydrous, inert reaction medium (as pyridine or dimethylbenzene).Method B and method C are to adopt second amine to react through the suitable reaction conditions that alkylation prepares triamine.Reactant is put in the suitable organic solvent, in the presence of acid binding agent, arrived about 100 ℃ temperature heating at about 60 ℃.Benzene, dimethyl formamide, ethanol, acetonitrile, toluene and just-butanols all is the better example of the liquid organic reactant medium that suits.The preferential acid binding agent that adopts is salt of wormwood, still also can uses other mineral alkali and the 3rd amine organic bases, comprises the carbonate of other basic metal and alkaline-earth metal, supercarbonate, or hydride and the 3rd amine.Suitably be described in all three kinds of patent documentations that method is all drawn in the above, here with reference to the full content of incorporating the document into.For compound of the present invention, method C is best synthetic method.Required intermediate II c can synthesize according to above-mentioned method of drawing references.

Preparation structural formula I product, wherein Z=(e), adopt the following method C that revises:

As an example for preparing structural formula I compound with slightly different method, Z-substituted alkyl piperazine (IV) can react with suitable condensed-bicyclic pyridine system (V), the product of generating structure formula I, for example

Narrated the method for preparing structural formula I compound above, this method comprises from by selecting arbitrary method the following group of methods:

(a) will have the intermediate of structural formula II a,

With the intermediate reaction with structural formula III c, wherein R ¹, R ², n, X and Y obtain having the product of structural formula I all according to the regulation of front

(b) will have the compound of structural formula II b

With intermediate reaction with structural formula III b,

Wherein Q is a suitable substituents group, as chlorine, bromine, iodine, sulfuric ester, phosphoric acid ester, and p-toluenesulfonic esters, methanesulfonates, and D, R ¹, R ², n, X and Y obtain having the product of structural formula I all according to the regulation of front;

(c) will have the compound of structural formula II b and the intermediate of structural formula III b ' and react,

Q wherein, R ¹, R ², X and Y obtain having the product of structural formula I all according to the regulation of front, and wherein n is fixed as integer 4

(d) will have the compound of structural formula II c

With intermediate reaction with structural formula III c,

D wherein, n, Q, R ¹, R ², X and Y obtain having the product of structural formula I all according to the regulation of front;

(e) will have the compound of structural formula IV

With intermediate reaction with structural formula V,

Z wherein, n, R ¹, R ², Q, X and Y obtain having the product of structural formula I all according to the regulation of front;

(f) (1) will have the compound of structural formula II d

With intermediate reaction, obtain having the compound of structural formula I f with structural formula III c;

(2), obtain having the compound of structural formula I g with I f hydrolysis in acidic medium;

(3) will have the compound sodium borohydride reduction of formula I g, obtain product I e.

About having the intermediate of structural formula II or IV, the references of quoting in the above with and appended reference in done suitable introduction, and the several seriess of compounds with structural formula II are buied from market.Bicyclic pyridine piperazine intermediate with structural formula III, and raw material bicyclic heterocycle (V) itself perhaps from market, are seen perhaps to make by method that this paper chats from chemical literature.The used method of composite structure formula III intermediate illustrates in the figure I.

In the figure I, furans-, the pyrroles-, cyclopentadiene-or the thienopyridine loop systems is synthetic, is to be that raw material is finished with the intermediate aldehydes with structural formula X.List 2-aldehyde radical intermediate in the figure I, and listed the reaction process of the intermediate III c of last generation.If employing 3-aldehyde radical intermediate X in the figure I ', then reaction product would become " oppositely " isomer III c '.

General structure III (wherein J=H) in unit, the front method for making is represented the structure of III c and two kinds of intermediates of III c ' usually.

