CN107793350A - Fragrant ethyl piperidine radical derivative and its schizoid application for the treatment of - Google Patents

Fragrant ethyl piperidine radical derivative and its schizoid application for the treatment of Download PDF

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CN107793350A
CN107793350A CN201610801210.XA CN201610801210A CN107793350A CN 107793350 A CN107793350 A CN 107793350A CN 201610801210 A CN201610801210 A CN 201610801210A CN 107793350 A CN107793350 A CN 107793350A
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China
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bases
ethyl
piperazine
piperidin
compound
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CN107793350B (en
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李建其
陈晓文
李林
周爱南
张怡
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/98—Nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention discloses a kind of fragrant ethyl piperidine radical derivative and its application in antipsychotic.The Pharmacological experiment result shows that fragrant ethyl piperidine class compound of the present invention, to dopamine D2、D3、5‑HT1A、5‑HT2AAcceptor has higher affinity, to D3/D2Receptor-selective is good.Results from vivo experiments shows that preferred compound has good antipsychotic effect, and acute toxicity is relatively low, and security is higher, and medicine is good for characteristic, has the Development volue as the new anti-spiritual neurogenic disease new drug of high-efficiency low-toxicity.The fragrant ethyl piperidine class compound is with the compound or its salt or the hydrate of salt as shown in general structure (I)：

Description

Fragrant ethyl piperidine radical derivative and its schizoid application for the treatment of
Technical field
The present invention relates to the fragrant ethyl piperidine radical derivative with antipsychotic activity or its is pharmaceutically acceptable The hydrate of hydrate, salt or salt, the hydrate comprising the compound or its pharmaceutically acceptable hydrate, salt or salt Pharmaceutical composition, medicine box, and its schizoid application for the treatment of.
Background technology
Schizophrenia is a kind of chronic persistent disease, is most serious in mental disorder, endangers maximum one kind, shadow The normal life of about 1% population of the whole world is rung, China's number of patients is the 7th big disease of burden on society more than 10,000,000.Spirit Split disease illness is complicated, and often difference is presented with the course of disease in symptom.The symptoms of schizophrenia mainly includes positive symptom, such as vain hope, Illusion；Negative symptoms, such as Social Withdrawal, apathy；Cognition dysfunction, such as three big symptom of working memory deficit.
The schizophrenia cause of disease is complicated, not yet clear and definite so far.Academia is primarily present several hypothesis, including neurodevelopment The influence of hypothesis, the biochemical hypothesis of nerve and inherent cause hypothesis and social environmental factor.And the biochemical hypothesis of nerve is relatively mostly science Boundary receives and approved.It is a variety of that related basic research and anti-schizophrenia clinical drug data show that schizophrenia there may be The exception of neurotransmitter function, predominantly dopamine (DA) neuronal function is hyperfunction, serotonin (5-HT) energy systemic-function Missing etc..DA hypothesis think that midbrain-cortical pathway dopamine of schizophreniac is movable unbalance and causes schizophrenia Symptom.5-HT hypothesis think that the change of patient's prefrontal cortex 5-HT energy mechanism causes cerebral cortex can not be to dopamine under cortex Appropriate suppression is carried out, so as to cause dopaminergic hyperfunction.
At present, commercially available and clinical antischizophrinic is mainly atypical antipsychotics.Such medicine main function In DA systems and 5-HT systems.Act on dopamine D2Acceptor is the common mechanism of antipsychotic drug.D2Acceptor is distributed widely in greatly In brain, and participate in numerous physiological functions and pathological condition.D2Receptor antagonist is widely used as anti-antipsychotic drug.It is but a large amount of short of money Anti- D2The D of acceptor especially nigro-striatal path2Acceptor causes patient to produce extrapyramidal side effect (EPS) etc..And simultaneously 5-HT systems are acted on, such as antagonism 5-HT2AD is reduced by physical efficiency2The extra-inhibitory of acceptor, so as to reduce EPS, hyperprolactinemia Deng the generation of side reaction.Thus atypical antipsychotics are keeping the anti-positive symptom activity similar to classic antipsychotics Outside, negative symptoms, such as marketed drug Risperidone, Aripiprazole, Ziprasidone can further be treated.But as clinical application is real That tramples gos deep into, and improvement of the said medicine to negative symptoms is limited, it is impossible to meets clinical needs, and phase interaction occurs to multiple acceptors With, it is also easy to produce obesity, cathisophobias, has a sleepless night, the side effect such as anxiety.Meanwhile clinical test results are shown, existing antipsychotic drug Without the effect for significantly improving cognitive disorder.Thus find high-efficiency low-toxicity, the new anti-schizophrenia medicine for the treatment of spectrum width is made for the whole world The challenge of medicine enterprise facing, also it is the focus of such drug research.
Clinical and animal test results show, selective antagonism dopamine D3Acceptor can reduce extrapyramidal side effect Occur, and improve cognitive function of patients.But with D2Acceptor is compared, D3Receptor mrna is less in intracerebral distribution, thus requires that medicine is same When act on D2、D3, and should have certain D3Receptor-selective, i.e., to D3Affinity be better than to D210 times of receptor affinity or It is higher, to play the physiological effects such as cognition improvement.Clinical and preclinical test result shows, too high D3Receptor-selective, such as Compound is to D3Receptor affinity is better than D2More than hundred times of acceptor, or D3/D2When receptor-selective is more than 100 times or higher, chemical combination Thing can not show antipsychotic activity, the especially positive symptom of antipsychotic.In recent years, 5-HT1AAcceptor pair The approval of academia is increasingly obtained in the side effect for reducing schizophrenia drug, the improvement result for improving cognitive function.Have Research shows, 5-HT1AExcitement (or partial agonist) effect can effectively reduce because of D2EPS etc. is secondary caused by excessively blocking makees With, and play the role of to improve schizophreniac's cognitive disorder.Therefore, selectively acting is in D2、D3、5-HT1AAnd 5-HT2A The anti-schizophrenia Drug development and research of new Mutiple Targets of acceptor has broad prospects, and belongs to the new anti-of the mechanism of action Schizophrenia drug Cariliprazine (Cariprazine) lists in September, 2015 in the U.S..
The present inventors have noted that Chinese patent CN1829703A, CN102159557A, CN103130737A, Series compound disclosed in CN104140421A has the activity for treating spiritual neural class disease.In these compound structures Fragment containing fragrant ethylcyclohexyl, but the slight change in structure, such as substituent different on aryl that piperazine connects, amino and Change in middle connects chain, i.e., largely cause chemical combination physical characteristics, medicine for parameter, extracorporeal receptor function Characteristics, The difference of internal pharmacological activity and related side effects.It is described in detail below.
1st, patent CN1829703A, it discloses following structure, as D2And D3Receptor dual conditioning agent：
Wherein
R1And R2Independently represent selected from hydrogen, alkyl, alkenyl, aryl, cycloalkyl, the substituent of aroyl, or R1With R2Heterocycle can be formed with adjacent nitrogen atom；
X represents oxygen or sulphur atom；
N is 1 to 2 integer,
And/or its geometric isomer and/or stereoisomer and/or diastereoisomer and/or salt and/or hydrate And/or solvate.
2nd, patent CN102159557A, it discloses following structure, it is alternatively that property 5-HT2AAnd D3Receptor modulators：
Wherein：
X is halogen or C independently of one another1-6- alkyl；
N is 0,1 or 2；
R1It is-COR2Or-SO2-C1-6- alkyl；
R2It is C1-6- alkyl, C1-6- haloalkyl, C1-6- hydroxy alkyl, C1-6- alkoxy, 3 to 10 yuan of cycloalkyl, 4 to 10 Circle heterocycles alkyl or 5 to 10 unit's heteroaryls, they are optionally substituted by one or more selected from following substituent：
Halogen,
Hydroxyl,
C1-6- alkyl,
C1-6- haloalkyl,
C1-6- hydroxy alkyl,
C1-6- alkoxy,
Optionally by one or more RaSubstituted C1-6- alkoxy,
-S-C1-6- alkyl,
-SO2-C1-6- alkyl,
-CONH2,
CHO
Optionally by one or more Ra3 to 10 yuan of cycloalkyl of substitution,
Optionally by one or more RaSubstitution 4 to 10 circle heterocycles alkyl and
Optionally by one or more Ra5 to 10 unit's heteroaryls of substitution；
Wherein RaIt is selected from：
Halogen
Hydroxyl,
C1-6- alkyl,
C1-6- hydroxy alkyl,
C1-6- haloalkyl and
C1-6- alkoxy.
3rd, patent CN103130737A.It discloses following structure, as D2、D3、5-HT1AReceptor modulators：
Wherein：
R is
R1, R2, R3Hydrogen, trifluoromethyl, C are represented respectively1~C4Alkyl and substitution alkyl, C3~C6Cycloalkyl and substitution Cycloalkyl, C5~C7Heterocyclylalkyl and substituted heterocycle alkyl, phenyl and substituted-phenyl, pyridine radicals and substituted pyridinyl or halogen；
R4And R5Independently represent hydrogen, C1~C4Alkyl and substitution alkyl, C3~C6Cycloalkyl and substituted cycloalkyl, C5 ~C7Heterocyclylalkyl and substituted heterocycle alkyl, R4And R5The pyrrolidine ring, unsubstituted or substituted formed with adjacent nitrogen atom Piperazine, morpholine or unsubstituted or substituted piperidines；
R6And R7Independently represent hydrogen, C1~C4Alkyl and substitution alkyl, C3~C6Cycloalkyl and substituted cycloalkyl, C5 ~C7Heterocyclylalkyl and substituted heterocycle alkyl, R4And R5The pyrrolidine ring, unsubstituted or substituted formed with adjacent nitrogen atom Piperazine, morpholine or unsubstituted or substituted piperidines；
R8And R9Independently represent hydrogen, C1~C4Alkyl and substitution alkyl, C3~C6Cycloalkyl and substituted cycloalkyl, C5 ~C7Heterocyclylalkyl and substituted heterocycle alkyl, R4And R5The pyrrolidine ring, unsubstituted or substituted formed with adjacent nitrogen atom Piperazine, morpholine or unsubstituted or substituted piperidines.
4th, patent CN104140421A, it discloses following structure, as D2、D3、5-HT1A、5-HT2AReceptor modulators：
Wherein：
W is：
R1、R2Heteroaryl or substituted heteroaryl are represented respectively；
N is 0,1,2 or 3；M is 0,1 or 2；
R3Represent C1~C4Alkyl, substitution C1~C4Alkyl, C3~C6Cycloalkyl, substitution C3~C6Cycloalkanes Base, phenyl, substituted-phenyl, benzyl, substituted benzyl, heteroaryl, the heteroaryl of substitution, heteroarylmethyl or substitution heteroarylmethyl；
R4For hydrogen atom or C1~C4Alkyl；
R5For aryl or substituted aryl.
Representation compound activity difference enumerates as follows in above-mentioned patent：
To sum up, prompt for the structure containing fragrant ethylcyclohexyl fragment, aryl, different on Cyclohexylamino is connected on piperazine The change of acyl substituent, it is entirely different with extracorporeal receptor effect, or activity difference is larger.
In addition, representation compound also has a poor solubility in above-mentioned patent, vivo biodistribution availability is not ideal enough and brain target The druggability defect such as tropism difference.
In existing antipsychotic drug, be also easy to produce metabolic side effect (such as obesity) and arrhythmia cordis, constipation, Drowsiness, extrapyramidal system (EPS) side effect (such as catalepsy) and its serious side effect, make patient's poor compliance, and to spirit Schizophrenic patients cognitive disorder is not improved effect.Therefore, it is necessary to study the compound of different structure, or structure has difference Degree difference but the good noval chemical compound of physicochemical property, to overcome the drawbacks described above of existing compound.
Document (Journal of Medicinal Chemistry, 2013,56,9199-9221) is reported for dopamine D2、D3Deng g protein coupled receptor, compound centre connects chain, including its length, flexibility, configuration etc., compound and acceptor are influenceed The size of adhesion, the pharmacological activity of compound, such as excitement, partial agonist effect.In view of central nervous system target spot is special Property and selectivity, the change to receptor acting, can make pharmacological activity and related side effects inside compound display difference compared with Big difference, its influence to receptor acting and In vitro and in vivo activity, need to carry out experiment is further confirmed.
The present invention devises a kind of fragrant ethyl piperidine derivative, contains Isosorbide-5-Nitrae-disubstituted piperidine base in structure, it is than existing There is the substituted cyclohexyl of Isosorbide-5-Nitrae-two of technology, it is larger without cis/trans isomers, its flexible and steric configuration and cyclohexyl difference；Secondly, There are lone pair electrons in " N " atom of Isosorbide-5-Nitrae-disubstituted piperidine base, electron density has larger difference with cyclohexyl.Thus tool 1, The compound of 4- disubstituted piperidine base connects chains, than the compound of the substituted cyclohexyl connects chain containing Isosorbide-5-Nitrae-two, with acceptor In terms of binding pattern, the size of adhesion, water solubility and pharmacological activity and security, it is understood that there may be notable difference, but need logical Experiment is crossed to confirm.
Invention summary
For it is above-mentioned in the prior art the shortcomings that, it is existing to overcome the invention discloses a kind of fragrant ethyl piperidine radical derivative There are medicine such as obesity, the side effect of blood glucose rise metabolic, arrhythmia cordis, EPS (such as catalepsy) side effects and to negative disease The defects of shape, cognitive disorder weak curative effect, to meet the needs of clinical application.
Invention additionally discloses treat schizoid method using above-claimed cpd.Invention additionally discloses above-claimed cpd As the application in preparing tool wide spectrum antipsychotic and treating schizophrenia drug.
According to the one side of the application, this application provides fragrant ethyl piperidine radical derivative, for such as general structure (I) hydrate of compound or its pharmaceutically acceptable hydrate, salt or salt shown in：
Wherein：
R is
R3Selected from C1~C3Alkyl, C1~C2Alkoxy, C3~C6Cycloalkyl, phenyl, substituted-phenyl or heteroaryl；
R4、R5Separately represent hydrogen, C1~C3Alkyl, C3~C6Cycloalkyl, phenyl, benzyl or pyridine radicals；
Or R4、R5Morpholine ring is formed with the N atoms being connected；
N is 0~1 integer；
R1、R2Separately represent chlorine, methyl, methoxyl group, phenyl；
Or R1、R2It is collectively forming phenyl ring, azolactones ring or thiphene ring.
According to some embodiments of the present invention, the substituted-phenyl is selected from halogen, cyano group, methoxyl group or C1~C2Alkane The substituted-phenyl of base substitution.
