CN105315267B - A kind of amide derivatives and its application - Google Patents

Abstract

The invention belongs to field of medicinal chemistry, and in particular to a kind of amide derivatives and its application.Amide derivatives have formula (I) structure.Through experiments, it was found that in terms of such compound can be applied to preparation treatment Nervous and mental diseases drug.

Description

A kind of amide derivatives and its application

Technical field

The invention belongs to field of medicinal chemistry, and in particular to a kind of amide derivatives and its application.

Background technique

Schizophrenia has over one hundred year history as a kind of independent entity.In Kraepelin in 1896 total On the basis of tying previous work, several clinical pictures proposed before this are generalized into a kind of disease, referred to as dementia praecox；20th century Just, Bleuler states its new viewpoint, it is believed that this disease has the obstacle of association, emotion, will and schizosis etc. its core and is Schizophrenia, and use till today always.

Schizophrenia is most serious in all mental diseases, endangers a kind of maximum disease, global incidence is about 1- 2%.Schizophreniac's lifetime prevalence is 0.7-0.8%, and with gender, race, or social boundary do not have obvious correlation, The death rate is higher by 2-3 times than general population simultaneously.Current research shows, the burden on society of mental disease ranking in Chinese disease It tops the list, has been more than the illness such as cardiovascular and cerebrovascular, respiratory system and malignant tumour.

Existing schizophrenia drug mainly has two major classes: typical anti-schizophrenia drug and atypia anti-schizophrenia medicine Object.Typical anti-schizophrenia drug (such as chlorpromazine and haloperidol) blocks dopamine D₂Receptor, to schizophrenia positive disease Shape has good efficacy.But due to blocking dopamine receptor strongly, result in the extrapyramidal symptoms (EPS), tardive barrier Hinder and the adverse reactions such as prolactin(PRL increases, and it is invalid to negative symptoms of schizophrenia.

Atypia anti-schizophrenia medicine object is using Clozapine and Risperidone as representative, not only to dopamine (D₂) receptor has Strong effect, while to serotonin (5-HT_2A) receptor also has strong effect.This kind of medicine compared with typical anti-schizophrenia drug Object has very big advantage: having good efficacy to schizophrenia positive symptom；The extrapyramidal symptoms and tardive dyskinesia etc. Side effect significantly reduces；Part atypia anti-schizophrenia medicine object has certain improvement result to negative symptoms and cognitive disorder.So And the atypia anti-schizophrenia medicine object of clinical application at present has different degrees of QT interval prolongation and high prolactin(PRL etc. bad Reaction^].Therefore, it is extremely important for finding new can effectively cure schizophrenia and the drug of Small side effects.

By the research of decades, D is found₂, 5-HT_1A, 5-HT_2AAnd H₁It is extremely important to schizophrenia Deng five receptors Effect.With D₂Receptor acting can effectively treat schizophrenia positive symptom.Forehead leaf skin of the serotonin system in adjusting It plays an important role in the function of layer, including emotion control, cognitive behavior and working memory.The cone neurone of prefrontal cortex It include 5-hydroxytryptamine receptor 5-HT with GABA intrerneuron_1AAnd 5-HT_2A.Prefrontal cortex of the serotonin system in adjusting Function in play an important role, including emotion control, cognitive behavior and working memory^]。5‐HT_1AWith atypical antipsychotic agents Object treatment is related, can improve negative symptoms and cognitive disorder.5‐HT_2AReceptor is related to perception, mood regulation and motion control Various aspects, block 5-HT_2AReceptor can make the release normalization of dopamine, and play antipsycholic action.

Simultaneously during treating the Long-term taking medicine of schizophrenia, some drugs are easy to cause the side effect of weight gain, Research shows that these side effects and histamine H₁Receptor is closely related.

Therefore, the mode that a polyceptor combines is found now, improves the sphere of action of anti-schizophrenia drug, and energy Reduce the side effects such as EPS and weight gain.

Summary of the invention

The purpose of the present invention is on the basis of existing technology, provide a kind of amide derivatives with pharmaceutical activity.

It is a further object of the present invention to provide a kind of pharmaceutical compositions containing above compound.

It is a still further object of the present invention to provide above compounds in terms of preventing or treating Neuropsychic diseases Using.

The purpose of the present invention can be achieved by the following measures:

The compound or its pharmaceutically acceptable salt of logical formula (I) of the invention:

Wherein:

X is-NR₁C (O)-,-C (O)-or-S (O₂)‐；

N is 1 or 2；

R is C substituted or unsubstituted_1‐5Alkane, C substituted or unsubstituted_3‐7Cycloalkane, shown in Formula II, formula III, formula IV or Formula V Group,

R₁、R₂、R₃、R₄Or R₅Separately selected from hydrogen, halogen, cyano, nitro, hydroxyl, substituted or unsubstituted C_1‐5 Alkoxy, substituted or unsubstituted C_1‐5Alkyl, wherein the C_1‐5The substituent group of alkyl is selected from one of amino, hydroxyl or fluorine Or it is several；

Y is selected from O, N or S.

In logical formula (I) compound, when X is-NR₁When C (O)-, preferably R₁For hydrogen or substituted or unsubstituted C_1‐5Alkyl, R are Substituted or unsubstituted C_1‐5Group shown in alkyl, Formula II or formula III, wherein the substituent R in the Formula II₂For hydrogen, replace or Unsubstituted C_1‐5Alkyl, substituted or unsubstituted C_1‐5Alkoxy or halogen；The C_1‐5The substituent group of alkyl is selected from amino, hydroxyl One or more of base or fluorine.

In logical formula (I) compound, when X is-NR₁When C (O)-, further preferably, R₁For hydrogen, methyl, ethyl, propyl, isopropyl Base, butyl, isobutyl group, amyl or isopentyl；R is methyl, ethyl, propyl, group shown in structure I I or III, wherein the formula Substituent R on II₂For hydrogen, methyl, ethyl, propyl, chlorine or fluorine.

In logical formula (I) compound, when X is-C (O)-, preferably: R is C substituted or unsubstituted_3‐7Cycloalkane, replace or not Substituted C_1‐5Group shown in alkyl or Formula II, wherein substituent R in Formula II₂For substituted or unsubstituted C_1‐5Alkoxy or halogen Element；The non-C_3‐7Cycloalkane is more preferably cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl；The C_1‐5Alkyl into The preferred tert-butyl of one step；R in the Formula II₂Substituent group is more preferably fluorine or methoxyl group.

In logical formula (I) compound, when X is-S (O₂)-, preferably R is Formula II, group shown in formula IV or Formula V, wherein Formula II, Substituent R in formula IV or Formula V₂、R₄、R₅Selected from hydrogen, substituted or unsubstituted C_1‐5Alkyl, nitro, halogen or cyano, it is described to take The C in generation_1‐5The substituent group of alkyl is selected from halogen；The R₂、R₄、R₅Further preferably from hydrogen, methyl, ethyl, propyl, nitro, Trifluoromethyl, fluorine, chlorine.