In the figure I, desired raw material aldehyde system buys from market, is perhaps made by simple synthesizing, and adopts the method for being familiar with from the people of easy method that obtains of chemical literature and grasp chemical technology, for example N-alkyl pyrroles's Vilsmeier-Haack formylation.100 ℃ of condensations, is solvent with pyridine usually with intermediate X and propanedioic acid, is catalyzer with the piperidines, and reaction was carried out about 12 hours, with after the short period of time refluxes so that strengthen decarboxylic reaction, obtains corresponding vinylformic acid intermediate (structural formula IX).The acid that will have the formula IX is carried out chlorination with sulfur oxychloride in chloroform, and adds the dimethylamino methane amide of catalytic amount, the chloride derivative of generating structure formula VIII, and it can the crude product form be used to prepare the acyl azide with formula VII without purifying.These acyl azides are in the biphase mixture of acetone and water, make in 5 ℃ of effects by sodium azide, perhaps make with the trimethyl silyl trinitride in backflow benzene.With not purified acyl azide (formula VII); the solution gradation that is dissolved in the methylene dichloride is added in phenyl ether or the ditane; and be heated to 230 ℃, and impelling through the Curtius of isocyanic ester type and reset, cyclization immediately forms fused 6-5 dicyclo intermediate (formula VI).VI is carried out chlorination with Phosphorus Oxychloride or phosphorus pentachloride-Phosphorus Oxychloride mixture, generate the heterocycle product (V formula) that chlorine replaces.V and excessive suitable piperazine are reacted in 120 ℃-140 ℃ in pressure vessel, and time length can change, and promptly generates required piperazine intermediate III c.This general synthetic method with intermediate of formula III c, and existing in the past report (referring to: Eloy etc., Bull.Soc.Chim.Belges., 79,301(1976); J.Heterocyclic Chem., No.8,57(1971); Helv.Chim.ACta.53,645(1970).Substituent R ²Introducing, can be by with R ²Be included in the starting compound X and finish, perhaps it is placed on the rear portion of reacting flow chart, for example V (X=S, R ²=H) metallize with the tert-butyl lithium, with the dimethyl disulphide reaction, can obtain the intermediate V, wherein R then ²=SCH ₃

The midbody compound III is used for the unit method for making, in aforementioned.Use method A-C, method C has preferably finished the synthetic of formula I compound with antipsycholic action.

Explanation to special example

Constituting compound of the present invention and preparation method thereof can understand in the following example fully.Introducing these examples only is in order to explain, is not restriction the field of the invention or scope.All temperature are degree centigrade, unless otherwise specified.Resonance spectrum characteristic of nuclear magnetic refers to chemical shift (δ), with 1,000,000/(ppm) expressions, is reference standard with tetramethylsilane (TMS).The relative area of various displacement absorption peaks meets the quantity of the hydrogen atom of special functional group type in this molecule in hydrogen spectrum (PMR) data of being reported.About the displacement property of multiplicity aspect, be reported as broad peak (bs), unimodal (s), multiplet (m), bimodal (d), two even peaks (dd), triplet (t), or quartet (q).Employed abbreviation is: DMSO-d ₆(high deuterium-labelled methyl-sulphoxide), CDCl ₃(deuterium-labelled chloroform), other abbreviation are traditional usages.Infrared spectra (IR) illustrates and only comprises that having functional group differentiates the absorption wavenumber (Cm that is worth ^-1).Use Potassium Bromide (KBr) as thinner when measuring infrared spectra.All compounds all obtain satisfied results of elemental analyses.

Synthesizing of formula III c intermediate

Following representative example with chemical intermediate of structural formula V-X has illustrated the synthetic of key intermediate III c, and employing this paper quotes the currently known methods in the patent as proof, they further can be become other synthetic intermediate, for example III a or III b.

Example 1

N-methylpyrrole-2-formaldehyde (X)

Get N-methylpyrrole (10 grams, 0.12 mole), ethylene dichloride (80 milliliters) and dimethyl formamide (11.3 grams, 0.15 mole), mix, dropwise (23.6 restrain with Phosphorus Oxychloride at 5 ° under stirring, 0.15 mole) add, produce thermopositive reaction during dropping, and throw out occurs.Finish, continue again to stir 15 minutes, filter the collecting precipitation thing.Throw out is suspended in the 3N sodium hydroxide solution (300 milliliters), with chloroform extraction (3 * 100 milliliters).The combined chloroform extracting solution is used dried over mgso, filters, and concentrating under reduced pressure gets 6.1 gram (productive rate 49%) dark oily matter, and boiling point 87-90 ℃/22 mmhg, its NMR (Nuclear Magnetic Resonance) spectrum meets specified structure.This intermediate is not usually purified, and to can be used in the figure I next step synthetic.