According to some embodiments of the present invention, the heteroaryl is selected from furyl, pyrrole radicals, thienyl, pyridine radicals, 2- Benzothienyl, 2- benzofuranyls or 2- indyls.
According to some embodiments of the present invention, the salt is the salt containing pharmaceutically acceptable anion.
According to some embodiments of the present invention, the preferred hydrochloride of salt, the hydrogen bromine of the pharmaceutically acceptable anion It is hydrochlorate, sulfate, acetate, trifluoroacetate, citrate, tartrate, maleate, fumarate, mesylate, right Toluene fulfonate or oxalates.
According to some embodiments of the present invention, the hydrate of the salt of the compound contains the crystallization of 0.5~3 molecule Water.
According to some embodiments of the present invention, the salt in the hydrate of the salt of the compound is preferably oxalates, first Sulfonate, hydrobromic acid hydrochlorate or trifluoroacetate.
According to some embodiments of the present invention, fragrant ethyl piperidine radical derivative of the invention may include, but be not limited to down Preferable compound described in face：
I-1 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) acetamide,
I-2 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) butyramide,
I-3 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -2- methoxyl group acetyl Amine,
I-4 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -2- Ethoxyacetyls Amine,
I-5 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) cyclopropyl carboxamide,
I-6 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) cyclohexyl formamide,
I-7 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) benzamide,
I-8 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -4- fluorobenzamides,
I-9 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -4- Cyanophenacyls Amine,
I-10 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -4- toluyls Amine,
I-11 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) niacinamide,
I-12 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) formamide of furans -2,
I-13 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) formamide of pyrroles -2,
I-14 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) formamide of thiophene -2,
I-15 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) formamide of indoles -2,
II-1 1- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -3- MUs,
II-2 3- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -1,1- dimethyl ureas,
II-3 1- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -3- propyl group urea,
II-4 1- cyclopropyl -3- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) urea,
II-5 1- cyclohexyl -3- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) urea,
II-6 1- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -3- phenylureas,
II-7 1- benzyls -3- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) urea,
II-8 1- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -3- (pyridin-3-yl) Urea,
II-9 N- (4- (2- (4- (2,3- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) morpholine -4- first Acid amides,
III-1 N- (4- (2- (4- (2,3- 3,5-dimethylphenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -4- methoxybenzenes Formamide,
III-2 N- (4- (2- (4- (2,3- 3,5-dimethylphenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -4- ethylamino benzonitriles Acid amides,
III-3 1- ethyls -3- (4- (2- (4- (2- methoxyphenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -1- first Base urea,
III-4 3- (4- (2- (4- (2- methoxyphenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -1- methyl isophthalic acids-benzene Base urea,
III-5 N- (4- (2- (4- ([1,1'- diphenyl] -3- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -2- methoxies Yl acetamide,
III-6 3- (4- (2- (4- ([1,1'- diphenyl] -3- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -1,1- two MU,
III-7 N- (4- (2- (4- (naphthalene -1- bases) piperazine -1- bases) ethyl) piperidin-1-yl) furans -2- formamides,
III-8 1,1- dimethyl -3- (4- (2- (4- (naphthalene -1- bases) piperazine -1- bases) ethyl) piperidin-1-yl) urea,
III-9 N- (4- (2- (4- (2 (3H) H- benzoxazolone -7- bases) piperazine -1- bases) ethyl) piperidin-1-yl) furan Mutter -2- formamides,
III-10 1,1- dimethyl -3- (4- (2- (4- (2 (3H) H- benzoxazolone -7- bases) piperazine -1- bases) ethyl) Piperidin-1-yl) urea,
IV-1 N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) pentanamide,
IV-2 N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -2- methoxyl groups Acetamide,
IV-3 N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) benzamide,
IV-4 N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) cyclopropyl formyl Amine,
IV-5 N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) niacinamide,
IV-6 N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) furans -2- first Acid amides,
IV-7 3- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -1,1- diformazans Base urea,
IV-8 1- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -3- phenylureas,
IV-9 1- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -3- (pyridine - 3- yls) urea,
IV-10 3- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -1- methyl - 1- phenylureas,
IV-11 1- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -3- cyclopropyl Urea,
IV-12 N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) morpholine -4- first Acid amides.
The structure of above-mentioned preferred compound is as shown in the table：
According to an aspect of the present invention, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition includes controlling Treat the fragrant ethyl piperidine radical derivative of effective dose or the hydrate of its pharmaceutically acceptable hydrate, salt or salt, and medicine Acceptable carrier on.
According to an aspect of the present invention, the invention provides a kind of medicine box, the medicine box to include described fragrant ethyl piperazine The hydrate of piperidinyl derivative or its pharmaceutically acceptable hydrate, salt or salt.
According to an aspect of the present invention, the invention provides one kind to treat schizoid method, and methods described is given Give the hydrate of fragrant ethyl piperidine radical derivative or its pharmaceutically acceptable hydrate, salt or salt described in patient.
According to an aspect of the present invention, the invention provides the fragrant ethyl piperidine radical derivative or its can pharmaceutically connect The hydrate of hydrate, salt or the salt received is preparing the application in treating schizophrenia drug.
Detailed description of the invention
Definition
Unless otherwise defined, all technical terms used herein or proprietary vocabulary have the common of technical field The implication that technical staff is generally understood.
Term " halogen " or " halogen atom " refer to fluorine (F) atom, chlorine (Cl) atom, bromine (Br) atom or iodine (I) atom.Art When language " halo " is for before chemical group, refers to the substituent and substituted with one or more halogenic substituents.Term " alkyl halide Base " refers in abovementioned alkyl group that the hydrogen atom in one or more optional positions is identical or different by one or more Halogen atom substitutes.
Term " cycloalkyl " refers to that the cycloalkyl can be saturation or part by the monocyclic or polycyclic of carbon atom cyclization Full.In some embodiments of the application, the cycloalkyl includes first (such as 3,4, the 5 or 6 yuan) cycloalkyl of 3-6, such as 3 Unit monocycle or 5 membered monocyclic ring.The example of cycloalkyl includes cyclobutyl, cyclopenta etc..
Term " aryl " refers to the homocyclic aromatic ring for including monocyclic or polycyclic (such as 2,3 or 4 fused rings).In this Shen In some embodiments please, the example of aryl includes but is not limited to phenyl, naphthyl, anthryl, phenanthryl and indenyl etc..In the application Some embodiments in, the aryl includes first (such as 5,6,7, the 8 or 9 yuan) aryl of 5-9.
Term " heteroaryl " refer to one or more of above-mentioned aryl formed the carbon atom of ring by hetero atom such as S, O or N atoms are substituted." heteroaryl " can be monocyclic or polycyclic heteroaryl.The example of " heteroaryl " includes but unlimited In furyl, pyridine radicals, pyrimidine radicals, imidazole radicals, indyl, pyrrole radicals, benzofuranyl, benzothienyl, benzothiazolyl, Isoxazolyl, pyrazolyl, purine radicals, benzimidazolyl etc..In some embodiments of the application, the Heterocyclylalkyl has 4- 8 (such as 4,5,6,7 or 8) carbon atoms.
Term " fragrant ethyl " refers toWherein R1, R2 are defined as described above.
In some embodiments of the application, above-mentioned cycloalkyl, aryl, Heterocyclylalkyl or heteroaryl can be substituted Or it is unsubstituted.In some embodiments of the application, substituent can be one or more, and the substituent is independently Selected from halogen, cyano group, alkoxy, alkyl etc..
Compound described herein includes the anhydride form and hydrate forms of the compound.Can in the hydrate With comprising such as 0.5-3 hydrone, such as 0.5,1,1.5,2,2.5 or 3 hydrone can be included.
According to some embodiments of the application, the hydrate of the salt of the compound contains the crystallization water of 0.5~3 molecule, Such as containing 0.5 molecule, 1 molecule, 2 molecules, 3 molecules the crystallization water.According to some embodiments of the application, the compound Salt be oxalates, mesylate, hydrobromic acid hydrochlorate or trifluoroacetate.
Term " pharmaceutical composition " represents one or more compounds containing therapeutically effective amount and its pharmaceutically may be used The hydrate or salt of receiving, the mixture with other pharmaceutically acceptable carriers.The compound is prepared into drug regimen The purpose of thing is to be more easily administered to object.
The compound of the present invention can use method well known in the art, and common pharmaceutical formulation is made.Such as can be piece Agent, capsule, parenteral solution etc..
According to some embodiments of the present invention, in the preparation, the content of active component is 0.1%~100% (weight Than).
Herein described compound or pharmaceutical composition can be administered alone, and suitable medication combined can also be given with other Medicine.
Term " pharmaceutically acceptable carrier " is pharmaceutically acceptable composition or medium, including but not limited to molten Agent, excipient, diluent, adjuvant, filler etc..
Term " pharmaceutically acceptable salt " refers to the acid-addition salts that the compound is formed.The acid for forming acid-addition salts can be with Inorganic acid or organic acid, the inorganic acid is included such as hydrochloric acid, hydrobromic acid, sulfuric acid, the organic acid include such as acetic acid, Oxalic acid, methanesulfonic acid, citric acid etc..
According to some embodiments of the present invention, the salt of the compound is to contain pharmaceutically acceptable anion Salt.
According to some embodiments of the present invention, the preferred hydrochloride of salt, the hydrogen bromine of the pharmaceutically acceptable anion It is hydrochlorate, sulfate, acetate, trifluoroacetate, citrate, tartrate, maleate, fumarate, mesylate, right Toluene fulfonate or oxalates.
Term " 503nhibiting concentration (IC50) ", or " semi-inhibit rate ", refer to inhibitor in suppression target substance process, When the activity inhibited of target substance is to half, the concentration of inhibitor.Generally, the rejection ability of inhibitor is stronger, IC50More It is low.According to some embodiments of the application, the IC of herein described compound50It is to work as D2、D3、5-HT1A、5-HT2AAcceptor quilt When suppressing 50%, the concentration of the compound.
In this application when " about " is used to modify numerical value, refer to the numerical value can fluctuate ± 5%, ± 9%, ± 8%th, in the range of ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2% or ± 1%.
The logical method of synthesis
The compound of the present invention can use the logical method of the following two kinds synthesis to be synthesized.
Logical method one：
Methods described include by raw material 1 and phosphonoacetate under the conditions of potassium tert-butoxide in tetrahydrofuran solution In, reaction prepares intermediate 2.2 after palladium carbon hydro-reduction, ethyl ester reduction, Mesylation, with aryl piperazines fragment in alkaline bar Important intermediate 6 is condensed to yield under part.6 under the conditions of trifluoracetic acid, dichloromethane deprotection base, and in natrium nitrosum, vinegar Prepare compound 8 under the conditions of acid.8 through zinc powder reduction, and is reacted from different acylating reagent, obtain compound I-1 of the invention~ I-15, III-1~III-2, III-5, III-7, III-9, IV-1~IV-6.It is described in detail below：
By potassium tert-butoxide (360mmol)) it is added in THF (300mL), phosphinylidyne guanidine-acetic acid three is added dropwise under the conditions of 5~10 DEG C THF (60mL) solution of ethyl ester (300mmol), finish and stir 2h, the THF of raw material 1 (270mmol) is added dropwise under the conditions of 5~10 DEG C (100mL) solution, is finished, react at room temperature 2h, stop reaction, be added dropwise water (50mL) quenching reaction, with ethyl acetate (100mL × 3) extractive reaction liquid, combined ethyl acetate layer, washed successively with water (50mL × 2), saturated aqueous common salt (50mL × 2), anhydrous slufuric acid Sodium is dried, and filtering, is concentrated to give 70g white solids (intermediate 2), yield 96%.
Intermediate 2 (250mmol), 5%Pd/C, THF (500mL) are added in 1L hydriding reactors, outer 60 DEG C of temperature, 2.0MPa 10h is reacted under pressure, stops reaction, is filtered, obtains the THF solution of intermediate 3.Add lithium borohydride (500mmol), back flow reaction 20h, stop reaction, be cooled to 5~10 DEG C, sequentially add the 30%HCl aqueous solution (100mL), the 20%HCl aqueous solution (100mL), 1h is stirred, to be extracted with ethyl acetate (100mL × 3), combined ethyl acetate layer, successively with water (50mL × 2), saturated aqueous common salt (50mL × 2) are washed, anhydrous sodium sulfate drying, filtering, are concentrated to give 53g white solids (intermediate 4), two step yields amount to 92%.
Intermediate 4 (240mmol), dichloromethane (200mL), triethylamine (480mmol) are added to 500mL there-necked flasks In, 0~5 DEG C be added dropwise mesyl chloride (260mmol) dichloromethane (50mL) solution, react at room temperature 2h, stop reaction, successively with Aqueous sodium carbonate (20mL × 2), saturated aqueous common salt (50mL × 2) are washed, anhydrous sodium sulfate drying, filtering, it is light to be concentrated to give 61.5g Yellow solid (intermediate 5), yield 83%.
By intermediate 5 (180mmol), potassium carbonate (540mmol), KI (1mmol), acetonitrile (1000mL), aryl piperazine Piperazine (162mmol) is added in 2000mL single port bottles, back flow reaction 24h, is cooled to room temperature, stirs 1h, filtering, filter cake is with acetonitrile (50mL × 2) are washed, and the dry 5h of (60 DEG C) of air dry oven, obtain white solid intermediate 6, yield 70~81%.
Intermediate 6 (100mmol), trifluoracetic acid (300mmol), dichloromethane (500mL) are added to 1000mL single port In bottle, 12h is reacted at room temperature, reaction solution is adjusted to pH~10 with 20% sodium hydroxide, and liquid separation, dichloromethane layer is successively with water (100mL × 2), saturated aqueous common salt (60mL × 2) is washed, anhydrous sodium sulfate drying, filtering, is concentrated to give off-white color semisolid (intermediate 7), is received Rate 90~95%.
Intermediate 7 (80mmol), acetic acid (100mL), natrium nitrosum (160mL), water (50mL) are added to 500mL single port In bottle, 5h is reacted at room temperature, reaction solution concentration, water (200mL) is added, is extracted with dichloromethane (100mL × 2), organic layer concentration, Obtain off-white powder (intermediate 8), yield 86~90%.
By intermediate 8 (50mmol), acetic acid (100mL), zinc powder (150mmol (10mL) is added in 250mL single port bottles, 8h is reacted at room temperature, filtering, filtrate concentration, water (200mL) is added, is extracted with dichloromethane (100mL × 2), organic layer concentration, is obtained White solid (intermediate 9), yield 70~80%.