Compound of the present invention or its pharmaceutically acceptable salt, the logical formula (I) compound represented or its Pharmaceutically acceptable salt is most selected from any one following compound or its pharmaceutically acceptable salt::

The present invention leads to the pharmaceutically acceptable salt of the compound of formula (I), wherein the salt is containing can connect on drug The anion salt received: such as hydrochloride, hydrobromate, hydriodate, nitrate, sulfate or disulfate, phosphate or acid Phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, mesylate, gluconate, sugar Diacid salt, benzoate, esilate, benzene sulfonate, tosilate etc..

In the present invention, unsubstituted C_1‐5Alkyl indicate methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, amyl or Isopentyl；Substituted C_1‐5Alkyl indicates the C that halogen replaces_1‐5Alkyl, methyl substituted C_1‐5Alkyl, the C that ethyl replaces_1‐5Alkane Base；Halogen indicates fluorine, chlorine, bromine, iodine；The unsubstituted C_3‐7Cycloalkanes basis representation cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Substituted C_3‐‐7The C that cycloalkanes basis representation halogen replaces_3‐7Naphthenic base, C_1‐5Alkyl-substituted C_3‐7Naphthenic base；The substitution or not Substituted aryl indicates substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted naphthalene, described Substituent group is selected from one or more of alkyl, cyano, hydroxyl or halogen；Unsubstituted C_1‐5Alcoxyl basis representation methoxyl group, ethoxy Base, propoxyl group or butoxy.The substituted phenyl indicates C_1‐5Phenyl, the methoxyphenyl, halogenated benzene of alkoxy substitution Base；Substituted benzyl is methoxy-benzyl, halogenated benzyl.

The universal synthesis method of logical formula (I) compound is that boc-protected piperidine carbinols are reacted with paratoluensulfonyl chloride, then It is reacted under conditions of triethylamine with the fluoro- 3- of 6- (4- piperidyl) -1,2- benzo isoxazole and obtains product, be saturated with ethyl acetate Hydrochloric acid qi exhaustion BOC finally reacts to obtain the embodiment of the present invention with corresponding acyl chlorides or isocyanates and reacts to obtain target product, Specific reaction route is as follows:

Reaction condition: (a) TsCl, Et₃N,0℃‐rt；(b),Et₃N,CH₃CN,24h；(c)EA/HCl；(d),Et₃N, CH₂Cl₂,0℃‐rt。

In turn, the present invention provides a kind of pharmaceutical composition, and it includes the compound of logical formula (I) or its is pharmaceutically acceptable Salt and pharmaceutically acceptable auxiliary material (such as carrier and/or excipient), the pharmaceutical composition are containing being enough to generate anti-spirit The antipsychotic composition of the compounds of this invention of disease effect.

The effective dose of the compounds of this invention can take orally together with such as inert diluent or certain carrier.It can be wrapped in bright It is in glue capsule or tabletted.For the purpose of oral medication, the compounds of this invention can be used together with excipient and with tablet, ingot The forms such as agent, capsule, suspension, syrup use.These preparations should contain the active ingredient of the invention of at least 0.5wt% Object, but can be changed according to specific dosage form, account for Unit Weight 4% to about 70% is convenient.It is living in such composition The amount of property compound should reach dosage appropriate.The oral dosage of the preferential composition of the present invention and preparation contains 1.0- 300 milligrams of reactive compound of the present invention.

The compound or its pharmaceutically acceptable salt of logical formula (I) provided by the invention, solvate and hydrate can be with Pharmaceutical preparation is formed with pharmaceutically acceptable carrier or diluent use in conjunction.Pharmaceutically acceptable carrier packet appropriate Include inert solid filler or diluent and aseptic aqueous solution or organic solution.

The dosage of the compounds of this invention depends on the type and seriousness of disease or illness, additionally depends on the feature of object, Such as general health, age, gender, weight and drug tolerance.Technical staff can determine according to these or other factors Dosage appropriate.The effective dose of conventionally used medicine for central nervous system is known to technical staff.Every total daily dose is logical Between Chang Yue 0.05mg to 2000mg.

The present invention relates to pharmaceutical composition, per unit dose can provide about 0.01 active constituent for arriving 1000mg.Combination Object can be applied by any approach appropriate, such as capsules per os, the parenteral administration in the form of injection, with paste or The form local application of lotion, the rectal administration in the form of suppository, the transdermal administration in the form of the transmission system of patch.

Compound provided by the invention can be combined with solid appropriate or liquid-carrier or diluent to be formed capsule, tablet, Pill, powder, syrup, solution etc..Tablet, pill, capsule etc. include about 0.01 to about 99 weight percent it is active at Divide and adhesive such as gelatin, cornstarch, gum arabic；Excipient such as calcium monohydrogen phosphate；Disintegrating agent such as cornstarch, Potato starch or alginic acid；Lubricant such as magnesium stearate；With Sweetening agents such as sucrose, lactose.When dosage form is capsule, It also may include liquid-carrier, such as grease in addition to the raw material of the above-mentioned type.

For parenteral administration, compound provided by the invention can combine to form injectable with sterile water or organic media Solution or suspension.

Compounds of formula I can contain chiral centre, and it is possible thereby to be deposited in the form of different enantiomers and diastereomer ?.The present invention relates to all optical isomers of compound of Formula I and all stereoisomers, outer as this kind of compound disappears The form of mixture and each enantiomer and diastereomer is revolved, and the present invention relates separately to contain as defined above or uses it All pharmaceutical compositions and treatment method.

In addition, compound provided by the invention and the pharmaceutical composition being made of compound are in preparation for psychoneural Application in class disease medicament, the Nervous and mental diseases are schizophrenia.

Extracorporeal receptor combine experiments have shown that, compounds against dopamine D2 according to the present invention, 5HT1A and 5HT2A receptor Affinity with higher, it is low with H1 (risk of obesity under reduction is chronic is treated) affinity, the effect of drug can be increased (such as Improve negative symptoms) reduce side effect (such as EPS, newborn secretin increase, weight gain and QI gap extension).

Animal test results show, this kind of compound can be obviously improved the high activity of MK-801 induction and effective The climbing symptom for improving apomorphine induction, and do not cause EPS under effective dose.Show that it has apparent anti-spirit point Split effect.The nervous system disease as caused by these interaction in vitro target spots and internal pharmacological model and Dopamine disorder, Especially schizophrenia is closely related, therefore compound of the present invention is prompted to have the work for treating Nervous and mental diseases With especially having therapeutic effect to schizophrenia.Each detailed pharmacological datum of compound is shown in Table 2.