Example 2

The 3-(2-thienyl) vinylformic acid (IX)

Get 2 thiophene carboxaldehyde (100 grams, 0.89 mole), propanedioic acid (182.5 grams, 1.70 moles), pyridine (446 milliliters), piperidines (8.9 milliliters) mixed, 100 ℃ of heating 12 hours.Then reaction soln was refluxed 20 minutes, put and pour into again in 1000 ml waters after cold, the water mixture that obtains with the concentrated hydrochloric acid acidifying, the off-white color throw out that generates is collected after filtration, with alcohol-water (1: 1) recrystallization, get product 109 grams (productive rate 80%), fusing point 145-148 ℃.

Example 3

The 3-(2-thienyl) acrylate chloride (VIII)

Get the 3-(2-thienyl) vinylformic acid (118.9 grams, 0.77 mole) be suspended in dimethyl formamide (12 milliliters) and the chloroform (600 milliliters), stir also at room temperature dropwise with sulfur oxychloride (110.1 grams, 0.93 mole) add, then reactant was refluxed 2 hours, put cold, concentrating under reduced pressure becomes brown oil, solidify when this oily matter is further placed, get low melting point solid 131 grams (productive rate 99%), do not need to be further purified processing.

Example 4

4-ketone group-4,5-dihydro-thiophene be (3,2-c) pyridines (VI) also

Get sodium azide (168.6 gram, 2.6 moles) and be suspended in 1, in 4-dioxane (400 milliliters) and water (400 milliliters) mixed solution, stir down at 5 ℃ dropwise with the 3-(2-thienyl) the dioxane solution adding of acrylate chloride (223.9 grams, 1.3 moles).From the two-phase mixed solution that forms, tell the dioxane layer, it is under reduced pressure concentrated, be dissolved in methylene dichloride (500 milliliters),, filter through dried over mgso.Phenyl ether (400 milliliters) is put in the there-necked flask, loaded onto two air set pipes, refluxing dropwise adds above-mentioned methylene dichloride filtrate down, finish, continue to reflux 1 hour, and put coldly, concentrating under reduced pressure gets dark syrup thing, use the acetonitrile recrystallization, get brown solid, collect after filtration, again water (650 milliliters) recrystallization, get 106 gram (productive rate 54%) faint yellow solids, fusing point 213-214 ℃.

Example 5

The 4-chlorothiophene is (3,2-c) pyridines (V) also

Get finely powdered 4-ketone group-4, the 5-dihydro-thiophene is (3,2-c)-pyridine (105.6 grams, 0.69 mole) also, stirs down dropwise Phosphorus Oxychloride (321.5 grams, 2.1 moles) to be added at 0 ℃.Then with reaction mixture refluxed 2.5 hours, put coldly, it is poured in the rubble ice (1000 milliliters) carefully.With the solution stirring that produces 30 minutes, with dichloromethane extraction (3 * 400 milliliters).Merge organic extracting solution, dry (sal epsom) filters, and is evaporated to solid, with acetonitrile (400 milliliters) recrystallization, gets 101 gram (productive rate 85%) light yellow solids, 91 ℃ of fusing points.

Example 6

The 4-(1-piperazinyl) thieno-(3,2-c) pyridines (III c)

Get also (3,2-c) pyridine (22.7 grams, 0.13 mole) of 4-chlorothiophene, piperazine (57.7 grams, 0.67 mole) mixes, and puts in the pressure vessel, adds small amount of ethanol (50 milliliters), 120 ℃ of heating 24 hours.With the reactant cooling, put between methylene dichloride and the water and distribute, tell organic layer, dry (sal epsom) filters, and concentrating under reduced pressure becomes oily matter.This oily matter flash chromatography (with methylene dichloride-10% methyl alcohol-1% ammonium hydroxide wash-out) is got 16 gram (productive rate 54%) golden yellow oily matter, it is dissolved in the ethanol, drip ethanol solution of hydrogen chloride and generate hydrochloride, get similar white crystals product with ethyl alcohol recrystallization, fusing point 275-283 ℃.