Intermediate 9 (30mmol), dichloromethane (100mL), triethylamine (45mmol) are added in 250mL there-necked flasks, 0 ~5 DEG C are added dropwise different acylating reagents (33mmol), 3h are reacted at room temperature, successively with water (100mL × 2), saturated aqueous common salt (60mL × 2) wash, anhydrous sodium sulfate drying, filter, be concentrated to give white solid, through 95% ethanol solution crystallizing, obtain white solid, be Compound I-1~I-15, III-1~III-2, III-5, III-7, III-9, IV-1~IV-6 of the present invention, yield 82~ 95%.
By compound I-1~I-15, III-1~III-2, III-5, III-7, III-9, IV-1~IV-6 be placed in 5% acid/ Flow back dissolving in ethanol, cooling precipitation compounds I-1~I-15, III-1~III-2, III-5, III-7, III-9, IV-1~ IV-6 salt, described acid are hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, trifluoracetic acid, citric acid, tartaric acid, maleic acid, rich horse Acid, methanesulfonic acid, p-methyl benzenesulfonic acid or oxalic acid.
R in above-mentioned logical method one1、R2、R3Definition it is consistent with the definition in aforesaid compound, i.e.
R3Selected from C1~C3Alkyl, C1~C2Alkoxy, C3~C6Cycloalkyl, phenyl, substituted-phenyl or heteroaryl；
N is 0~1 integer；
R1、R2Separately represent chlorine, methyl, methoxyl group, phenyl；
Or R1、R2It is collectively forming phenyl ring, azolactones ring or thiphene ring.
Logical method two：
Compound 9 (being prepared by leading to method one), the amine of substitution, triethylamine are added in the solvent dissolved with triphosgene, reacted Obtain compound II-1~II-9 of the invention, III-3~III-4, III-6, III-8, III-10, IV-7~IV-12.Specifically retouch State as follows：
Triphosgene (10mmol) is dissolved in dichloromethane (50mL), under the conditions of~0 DEG C be added dropwise compound 9 (0.9mmol), Dichloromethane (50mL) solution of triethylamine (10mmol), insulated and stirred 3h, under the conditions of -5~0 DEG C, reaction solution is added drop-wise to and taken For in amine (50mmol) isopropanol (100mL) solution, insulation reaction 5h, stop reaction, add saturated ammonium chloride solution (50mL), distribution, organic phase are washed with water (50mL × 2), saturated aqueous common salt (50mL × 2) successively, anhydrous sodium sulfate drying.Cross Filter, takes filtrate, is concentrated under reduced pressure, and obtains off-white color or white solid, and recrystallization or Flash post separations obtain compound II-1 of the invention ~II-9, III-3~III-4, III-6, III-8, III-10, IV-7~IV-12, yield 73~90%.Compound II-1~ II-9, III-3~III-4, III-6, III-8, III-10, IV-7~IV-12 salt production process and acid used, gained salt form With logical method one.
R in above-mentioned logical method two1、R2、R4、R5Definition it is consistent with the definition in aforesaid compound, i.e.
R1、R2Separately represent chlorine, methyl, methoxyl group, phenyl；
Or R1、R2It is collectively forming phenyl ring, azolactones ring or thiphene ring；
R4、R5Separately represent hydrogen, C1~C3Alkyl, C3~C6Cycloalkyl, phenyl, benzyl or pyridine radicals；
Or R4、R5Morpholine ring is formed with the N atoms being connected.
In addition, the present invention synthesizes its representation compound 1 with reference to the patent CN1829703A methods reported, and with reference to patent (CN1829703A is reported the compound Cariliprazine of the method synthesis document report of WO2010070370 and WO2011073705 reports The hydrochloride of the compound 1 in road), synthesize its representation compound 84 with reference to the patent CN102159557A methods reported；With reference to specially The method of sharp CN102159557A reports synthesizes its representation compound 84, with reference to the method synthesis of patent CN103130737A reports Its representation compound IV-2, its representation compound I-1 is synthesized with reference to the patent CN104140421A methods reported.Above-mentioned synthesis Patent representation compound, inside and outside pharmacological screening and the control sample of physicochemical property research are carried out for the compounds of this invention.
Pharmaceutical composition and medicine box
According to an aspect of the present invention, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition includes controlling Treat the fragrant ethyl piperidine radical derivative of effective dose or the hydrate of its pharmaceutically acceptable hydrate, salt or salt, and medicine Acceptable carrier on.
According to an aspect of the present invention, the invention provides a kind of method for preparing described pharmaceutical composition, its feature It is, methods described is by the fragrant ethyl piperidine radical derivative or the hydrate of its pharmaceutically acceptable hydrate, salt or salt Mixed with pharmaceutically acceptable carrier to prepare.
According to an aspect of the present invention, the invention provides a kind of medicine box, the medicine box to include described fragrant ethyl piperazine The hydrate of piperidinyl derivative or its pharmaceutically acceptable hydrate, salt or salt.
Pharmacological research
Act on dopamine D2Acceptor is the classical and common mechanism of atypical antipsychotics.Antagonism D2Acceptor can be notable Treat the positive symptom of schizophreniac.Meanwhile antagonism serotonin 5-HT2AD is reduced by physical efficiency2The excessive suppression of acceptor System, so as to reduce the generation of the side reactions such as EPS, hyperprolactinemia.Selective antagonism dopamine D3Acceptor can reduce cone The generation of outer system's side effect, and significantly improve the cognitive defect of schizophreniac.But with D2Acceptor is compared, D3Receptor mrna It is less in intracerebral distribution, thus require that medicine should have certain D3Receptor-selective, i.e., to D3Affinity be better than to D2Acceptor 10 times or higher of affinity, to play the physiological effects such as cognition improvement.However, too high D3Receptor-selective, if compound is to D3 Receptor affinity is better than D2More than hundred times of acceptor, or D3/D2When receptor-selective is more than 100 times or higher, compound can not show Go out antipsychotic activity, the especially positive symptom of antipsychotic.5-HT1AAcceptor is for reducing schizophrenia medicine The side effect of thing, the improvement result of raising cognitive function increasingly obtain the approval of academia.Therefore, selectively acting is in D2、 D3、5-HT1AAnd 5-HT2AThe anti-schizophrenia Drug development and research of new Mutiple Targets of acceptor has broad prospects.
External pharmacological experiments show：
1st, fragrant ethyl piperidine radical derivative (I) of the present invention has strong affinity to schizoid drug effect target spot, Such as dopamine D2、D3Acceptor, serotonin 5-HT1A、5-HT2AAcceptor, wherein most compound is to 5-HT2AReceptor affinity is excellent Representation compound 1 in patent CN1829703A；Majority of compounds is to D2Receptor affinity is significantly better than patent Compound in CN102159557A (representation compound 84) and CN103130737A (representation compound IV-2).
2nd, the compounds of this invention has suitable dopamine D3/D2Receptor-selective, majority of compounds D3/D2Acceptor selects Selecting property is in the range of 5~60 times, than patent CN1829703A (D3/D25~200 times of receptor-selective), CN102159557A (majority of compounds D3/D2Receptor-selective is more than 100 times) and CN103130737A (majority of compounds D3/D2Acceptor selection Property be more than 100 times) further illustrate the good effect for improving cognitive disorder of such compound tool and be not likely to produce extrapyramidal system (EPS) side effect such as.
3rd, further receptor functional assays result shows that part of compounds shows certain D2Acceptor portion excitement, 5- HT1AReceptor agonism (part) agonism, meet the anti-schizophrenia vitro Drug pharmacological model feature of listing.
Animal In vivo model test result indicates that：
The compound of the present invention can significantly improve the related symptoms of mouse apomorphine model and MK-801 models, partization Compound activity is better than marketed drug Cariliprazine (see embodiment 54).And above-mentioned action target spot and animal model and dopaminergic system The nervous system disease especially schizophrenia caused by system etc. is disorderly is closely related, therefore compound of the present invention is to spirit Split disease has therapeutic action.
Compound ira vitro physical and chemical experiment shows：
The compound water soluble of the present invention is significantly better than patent CN1829703A, CN102159557A, CN103130737A With the representation compound (see embodiment 55) in CN104140421A, therefore compound of the present invention is more conducive to preparation and prescription Preparation and research.
Pharmacokinetic studies show in compound body：
Very high (the brain AUC/ plasma As UC of the saturating brain rate of the compounds of this invention>8), oral absolute bioavailability well (is more than 30%), brain transmitance and oral administration biaavailability are superior to patent CN1829703A, CN102159557A, CN103130737A With the representation compound (see embodiment 56) in CN104140421A, this is related to the good physicochemical property of compound, thus this The good potential druggability of invention compound tool.
In summary, compared with prior art, the compounds of this invention has following advantage and feature：
1st, compound of the invention is not only to D2Acceptor has partial agonist, 5-HT1AAcceptor tool exciting (part) excitement is made With than prior art, to D3/D2The selectivity of acceptor is more suitable, and receptor acting mechanism features are notable.
2nd, compound of the invention shows good anti-schizophrenia effect to many animals In vivo model, and tool wide spectrum resists Schizophrenia acts on, and preferred compound is better than positive drug or marketed drug.
3rd, toxicity of compound of the invention is small, and side effect is low.
4th, compound brain targeting of the invention is stronger, and oral administration biaavailability is higher, and medicine meets maincenter class medicine for parameter Thing feature, has good druggability.
5th, compound of the invention is than prior art, and water solubility is more preferable, more conducively preparation and formulation study.
Therefore, the compounds of this invention has good action feature for schizoid drug effect target spot, anti-essence in animal body Clearly, water-soluble more excellent, medicine is good for characteristic, available for schizoid treatment for refreshing Split disease activity.
The present invention relates to the fragrant ethyl piperidine radical derivative to have improvement and therapeutic action to schizophrenia, can For schizoid treatment.The schizophrenia refers to serious mental handicape, the understanding of patient, emotion, will, dynamic Make the psychological activities such as behavior and may occur in which lasting obvious exception；It can not normally learn, work, live；Action row is difficult To be understood by common people；Under the domination of morbid psychology, there are suicide or attack, injure other people action behavior.
According to an aspect of the present invention, the invention provides one kind to treat schizoid method, and methods described is given Give the hydrate of fragrant ethyl piperidine radical derivative or its pharmaceutically acceptable hydrate, salt or salt described in patient.
According to an aspect of the present invention, the invention provides the fragrant ethyl piperidine radical derivative or its can pharmaceutically connect The hydrate of hydrate, salt or the salt received is preparing the application in treating schizophrenia drug.
To sum up, than the fragrant cyclohexyl based structures of prior art, the compounds of this invention is fragrant ethyl piperidine based structures, piperazine Essential distinction, therefore this hair be present in physicochemical property, such as water solubility, flexibility, configuration, electron density etc. with cyclohexyl in piperidinyl Bright compound not only embodies novelty in chemical constitution, and in physicochemical property, medicine for characteristic, inside and outside pharmacological activity, safety Property etc. more advantage, embody creative and essence scientific progress.
All patents, patent application and the bibliography quoted in the application are incorporated by this Shen by reference Please, its incorporated extent is individually recited as reference just as each document.If the application and provided herein is document between In the presence of conflict, should be defined by the content in the application.
Embodiment
Below in conjunction with the instantiation content that the present invention is furture elucidated, but protection scope of the present invention is not limited to this A little examples.
Embodiment 1：N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) acetamide (chemical combination Thing I-1) and its salt preparation
By 4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidines -1- amine (9) (being prepared according to logical method one) (1.0g, 2.8mmol), triethylamine (4.2mmol) are added in dichloromethane (10mL), dropwise addition chloroacetic chloride (0.24g, Dichloromethane (5mL) solution 3.1mmol), 3h is reacted, is washed successively with water (20mL × 2), saturated aqueous common salt (10mL × 2), nothing Aqueous sodium persulfate is dried, and filtering, is concentrated to give white solid, through 95% ethanol solution crystallizing, is obtained white solid 1.1g, yield 95%.
1HNMR(CDCl3,δ:ppm):1.19-1.36(m,2H,A-H),1.44-1.53(m,4H,A-H),1.71-1.74 (m, 1H, A-H), 2.15 (s, 3H, A-H), 2.29-2.35 (m, 2H, A-H), 2.40 (t, 2H, J=8.0Hz, N-CH2),2.61 (brs,4H,A-H),3.03(brs,4H,A-H),3.10-3.12(m,2H,A-H),6.92-6.95(m,1H,Ar-H),7.08- 7.13(m,2H,Ar-H).
ESI-MS:399[M+H+].
The preparation of compound I-1 hydrochlorides
Compound I-1 (0.3g, 0.8mmol), 5% aqueous hydrochloric acid solution (0.8mmol) are added in ethanol (10mL), returned Stream dissolving, cooling separate out white solid, filtering, obtain 0.3g white solids, yield 88%.
Elementary analysis：C19H28Cl2N4OHCl (theoretical value %：C 52.36, H 6.71, N 12.86；Experiment value %：C 52.32, H 6.79, N 12.88).
Within ± 0.3%, illustrate to obtain in this experiment is prepared salt or salt for theoretical value and experiment value difference Hydrate.Theoretical value and the implication of experiment value are identical with this in testing below.
The preparation of compound I-1 methanesulfonate hemihydrates
Compound I-1 (0.3g, 0.8mmol), aqueous methane sulfonic acid (0.8mmol) are added in ethanol (10mL), returned Stream dissolving, cooling separate out white solid, filtering, obtain 0.28g white solids, yield 69%.
Elementary analysis：C19H28Cl2N4O·CH4O3S·1/2H2O (theoretical value %：C 47.62, H 6.59, N 11.11；It is real Test value %：C 47.51, H 6.48, N 11.23).
The preparation of compound I-1 hydrobromic acid hydrochlorate trihydrates
Compound I-1 (0.3g, 0.8mmol), 5% hydrobromic acid aqueous solution (0.8mmol) are added in ethanol (10mL), Backflow dissolving, cooling separate out white solid, filtering, obtain 0.34g white solids, yield 80%.
Elementary analysis：C19H28Cl2N4O·HBr·3H2O (theoretical value %：C 42.71, H 6.60, N 10.49；Experiment Value %：C 42.80, H 6.66, N 10.42).
The preparation of compound I-1 oxalates dihydrates
Compound I-1 (0.3g, 0.8mmol), oxalic acid dihydrate (0.8mmol) are added in ethanol (10mL), returned Stream dissolving, cooling separate out white solid, filtering, obtain 0.35g white solids, yield 83%.
Elementary analysis：C19H28Cl2N4O·C2H2O4·2H2O (theoretical value %：C 48.00, H 6.52, N 10.66；Experiment Value %：C 47.89, H 6.61, N 10.54).
Embodiment 2：N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) butyramide (chemical combination Thing I-2) and its salt preparation
With intermediate 9 (2.8mmol), butyl chloride (3.1mmol) for raw material, according to compound I-1 preparation method, mesh is obtained Mark compound I-2 white solid 1.14g, yield 95%.