Specific embodiment

The following examples are only for the purpose of description and not as limitation of the invention.

A, the embodiment of synthesis aspect

Embodiment 1,4- ((4- (6- fluoro benzothiazole -3- base) piperidin-1-yl) methyl)-N, N- lupetidine -1- acyl Amine

(1) N-Boc-4- piperidine carbinols (0.1mol) are dissolved in 300ml methylene chloride, and ice bath is cooled to 10 DEG C, triethylamine 20ml is added, and p-methyl benzene sulfonic chloride (0.11mmol) is then added portionwise, reacts 12h after adding at room temperature.End of reaction, Reaction solution is washed with water, and saturated sodium bicarbonate solution is washed, and organic layer is dry with anhydrous magnesium sulfate, and decompression boils off solvent, residue mistake Column (eluant, eluent PE:EA=1:1) obtains colorless oil 34g, yield 92.1%, MS (ESI) m/z370.2 ([M+H]⁺).

(2) the fluoro- 3- of colorless oil 0.1mol, 6- (4- piperidyl) -1, the 2- benzo isoxazole for taking the first step to prepare (0.1mol), in triethylamine 25ml and 500ml acetonitrile, heating reflux reaction 12h, end of reaction is spin-dried for solvent, and 500ml is added Methylene chloride, washing, lemon pickling, organic layer is dry with anhydrous magnesium sulfate, and decompression boils off solvent, and residue crosses column (eluant, eluent CH₂Cl₂: methanol=10:1) obtain colorless oil 35g, yield 83.7%, MS (ESI) m/z418.2 ([M+H]⁺).

(3) the colorless oil 0.1mol for taking second step to prepare is added 200ml and is saturated hcl ethyl acetate gas, and room temperature is stirred Reaction 6h is mixed, end of reaction, filtering obtains white solid, white solid is dissolved with water, with sodium hydroxide tune PH to 11, with two Chloromethanes extracts 2 times (2 × 200ml), and organic layer is dry with anhydrous magnesium sulfate, is spin-dried for solvent and obtains white solid 25g, yield 78.9%, MS (ESI) m/z318.2 ([M+H]⁺).

(4) the white solid 2mmol for taking third step to prepare, triethylamine 2ml and 20ml methylene chloride, ice bath are cooled to 10 DEG C, N is added dropwise, N- dimethyl methyl acyl chlorides (2mmol) reacts 4h, end of reaction, washing, saturated carbon at room temperature after being added dropwise Sour hydrogen sodium solution is washed, and organic layer is dry with anhydrous magnesium sulfate, is spin-dried for solvent, residue obtains white solid with recrystallized from acetonitrile It is numbered shown in (1) in 0.62g, yield 80.5%, structural formula such as table 1.¹H‐NMR(600MHz,CDCl₃)δ1.10‐1.17(m, 2H), 1.66-1.68 (m, 1H), 1.75 (d, 2H, J=6.4Hz), 2.01-2.10 (m, 6H), 2.20 (d, 2H, J=4Hz), 2.70 (t, 2H, J=6.4Hz), 2.78 (s, 6H), 2.95-3.04 (m, 3H), 3.64 (d, 2H, J=6.4Hz), 7.00-7,05 (m, 1H), 7.19 (d, 1H, J=6.4Hz), 7.65-7.67 (m, 1H) .MS (ESI) m/z389.3 ([M+H]⁺).

2,4- ((4- (6- fluoro benzothiazole -3- base) piperidin-1-yl) methyl)-N- (4- tolyl) piperidines -1- amide

N is replaced with aromatic isocyanatcs, N- dimethyl methyl acyl chlorides is raw material, prepares target as described in Example 1 It is numbered shown in (2) in compound, structural formula such as table 1.¹H‐NMR(600MHz,CDCl₃)δ1.25‐1.43(m,3H),1.82‐1.85 (m, 2H), 2.00-2.10 (m, 6H), 2.18-2.26 (m, 4H), 2.42 (s, 3H), 2.91 (d, 2H, J=4Hz) 3.01-3.03 (m, 1H), 3.79 (d, 2H, J=4Hz), 7.03-7.07 (m, 1H), 7.22-7.25 (m, 1H), 7.29-7.31 (m, 2H), 7.65‐7.68(m,3H).MS(ESI)m/z436.2([M+H]⁺).

3,4- ((4- (6- fluoro benzothiazole -3- base) piperidin-1-yl) methyl)-N- (4- chlorphenyl) piperidines -1- amide

N is replaced with chlorophenyl isocyanate, N- dimethyl methyl acyl chlorides is raw material, prepares targeted as described in Example 1 Object is closed, in structural formula such as table 1 shown in number (3).¹H‐NMR(600MHz,CDCl₃)δ1.19‐1.28(m,2H),1.77‐1.79 (m, 1H), 1.89 (d, 2H, J=6.4Hz), 2.06-2.18 (m, 6H), 2.27 (d, 2H, J=4Hz), 2.90-2.95 (m, 2H), 3.01-3.11 (m, 3H), 4.09 (d, 2H, J=6.4Hz), 7.07-7.10 (m, 1H), 7.25-7.27 (m, 3H), 7.32-7.34 (m,2H),7.70‐7.72(m,1H).MS(ESI)m/z471.2([M+H]⁺).

4,4- ((4- (6- fluoro benzothiazole -3- base) piperidin-1-yl) methyl)-N- (benzyl) piperidines -1- amide

N is replaced with benzyl isocyanate ester, N- dimethyl methyl acyl chlorides is raw material, prepares target chemical combination as described in Example 1 It is numbered shown in (4) in object, structural formula such as table 1.¹H‐NMR(600MHz,CDCl₃)δ1.13‐1.20(m,2H),1.72‐1.74(m, 1H), 1.82 (d, 2H, J=6.4Hz), 2.06-2.16 (m, 6H), 2.24 (d, 2H, J=4Hz), 2.79-2.84 (m, 2H), 3.02-3.09 (m, 3H), 3.99 (d, 2H, J=6.4Hz), 4.05 (d, 2H, J=4Hz), 7.06-7.09 (m, 1H), 7.25- 7.27(m,2H),7.32‐7.34(m,4H),7.69‐7.71(m,1H).MS(ESI)m/z451.2([M+H]⁺).

5, (4- ((4- (6- fluoro benzothiazole -3- base) piperidin-1-yl) methyl) piperidin-1-yl) (cyclopropyl) ketone

N is replaced with cyclopropyl formyl chloride, N- dimethyl methyl acyl chlorides is raw material, target compound is prepared as described in Example 1, It is numbered shown in (5) in structural formula such as table 1.¹H‐NMR(600MHz,CDCl₃)δ0.75‐0.77(m,2H),0.99‐1.21(m,4H), 1.78‐1.82(m,4H),2.07‐2.10(m,8H),2.26‐2.28(m,1H),2.99‐3.09(m,4H),4.24‐4.26(m, 1H),4.61‐4.63(m,1H),7.06‐7.09(m,1H),7.25‐7.27(m,1H),7.71‐7.73(m,1H).MS(ESI)m/ z386.2([M+H]⁺).