Example 7

The 7-(1-piperazinyl) thieno-(2,3-c) pyridines (III c ') is synthetic

The synthetic of this compound finished according to the identical reaction mechanism of preparation III c, and different is that raw material in this example (X) is the 3-thiophenecarboxaldehyde.Yet the complicated part of the multistep preparation method of this positional isomers III c ' is, it is very low that Curtius type rearrangement reaction (example 4) generates desirable intermediate VI productive rate, because the primary product of this reaction is the sym-triazine by product, this by product is from the trimerization reaction of intermediate isocyanic ester.But the reaction of adopting Fig. 1 to represent has generated product III c ', and it is brown jelly, need not be further purified and can use.

By appropriate change Fig. 1 reaction mechanism and the various building-up reactionss that exemplify above, can synthesize other III c compound.That a part is other representative III c compound is listed in table 3.

Table 3

Other III c compound

Example R ¹R ²M.p.(℃ of X Y)

8 H H CH N-CH ₃＞250

9 H H CH O

10 H H CH CH ₂

11 H H N-CH ₃CH

12 H H O CH

13 CH ₃H CH S

14 H CH ₃CH N-CH ₃

15 CH ₃OCH ₃CH O

16 H SCH ₃CH S 203-205

（.HCl.H ₂O）

17 CH ₃Cl O CH

18 H Br S CH

19 H CH CH CH ₂

20 H C ₂H ₅CH S

21 H H S CH

22 H SCH ₃CH S

Synthesizing of formula I compound

Example 23

Synthetic logical method

Having product compound synthetic of formula I, is to finish by the alkylated reaction of the inferior amide derivatives of suitable halo (II c), and wherein D is a '-d ', and E is N-(CH ₂) n-Q, and Q is a halogenide; Or fluorophenyl butyrophenone derivatives (II d) and suitable intermediate III c compound, add 3 normal salt of wormwood and in the backflow acetonitrile, react.Corresponding butyrophenone generates alcohol derivatives through sodium borohydride reduction.The time of alkylated reaction changed between 5 to 72 hours, and the product of generation is purified through flash chromatography usually, with ethanol-chloroform mixture wash-out.The product of formula I is made hydrochloride usually and is tested.

Example 24

4,4-dimethyl-1-(4-(4-(thieno-(3,2-c) pyridin-4-yl)-1-piperazinyl) butyl)-2, the 6-dioxopiperidine

Get the 4-(1-piperazinyl) thieno-(3,2-c) pyridine (III c, 2.79 grams, 0.012 mole), the N-(4-brombutyl)-and 3-dimethyl-penten imide (3.3 grams, 0.012 mole), salt of wormwood (3.3 grams, 0.024 mole) mix, add acetonitrile (150 milliliters), refluxed 24 hours.Reaction mixture is filtered, concentrating under reduced pressure, residue adds methylene dichloride and water distributes extraction, tells organic layer, dry (sal epsom), and concentrating under reduced pressure gets golden oily matter, through flash chromatography, (with 5% ethanol-chloroform wash-out).Gained chromatography product is dissolved in the acetonitrile, and drips ethanol solution of hydrogen chloride, gets hydrochloride 1.3 grams (productive rate 24%) of desired product, fusing point 195-197 ℃.

Analyze C ₂₂H ₃₀N ₄O ₂S-HCl calculated value: C, 58.59; H, 6.93; N, 12.42, experimental value: C, 58.64; H, 7.02; N, 12.72.

NMR (Nuclear Magnetic Resonance) spectrum (DMSO-d ₆): 1.08(6, s); 1.71(4, m); 2.60(4, s); 3.40(10, m); 4.00(2, m); 7.65(2, m); 7.87(1, m); 8.08(1, d (5.0Hz)); 11.75(1, bs).