1HNMR(CDCl3,δ:ppm):0.95 (t, 3H, J=6.8Hz, A-H), 1.17-1.34 (m, 2H, A-H), 1.43- 1.52 (m, 4H, A-H), 1.68-1.71 (m, 3H, A-H), 2.28-2.34 (m, 2H, A-H), 2.36 (t, 2H, J=7.2Hz, A- ), H 2.39 (t, 2H, J=8.0Hz, N-CH2),2.59(brs,4H,A-H),3.01(brs,4H,A-H),3.09-3.10(m, 2H,A-H),6.90-6.93(m,1H,Ar-H),7.06-7.12(m,2H,Ar-H).
ESI-MS:427[M+H+].
The preparation of compound I-2 hydrobromic acid hydrochlorates
With compound I-2 (2.0mmol), 5% hydrobromic acid aqueous solution (2.1mmol) for raw material, using compound I-1 hydrogen bromines The preparation method of hydrochlorate, obtain 0.9g white solids, yield 88%.
Elementary analysis：C21H32Cl2N4OHBr (theoretical value %：C 49.62, H 6.54, N 11.02；Experiment value %：C 49.51, H 6.67, N 11.28).
Embodiment 3：N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -2- methoxyl group second The preparation of acid amides (compound I-3) and its salt
With intermediate 9 (2.8mmol), 2- methoxyacetyl chlorides (3.1mmol) for raw material, according to compound I-1 preparation Method, obtain target compound I-3 white solid 1.1g, yield 92%.
1HNMR(CDCl3,δ:ppm):1.18-1.36(m,2H,A-H),1.44-1.70(m,5H,A-H),2.32-2.38 (m, 2H, A-H), 2.43 (t, 2H, J=8.0Hz, N-CH2),2.63(brs,4H,A-H),3.06(brs,4H,A-H),3.12- 3.14(m,2H,A-H),3.32(s,3H,A-H),4.30(s,2H,A-H),6.93-6.97(m,1H,Ar-H),7.10-7.16 (m,2H,Ar-H).
ESI-MS:429[M+H+].
The preparation of compound I-3 fumarates
With compound I-3 (2.3mmol), fumaric acid (2.4mmol) for raw material, using the system of compound I-1 hydrobromates Preparation Method, obtain 1.0g white solids, yield 72%.
Elementary analysis：C20H30Cl2N4O·C4H4O4(theoretical value %：C 52.85, H 6.28, N 10.27；Experiment value %：C 52.72, H 6.34, N 10.14).
Embodiment 4：N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -2- ethyoxyl second The preparation of acid amides (compound I-4) and its salt
With intermediate 9 (2.8mmol), 2- Ethoxyacetyl chlorides (3.1mmol) for raw material, according to compound I-1 preparation Method, obtain target compound I-4 white solid 1.0g, yield 81%.
1HNMR(CDCl3,δ:ppm):1.01 (t, 3H, J=6.8Hz, A-H), 1.17-1.35 (m, 2H, A-H), 1.43- 1.70 (m, 5H, A-H), 2.31-2.36 (m, 2H, A-H), 2.43 (t, 2H, J=8.0Hz, N-CH2), 2.62 (brs, 4H, A- ), H 3.05 (brs, 4H, A-H), 3.12-3.15 (m, 2H, A-H), 3.44 (q, 2H, J=6.8Hz, A-H), 4.28 (s, 2H, A- H),6.92-6.95(m,1H,Ar-H),7.10-7.15(m,2H,Ar-H).
ESI-MS:443[M+H+].
The preparation of compound I-4 succinates
With compound I-4 (2.2mmol), succinic acid (2.4mmol) for raw material, using the system of compound I-1 hydrobromates Preparation Method, obtain 1.1g white solids, yield 89%.
Elementary analysis：C21H32Cl2N4O·C4H6O4(theoretical value %：C 53.68, H 6.82, N 9.98；Experiment value %：C 53.79, H 6.70, N 10.07).
Embodiment 5：N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) cyclopropyl formyl The preparation of amine (compound I-5) and its salt
With intermediate 9 (2.8mmol), Cyclopropyl carbonyl chloride (3.1mmol) for raw material, according to compound I-1 preparation side Method, obtain target compound I-5 white solid 1.0g, yield 83%.
1HNMR(CDCl3,δ:ppm):0.69-0.80(m,4H,A-H),1.17-1.34(m,3H,A-H),1.43-1.52 (m, 4H, A-H), 1.70-1.73 (m, 1H, A-H), 2.28-2.34 (m, 2H, A-H), 2.38 (t, 2H, J=8.0Hz, N-CH2), 2.59(brs,4H,A-H),3.01(brs,4H,A-H),3.08-3.10(m,2H,A-H),6.91-6.94(m,1H,Ar-H), 7.07-7.12(m,2H,Ar-H).
ESI-MS:425[M+H+].
The preparation of compound I-5 tartrates
With compound I-5 (2.0mmol), tartaric acid (2.1mmol) for raw material, using the system of compound I-1 hydrobromates Preparation Method, obtain 1.0g white solids, yield 91%.
Elementary analysis：C21H30Cl2N4O·C4H6O6(theoretical value %：C 52.18, H 6.31, N 9.74；Experiment value %：C 52.26, H 6.38, N 9.88).
Embodiment 6：N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) cyclohexyl formyl The preparation of amine (compound I-6) and its salt
With intermediate 9 (2.8mmol), cyclohexyl formyl chloride (3.1mmol) for raw material, according to compound I-1 preparation side Method, obtain target compound I-6 white solid 1.1g, yield 84%.
1HNMR(CDCl3,δ:ppm):1.18-1.42(m,5H,A-H),1.45-1.55(m,10H,A-H),1.81-1.83 (m,2H,A-H),2.29-2.35(m,2H,A-H),2.372.39(m,3H,A-H),2.59(brs,4H,A-H),3.01(brs, 4H,A-H),3.07-3.09(m,2H,A-H),6.90-6.93(m,1H,Ar-H),7.08-7.12(m,2H,Ar-H).
ESI-MS:467[M+H+].
The preparation of compound I-6 hydrochlorides
With compound I-6 (1.8mmol), 5% aqueous hydrochloric acid solution (1.9mmol) for raw material, using compound I-1 hydrobromic acids The preparation method of salt, obtain 0.85g white solids, yield 93%.
Elementary analysis：C24H36Cl2N4OHCl (theoretical value %：C 57.20, H 7.40, N 11.12；Experiment value %：C 57.32, H 7.58, N 11.01).
Embodiment 7：N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) benzamide (is changed Compound I-7) and its salt preparation
With intermediate 9 (2.8mmol), chlorobenzoyl chloride (3.1mmol) for raw material, according to compound I-1 preparation method, obtain Target compound I-7 white solid 0.9g, yield 69%.
1HNMR(CDCl3,δ:ppm):1.22-1.39(m,2H,A-H),1.47-1.56(m,4H,A-H),1.74-1.76 (m, 1H, A-H), 2.32-2.38 (m, 2H, A-H), 2.43 (t, 2H, J=8.0Hz, N-CH2),2.64(brs,4H,A-H), 3.06(brs,4H,A-H),3.13-3.15(m,2H,A-H),6.95-6.98(m,1H,Ar-H),7.11-7.15(m,2H,Ar- H),7.56-7.73(m,3H,Ar-H),7.97-7.98(m,2H,Ar-H).
ESI-MS:462[M+H+].
The preparation of compound I-7 hydrobromates
With compound I-7 (1.9mmol), 5% hydrobromic acid aqueous solution (2.0mmol) for raw material, using compound I-1 hydrogen bromines The preparation method of hydrochlorate, obtain 0.93g white solids, yield 90%.
Elementary analysis：C24H30Cl2N4OHBr (theoretical value %：C 53.15, H 5.76, N 10.33；Experiment value %：C 53.28, H 5.59, N 10.56).
Embodiment 8：N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -4- fluorobenzoyls The preparation of amine (compound I-8) and its salt
With intermediate 9 (2.8mmol), 4- fluorobenzoyl chlorides (3.1mmol) for raw material, according to compound I-1 preparation side Method, obtain target compound I-8 white solid 1.2g, yield 89%.
1HNMR(CDCl3,δ:ppm):1.23-1.40(m,2H,A-H),1.49-1.75(m,5H,A-H),2.33-2.39 (m, 2H, A-H), 2.44 (t, 2H, J=8.0Hz, N-CH2),2.64(brs,4H,A-H),3.07(brs,4H,A-H),3.14- 3.16(m,2H,A-H),6.96-6.99(m,1H,Ar-H),7.12-7.16(m,2H,Ar-H),7.61-7.63(m,2H,Ar- H),8.08-8.09(m,2H,Ar-H).
ESI-MS:479[M+H+].
The preparation of compound I-8 oxalates
With compound I-8 (2.4mmol), two oxalic acid hydrates (2.5mmol) for raw material, using compound I-1 hydrobromates Preparation method, obtain 1.2g white solids, yield 85%.
Elementary analysis：C24H29Cl2FN4O·C2H2O4(theoretical value %：C 56.28, H 5.90, N 9.38；Experiment value %：C 56.42, H 5.79, N 9.51).
Embodiment 9：N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -4- cyano group benzene first The preparation of acid amides (compound I-9) and its salt
With intermediate 9 (2.8mmol), 4- cyano-benzoyl chlorides (3.1mmol) for raw material, according to compound I-1 preparation Method, obtain target compound I-9 white solid 1.1g, yield 80%.
1HNMR(CDCl3,δ:ppm):1.24-1.41(m,2H,A-H),1.50-1.76(m,5H,A-H),2.34-2.40 (m, 2H, A-H), 2.45 (t, 2H, J=8.0Hz, N-CH2),2.65(brs,4H,A-H),3.07(brs,4H,A-H),3.14- 3.15(m,2H,A-H),6.97-7.00(m,1H,Ar-H),7.11-7.15(m,2H,Ar-H),8.13-8.15(m,2H,Ar- H),8.23-8.25(m,2H,Ar-H).
ESI-MS:486[M+H+].
The preparation of compound I-9 acetate
With compound I-9 (2.2mmol), glacial acetic acid (2.3mmol) for raw material, using the system of compound I-1 hydrobromates Preparation Method, obtain 1.1g white solids, yield 92%.
Elementary analysis：C25H29Cl2N5O·C2H4O2(theoretical value %：C 59.34, H 6.09, N 12.82；Experiment value %：C 59.18, H 6.21, N 12.93).
Embodiment 10：N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -4- methylbenzenes The preparation of formamide (compound I-10) and its salt
With intermediate 9 (2.8mmol), 4- methyl benzoyl chlorides (3.1mmol) for raw material, according to compound I-1 preparation Method, obtain target compound I-10 white solid 1.18g, yield 89%.
1HNMR(CDCl3,δ:ppm):1.21-1.38(m,2H,A-H),1.46-1.55(m,4H,A-H),1.73-1.75 (m, 1H, A-H), 2.31-2.37 (m, 5H, A-H), 2.42 (t, 2H, J=8.0Hz, N-CH2),2.63(brs,4H,A-H), 3.05(brs,4H,A-H),3.12-3.14(m,2H,A-H),6.94-6.97(m,1H,Ar-H),7.10-7.14(m,2H,Ar- H),7.38-7.40(m,2H,Ar-H),7.88-7.90(m,2H,Ar-H).
ESI-MS:475[M+H+].
The preparation of compound I-10 hydrochlorides
With compound I-10 (2.3mmol), 5% aqueous hydrochloric acid solution (2.4mmol) for raw material, using compound I-1 hydrogen bromines The preparation method of hydrochlorate, obtain 0.9g white solids, yield 79%.
Elementary analysis：C25H32Cl2N4OHCl (theoretical value %：C 58.66, H 6.50, N 10.94；Experiment value %：C 58.51, H 6.68, N 10.78).
Embodiment 11：N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) niacinamide (is changed Compound I-11) and its salt preparation
With intermediate 9 (2.8mmol), nicotinoyl chlorine (3.1mmol) for raw material, according to compound I-1 preparation method, mesh is obtained Mark compound I-11 white solid 1.05g, yield 81%.
1HNMR(CDCl3,δ:ppm):1.25-1.42(m,2H,A-H),1.51-1.77(m,5H,A-H),2.35-2.41 (m, 2H, A-H), 2.47 (t, 2H, J=8.0Hz, N-CH2),2.67(brs,4H,A-H),3.09(brs,4H,A-H),3.16- 3.17(m,2H,A-H),6.99-7.02(m,1H,Ar-H),7.15-7.19(m,2H,Ar-H),7.61-7.63(m,1H,Ar- ), H 8.18-8.22 (m, 2H, Ar-H), 8.89 (d, 1H, J=1.6Hz, Ar-H)
ESI-MS:462[M+H+].
The preparation of compound I-11 maleates
With compound I-11 (2.1mmol), maleic acid (2.2mmol) for raw material, using the system of compound I-1 hydrobromates Preparation Method, obtain 1.06g white solids, yield 88%.
Elementary analysis：C23H29Cl2N5O·C4H4O4(theoretical value %：C 56.06, H 5.75, N 12.11；Experiment value %：C 56.18, H 5.89, N 12.19).
Embodiment 12：N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) formyl of furans -2 The preparation of amine (compound I-12) and its salt
With intermediate 9 (2.8mmol), the formyl chloride of furans -2 (3.1mmol) for raw material, according to compound I-1 preparation side Method, obtain target compound I-12 white solid 1.06g, yield 84%.
1HNMR(CDCl3,δ:ppm):1.20-1.37(m,2H,A-H),1.45-1.54(m,4H,A-H),1.73-1.75 (m, 1H, A-H), 2.31-2.37 (m, 2H, A-H), 2.41 (t, 2H, J=8.0Hz, N-CH2),2.63(brs,4H,A-H), 3.05(brs,4H,A-H),3.12-3.14(m,2H,A-H),6.94-6.98(m,2H,Ar-H),7.10-7.18(m,3H,Ar- H),7.95-7.96(m,1H,Ar-H).
ESI-MS:451[M+H+].
The preparation of compound I-12 mesylates
With compound I-12 (2.2mmol), methanesulfonic acid (2.3mmol) for raw material, using the system of compound I-1 hydrobromates Preparation Method, obtain 1.12g white solids, yield 93%.
Elementary analysis：C22H28Cl2N4O·CH4O3S (theoretical value %：C 50.46, H 5.89, N 10.23；Experiment value %：C 50.60, H 5.74, N 10.11).
Embodiment 13：N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) formyl of pyrroles -2 The preparation of amine (compound I-13) and its salt
With intermediate 9 (2.8mmol), the formyl chloride of pyrroles -2 (3.1mmol) for raw material, according to compound I-1 preparation side Method, obtain target compound I-13 white solid 1.13g, yield 90%.