6, (4- ((4- (6- fluoro benzothiazole -3- base) piperidin-1-yl) methyl) piperidin-1-yl) (tert-butyl) ketone

N is replaced with tert-butyl formyl chloride, N- dimethyl methyl acyl chlorides is raw material, prepares target chemical combination as described in Example 1 It is numbered shown in (6) in object, structural formula such as table 1.¹H‐NMR(600MHz,CDCl₃)δ1.09‐1.16(m,2H),1.29(s,9H), 1.79-1.85 (m, 3H), 2.05-2.13 (m, 6H), 2.24 (d, 2H, J=4Hz), 2.78-2.81 (m, 2H), 2.99-3.06 (m, 3H), 4.44 (d, 2H, J=4Hz), 7.05-7.08 (m, 1H), 7.24-7.27 (m, 1H), 7.69-7.72 (m, 1H) .MS (ESI)m/z402.2([M+H]⁺).

7, (4- ((4- (6- fluoro benzothiazole -3- base) piperidin-1-yl) methyl) piperidin-1-yl) (phenyl) ketone

N is replaced with chlorobenzoyl chloride, N- dimethyl methyl acyl chlorides is raw material, prepares target compound as described in Example 1, is tied It is numbered shown in (7) in structure formula such as table 1.¹H‐NMR(600MHz,CDCl₃)δ1.16‐1.27(m,2H),1.79‐1.93(m,3H), 2.06-2.16 (m, 6H), 2.28 (d, 2H, J=4Hz), 2.78-2.81 (m, 1H), 3.02-3.09 (m, 4H), 3.75-3.81 (m,1H),4.72‐4.80(m,1H),7.05‐7.08(m,1H),7.24‐7.27(m,1H),7.69‐7.72(m,1H).MS (ESI)m/z422.2([M+H]⁺).

8, (4- ((4- (6- fluoro benzothiazole -3- base) piperidin-1-yl) methyl) piperidin-1-yl) (4- fluorophenyl) ketone

N is replaced with to fluorobenzoyl chloride, N- dimethyl methyl acyl chlorides is raw material, prepares target chemical combination as described in Example 1 It is numbered shown in (8) in object, structural formula such as table 1.¹H‐NMR(600MHz,CDCl₃)δ1.10‐1.27(m,2H),1.82‐1.91(m, 3H), 2.04-2.16 (m, 6H), 2.28 (d, 2H, J=4Hz), 2.79-2.81 (m, 1H), 3.00-3.09 (m, 4H), 3.73- 3.78(m,1H),4.71‐4.79(m,1H),7.05‐7.12(m,3H),7.24‐7.26(m,1H),7.41‐7.44(m,2H), 7.68‐7.72(m,1H).MS(ESI)m/z440.2([M+H]⁺).

9, (4- ((4- (6- fluoro benzothiazole -3- base) piperidin-1-yl) methyl) piperidin-1-yl) (4- methoxyphenyl) first Ketone

N is replaced with anisoyl chloride, N- dimethyl methyl acyl chlorides is raw material, prepares target as described in Example 1 It is numbered shown in (9) in compound, structural formula such as table 1.¹H‐NMR(600MHz,CDCl₃)δ1.10‐1.26(m,2H),1.80‐1.90 (m, 3H), 2.05-2.16 (m, 6H), 2.26 (d, 2H, J=4Hz), 2.77-2.80 (m, 1H), 3.00-3.09 (m, 4H), 3.53 (s,3H),3.72‐3.77(m,1H),4.71‐4.76(m,1H),7.03‐7.11(m,3H),7.23‐7.26(m,1H),7.40‐ 7.45(m,2H),7.69‐7.71(m,1H).MS(ESI)m/z452.3([M+H]⁺).

10,3- (1- ((1- ((4- fluorophenyl) sulfonyl) piperidin-4-yl) methyl) piperidin-4-yl) -6- fluoro benzothiazole

N is replaced with to fluorophenylsulfonyl chloride, N- dimethyl methyl acyl chlorides is raw material, prepares target chemical combination as described in Example 1 It is numbered shown in (10) in object, structural formula such as table 1.¹H‐NMR(600MHz,CDCl₃)δ1.28‐1.33(m,2H),1.45‐1.48(m, 1H), 1.85-1.87 (m, 2H), 2.00-2.12 (m, 6H), 2.20-2.31 (m, 4H), 2.92 (d, 2H, J=4Hz) 3.00- 3.05 (m, 1H), 3.81 (d, 2H, J=4Hz), 7.04-7.07 (m, 1H), 7.21-7.25 (m, 3H), 7.66-7.68 (m, 1H), 7.78‐7.80(m,2H).MS(ESI)m/z476.2([M+H]⁺).

11,3- (1- ((1- ((4- nitrobenzophenone) sulfonyl) piperidin-4-yl) methyl) piperidin-4-yl) -6- fluorobenzene and thiophene Azoles

N is replaced with 4-Nitrobenzenesulfonyl chloride, N- dimethyl methyl acyl chlorides is raw material, prepares targeted as described in Example 1 Object is closed, in structural formula such as table 1 shown in number (11).¹H‐NMR(600MHz,CDCl₃)δ1.28‐1.35(m,2H),1.49‐1.51 (m, 1H), 1.88-1.90 (m, 2H), 2.01-2.13 (m, 6H), 2.21-2.36 (m, 4H), 2.93 (d, 2H, J=4Hz) 3.03- 3.07 (m, 1H), 3.88 (d, 2H, J=4Hz), 7.05-7.08 (m, 1H), 7.24-7.26 (m, 1H), 7.66-7.68 (m, 1H), 7.97‐7.98(m,2H),8.40‐8.42(m,2H).MS(ESI)m/z503.2([M+H]⁺).

12,3- (1- ((1- ((4- cyano-phenyl) sulfonyl) piperidin-4-yl) methyl) piperidin-4-yl) -6- fluorobenzene and thiophene Azoles

N is replaced with to cyanobenzenesulfonyl chloride, N- dimethyl methyl acyl chlorides is raw material, prepares targeted as described in Example 1 Object is closed, in structural formula such as table 1 shown in number (12).¹H‐NMR(600MHz,CDCl₃)δ1.25‐1.31(m,2H),1.48‐1.50 (m, 1H), 1.85-1.87 (m, 2H), 1.99-2.10 (m, 6H), 2.19-2.35 (m, 4H), 2.91 (d, 2H, J=4Hz) 3.01- 3.03 (m, 1H), 3.83 (d, 2H, J=4Hz), 7.03-7.06 (m, 1H), 7.22-7.24 (m, 1H), 7.65-7.67 (m, 1H) .7.85‐7.90(m,4H).MS(ESI)m/z483.2([M+H]⁺).