Infrared spectra (KBr): 715,965,1425,1535,1670,1720,2580,2960Cm ^-1

Example 25

4-(4-(4-(4-furo (3,2-c) pyridyl)-1-piperazinyl) butyl)-3, the 5-morpholine diketone

Get the 4-(1-piperazinyl) furo (3,2-c) pyridine (4.5 grams, 0.022 mole), the 4-(4-brombutyl)-3,5-morpholine diketone (5.5 grams, 0.022 mole) and salt of wormwood (9.1 grams, 0.066 mole) mix, and add acetonitrile, reflux 24 hours.Reaction mixture is filtered, concentrating under reduced pressure, residue adds methylene dichloride and water distributes extraction, tells organic layer, dry (sal epsom), concentrating under reduced pressure gets yellow oil, through flash chromatography.The suitable chromatography elutriant of Fractional Collections is merged, and concentrating under reduced pressure, residue Virahol recrystallization gets required free alkali 6.2 grams (productive rate 69%), fusing point 109-110 ℃.

Analyze: C ₁₉H ₂₄N ₄O ₄Calculated value: C, 61.28; H, 6.50; N, 15.04.Experimental value: C, 60.98; H, 6.60; N, 15.19.

NMR (Nuclear Magnetic Resonance) spectrum (CDCl ₃): 1.60(4, m); 2.40(2, m); 2.57(4, m); 3.74(6, m); 4.31(4, s); 6.78(1, d (2.0Hz)); 6.89(1, d (5.8Hz)); 7.49(1, d (2.0Hz)); 8.01(1, d (5.8Hz)).

Infrared spectra (KBr): 760,780,1250,1285,1440,1460,1570,1595,1690,1735,2830Cm ^-1

With the method for pointing out above, perhaps, can obtain various formula I products with the replacement synthetic method of reference with the patent report that comprises.Contain a series of other representative formula I products in table 4 and table 5, table 6 contains the intravital biological test data of formula I representative compounds.

Table 4

Formula I product

Example

Sequence number Z n R ¹R ²X Y molecular formula ^A)M.p.(-℃)

26

H H CH S C ₂₂H ₂₂N ₄O ₂O ₂· 180-182

1.4HCl

27 （e） 3 H H CH S C ₂₁H ₂₄FN ₃OS 115-118

28

4 H Br CH S C ₂₂H ₂₇BrN ₄O ₂S ₂· 203-205

HCl

29 4 H Br CH S C ₂₂H ₂₉BrN ₄O ₂S· 216-219

HCl.0.5H ₂O

3

H CH ₃CH S C ₂₃H ₃₀N ₄O ₂S ₂·HCl 195-197

Table 4(is continuous)

Example

Sequence number Z n R ¹R ²X Y molecular formula ^A)M.p.(-℃)

31

4 H H CH S C ₁₉H ₂₄N ₄O ₂S ₂·1· 186-188

IC ₇H ₈O ₃S.0.5H ₂O

32

4 H H CH S C ₂₂H ₂₄N ₄O ₃S ₂· 229-230

HCl

34 H H CH S C ₂₃H ₂₄N ₄O ₂S· 226-227

HCl

36

4 H H S CH C ₂₂H ₂₈N ₄O ₂S ₂· 120-122

2HCl·1·8H ₂O

37

4 H H CH O C ₂₂H ₂₈N ₄O ₃S· 251-253

2HCl·C ₂H ₆O

38

4 H H CH O C ₂₂H ₃₀N ₄O ₃· ＞250

1.4HCl

39 （e） 3 H H CH O C ₂₁H ₂₄FN ₃O ₂·HCl 205-207

Table 4(is continuous)

Example

Sequence number Z n R ¹R ²X Y molecular formula ^A)M.p.(-℃)

40

4 H CH ₃CH O C ₂₃H ₃₀N ₄O ₃S· 176-177

1.2HCl

41

4 H CH ₃CH O C ₂₃H ₃₂N ₄O ₃· 321-233

1.2HCl.0.5H ₂O

42

4 H H CH O C ₁₉H ₂₄N ₄O ₃S· 245-250

2HCl·0.5H ₂O

43 （e） 3 H CH ₃CH O C ₂₂H ₂₆FN ₃O ₂· 121-122

HCl

44

4 H H CH S C ₁₉H ₂₄N ₄O ₃S 114-115

45

4 H H CH S C ₂₁H ₂₈N ₄O ₂S 173-175

Table 4(is continuous)