1HNMR(CDCl3,δ:ppm):1.21-1.37(m,2H,A-H),1.45-1.53(m,4H,A-H),1.72-1.74 (m, 1H, A-H), 2.31-2.36 (m, 2H, A-H), 2.41 (t, 2H, J=8.0Hz, N-CH2),2.61(brs,4H,A-H), 3.04(brs,4H,A-H),3.13-3.15(m,2H,A-H),5.07(brs,1H,NH-H),6.93-6.97(m,2H,Ar-H), 7.09-7.18(m,3H,Ar-H),7.94-7.96(m,1H,Ar-H).
ESI-MS:450[M+H+].
The preparation of compound I-13 tosilate
With compound I-13 (2.4mmol), p-methyl benzenesulfonic acid (2.5mmol) for raw material, using compound I-1 hydrobromates Preparation method, obtain 1.35g white solids, yield 91%.
Elementary analysis：C22H29Cl2N5O·C7H8O3S (theoretical value %：C 55.94, H 5.99, N 11.25；Experiment value %： C 55.81, H 5.76, N 11.39).
Embodiment 14：N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) formyl of thiophene -2 The preparation of amine (compound I-14) and its salt
With intermediate 9 (2.8mmol), the formyl chloride of thiophene -2 (3.1mmol) for raw material, according to compound I-1 preparation side Method, obtain target compound I-14 white solid 1.02g, yield 78%.
1HNMR(CDCl3,δ:ppm):1.20-1.36(m,2H,A-H),1.44-1.53(m,4H,A-H),1.74-1.76 (m, 1H, A-H), 2.31-2.36 (m, 2H, A-H), 2.41 (t, 2H, J=8.0Hz, N-CH2),2.62(brs,4H,A-H), 3.04(brs,4H,A-H),3.13-3.15(m,2H,A-H),6.93-6.97(m,2H,Ar-H),7.10-7.17(m,3H,Ar- H),7.93-7.94(m,1H,Ar-H).
ESI-MS:467[M+H+].
The preparation of compound I-14 citrates
With compound I-14 (1.8mmol), citric acid (1.85mmol) for raw material, using compound I-1 hydrobromates Preparation method, obtain 1.1g white solids, yield 81%.
Elementary analysis：C22H28Cl2N4OS·C6H8O7(theoretical value %：C 50.99, H 5.50, N 8.49；Experiment value %：C 56.21, H 5.63, N 8.32).
Embodiment 15：N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) formyl of indoles -2 The preparation of amine (compound I-15) and its salt
With intermediate 9 (2.8mmol), the formyl chloride of indoles -2 (3.1mmol) for raw material, according to compound I-1 preparation side Method, obtain target compound I-15 white solid 1.2g, yield 85%.
1HNMR(CDCl3,δ:ppm):1.19-1.35(m,2H,A-H),1.44-1.52(m,4H,A-H),1.71-1.73 (m, 1H, A-H), 2.30-2.34 (m, 2H, A-H), 2.40 (t, 2H, J=8.0Hz, N-CH2),2.61(brs,4H,A-H), 3.03(brs,4H,A-H),3.12-3.14(m,2H,A-H),5.06(brs,1H,NH-H),6.88-6.95(m,3H,Ar-H), 7.07-7.11(m,2H,Ar-H),7.22(s,1H,Ar-H),7.44-7.53(m,2H,Ar-H).
ESI-MS:500[M+H+].
The preparation of compound I-15 hydrobromates
With compound I-15 (2.1mmol), 5% hydrobromic acid aqueous solution (2.2mmol) for raw material, using compound I-1 hydrogen The preparation method of bromate, obtain 1.07g white solids, yield 88%.
Elementary analysis：C26H31Cl2N5OHCl (theoretical value %：C 53.71, H 5.55, N 12.05；Experiment value %：C 53.88, H 5.36, N 12.21).
Embodiment 16：1- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -3- MUs The preparation of (compound II-1) and its salt
Triphosgene (6.2mmol) is dissolved in dichloromethane (10mL), 4- (2- (4- (2,3- bis- are added dropwise under the conditions of~0 DEG C Chlorphenyl) piperazine -1- bases) ethyl) piperidines -1- amine (9) (prepares) (2.0g, 5.6mmol), triethylamine according to logical method one Dichloromethane (20mL) solution of (6.2mmol), insulated and stirred 3h, under the conditions of -5~0 DEG C, it is water-soluble that reaction solution is added drop-wise to methylamine In isopropanol (60mL) solution of liquid (31mmol), insulation reaction 5h, stop reaction, add saturated ammonium chloride solution (30mL), Distribution, organic phase are washed with water (30mL × 2), saturated aqueous common salt (30mL × 2) successively, anhydrous sodium sulfate drying.Filtering, takes filter Liquid, it is concentrated under reduced pressure, obtains off-white powder, through Flash post (dichloromethane：Methanol=50：1) white solid 2.0g is separated to obtain, is received Rate 85%.
1HNMR(CDCl3,δ:ppm):1.21-1.37(m,2H,A-H),1.46-1.61(m,5H,A-H),2.32-2.38 (m, 2H, A-H), 2.41 (t, 2H, J=8.0Hz, N-CH2),2.80(s,3H,A-H),2.63(brs,4H,A-H),3.05 (brs,4H,A-H),3.12-3.14(m,2H,A-H),5.92(brs,1H,NH-H),6.94-6.97(m,1H,Ar-H),7.10- 7.15(m,2H,Ar-H).
ESI-MS:414[M+H+].
The preparation of compound II-1 sulfate
Compound II-1 (0.5g, 1.21mmol), 5% aqueous sulfuric acid (1.33mmol) are added to ethanol (10mL) In, backflow dissolving, cooling separates out white solid, filtering, obtains 0.49g white solids, yield 87%.
Elementary analysis：C19H29Cl2N5O (theoretical value %：C 49.24, H 6.53, N 15.11；Experiment value %：C 49.30, H 6.61, N 15.01).
The preparation of compound II-1 trifluoroacetate monohydrates
Compound II-1 (0.5g, 1.21mmol), 5% trifluoroacetic acid aqueous solution (1.33mmol) are added to ethanol In (10mL), backflow dissolving, cooling separates out white solid, filtering, obtains 0.58g white solids, yield 90%.
Elementary analysis：C19H29Cl2N5O·CF3COOH·H2O (theoretical value %：C 47.64, H 5.90, N 13.23；Experiment Value %：C 47.58, H 5.99, N 13.41).
The preparation of compound II-1 maleates
Compound II-1 (0.5g, 1.21mmol), maleic acid (1.33mmol) are added in ethanol (10mL), backflow is molten Solution, cooling separate out white solid, filtering, obtain 0.55g white solids, yield 85%.
Elementary analysis：C19H29Cl2N5O·C4H4O4(theoretical value %：C 52.08, H 6.27, N 13.20；Experiment value %：C 52.16, H 6.39, N 13.31).
Embodiment 17：3- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -1,1- diformazans The preparation of base urea (compound II-2) and its salt
With intermediate 9 (2.8mmol), dimethyl amine (15.4mmol) for raw material, according to compound II-1 preparation method, Obtain target compound II-2 white solid 1.1g, yield 91%.
1HNMR(CDCl3,δ:ppm):1.25-1.33(m,1H,A-H),1.42-1.50(m,4H,A-H),1.70-1.73 (m, 2H, A-H), 2.31-2.37 (m, 2H, A-H), 2.43 (t, 2H, J=8.0Hz, N-CH2),2.63(brs,4H,A-H), 2.91(s,6H,A-H),3.07(brs,4H,A-H),3.14-3.16(m,2H,A-H),6.95-6.98(m,1H,Ar-H), 7.12-7.17(m,2H,Ar-H).
ESI-MS:428[M+H+].
The preparation of compound II-2 hydrochlorides
With compound II-2 (2.5mmol), 5% aqueous hydrochloric acid solution (2.6mmol) for raw material, using compound II-1 sulfuric acid The preparation method of salt, obtain 0.95g white solids, yield 82%.
Elementary analysis：C20H31Cl2N5OHCl (theoretical value %：C 51.67, H 6.94, N 15.07；Experiment value %：C 51.83, H 6.86, N 15.19).
Embodiment 18：1- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -3- propyl group ureas The preparation of (compound II-3) and its salt
With intermediate 9 (2.8mmol), n-propylamine (15.4mmol) for raw material, according to compound II-1 preparation method, obtain Target compound II-3 white solid 1.04g, yield 84%.
1HNMR(CDCl3,δ:ppm):0.86 (t, 3H, J=7.2Hz, A-H), 1.19-1.35 (m, 2H, A-H), 1.45- 1.63 (m, 7H, A-H), 2.31-2.37 (m, 2H, A-H), 2.41 (t, 2H, J=8.0Hz, N-CH2),2.63(brs,4H,A- ), H 3.04 (brs, 4H, A-H), 3.11-3.13 (m, 2H, A-H), 3.28-3.31 (m, 2H, A-H), 5.91 (t, 1H, J= 3.6Hz),6.93-6.96(m,1H,Ar-H),7.10-7.14(m,2H,Ar-H)..
ESI-MS:442[M+H+].
The preparation of compound II-3 hydrobromates
With compound II-3 (2.2mmol), 5% hydrobromic acid aqueous solution (2.3mmol) for raw material, using compound II-1 sulphur The preparation method of hydrochlorate, obtain 1.04g white solids, yield 90%.
Elementary analysis：C21H33Cl2N5OHBr (theoretical value %：C 48.20, H 6.55, N 13.38；Experiment value %：C 48.01, H 6.71, N 13.52).
Embodiment 19：1- cyclopropyl -3- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) The preparation of urea (compound II-4) and its salt
With intermediate 9 (2.8mmol), cyclopropylamine (15.4mmol) for raw material, according to compound II-1 preparation method, obtain Target compound II-4 white solid 1.06g, yield 86%.
1HNMR(CDCl3,δ:ppm):0.61-0.64(m,2H,A-H),0.86-0.87(m,2H,A-H),1.19-1.35 (m, 2H, A-H), 1.45-1.60 (m, 5H, A-H), 2.31-2.37 (m, 2H, A-H), 2.39 (t, 2H, J=8.0Hz, N-CH2), 2.62(brs,4H,A-H),2.80(m,1H,A-H),3.05(brs,4H,A-H),3.11-3.13(m,2H,A-H),6.02 (brs,1H,NH-H),6.93-6.96(m,1H,Ar-H),7.08-7.13(m,2H,Ar-H).
ESI-MS:440[M+H+].
The preparation of compound II-4 hydrochlorides
With compound II-4 (2.2mmol), 5% aqueous hydrochloric acid solution (2.3mmol) for raw material, using compound II-1 sulfuric acid The preparation method of salt, obtain 0.87g white solids, yield 83%.
Elementary analysis：C21H31Cl2N5OHCl (theoretical value %：C 52.89, H 6.76, N 14.69；Experiment value %：C 52.76, H 6.90, N 14.55).
Embodiment 20：1- cyclohexyl -3- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) The preparation of urea (compound II-5) and its salt
With intermediate 9 (2.8mmol), cyclohexylamine (15.4mmol) for raw material, according to compound II-1 preparation method, obtain Target compound II-5 white solid 1.09g, yield 81%.
1HNMR(CDCl3,δ:ppm):1.18-1.36(m,6H,A-H),1.44-1.61(m,9H,A-H),1.68-1.70 (m, 2H, A-H), 2.30-2.36 (m, 2H, A-H), 2.38 (t, 2H, J=8.0Hz, N-CH2),2.61(brs,4H,A-H), 2.80(m,1H,A-H),3.04(brs,4H,A-H),3.10-3.13(m,2H,A-H),3.58(m,1H,A-H),6.04(brs, 1H,NH-H),6.93-6.95(m,1H,Ar-H),7.07-7.12(m,2H,Ar-H).
ESI-MS:482[M+H+].
The preparation of compound II-5 hydrobromates
With compound II-5 (2.2mmol), 5% hydrobromic acid aqueous solution (2.3mmol) for raw material, using compound II-1 sulphur The preparation method of hydrochlorate, obtain 1.14g white solids, yield 92%.
Elementary analysis：C24H37Cl2N5OHBr (theoretical value %：C 51.16, H 6.80, N 12.43；Experiment value %：C 51.31, H 6.88, N 12.51).
Embodiment 21：1- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -3- phenylureas The preparation of (compound II-6) and its salt
With intermediate 9 (2.8mmol), aniline (15.4mmol) for raw material, according to compound II-1 preparation method, mesh is obtained Mark compound II-6 white solid 1.23g, yield 92%.
1HNMR(CDCl3,δ:ppm):1.22-1.38(m,2H,A-H),1.48-1.63(m,5H,A-H),2.34-2.40 (m, 2H, A-H), 2.42 (t, 2H, J=8.0Hz, N-CH2),2.65(brs,4H,A-H),2.83(m,1H,A-H),3.08 (brs,4H,A-H),3.14-3.16(m,2H,A-H),6.06(brs,1H,NH-H),6.96-6.99(m,1H,Ar-H),7.11- 7.16(m,3H,Ar-H),7.48-7.50(m,2H,Ar-H),7.68-7.71(m,2H,Ar-H).
ESI-MS:476[M+H+].
The preparation of compound II-6 hydrochlorides
With compound II-6 (2.4mmol), 5% aqueous hydrochloric acid solution (2.5mmol) for raw material, using compound II-1 sulfuric acid The preparation method of salt, obtain 1.11g white solids, yield 90%.
Elementary analysis：C24H31Cl2N5OHCl (theoretical value %：C 56.20, H 6.29, N 13.65；Experiment value %：C 56.29, H 6.12, N 13.83).
Embodiment 22：1- benzyls -3- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) urea The preparation of (compound II-7) and its salt
With intermediate 9 (2.8mmol), benzylamine (15.4mmol) for raw material, according to compound II-1 preparation method, mesh is obtained Mark compound II-7 white solid 1.3g, yield 95%.
1HNMR(CDCl3,δ:ppm):1.21-1.36(m,2H,A-H),1.47-1.61(m,5H,A-H),2.33-2.38 (m, 2H, A-H), 2.41 (t, 2H, J=8.0Hz, N-CH2),2.64(brs,4H,A-H),2.82(m,1H,A-H),3.06 (brs,4H,A-H),3.13-3.15(m,2H,A-H),4.29(s,2H,A-H),6.03(brs,1H,NH-H),6.94-6.97 (m,1H,Ar-H),7.10-7.14(m,2H,Ar-H),7.20-7.24(m,2H,Ar-H),7.41-7.46(m,3H,Ar-H).