13,3- (1- ((1- ((4- trifluoromethyl) sulfonyl) piperidin-4-yl) methyl) piperidin-4-yl) -6- fluorobenzene And thiazole

N is replaced with to trifluoromethyl benzene sulfonyl chloride, N- dimethyl methyl acyl chlorides is raw material, prepares mesh as described in Example 1 Compound is marked, in structural formula such as table 1 shown in number (13).¹H‐NMR(600MHz,CDCl₃)δ1.28‐1.34(m,2H),1.48‐ 1.50 (m, 1H), 1.86-1.89 (m, 2H), 2.02-2.10 (m, 6H), 2.20-2.33 (m, 4H), 2.93 (d, 2H, J=4Hz) 3.03-3.05 (m, 1H), 3.87 (d, 2H, J=4Hz), 7.04-7.06 (m, 1H), 7.22-7.24 (m, 1H), 7.66-7.68 (m,1H),7.81‐7.83(m,2H),7.91‐7.92(m,2H).MS(ESI)m/z526.2([M+H]⁺).

14,3- (1- ((1- ((4- aminomethyl phenyl) sulfonyl) piperidin-4-yl) methyl) piperidin-4-yl) -6- fluorobenzene and thiophene Azoles

N is replaced with p-methyl benzene sulfonic chloride, N- dimethyl methyl acyl chlorides is raw material, prepares targeted as described in Example 1 Object is closed, in structural formula such as table 1 shown in number (14).¹H‐NMR(600MHz,CDCl₃)δ1.28‐1.45(m,3H),1.83‐1.85 (m, 2H), 2.00-2.11 (m, 6H), 2.19-2.27 (m, 4H), 2.44 (s, 3H), 2.92 (d, 2H, J=4Hz) 3.02-3.04 (m, 1H), 3.80 (d, 2H, J=4Hz), 7.04-7.07 (m, 1H), 7.23-7.25 (m, 1H), 7.29-7.32 (m, 2H), 7.65‐7.69(m,3H).MS(ESI)m/z472.2([M+H]⁺).

15,3- (1- ((1- ((phenyl) sulfonyl) piperidin-4-yl) methyl) piperidin-4-yl) -6- fluoro benzothiazole

N is replaced with benzene sulfonyl chloride, N- dimethyl methyl acyl chlorides is raw material, prepares target compound as described in Example 1, is tied It is numbered shown in (15) in structure formula such as table 1.¹H‐NMR(600MHz,CDCl₃)δ1.27‐1.34(m,2H),1.47‐1.50(m,1H), 1.84-1.86 (m, 2H), 2.02-2.10 (m, 6H), 2.21-2.30 (m, 4H), 2.93 (d, 2H, J=4Hz) 3.03-3.05 (m, 1H), 3.83 (d, 2H, J=4Hz), 7.04-7.07 (m, 1H), 7.24-7.26 (m, 1H), 7.52-7.56 (m, 3H), 7.60- 7.62(m,1H),7.78‐7.79(m,2H).MS(ESI)m/z458.2([M+H]⁺).

16,3- (1- ((1- (2- naphthalene sulfonyl base) piperidin-4-yl) methyl) piperidin-4-yl) -6- fluoro benzothiazole

N is replaced with 2- naphthalene sulfonyl chloride, N- dimethyl methyl acyl chlorides is raw material, target compound is prepared as described in Example 1, It is numbered shown in (16) in structural formula such as table 1.¹H‐NMR(600MHz,CDCl₃)δ1.26‐1.34(m,2H),1.45‐1.48(m, 1H), 1.85-1.87 (m, 2H), 2.00-2.10 (m, 6H), 2.20-2.28 (m, 4H), 2.92 (d, 2H, J=4Hz) 3.02- 3.05 (m, 1H), 3.81 (d, 2H, J=4Hz), 7.04-7.06 (m, 1H), 7.24-7.26 (m, 2H), 7.52-7.56 (m, 3H), 7.61‐7.63(m,1H),7.76‐7.78(m,2H),7.99‐8.01(m,1H)MS(ESI)m/z508.2([M+H]⁺).

17,3- (1- ((1- (2- thiophen sulfuryl) piperidin-4-yl) methyl) piperidin-4-yl) -6- fluoro benzothiazole

N is replaced with 2- thiophenesulfonyl chloride, N- dimethyl methyl acyl chlorides is raw material, prepares target chemical combination as described in Example 1 It is numbered shown in (17) in object, structural formula such as table 1.¹H‐NMR(600MHz,CDCl₃)δ1.33‐1.38(m,2H),1.48‐1.51(m, 1H), 1.88-1.90 (m, 2H), 2.02-2.11 (m, 6H), 2.22-2.34 (m, 4H), 2.95 (d, 2H, J=4Hz) 3.02- 3.07 (m, 1H), 3.84 (d, 2H, J=4Hz), 7.05-7.08 (m, 1H), 7.16-7.17 (m, 1H), 7.24-7.26 (m, 1H), 7.54‐7.56(m,1H),7.62‐7.63(m,1H),7.68‐7.70(m,1H).MS(ESI)m/z464.2([M+H]⁺).

18,3- (1- ((1- ((4- nitrobenzophenone) sulfonyl) piperidin-4-yl) ethyl) piperidin-4-yl) -6- fluorobenzene and thiophene Azoles

Replacing N-Boc-4- piperidine carbinols with N-Boc-4- piperidine ethanol is raw material, prepares targeted by the method for implementing 11 Object is closed, in structural formula such as table 1 shown in number (18).¹H‐NMR(600MHz,CDCl₃)δ1.34‐1.38(m,4H),1.47‐1.50 (m,1H),1.75‐1.81(m,2H),2.05‐2.14(m,6H),2.33‐2.39(m,4H),3.01‐3.08(m,3H),3.85 (d, 2H, J=4Hz), 7.04-7.08 (m, 1H), 7.24-7.26 (m, 1H), 7.66-7.68 (m, 1H), 7.96-7.98 (m, 2H),8.40‐8.41(m,2H).MS(ESI)m/z517.2([M+H]⁺).