Example

Sequence number Z n R ¹R ²X Y molecular formula ^A)M.p.(-℃)

46

4 H H CH S C ₂₀H ₂₆N ₄O ₂S 199-201

47

4 H H CH NMe C ₂₃H ₃₁N ₅O ₂S· 148-150

2HCl

48

4 H H CH NMe C ₂₀H ₂₇N ₅O ₃144-146

49 4 H H CH NMe C ₂₃H ₃₃N ₅O ₂192-194

2·1HCl.

2.6H ₂O

Annotate: a) C, H, the deviation of the calculated value of N results of elemental analyses and appointment molecular formula is in ± 0.4%

Table 5

Other formula I product

Example

Sequence number Z n R ¹R ²X Y

33 4 H H CH S

35

4 CH ₃H CH S

50

4 CH ₃OH CH N-CH ₃

51

4 H SCH ₃CH S

Table 5(is continuous)

Table 6

Biological test data (milligram/kilogram, oral) in the representational body

Example CAR test APO test is brought out numb

Sequence number ED ₅₀Value ED ₅₀Be worth numb test reversal experiment

ED ₅₀Value ED ₅₀Value

24 6 40 ＞24 1A ^a）

25 11 34 ＞46 2

26 12 35 - 1A

27 10 9 ＞40 1A

28 ＞100 ＞100 -b） 16

29 65 - - 1A

30 35 - ＞142 1A

31 32 - ＞128 1A

36 43 47 - 1A

37 9 18 23 1A

38 4 7 13 1A

39 3 5 11 1A

40 28 41 - -

41 14 22 40 1A

42 36 63 - 1A

43 23 - - 1A

47 60 61 - 1A

48 ＞100 ＞100 - 1A

49 67 ＞100 - 1A

Annotate: a) I A represents non-activity, perhaps ED ₅₀Value is greater than 20 milligrams/kilogram.

B)-expression do not provide data

Claims

1, preparation has formula I compound and pharmaceutically acceptable its method of acid salt,

Wherein Z is selected from following groups:

R wherein ³And R ⁴Be selected from hydrogen respectively, low alkyl group perhaps is taken as the alkylidene chain that contains 3 to 6 carbon atoms together;

R wherein ⁵And R ⁶Be selected from hydrogen respectively, low alkyl group, the phenyl (A is a hydrogen or halogen) that A-replaces, perhaps R ⁵And R ⁶Be taken as the butylidene chain, W can be a sulphur atom together

Perhaps methylene radical,

Wherein V is oxygen or sulphur;

Wherein G is selected from hydrogen, and low alkyl group, lower alkoxy, or halogen, m are integer 1-4, and U is carbonyl (C=O) or alkylsulfonyl (SO ₂); And

N is integer 2-4, but when Z was (e), n must be 3;

X or Y are selected from CH respectively ₂O, S, or NR ⁷, but remaining X or Y must be always=CH-;

R ¹And R ⁷Be selected from hydrogen or low alkyl group respectively, and R ²Be selected from hydrogen, low alkyl group, lower alkoxy, lower alkylthio, halogen and hydroxyl,

This method can be selected from a following group of methods:

(a) with intermediate formula II a

Wherein symbol D " is the formula a '-d ' of divalence structure

R wherein ³And R ⁴Respectively be selected from hydrogen, contain the alkyl of 1-4 carbon atom, perhaps R ³And R ⁴The common alkylidene chain that contains 3-6 carbon atom, the R of forming ⁵And R ⁶Be selected from hydrogen respectively, contain the alkyl of 1-4 carbon atom, the phenyl (A is a hydrogen or halogen atom) that A replaces, perhaps R ⁵And R ⁶Be taken as the butylidene chain together; W can be S (sulphur atom) or CH ₂(methylene radical), V are oxygen or sulphur atom, and G is selected from hydrogen, contain the alkyl of 1-4 carbon atom, contain the alkoxy or halogen of 1-4 carbon atom, and m equals 1-4, and U is C=O or SO ₂, with intermediate formula III A reaction, the product that obtains having the structural formula I;