ESI-MS:490[M+H+].
The preparation of compound II-7 hydrobromates
With compound II-7 (2.5mmol), 5% aqueous hydrochloric acid solution (2.6mmol) for raw material, using compound II-1 sulfuric acid The preparation method of salt, obtain 1.27g white solids, yield 89%.
Elementary analysis：C25H33Cl2N5OHBr (theoretical value %：C 52.55, H 6.00, N 12.26；Experiment value %：C 52.71, H 6.18, N 12.13).
Embodiment 23：1- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -3- (pyridine - 3- yls) urea (compound II-8) and its salt preparation
With intermediate 9 (2.8mmol), pyridine -3- amine (15.4mmol) for raw material, according to compound II-1 preparation side Method, obtain target compound II-8 white solid 1.06g, yield 79%.
1HNMR(CDCl3,δ:ppm):1.24-1.40(m,2H,A-H),1.50-1.65(m,5H,A-H),2.36-2.42 (m, 2H, A-H), 2.44 (t, 2H, J=8.0Hz, N-CH2),2.66(brs,4H,A-H),2.85(m,1H,A-H),3.10 (brs,4H,A-H),3.16-3.18(m,2H,A-H),6.08(brs,1H,NH-H),6.98-7.01(m,1H,Ar-H),7.13- 7.16(m,2H,Ar-H),7.42-7.44(m,1H,Ar-H),8.12-8.15(m,2H,Ar-H),9.01(m,1H,Ar-H).
ESI-MS:477[M+H+].
The preparation of compound II-8 hydrochlorides
With compound II-8 (2.1mmol), 5% aqueous hydrochloric acid solution (2.2mmol) for raw material, using compound II-1 sulfuric acid The preparation method of salt, obtain 0.88g white solids, yield 82%.
Elementary analysis：C23H30Cl2N6OHCl (theoretical value %：C 53.76, H 6.08, N 16.35；Experiment value %：C 53.54, H 6.19, N 16.27).
Embodiment 24：N- (4- (2- (4- (2,3- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) morpholine - The preparation of 4- formamides (compound II-9) and its salt
With intermediate 9 (2.8mmol), morpholine (15.4mmol) for raw material, according to compound II-1 preparation method, mesh is obtained Mark compound II-9 white solid 1.14g, yield 87%.
1HNMR(CDCl3,δ:ppm):1.26-1.34(m,1H,A-H),1.43-1.51(m,4H,A-H),1.71-1.74 (m, 2H, A-H), 2.32-2.38 (m, 2H, A-H), 2.44 (t, 2H, J=8.0Hz, N-CH2),2.64(brs,4H,A-H), 3.09(brs,4H,A-H),3.13-3.17(m,2H,A-H),3.37-3.43(m,4H,A-H),3.69-3.74(m,4H,A-H), 6.96-6.99(m,1H,Ar-H),7.14-7.19(m,2H,Ar-H).
ESI-MS:470[M+H+].
The preparation of compound II-9 hydrobromates
With compound II-9 (2.3mmol), 5% hydrobromic acid aqueous solution (2.4mmol) for raw material, using compound II-1 sulphur The preparation method of hydrochlorate, obtain 1.15g white solids, yield 91%.
Elementary analysis：C22H33Cl2N5O2HBr (theoretical value %：C 47.93, H 6.22, N 12.70；Experiment value %：C 47.80, H 6.36, N 12.55).
Embodiment 25：N- (4- (2- (4- (2,3- 3,5-dimethylphenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -4- methoxies The preparation of yl-benzamide (compound III-1) and its salt
4- (2- (4- (2,3- 3,5-dimethylphenyls) piperazine -1- bases) ethyl) piperidines -1- amine (9-1) (is made according to logical method one It is standby) (1.0g, 2.8mmol), triethylamine (4.2mmol) be added in dichloromethane (10mL), 4- methoxy benzoyl chlorides are added dropwise Dichloromethane (5mL) solution of (0.53g, 3.1mmol), react 3h, successively with water (20mL × 2), saturated aqueous common salt (10mL × 2) wash, anhydrous sodium sulfate drying, filter, be concentrated to give white solid, through 95% ethanol solution crystallizing, obtain white solid 1.14g, receive Rate 90%.
1HNMR(CDCl3,δ:ppm):1.20-1.37(m,2H,A-H),1.45-1.54(m,4H,A-H),1.72-1.74 (m, 1H, A-H), 2.26 (s, 3H, A-H), 2.30-2.36 (m, 2H, A-H), 2.39 (s, 3H, A-H), 2.41 (t, 2H, J= 8.0Hz,N-CH2),2.62(brs,4H,A-H),3.04(brs,4H,A-H),3.11-3.13(m,2H,A-H),3.91(s,3H, A-H),6.56-6.59(m,1H,Ar-H),6.72-6.78(m,2H,Ar-H),7.37-7.41(m,2H,Ar-H),7.85-7.88 (m,2H,Ar-H).
ESI-MS:451[M+H+].
The preparation of compound III-1 hydrochlorides
Compound III-1 (2.5mmol), 5% aqueous hydrochloric acid solution (2.6mmol) are added in ethanol (20mL), flowed back Dissolving, cooling separate out white solid, filtering, obtain 1.04g white solids, yield 85%.
Elementary analysis：C27H38N4O2HCl (theoretical value %：C 66.58, H 8.07, N 11.50；Experiment value %：C 66.71, H 7.86, N 11.69).
Embodiment 26：N- (4- (2- (4- (2,3- 3,5-dimethylphenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -4- ethyls The preparation of benzamide (compound III-2) and its salt
With intermediate 9-1 (2.8mmol), 4- ethylamino benzonitriles acyl chlorides (3.1mmol) for raw material, according to compound III-1's Preparation method, obtain target compound III-2 white solid 1.19g, yield 94%.
1HNMR(CDCl3,δ:ppm):1.19-1.39(m,5H,A-H),1.44-1.53(m,4H,A-H),1.71-1.73 (m, 1H, A-H), 2.27 (s, 3H, A-H), 2.31-2.37 (m, 2H, A-H), 2.40 (s, 3H, A-H), 2.40 (t, 2H, J= 8.0Hz,N-CH2), 2.61 (brs, 4H, A-H), 3.04 (brs, 4H, A-H), 2.68 (q, 2H, J=7.2Hz, A-H), 3.12- 3.15(m,2H,A-H),6.57-6.60(m,1H,Ar-H),6.73-6.79(m,2H,Ar-H),7.17-7.19(m,2H,Ar- H),7.78-7.81(m,2H,Ar-H).
ESI-MS:449[M+H+].
The preparation of compound III-2 hydrobromates
Compound III-2 (2.5mmol), 5% hydrobromic acid aqueous solution (2.6mmol) are added in ethanol (20mL), returned Stream dissolving, cooling separate out white solid, filtering, obtain 1.18g white solids, yield 89%.
Elementary analysis：C28H40N4OHBr (theoretical value %：C 63.51, H 7.80, N 10.58；Experiment value %：C 63.64, H 7.89, N 10.40).
Embodiment 27：1- ethyls -3- (4- (2- (4- (2- methoxyphenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -1- The preparation of MU (compound III-3) and its salt
Triphosgene (6.2mmol) is dissolved in dichloromethane (10mL), 4- (2- (4- (2- methoxies are added dropwise under the conditions of~0 DEG C Base phenyl) piperazine -1- bases) ethyl) piperidines -1- amine (9-2) (prepares) (2.0g, 5.6mmol), triethylamine according to logical method one Dichloromethane (20mL) solution of (6.2mmol), insulated and stirred 3h, under the conditions of -5~0 DEG C, it is water-soluble that reaction solution is added drop-wise to methylamine In isopropanol (60mL) solution of liquid (31mmol), insulation reaction 5h, stop reaction, add saturated ammonium chloride solution (30mL), Distribution, organic phase are washed with water (30mL × 2), saturated aqueous common salt (30mL × 2) successively, anhydrous sodium sulfate drying.Filtering, takes filter Liquid, it is concentrated under reduced pressure, obtains off-white powder, through Flash post (dichloromethane：Methanol=50：1) white solid 1.83g is separated to obtain, is received Rate 81%.
1HNMR(CDCl3,δ:ppm):1.23-1.31(m,1H,A-H),1.38-1.48(m,7H,A-H),1.68-1.71 (m, 2H, A-H), 2.29-2.36 (m, 2H, A-H), 2.40 (t, 2H, J=8.0Hz, N-CH2),2.61(brs,4H,A-H), 2.88 (q, 2H, J=7.6Hz, N-CH2),2.94(s,3H,A-H),3.09(brs,4H,A-H),3.16-3.18(m,2H,A- H),3.54(s,3H,A-H),6.45-6.48(m,2H,Ar-H),6.60-6.63(m,1H,Ar-H),6.72-6.75(m,1H, Ar-H).
ESI-MS:404[M+H+].
The preparation of compound III-3 hydrochlorides
Compound III-3 (2.5mmol), 5% aqueous hydrochloric acid solution (2.6mmol) are added in ethanol (20mL), flowed back Dissolving, cooling separate out white solid, filtering, obtain 0.92g white solids, yield 84%.
Elementary analysis：C22H37N5O2HBr (theoretical value %：C 60.05, H 8.70, N 15.92；Experiment value %：C 60.18, H 8.82, N 15.76).
Embodiment 28：3- (4- (2- (4- (2- methoxyphenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -1- methyl isophthalic acids - The preparation of phenylurea (compound III-4) and its salt
With intermediate 9-2 (2.8mmol), methylphenylamine (15.4mmol) for raw material, according to compound III-3 preparation Method, obtain target compound III-4 white solid 1.11g, yield 88%.
1HNMR(CDCl3,δ:ppm):1.26-1.34(m,1H,A-H),1.40-1.50(m,4H,A-H),1.71-1.74 (m, 2H, A-H), 2.31-2.38 (m, 2H, A-H), 2.44 (t, 2H, J=8.0Hz, N-CH2),2.64(brs,4H,A-H), 2.96(s,3H,A-H),3.11(brs,4H,A-H),3.17-3.19(m,2H,A-H),3.57(s,3H,A-H),6.45-6.48 (m,2H,Ar-H),6.60-6.63(m,1H,Ar-H),6.72-6.75(m,1H,Ar-H),6.99-7.02(m,1H,Ar-H), 7.23-7.27(m,2H,Ar-H),7.60-7.66(m,2H,Ar-H).
ESI-MS:452[M+H+].
The preparation of compound III-4 hydrobromates
Compound III-4 (2.5mmol), 5% hydrobromic acid aqueous solution (2.6mmol) are added in ethanol (20mL), returned Stream dissolving, cooling separate out white solid, filtering, obtain 1.07g white solids, yield 80%.
Elementary analysis：C26H37N5O2HBr (theoretical value %：C 58.64, H 7.19, N 13.15；Experiment value %：C 58.77, H 7.31, N 13.30).
Embodiment 29：N- (4- (2- (4- ([1,1'- diphenyl] -3- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -2- The preparation of methoxyl acetamide (compound III-5) and its salt
By 4- (2- (4- ([1,1'- diphenyl] -3- bases) piperazine -1- bases) ethyl) piperidines -1- amine (9-3) (according to logical method One prepares) (1.0g, 2.8mmol), triethylamine (4.2mmol) be added in dichloromethane (10mL), methoxyacetyl chloride is added dropwise Dichloromethane (5mL) solution of (0.34g, 3.1mmol), react 3h, successively with water (20mL × 2), saturated aqueous common salt (10mL × 2) wash, anhydrous sodium sulfate drying, filter, be concentrated to give white solid, through 95% ethanol solution crystallizing, obtain white solid 1.08g, receive Rate 88%.
1HNMR(CDCl3,δ:ppm):1.20-1.38(m,2H,A-H),1.46-1.72(m,5H,A-H),2.31-2.37 (m, 2H, A-H), 2.44 (t, 2H, J=8.0Hz, N-CH2),2.64(brs,4H,A-H),3.07(brs,4H,A-H),3.13- 3.15(m,2H,A-H),3.33(s,3H,A-H),4.32(s,2H,A-H),6.65-6.70(m,2H,Ar-H),6.81(d,1H,J =2.4Hz, Ar-H), 7.30-7.44 (m, 6H, Ar-H)
ESI-MS:437[M+H+].
The preparation of compound III-5 hydrochlorides
Compound III-5 (2.5mmol), 5% aqueous hydrochloric acid solution (2.6mmol) are added in ethanol (20mL), flowed back Dissolving, cooling separate out white solid, filtering, obtain 1.08g white solids, yield 91%.
Elementary analysis：C26H36N4O2HCl (theoretical value %：C 66.01, H 7.88, N 11.84；Experiment value %：C 66.23, H 7.69, N 11.60).
Embodiment 30：3- (4- (2- (4- ([1,1'- diphenyl] -3- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -1, The preparation of 1- dimethyl ureas (compound III-6) and its salt
With intermediate 9-3 (2.8mmol), N, N- dimethyl amines (15.4mmol) are raw material, according to compound III-3 system Preparation Method, obtain target compound III-6 white solid 1.12g, yield 92%.
1HNMR(CDCl3,δ:ppm):1.24-1.32(m,1H,A-H),1.41-1.49(m,4H,A-H),1.68-1.71 (m, 2H, A-H), 2.30-2.36 (m, 2H, A-H), 2.42 (t, 2H, J=8.0Hz, N-CH2),2.62(brs,4H,A-H), 2.89(s,6H,A-H),3.06(brs,4H,A-H),3.13-3.15(m,2H,A-H),6.67-6.72(m,2H,Ar-H),6.83 (d, 1H, J=2.4Hz, Ar-H), 7.31-7.46 (m, 6H, Ar-H)
ESI-MS:436[M+H+].
The preparation of compound III-6 hydrobromates
With compound III-6 (2.5mmol), 5% hydrobromic acid aqueous solution (2.6mmol) for raw material, using compound III-5 The preparation method of hydrochloride, obtain 1.07g white solids, yield 83%.
Elementary analysis：C26H37N5OHBr (theoretical value %：C 60.46, H 7.42, N 13.56；Experiment value %：C 60.59, H 7.30, N 13.78).
Embodiment 31：N- (4- (2- (4- (naphthalene -1- bases) piperazine -1- bases) ethyl) piperidin-1-yl) furans -2- formamides The preparation of (compound III-7) and its salt
With intermediate 4- (2- (4- (naphthalene -1- bases) piperazine -1- bases) ethyl) piperidines -1- amine (9-4) (2.8mmol, according to logical It is prepared by method one), furans -2- formyl chlorides (3.1mmol) be raw material, according to compound III-5 preparation method, obtain target compound III-7 white solid 1.16g, yield 96%.