19,3- (1- ((1- ((4- nitrobenzophenone) sulfonyl) piperidines -3- base) methyl) piperidin-4-yl) -6- fluorobenzene and thiophene Azoles

Replacing N-Boc-4- piperidine carbinols with N-Boc-3- piperidine carbinols is raw material, prepares targeted by the method for implementing 11 Object is closed, in structural formula such as table 1 shown in number (19).¹H‐NMR(600MHz,CDCl₃)δ0.94‐0.98(m,1H),1.77‐1.79 (m, 1H), 1.88-1.90 (m, 2H), 2.01-2.13 (m, 6H), 2.21-2.36 (m, 4H), 2.93 (d, 2H, J=4Hz) 3.03- 3.07 (m, 1H), 3.88 (d, 2H, J=4Hz), 7.05-7.08 (m, 1H), 7.24-7.26 (m, 1H), 7.66-7.68 (m, 1H), 7.97‐7.98(m,2H),8.40‐8.42(m,2H).MS(ESI)m/z503.2([M+H]⁺).

20,3- (1- ((1- ((2- nitrobenzophenone) sulfonyl) piperidin-4-yl) methyl) piperidin-4-yl) -6- fluorobenzene and thiophene Azoles

N is replaced with ortho-nitrophenyl sulfonic acid chloride, N- dimethyl methyl acyl chlorides is raw material, prepares targeted as described in Example 1 Object is closed, in structural formula such as table 1 shown in number (20).¹H‐NMR(600MHz,CDCl₃)δ1.25‐1.29(m,2H),1.61‐1.63 (m,1H),1.87‐1.89(m,2H),2.01‐2.10(m,6H),2.22‐2.24(m,2H),2.74‐2.77(m,2H),2.95 (d, 2H, J=4Hz) 3.01-3.07 (m, 1H), 3.86 (d, 2H, J=4Hz), 7.04-7.07 (m, 1H), 7.22-7.24 (m, 1H),7.69‐7.71(m,4H),7.97‐7.99(m,1H).MS(ESI)m/z503.2([M+H]⁺).

The compound number and its structural formula of 1 Examples 1 to 20 of table preparation

B, the embodiment in terms of pharmacology

Embodiment 21

5‐HT_1AThe preparation of film

Rat broken end, operates on ice, takes cortex rapidly, and 3ml buffer is added, and (the Tris-HCl buffer of 0.05M, contains 0.1% ascorbic acid, 10um pargyline and 4mM CaCl₂) be homogenized in 4 grades of 3-4s, it is homogenized 4 times, 5ml buffer is then added (the Tris-HCl buffer of 0.05M, containing 0.1% ascorbic acid, 10um pargyline and 4mM CaCl₂), hatch in 37 DEG C 10min, test tube balance adjustment weight abandons supernatant in 12000r, 4 DEG C of centrifugation 20min after having hatched, and 3ml buffering is added Liquid is mixed with vortex mixer, adds 5ml buffer, and centrifugation is centrifuged in triplicate, and centrifugation finishes, and is abandoned supernatant, will be sunk It forms sediment and is stored for future use in -80 DEG C.

Receptor Binding Assay material:

Isotope aglucon³H-8-OH-DPAT (67.0Ci/mmol) is purchased from PerkinElmer company；5-HT is purchased from RBI Company；GF/C glass fiber filter paper is purchased from Whatman company；Tris import packing；PPO, POPOP are purchased from Shanghai Reagent One Plant； Fat-soluble scintillation solution.Beckman LS-6500 type full-service fluid scintillation counter.

Experimental method:

(1) first the suitable buffer of the film prepared is uniformly dispersed with refiner, 15 test tubes is mixed into In the container of 100ml, the suspension that suitable buffer is in 50ml film is added, it is spare.

(2) each reaction tube is separately added into 100 μ L of film preparation object, 100 μ L of buffer.

(3) 100 μ L buffers are added in total binding pipe (TB), and it is (dense eventually that 100 μ L of 5-HT is added in non-specific binding pipe (NB) Degree 10^‐5M), 100 μ L test-compound (final concentrations 10 are added in each test-compound specific binding pipe (SB)^‐5M)；

(4) each reaction tube is separately added into radioligand³10 μ L of H-8-OH-DPAT (each reaction tube is all provided with 2 parallel pipes, Each pipe is placed on ice when sample-adding).

(5) 37 DEG C of temperature of each reaction tube are incubated into 10min, end of reaction, in conjunction with aglucon by decompression, quickly filtering, use are ice-cold Test buffer sufficiently wash, by filter disc taking-up be put into 3ml scintillating disc, the toluene scintillation solution of 2ml is added and mixes；

(6) scintillation vial liquid scintillation counter is put into count

Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm) × 100%

Compound is tested every time does two multiple pipes, carries out twice individually experiment.Experimental result is shown in Table 2

Embodiment 22

5‐HT_2AThe preparation of film

Rat broken end, operates on ice, takes cortex rapidly, and 3ml buffer is added and (the Tris-HCl buffer of 0.05M: takes 6.05gTris is dissolved in 1000ml distilled water, is 7.5) to be homogenized in 4 grades of 3-4s with dense HCl tune PH, is homogenized 4 times, is then added 5ml buffer, in 37 DEG C of hatching 10min, test tube balance adjustment weight is abandoned in 12000r, 4 DEG C of centrifugation 20min after having hatched Supernatant is added 3ml buffer, is mixed with vortex mixer, add 5ml buffer, is centrifuged, (being centrifuged in triplicate), from The heart finishes, and abandons supernatant, will be deposited in -80 DEG C and store for future use.

Receptor Binding Assay material:

Isotope aglucon [³H]-Ketanserin (67.0Ci/mmol), it is purchased from PerkinElmer company； Methysergide is purchased from RBI company；GF/C glass fiber filter paper is purchased from Whatman company；Tris import packing；PPO, POPOP is purchased from Shanghai Reagent One Plant；Fat-soluble scintillation solution.Beckman LS-6500 type full-service fluid scintillation counter.

Experimental method:

(1) first the suitable buffer of the film prepared is uniformly dispersed with refiner, 15 test tubes is mixed into In the container of 100ml, the suspension that suitable buffer is in 50ml film is added, it is spare.

(2) each reaction tube is separately added into 100 μ L of film preparation object, 100 μ L of buffer.

(3) 100 μ L buffers are added in total binding pipe (TB), and Methysergide 100 is added in non-specific binding pipe (NB) μ L (final concentration 10^‐5M), 100 μ L test-compound (final concentrations 10 are added in each test-compound specific binding pipe (SB)^‐5M)；

(4) each reaction tube is separately added into radioligand³(each reaction tube is all provided with 2 in parallel to 10 μ L of H-Ketanserin Pipe, when sample-adding, each pipe was placed on ice).