R wherein ¹, R ², n, X and Y be all according to the regulation of front,

(b) with the compound of formula II b

Wherein D as the front (a) qualification

With the intermediate reaction with formula III b, the product that obtains having the formula I;

Wherein Q be chlorine, bromine, iodine, sulfate group, phosphate-based, to a toluenesulphonic acids ester group, or methylsulfonic acid ester group, and, R ¹, R ², n, X and Y be all according to the regulation of front;

(c) compound that will have a formula II b and intermediate (wherein Q, R with formula III b ' ¹, R ², X and Y be all according to the regulation of front) reaction, the product that obtains having the formula I, wherein n is fixed as integer 4;

(d) will have the compound of formula II c

With the intermediate with formula III c (D wherein, n, Q, R ¹, R ², X and Y be all according to the regulation of front) reaction, the product that obtains having the formula I;

(e) will have the compound of formula IV

With the intermediate with formula V (wherein Z, n, R ¹, R ², Q, X and Y be all according to the regulation of front) reaction,

Obtain having the product of formula I;

(f) (I) will have the compound of formula II d

Wherein Q as above limits

With intermediate reaction, obtain having the compound of formula I f with formula III c

R wherein ¹, R ², X and Y all as above limit

(2), obtain having the compound of formula I g with I f hydrolysis in acidic medium;

R wherein ¹, R ², X and Y all as above limit

(3) will have the compound sodium borohydride reduction of formula I g, obtain having the product of formula I e.

R wherein ¹, R ², X and Y all as above limit

The routine fashion of its esters is that the base of structural formula I is mixed with a kind of selected acid, preferably by the solution state contact, uses excessive inert solvent ether, benzene, ethanol, ethyl acetate, acetonitrile and water commonly used.

2, method according to claim 1, Z is group (a) in its Chinese style I compound.

3, method according to claim 1, Z is group (b) in its Chinese style I compound.

4, method according to claim 1, Z is group (c) in its Chinese style I compound.

5, method according to claim 1, Z is group (d) in its Chinese style I compound.

6, method according to claim 1, Z is group (e) in its Chinese style I compound.

7, method according to claim 1, Y is a Sauerstoffatom in its Chinese style I compound.

8, method according to claim 1, Y is a sulphur atom in its Chinese style I compound.

9, method according to claim 3, R in its Chinese style I compound ⁵And R ⁶Form the butyl chain together, and W is a sulphur.

10, method according to claim 4, V is a Sauerstoffatom in its Chinese style I compound.

11, method according to claim 7, Z is group (a) in its Chinese style I compound, (c) or (e).

12, method according to claim 8, Z is group (a) in its Chinese style I compound, (d) or (e).

13, method according to claim 2, its Chinese style I compound are 1-(4-(4-(furo (3,2-C) pyridin-4-yl)-1-piperazinyl) butyl)-4,4-dimethyl-2,6-dioxopiperidine.

14, method according to claim 2, its Chinese style I compound is 4,4-dimethyl-1-(4-(the 4-(2-methyl furan is (3,2-C) pyridin-4-yl also)-1-piperazinyl) butyl-2,6-dioxopiperidine.

15, method according to claim 2, its Chinese style I compound is 4,4-dimethyl-1-(4-(4-(thieno-(3,2-C) pyridin-4-yl)-1-piperazinyl) butyl) butyl) 2, the 6-dioxopiperidine.

16, preparation method according to claim 2, its Chinese style I compound is 4,4-dimethyl-1-(4-(4-(1-methyl isophthalic acid H-pyrrolo-(3,2-C) pyridin-4-yl)-1-piperazinyl) butyl)-2, the 6-dioxopiperidine.

17, method according to claim 2, its Chinese style I compound is 4,4-dimethyl-1-(4-(the 4-(2-bromothiophene is (3,2-C) pyridin-4-yl also)-1-piperazinyl) butyl) 2 ,-6 dioxopiperidines.