1HNMR(CDCl3,δ:ppm):1.20-1.36(m,2H,A-H),1.44-1.54(m,4H,A-H),1.72-1.74 (m, 1H, A-H), 2.32-2.38 (m, 2H, A-H), 2.39 (t, 2H, J=8.0Hz, N-CH2),2.66(brs,4H,A-H), 3.08(brs,4H,A-H),3.17-3.19(m,2H,A-H),6.86-6.90(m,2H,Ar-H),7.02-7.10(m,3H,Ar- H),7.34-7.38(m,2H,Ar-H),7.90-7.91(m,1H,Ar-H),8.11-8.17(m,2H,Ar-H).
ESI-MS:433[M+H+].
The preparation of compound III-7 hydrochlorides
With compound III-7 (2.5mmol), 5% aqueous hydrochloric acid solution (2.6mmol) for raw material, using compound III-5 salt The preparation method of hydrochlorate, obtain 1.09g white solids, yield 93%.
Elementary analysis：C26H32N4O2HBr (theoretical value %：C 66.58, H 7.09, N 11.95；Experiment value %：C 66.73, H 7.28, N 11.84).
Embodiment 32：1,1- dimethyl -3- (4- (2- (4- (naphthalene -1- bases) piperazine -1- bases) ethyl) piperidin-1-yl) urea The preparation of (compound III-8) and its salt
With intermediate 9-4 (2.8mmol), N, N- dimethyl amines (15.4mmol) are raw material, according to compound III-3 system Preparation Method, obtain target compound III-8 white solid 0.99g, yield 86%.
1HNMR(CDCl3,δ:ppm):1.25-1.34(m,1H,A-H),1.40-1.48(m,4H,A-H),1.67-1.70 (m, 2H, A-H), 2.29-2.35 (m, 2H, A-H), 2.40 (t, 2H, J=8.0Hz, N-CH2),2.60(brs,4H,A-H), 2.88(s,6H,A-H),3.06(brs,4H,A-H),3.12-3.14(m,2H,A-H),6.83-6.87(m,2H,Ar-H), 7.00-7.07(m,3H,Ar-H),7.32-7.36(m,2H,Ar-H),7.87-7.89(m,1H,Ar-H),8.09-8.15(m, 2H,Ar-H).
ESI-MS:410[M+H+].
The preparation of compound III-8 hydrobromates
With compound III-8 (2.4mmol), 5% hydrobromic acid aqueous solution (2.5mmol) for raw material, using compound III-5 The preparation method of hydrochloride, obtain 1.07g white solids, yield 91%.
Elementary analysis：C24H35N5OHBr (theoretical value %：C 58.77, H 7.40, N 14.28；Experiment value %：C 58.89, H 7.61, N 14.11).
Embodiment 33：N- (4- (2- (4- (2 (3H) H- benzoxazolone -7- bases) piperazine -1- bases) ethyl) piperidin-1-yl) The preparation of furans -2- formamides (compound III-9) and its salt
With intermediate 7- (4- (2- (1 amino piperidine -4- bases) ethyl) piperazine -1- bases) benzo [d] oxazole -2 (3H) -one (9-5) (2.8mmol, being prepared according to logical method one), furans -2- formyl chlorides (3.1mmol) are raw material, according to compound III-5's Preparation method, obtain target compound III-9 white solid 1.11g, yield 90%.
1HNMR(CDCl3,δ:ppm):1.23-1.39(m,2H,A-H),1.47-1.57(m,4H,A-H),1.75-1.77 (m, 1H, A-H), 2.35-2.41 (m, 2H, A-H), 2.42 (t, 2H, J=8.0Hz, N-CH2),2.69(brs,4H,A-H), 3.11(brs,4H,A-H),3.20-3.22(m,2H,A-H),6.89-6.93(m,2H,Ar-H),7.08-7.15(m,3H,Ar- H),7.40-7.43(m,1H,Ar-H).
ESI-MS:440[M+H+].
The preparation of compound III-9 hydrochlorides
With compound III-9 (2.5mmol), 5% aqueous hydrochloric acid solution (2.6mmol) for raw material, using compound III-5 salt The preparation method of hydrochlorate, obtain 1.04g white solids, yield 87%.
Elementary analysis：C23H29N5O4HCl (theoretical value %：C 58.04, H 6.35, N 14.71；Experiment value %：C 58.19, H 6.48, N 14.54).
Embodiment 34：1,1- dimethyl -3- (4- (2- (4- (2 (3H) H- benzoxazolone -7- bases) piperazine -1- bases) second Base) piperidin-1-yl) urea (compound III-10) and its salt preparation
With intermediate 9-5 (2.8mmol), N, N- dimethyl amines (15.4mmol) are raw material, according to compound III-3 system Preparation Method, obtain target compound III-10 white solid 1.06g, yield 91%.
1HNMR(CDCl3,δ:ppm):1.27-1.36(m,1H,A-H),1.44-1.52(m,4H,A-H),1.71-1.74 (m, 2H, A-H), 2.33-2.39 (m, 2H, A-H), 2.46 (t, 2H, J=8.0Hz, N-CH2),2.66(brs,4H,A-H), 2.94(s,6H,A-H),3.12(brs,4H,A-H),3.18-3.20(m,2H,A-H),6.91-6.95(m,2H,Ar-H), 7.09-7.16(m,3H,Ar-H),7.40-7.44(m,1H,Ar-H).
ESI-MS:417[M+H+].
The preparation of compound III-10 hydrobromates
With compound III-10 (2.5mmol), 5% hydrobromic acid aqueous solution (2.6mmol) for raw material, using compound III- The preparation method of 5 hydrochlorides, obtain 1.16g white solids, yield 93%.
Elementary analysis：C21H32N6O3HBr (theoretical value %：C 50.71, H 6.69, N 16.89；Experiment value %：C 50.58, H 6.81, N 16.62).
Embodiment 35：N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) pentanamide The preparation of (compound IV-1) and its salt
With intermediate 4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl-amine 9-6 (2.8mmol, being prepared according to the logical method one of synthesis), valeric chloride (3.1mmol) are raw material, according to compound I-1 preparation method, are obtained Target compound IV-1 white solid 1.17g, yield 97%.
1HNMR(CDCl3,δ:ppm):0.81 (t, 3H, J=7.2Hz, A-H), 1.17-1.36 (m, 4H, A-H), 1.42- 1.53 (m, 6H, A-H), 1.69-1.72 (m, 1H, A-H), 2.29-2.35 (m, 2H, A-H), 2.29 (t, 2H, J=7.6Hz, A- ), H 2.38 (t, 2H, J=8.0Hz, N-CH2),3.08-3.10(m,2H,A-H),3.32(s,8H,CH2- H), 6.97 (d, J= 7.6Hz, 1H, Ar-H), 7.31 (t, J=7.9Hz, 1H, Ar-H), 7.54 (d, J=5.5Hz, 1H, Ar-H), 7.69 (d, J= 8.1Hz, 1H, Ar-H), 7.75 (d, J=5.5Hz, 1H, Ar-H)
ESI-MS:429[M+H+].
The preparation of compound IV-1 hydrochlorides
With compound IV-1 (2.7mmol), 5% aqueous hydrochloric acid solution (2.8mmol) for raw material, using compound I-1 hydrochloric acid The preparation method of salt, obtain 1.13g white solids, yield 90%.
Elementary analysis：C24H36N4OSHCl (theoretical value %：C 61.98, H 8.02, N 12.05；Experiment value %：C 61.75, H 8.22, N 12.18).
Embodiment 36：N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -2- first The preparation of epoxide acetamide (compound IV-2) and its salt
With intermediate 9-6 (2.8mmol), methoxyl group, acyl chlorides (3.1mmol) is raw material, according to compound I-1 preparation Method, obtain target compound IV-2 white solid 1.04g, yield 89%.
1HNMR(CDCl3,δ:ppm):1.16-1.33(m,2H,A-H),1.42-1.68(m,5H,A-H),2.30-2.36 (m, 2H, A-H), 2.39 (t, 2H, J=8.0Hz, N-CH2),3.10-3.13(m,2H,A-H),3.28(s,8H,CH2-H),3.30 (s, 3H, A-H), 4.25 (s, 2H, A-H), 6.95 (d, J=7.6Hz, 1H, Ar-H), 7.29 (t, J=7.9Hz, 1H, Ar-H), 7.52 (d, J=5.5Hz, 1H, Ar-H), 7.67 (d, J=8.1Hz, 1H, Ar-H), 7.73 (d, J=5.5Hz, 1H, Ar-H)
ESI-MS:417[M+H+].
The preparation of compound IV-2 hydrobromates
With compound IV-2 (2.7mmol), 5% hydrobromic acid aqueous solution (2.8mmol) for raw material, using compound I-1 salt The preparation method of hydrochlorate, obtain 1.14g white solids, yield 85%.
Elementary analysis：C22H32N4O2SHBr (theoretical value %：C 53.11, H 6.69, N 11.26；Experiment value %：C 53.34, H 6.86, N 11.04).
Embodiment 37：N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) benzoyl The preparation of amine (compound IV-3) and its salt
With intermediate 9-6 (2.8mmol), chlorobenzoyl chloride (3.1mmol) for raw material, according to compound I-1 preparation method, Obtain target compound IV-3 white solid 1.16g, yield 92%.
1HNMR(CDCl3,δ:ppm):1.21-1.38(m,2H,A-H),1.47-1.55(m,4H,A-H),1.73-1.76 (m, 1H, A-H), 2.31-2.37 (m, 2H, A-H), 2.42 (t, 2H, J=8.0Hz, N-CH2),2.66(brs,4H,A-H), 3.01 (brs, 4H, A-H), 3.12-3.16 (m, 2H, A-H), 6.93 (d, J=7.6Hz, 1H, Ar-H), 7.26 (t, J= 7.9Hz, 1H, Ar-H), 7.52-7.58 (m, 3H, Ar-H), 7.64-7.68 (m, 2H, Ar-H), 7.73 (d, J=5.5Hz, 1H, Ar-H),7.93-7.96(m,2H,Ar-H).
ESI-MS:449[M+H+].
The preparation of compound IV-3 hydrochlorides
With compound IV-3 (2.6mmol), 5% aqueous hydrochloric acid solution (2.7mmol) for raw material, using compound I-1 hydrochloric acid The preparation method of salt, obtain 1.0g white solids, yield 79%.
Elementary analysis：C26H32N4OSHCl (theoretical value %：C 64.38, H 6.86, N 11.55；Experiment value %：C 64.51, H 6.61, N 11.78).
Embodiment 38：N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) cyclopropyl The preparation of formamide (compound IV-4) and its salt
With intermediate 9-6 (2.8mmol), Cyclopropyl carbonyl chloride (3.1mmol) for raw material, according to compound I-1 preparation Method, obtain target compound IV-4 white solid 1.1g, yield 95%.
1HNMR(CDCl3,δ:ppm):0.65-0.76(m,4H,A-H),1.13-1.30(m,3H,A-H),1.39-1.48 (m, 4H, A-H), 1.66-1.69 (m, 1H, A-H), 2.24-2.30 (m, 2H, A-H), 2.34 (t, 2H, J=8.0Hz, N-CH2), 2.55 (brs, 4H, A-H), 2.97 (brs, 4H, A-H), 3.04-3.06 (m, 2H, A-H), 6.93 (d, J=7.6Hz, 1H, Ar- ), H 7.27 (t, J=7.9Hz, 1H, Ar-H), 7.50 (d, J=5.5Hz, 1H, Ar-H), 7.65 (d, J=8.1Hz, 1H, Ar- ), H 7.71 (d, J=5.5Hz, 1H, Ar-H)
ESI-MS:413[M+H+].
The preparation of compound IV-4 hydrobromates
With compound IV-4 (2.5mmol), 5% hydrobromic acid aqueous solution (2.6mmol) for raw material, using compound I-1 salt The preparation method of hydrochlorate, obtain 1.04g white solids, yield 84%.
Elementary analysis：C23H32N4OSHBr (theoretical value %：C 55.98, H 6.74, N 11.35；Experiment value %：C 55.72, H 6.89, N 11.17).
Embodiment 39：N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) niacinamide The preparation of (compound IV-5) and its salt
With intermediate 9-6 (2.8mmol), nicotinoyl chlorine (3.1mmol) for raw material, according to compound I-1 preparation method, obtain Target compound IV-5 white solid 1.08g, yield 86%.
1HNMR(CDCl3,δ:ppm):1.27-1.44(m,2H,A-H),1.53-1.61(m,4H,A-H),1.79-1.82 (m, 1H, A-H), 2.37-2.43 (m, 2H, A-H), 2.48 (t, 2H, J=8.0Hz, N-CH2),2.72(brs,4H,A-H), 3.07 (brs, 4H, A-H), 3.18-3.22 (m, 2H, A-H), 6.99 (d, J=7.6Hz, 1H, Ar-H), 7.33 (t, J= 7.9Hz, 1H, Ar-H), 7.51-7.56 (m, 2H, Ar-H), 7.71 (d, J=8.1Hz, 1H, Ar-H), 7.77 (d, J=5.5Hz, 1H,Ar-H),8.15-8.20(m,2H,Ar-H),8.89-8.92(m,1H,Ar-H).
ESI-MS:450[M+H+].
The preparation of compound IV-5 hydrochlorides
With compound IV-5 (2.2mmol), 5% aqueous hydrochloric acid solution (2.3mmol) for raw material, using compound I-1 hydrochloric acid The preparation method of salt, obtain 0.98g white solids, yield 92%.
Elementary analysis：C25H31N5OSHCl (theoretical value %：C 61.77, H 6.64, N 14.41；Experiment value %：C 61.50, H 6.83, N 14.25).
Embodiment 40：N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) furans - The preparation of 2- formamides (compound IV-6) and its salt
With intermediate 9-6 (2.8mmol), furans -2- formyl chlorides (3.1mmol) for raw material, according to compound I-1 preparation Method, obtain target compound IV-6 white solid 1.08g, yield 90%.
1HNMR(CDCl3,δ:ppm):1.18-1.35(m,2H,A-H),1.44-1.70(m,5H,A-H),2.31-2.37 (m, 2H, A-H), 2.40 (t, 2H, J=8.0Hz, N-CH2),3.11-3.14(m,2H,A-H),3.29(s,8H,CH2-H), 6.76-6.80 (m, 2H, Ar-H), 7.27-7.30 (m, 2H, Ar-H), 7.53 (d, J=5.5Hz, 1H, Ar-H), 7.68 (d, J= 8.1Hz,1H,Ar-H),7.74-7.79(m,2H,Ar-H).
ESI-MS:439[M+H+].