(5) 37 DEG C of temperature of each reaction tube are incubated into 15min, end of reaction, in conjunction with aglucon by decompression, quickly filtering, use are ice-cold Test buffer sufficiently wash, by filter disc taking-up be put into 3ml scintillating disc, the toluene scintillation solution of 2ml is added and mixes；

(6) scintillation vial liquid scintillation counter is put into count

Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm) × 100%

Compound is tested every time does two multiple pipes, carries out twice individually experiment.Experimental result is shown in Table 2

Embodiment 23

D₂The preparation of film

Rat broken end, operates on ice, takes brain striatum rapidly, be added 3ml buffer (the Tris-HCl buffer of 0.05M, 120mM containing NaCl, KCl 5mM, MgCl2 1mM, CaCl2 1mM), it is homogenized in 4 grades of 3-4s, is homogenized 4 times, it is slow that 5ml is then added The test tube being homogenized balance is adjusted weight, in 12000r, 4 DEG C of centrifugation 20min, abandons supernatant, 3ml buffering is added by fliud flushing Liquid is mixed with vortex mixer, adds 5ml buffer, and centrifugation is centrifuged in triplicate, and centrifugation finishes, and is abandoned supernatant, will be sunk It forms sediment and is stored for future use in -80 DEG C.

Receptor Binding Assay material:

Isotope aglucon³H-Spiperone (67.0Ci/mmol) is purchased from PerkinElmer company；Butaclamol, purchase From RBI company；GF/C glass fiber filter paper is purchased from Whatman company；Tris import packing；PPO, POPOP are purchased from Shanghai reagent One factory；Fat-soluble scintillation solution.Beckman LS-6500 type full-service fluid scintillation counter.

Experimental method:

(1) first the suitable buffer of the film prepared is uniformly dispersed with refiner, 15 test tubes is mixed into In the container of 100ml, the suspension that suitable buffer is in 50ml film is added, it is spare.

(2) each reaction tube is separately added into 100 μ L of film preparation object, 100 μ L of buffer.

(3) 100 μ L buffers are added in total binding pipe (TB), and 100 μ L Butaclamol are added in non-specific binding pipe (NB) (final concentration 10^‐5M), 100 μ L test-compound (final concentrations 10 are added in each test-compound specific binding pipe (SB)^‐5M)；

(4) each reaction tube is separately added into radioligand³10 μ L of H-Spiperone (each reaction tube is all provided with 2 parallel pipes, Each pipe is placed on ice when sample-adding).

(5) 37 DEG C of temperature of each reaction tube are incubated into 20min, end of reaction, in conjunction with aglucon by decompression, quickly filtering, use are ice-cold Test buffer sufficiently wash, by filter disc taking-up be put into 3ml scintillating disc, the toluene scintillation solution of 2ml is added and mixes；

(6) scintillation vial liquid scintillation counter is put into count

Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm) × 100%

Compound is tested every time does two multiple pipes, carries out twice individually experiment.Experimental result is shown in Table 2.

Embodiment 24

Histamine H₁The preparation of receptor membrane

Cavy broken end, operates on ice, takes guinea pig cerebellum rapidly, be added 3mL buffer (1.36 grams of potassium dihydrogen phosphate potassium, The sodium hydroxide 79mL of 0.1mol/L, is diluted to 200mL with distilled water), it is mixed with vortex mixer, in 48000g, 4 DEG C of centrifugations 10min abandons supernatant, takes precipitating, adds buffer washing, is centrifuged in triplicate, and centrifugation finishes, and abandons supernatant, will precipitate It is stored for future use in -80 DEG C.

Receptor Binding Assay material:

Isotope aglucon³H-pyrilamine (67.0Ci/mmol) is purchased from PerkinElmer company； Promethazine is purchased from RBI company；GF/C glass fiber filter paper is purchased from Whatman company；Tris import packing；PPO, POPOP is purchased from Shanghai Reagent One Plant；Fat-soluble scintillation solution.Beckman LS-6500 type full-service fluid scintillation counter.Experiment Method:

Step 1: first the suitable buffer of the film prepared is uniformly dispersed with refiner, 15 test tubes are mixed into In the container of 100ml, the suspension that suitable homogenate is in 50ml film is added, it is spare.

Step 2: each reaction tube is separately added into 100 μ L of film preparation object.

Step 3: 100 μ L buffers are added in total binding pipe (TB), 100 μ L are added in non-specific binding pipe (NB) 100 μ L test-compounds are added (eventually in promethazine (final concentration 10-5M), each test-compound specific binding pipe (SB) Concentration 10-5M)；

Step 4: each reaction tube is separately added into radioligand³(each reaction tube is all provided with 2 and puts down 10 μ L of H-pyrilamine Row pipe, when sample-adding, each pipe was placed on ice).

Step 5: 30 DEG C of temperature of each reaction tube are incubated 60min, end of reaction, in conjunction with aglucon by decompression quickly filtering, use Ice-cold test buffer sufficiently washs, and filter disc taking-up is put into 3ml scintillating disc, the toluene scintillation solution of 2ml is added and mixes；

It is counted step 6: scintillation vial is put into liquid scintillation counter

Inhibiting rate (I%)=(total binding pipe cpm-compound cpm)/(total binding pipe cpm-non-specific binding pipe cpm) × 100%

Compound is tested every time does two multiple pipes, carries out twice individually experiment.Experimental result is shown in Table 2.

Inhibiting rate (in triplicate test, ± SD) of 2 compound of table to each receptor

Above-mentioned Vitro Experimental Results show compound 11 to three kinds of receptor (D₂,5‐HT_1A, and 5-HT_2A) have it is stronger affine Power, and compound 11 is to H₁Affinity it is low, compared with Risperidone, the side effect possibility for generating weight gain is smaller.

Anti- schizophrenia activity in the high activity compound body that embodiment 25, MK-801 are induced

Experimental animal and reagent

Healthy Kunming mouse, half male and half female, weight (20 ± 2) g are provided by Nanjing Qinglongshan animal-breeding center.

Ascorbic acid, Sinopharm Chemical Reagent Co., Ltd.；

MK-801 is produced by Sigma Co., USA, preparation method: the solution of 1mg/ml is made into 0.1% vitamin C；

Tested positive drug: haloperidol, Clozapine, Risperidone, Olanzapine, Aripiprazole, Ziprasidone, kui gentle ziprasidone；

Tween 80, concentration 10%.

Experimental method

The re-qualified mouse of selective body is randomly divided into blank group, model group, positive controls (Risperidone group), medicine group. Risperidone 0.1mg/kg, medicine group difference are given in blank group, 10% tween 0.1ml/10g of model group stomach-filling, positive controls stomach-filling Stomach-filling gives corresponding dosage drug.0.1% ascorbic acid 0.1ml/10g, model group, the positive is injected intraperitoneally in 1h blank group after administration MK-801 solution 0.1mg/kg is injected intraperitoneally in control group (30min), medicine group.Thereafter spontaneous work in each group mouse 90 minutes is measured It is dynamic.It the results are shown in Table 3.

Embodiment 26, the climbing experiment of apomorphine inducing mouse

Experimental animal

Healthy KM mouse, male, 18~22g of weight are provided by Nanjing Qinglongshan animal-breeding center.