18, method according to claim 2, its Chinese style I compound are 1-(4-(4-(thieno-(3,2-C) pyridin-4-yl)-1-piperazinyl) butyl)-1, the 6-dioxopiperidine.

19, method according to claim 2, its Chinese style I compound are 4-methyl isophthalic acid-(4-(4-(thieno-(3,2-C) pyridin-4-yl)-1-piperazinyl) butyl)-1, the 6-dioxopiperidine.

20, method according to claim 3, its Chinese style I compound are 3-(4-(4-furo (3,2-C)-pyridin-4-yl)-1-piperazinyl) butyl-1-thia-3-azaspiro (4.4)-nonane-2, the 4-diketone.

21, method according to claim 3, its Chinese style I compound are 3-(4-(4-92-methyl-furo (3,2-C) pyridin-4-yl)-1-piperazinyl) butyl-1-thia-3-azepine-volution (44) nonane-2, the 4-diketone.

22, method according to claim 3, its Chinese style I compound are 3-(4-(4-(thieno-(3,2-C) pyridin-4-yl)-1-piperazinyl) butyl-1-thia-3-azaspiro (44) nonane-2, the 4-diketone.

23, method according to claim 3, its Chinese style I compound are 3-(4-(4-(1-methyl-pyrrolo-(3,2-C) pyridin-4-yl)-1-piperazinyl) butyl)-1-thia-3-azaspiro (44) nonane-2, the 4-diketone.

24, method according to claim 3, its Chinese style I compound are 3-(4-(4-(2-bromo-thieno-(3,2-C) pyridin-4-yl)-1-piperazinyl) butyl)-1-thia-3-azaspiro (44) nonane-2, the 4-diketone.

25, method according to claim 3, its Chinese style I compound are 3-(4-(4-(2-methyl-thieno-(3,2-C) pyridin-4-yl)-1-piperazinyl) butyl-1-thia-3-azaspiro (44) nonane-2, the 4-diketone.

26, method according to claim 1, its Chinese style I compound are 3-(4-(4-(thieno-(2,3-C) pyridine-7-yl)-1-piperazinyl) butyl)-1-thia-3-azaspiro (44) nonane-2, the 4-diketone.

27, method according to claim 4, its Chinese style I compound are 4-(4-(4-(4-furo (3,2-C) pyridyl)-1-piperazinyl) butyl)-3, the 5-morpholine diketone.

28, method according to claim 4, its Chinese style I compound are 4-(4-(4-(1-methyl isophthalic acid H-pyrrolo-(3,2-C) pyridin-4-yl)-1-piperazinyl) butyl)-3, the 5-morpholine diketone.

29, method according to claim 4, its Chinese style I compound are 4-(4-(4-(4-thieno-(3,2-C) pyridyl)-1-piperazinyl) butyl)-3,5-thiomorpholine diketone.

30, method according to claim 4, its Chinese style I compound are 4-(4-(4-(4-thieno-(3,2-C) pyridyl) butyl)-3, the 5-morpholine diketone.

31, method according to claim 5, its Chinese style I compound are 2-(4-(4-(thieno-(3,2-C) pyridin-4-yl)-1-piperazinyl) butyl)-1H-isoindole-1,3-(2H)-diketone.

32, method according to claim 5, its Chinese style I compound are 2-(4-(4-(thieno-(3,2-C) pyridin-4-yl)-1-piperazinyl) butyl-1, the 2-benzisothiazole-3(2H)-and ketone-1, the 1-dioxide.

33, method according to claim 6, its Chinese style I compound are α-(4-fluorophenyl)-4-(furo (3,2-C) pyridin-4-yl)-1-piperazine butanols.

34, method according to claim 6, its Chinese style I compound are also (3,2-C) pyridin-4-yl of α-(4-fluorophenyl)-4-(2-methyl furan)-1-piperazine butanols.

35, method according to claim 6, its Chinese style I compound are α-(4-fluorophenyl)-4-(thieno-(3,2-C) pyridin-4-yl)-1-piperazine butanols.