Main agents

Tested positive drug: haloperidol, Clozapine, Risperidone, Olanzapine, Aripiprazole, Ziprasidone, kui gentle ziprasidone；

Apomorphine, Sigma company provide, and 0.9%NaCl (containing 0.1% vitamin C) dissolution, ready-to-use before use；

Vitamin C, F20061113, Sinopharm Chemical Reagent Co., Ltd.；

Sodium chloride injection, H32026305, the 5th pharmacy Co., Ltd., Factory, Xuzhou City.

Instrument: self-control climbing cage, stopwatch.

Experimental method: apomorphine inducing mouse climbing experiment

KM mouse, male, 18~22g of weight are randomly divided into each dosage group of negative control group, model group, positive drug (benefit Train ketone, Aripiprazole, Ziprasidone, kui gentle ziprasidone, Olanzapine, haloperidol, Clozapine) and each dosage group of compound is (specifically Dosage see the table below), every group 10.Coordinative solvent distilled water, positive drug group are given in negative control group and model group stomach-filling Corresponding positive drug (dissolution Shi Xianjia micro-acetic acid, then plus distilled water) is given in stomach-filling, and phase is given in each dosage group stomach-filling of compound Doses of compound is answered, stomach-filling volume is 0.1ml/10g.Apomorphine (1mg/kg) is subcutaneously injected after gastric infusion 1 hour, volume For 0.1ml/10g.After injecting apomorphine, it is immediately placed in climbing cage, adapts to 5 minutes, 10- after observation injection apomorphine Behavior in 11,20-21,30-31 minutes is simultaneously scored, and standards of grading: four-footed is scored at 0 on floor；Two front foots are in cylinder mould On be scored at 1；Four foots are scored at 2 on cylinder mould.It the results are shown in Table 3.

Embodiment 27, catalepsy experimental method

Experimental animal

Healthy Kunming mouse, half male and half female, (22 ± 2) g are provided by Nanjing Qinglongshan animal-breeding center.

Main agents:

Test drug, haloperidol, Clozapine, Risperidone, Olanzapine, Aripiprazole, Ziprasidone

Instrument:

Stick equipment is grabbed in self-control: diameter 0.3cm is placed in mouse box, higher than the stainless steel bar of workbench 5cm.

Experimental method:

KM mouse, half male and half female, 20~24g of weight are randomly divided into each dosage of negative control group, model group, positive drug Group (Risperidone, Aripiprazole, Ziprasidone, kui gentle ziprasidone, Olanzapine, haloperidol, Clozapine) and each dosage group of compound, Every group 10.Coordinative solvent distilled water is given in negative control group and model group stomach-filling, and the corresponding positive is given in positive drug group stomach-filling Drug (dissolution Shi Xianjia micro-acetic acid, then plus distilled water), corresponding dosage compound, stomach-filling are given in each dosage group stomach-filling of compound Volume is 0.1ml/10g.When gastric infusion 30min, 60min, 90min, two fore paws of mouse are gently placed on long 20cm, directly Diameter 0.3cm on the spillikin higher than workbench 5.5cm, then animal hind leg is put down gently in cassette bottom face, records two fore paws of mouse in stick It is the upper duration for keeping posture, stiff motionless for positive reaction with 30s.It is whole when 60s if mouse fore paw is never put down Only observe.Each compound dosage group positive reaction number of animals is counted, the results are shown in Table 3.

Embodiment 28, studies on acute toxicity

The limit experiment of sequential method takes KM mouse, and half male and half female is randomly divided into several groups, every group 2-5, respectively eachization Object 2000mg/kg group and solvent group are closed, by 0.2ml/10g gastric infusion.Death condition in observation animal 3 days.If (animal There are 3 or 3 or more to survive in three days, when life state Non Apparent Abnormality, continue to observe, until testing after 7 days terminates.Such as Fruit animal at dead 3 or 3 or more, measured its LD50 using median lethal dose method in three days.)

Median lethal dose method trial test takes KM mouse, half male and half female, divides several groups at random, and every group 4, respectively each chemical combination Object 1500mg/kg, 1000mg/kg, 500mg/kg group and solvent group, by 0.2ml/10g gastric infusion, in observation animal 1-3 days Death condition.

As a result: the LD that mouse single gavages₅₀Greater than 2000mg/kg, there is lesser acute toxicity.

Animal model test result in 3. preferred compound body of table

Above-mentioned results of animal shows: compared with model group, Risperidone, compound 11 can be obviously improved MK-801 and lure The high activity led, and can effectively improve the climbing symptom of apomorphine induction, and do not cause EPS under effective dose, Show that it has apparent anti-schizophrenia effect.

C, composition embodiment

Embodiment 29, tablet

It is spare that supplementary material crosses 80 meshes, weighs recipe quantity active constituent, microcrystalline cellulose, lactose, PVP K30, is added It into mixed at high speed preparation machine, stirs at low speed uniformly mixed, appropriate purified water is added, stirs at low speed, high-speed cutting granulation, wet Recipe quantity carboxyrnethyl starch sodium, silica and magnesium stearate, total mix, rotary tablet compression is added in 60 DEG C of dry 3h of grain, 24 mesh sieves Machine tabletting.

Embodiment 30, capsule (230mg)

It is spare that supplementary material crosses 80 meshes, weighs recipe quantity active constituent, lactose, starch, PVP K30, is added to high speed It in mix preparation machine, stirs at low speed uniformly mixed, appropriate purified water is added, stirs at low speed, high-speed cutting granulation, 60 DEG C of wet granular Recipe quantity silica and magnesium stearate, total mix is added in dry 3h, 24 mesh sieves, and capsule filling machine fills capsule.

Claims (5)

1. the compound of logical formula (I) or its pharmaceutically acceptable salt:

Wherein:

X is-S (O₂)-；

N is 1 or 2；

R is Formula II, group shown in formula IV or Formula V,

R₂Independently selected from hydrogen, halogen, cyano, nitro, substituted or unsubstituted C_1-5Alkyl, R₄Or R₅For hydrogen, wherein the C_1-5 The substituent group of alkyl is fluorine；

Y is selected from O or S.

2. the compound or its pharmaceutically acceptable salt of logical formula (I) according to claim 1, it is characterised in that described General formula I compound represented or its pharmaceutically acceptable salt is selected from any one following compound or its is pharmaceutically acceptable Salt:

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

3. the compound of the logical formula (I) according to any one of claims 1 to 2 containing therapeutically effective amount or its can pharmaceutically connect The pharmaceutical composition of the salt and medically acceptable carrier received.

4. the compound or its pharmaceutically acceptable salt of logical formula (I) according to any one of claims 1 to 2 are treated in preparation Application in Nervous and mental diseases drug.

5. application according to claim 4, which is characterized in that the Nervous and mental diseases are schizophrenia.