The preparation of compound IV-6 hydrobromates
With compound IV-6 (2.3mmol), 5% hydrobromic acid aqueous solution (2.4mmol) for raw material, using compound I-1 salt The preparation method of hydrochlorate, obtain 1.05g white solids, yield 88%.
Elementary analysis：C24H30N4O2SHBr (theoretical value %：C 55.49, H 6.01, N 10.78；Experiment value %：C 55.33, H 6.24, N 10.54).
Embodiment 41：3- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -1,1- The preparation of dimethyl urea (compound IV-7) and its salt
With intermediate 9-6 (2.8mmol), N, N- dimethyl amines (15.4mmol) are raw material, according to compound II-1 system Preparation Method, obtain target compound IV-7 white solid 0.94g, yield 81%.
1HNMR(CDCl3,δ:ppm):1.23-1.32(m,1H,A-H),1.37-1.45(m,4H,A-H),1.64-1.67 (m, 2H, A-H), 2.27-2.33 (m, 2H, A-H), 2.37 (t, 2H, J=8.0Hz, N-CH2),2.86(s,6H,A-H),3.10- 3.12(m,2H,A-H),3.33(s,8H,CH2- H), 6.96 (d, J=7.6Hz, 1H, Ar-H), 7.30 (t, J=7.9Hz, 1H, ), Ar-H 7.53 (d, J=5.5Hz, 1H, Ar-H), 7.68 (d, J=8.1Hz, 1H, Ar-H), 7.74 (d, J=5.5Hz, 1H, Ar-H).
ESI-MS:416[M+H+].
The preparation of compound IV-7 hydrochlorides
With compound IV-7 (2.3mmol), 5% aqueous hydrochloric acid solution (2.4mmol) for raw material, using compound I-1 hydrochloric acid The preparation method of salt, obtain 0.83g white solids, yield 80%.
Elementary analysis：C22H33N5OSHCl (theoretical value %：C 58.45, H 7.58, N 15.49；Experiment value %：C 58.61, H 7.33, N 15.67).
Embodiment 42：1- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -3- benzene The preparation of base urea (compound IV-8) and its salt
With intermediate 9-6 (2.8mmol), aniline (15.4mmol) for raw material, according to compound II-1 preparation method, obtain Target compound IV-8 white solid 1.22g, yield 94%.
1HNMR(CDCl3,δ:ppm):1.21-1.37(m,2H,A-H),1.47-1.62(m,5H,A-H),2.33-2.39 (m, 2H, A-H), 2.41 (t, 2H, J=8.0Hz, N-CH2),3.14-3.16(m,2H,A-H),3.31(s,8H,CH2-H),6.05 (brs, 1H, NH-H), 7.01 (d, J=7.6Hz, 1H, Ar-H), 7.13-7.15 (m, 1H, Ar-H), 7.32-7.36 (m, 3H, ), Ar-H 7.54-7.58 (m, 3H, Ar-H), 7.71 (d, J=8.1Hz, 1H, Ar-H), 7.78 (d, J=5.5Hz, 1H, Ar-H)
ESI-MS:464[M+H+].
The preparation of compound IV-8 hydrobromates
With compound IV-8 (2.5mmol), 5% hydrobromic acid aqueous solution (2.6mmol) for raw material, using compound I-1 salt The preparation method of hydrochlorate, obtain 1.16g white solids, yield 85%.
Elementary analysis：C26H33N5OSHBr (theoretical value %：C 57.35, H 6.29, N 12.86；Experiment value %：C 57.49, H 6.14, N 12.61).
Embodiment 43：1- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -3- (pyrroles Pyridine -3- bases) urea (compound IV-9) and its salt preparation
With intermediate 9-6 (2.8mmol), pyridine -3- amine (15.4mmol) for raw material, according to compound II-1 preparation side Method, obtain target compound IV-9 white solid 1.18g, yield 91%.
1HNMR(CDCl3,δ:ppm):1.26-1.42(m,2H,A-H),1.52-1.67(m,5H,A-H),2.38-2.44 (m, 2H, A-H), 2.46 (t, 2H, J=8.0Hz, N-CH2),3.19-3.21(m,2H,A-H),3.36(s,8H,CH2-H),6.10 (brs, 1H, NH-H), 7.06 (d, J=7.6Hz, 1H, Ar-H), 7.37-7.41 (m, 2H, Ar-H), 7.59-7.63 (m, 3H, ), Ar-H 7.76 (d, J=8.1Hz, 1H, Ar-H), 7.83 (d, J=5.5Hz, 1H, Ar-H), 8.85-8.88 (m, 1H, Ar-H)
ESI-MS:465[M+H+].
The preparation of compound IV-9 hydrochlorides
With compound IV-9 (2.5mmol), 5% aqueous hydrochloric acid solution (2.6mmol) for raw material, using compound I-1 hydrochloric acid The preparation method of salt, obtain 1.09g white solids, yield 87%.
Elementary analysis：C25H32N6OSHCl (theoretical value %：C 59.92, H 6.64, N 16.77；Experiment value %：C 59.71, H 6.44, N 16.62).
Embodiment 44：3- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -1- first The preparation of base -1- phenylureas (compound IV-10) and its salt
With intermediate 9-6 (2.8mmol), methylphenylamine (15.4mmol) for raw material, according to compound II-1 preparation Method, obtain target compound IV-10 white solid 1.04g, yield 78%.
1HNMR(CDCl3,δ:ppm):1.24-1.32(m,1H,A-H),1.38-1.48(m,4H,A-H),1.69-1.72 (m, 2H, A-H), 2.29-2.36 (m, 2H, A-H), 2.42 (t, 2H, J=8.0Hz, N-CH2),2.62(brs,4H,A-H), 3.09(brs,4H,A-H),3.15-3.17(m,2H,A-H),3.54(s,3H,A-H),6.83-6.86(m,2H,Ar-H), 7.02-7.07(m,2H,Ar-H),7.28-7.31(m,1H,Ar-H),7.46-7.48(m,1H,Ar-H),7.66-7.70(m, 2H,Ar-H),7.81-7.85(m,2H,Ar-H).
ESI-MS:478[M+H+].
The preparation of compound IV-10 hydrobromates
With compound IV-10 (2.0mmol), 5% hydrobromic acid aqueous solution (2.1mmol) for raw material, using compound I-1 salt The preparation method of hydrochlorate, obtain 1.01g white solids, yield 90%.
Elementary analysis：C27H35N5OSHBr (theoretical value %：C 58.06, H 6.50, N 12.54；Experiment value %：C 58.22 H 6.40, N 12.37).
Embodiment 45：1- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -3- rings The preparation of propyl group urea (compound IV-11) and its salt
With intermediate 9-6 (2.8mmol), cyclopropylamine (15.4mmol) for raw material, according to compound II-1 preparation side Method, obtain target compound IV-11 white solid 0.94g, yield 88%.
1HNMR(CDCl3,δ:ppm):0.59-0.62(m,2H,A-H),0.84-0.85(m,2H,A-H),1.17-1.33 (m, 2H, A-H), 1.43-1.58 (m, 5H, A-H), 2.29-2.35 (m, 2H, A-H), 2.37 (t, 2H, J=8.0Hz, N-CH2), 2.60(brs,4H,A-H),2.78(m,1H,A-H),3.03(brs,4H,A-H),3.09-3.11(m,2H,A-H),5.98 (brs, 1H, NH-H), 6.96 (d, J=7.6Hz, 1H, Ar-H), 7.30 (t, J=7.9Hz, 1H, Ar-H), 7.54 (d, J= 5.5Hz, 1H, Ar-H), 7.68 (d, J=8.1Hz, 1H, Ar-H), 7.74 (d, J=5.5Hz, 1H, Ar-H)
ESI-MS:428[M+H+].
The preparation of compound IV-11 hydrochlorides
With compound IV-11 (2.3mmol), 5% aqueous hydrochloric acid solution (2.4mmol) for raw material, using compound I-1 hydrochloric acid The preparation method of salt, obtain 0.90g white solids, yield 84%.
Elementary analysis：C23H33N5OSHCl (theoretical value %：C 59.53, H 7.38, N 15.09；Experiment value %：C 59.41, H 7.21, N 15.31).
Embodiment 46：N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) morpholine - The preparation of 4- formamides (compound IV-12) and its salt
With intermediate 9-6 (2.8mmol), morpholine (15.4mmol) for raw material, according to compound II-1 preparation method, obtain Target compound IV-12 white solid 1.09g, yield 85%.
1HNMR(CDCl3,δ:ppm):1.23-1.31(m,1H,A-H),1.41-1.49(m,4H,A-H),1.69-1.72 (m, 2H, A-H), 2.30-2.36 (m, 2H, A-H), 2.42 (t, 2H, J=8.0Hz, N-CH2),2.62(brs,4H,A-H), 3.07(brs,4H,A-H),3.11-3.15(m,2H,A-H),3.36-3.42(m,4H,A-H),3.68-3.73(m,4H,A-H), 7.00 (d, J=7.6Hz, 1H, Ar-H), 7.34 (t, J=7.9Hz, 1H, Ar-H), 7.58 (d, J=5.5Hz, 1H, Ar-H), 7.70 (d, J=8.1Hz, 1H, Ar-H), 7.76 (d, J=5.5Hz, 1H, Ar-H)
ESI-MS:458[M+H+].
The preparation of compound IV-12 hydrobromates
With compound IV-12 (2.3mmol), 5% hydrobromic acid aqueous solution (2.4mmol) for raw material, using compound I-1 salt The preparation method of hydrochlorate, obtain 1.13g white solids, yield 91%.
Elementary analysis：C24H35N5O2SHBr (theoretical value %：C 53.53, H 6.74, N 13.00；Experiment value %：C 53.27, H 6.87, N 13.25).
Embodiment 47：The preparation of tablet
The present embodiment is that prepared by compound of the present invention into piece agent.By all chemical combination of the present invention in the present embodiment Thing prepares piece agent.
The composition of tablet：
Preparation method：Active component is mixed with sucrose, cornstarch, adds water to soak, stirs, dry, pulverize Sieve, magnesium stearate is added, be well mixed, tabletting.Every weight 200mg, active component content 5mg.
Embodiment 48：The preparation of injection
The present embodiment is that compound of the present invention is prepared into injection.By all chemical combination of the present invention in the present embodiment Thing is prepared into injection.
The composition of injection：
The compound 10mg of the present invention
Water for injection 90mg
Preparation method：Active component is dissolved in water for injection, is well mixed, filtering, by the solution obtained sterile Under the conditions of be sub-packed in ampoule bottle, every bottle of 10mg, active component content is 1.0mg/ bottles.
Embodiment 49：Dopamine D2Receptor binding assays
All compounds of the present invention are subjected to dopamine D in the present embodiment2Receptor binding assays, so as to detect the present invention The compound and dopamine D2The affinity of acceptor.
1st, experiment material
D2Acceptor isotope part [3H] methyl-spiperone (Spiperone) (0.3nM), butaclamol (Butaclamol) (10 μM), fat-soluble scintillation solution, expression people source restructuring (human recombinant) D2RECEPTOR FUNCTIONAL egg White HEK-293 cells.Cariliprazine is as positive drug control.
2nd, experimental method
Reference literature Hall, D.A. and Strange, P.G. (1997), Brit.J.Pharmacol., 121:731-736. Operating method, use [3H] methyl-spiperone (Spiperone) (0.3nM) is used as D2Acceptor isotope part, in table Intelligent source recombinates D2D is carried out on the HEK-293 cells of receptor protein2Receptor binding assay.In 10 μM of butaclamols (Butaclamol) non-specific binding is determined in the presence of.
Inhibiting rate is calculated by following formula：
Inhibiting rate (I%)=(total binding pipe cpm- compound cpm)/(total binding pipe cpm- non-specific bindings pipe cpm) × 100%.
Inhibiting rate carries out a series of receptor binding assays of concentration higher than 95% compound, determines half amount of suppression (IC50, Suppression 50% [3H] methyl-spiperone and D2Acceptor compound concentration with reference to needed for).Per the looped pipeline of concentration mensuration two, Mei Gehua Compound carries out independent experiment twice.
The affinity of medicine and acceptor is calculated by following formula：
Ki=IC50/(1+[L]KD)
(Ki：The affinity of medicine and acceptor, L：The concentration of radioligand, KD：The affinity of radioligand and acceptor Value)
The compounds of this invention and D2Receptor binding assays the results are shown in Table 1.The result of the test of table 1 shows：Of the present inventionization Compound is to dopamine D2Acceptor has strong or moderate strength affinity.
Embodiment 50：Dopamine D3Receptor binding assays
All compounds of the present invention are subjected to dopamine D in the present embodiment3Receptor binding assays, so as to detect the present invention The compound and dopamine D3The affinity of acceptor.
1st, experiment material
D3Acceptor isotope part [3H] methyl-spiperone (0.3nM), (+) butaclamol (Butaclamol) (10 μ M), fat-soluble scintillation solution, expression people source restructuring D3The Chinese hamster ovary celI of RECEPTOR FUNCTIONAL albumen.Cariliprazine is as positive drug pair According to.
2nd, experimental method
(1994) such as reference literature Mackenzie, R.G., Eur.J.Pharmacol., 266:79-85. operating method, Use [3H] methyl-spiperone (0.3nM) is used as D3Acceptor isotope part, in expression people source restructuring D3Receptor protein D is carried out on Chinese hamster ovary celI3Receptor binding assay.Non-specific binding is determined in the presence of 10 μM of (+) butaclamols.
Inhibiting rate is calculated by following formula：
Inhibiting rate (I%)=(total binding pipe cpm- compound cpm)/(total binding pipe cpm- non-specific bindings pipe cpm) × 100%.
Inhibiting rate carries out a series of receptor binding assays of concentration higher than 95% compound, determines half amount of suppression (IC50, Suppression 50% [3H] methyl-spiperone and D3Acceptor compound concentration with reference to needed for).Per the looped pipeline of concentration mensuration two, Mei Gehua Compound carries out independent experiment twice.
The affinity of medicine and acceptor is calculated by following formula：
Ki=IC50/(1+[L]KD)
(Ki：The affinity of medicine and acceptor, L：The concentration of radioligand, KD：The affinity of radioligand and acceptor Value)
The compounds of this invention and D3Receptor binding assays the results are shown in Table 1.Compound pair of the present invention as can be seen from Table 1 D3Acceptor has strong affinity, suitable with positive drug Cariliprazine, in conjunction with the embodiments 49 result, and this series compound is to D3/D2 Acceptor also has suitable selectivity, i.e., selectivity is between 10~60 times.
Embodiment 51：5-HT1AReceptor binding assays
All compounds of the present invention are subjected to 5-HT in the present embodiment1AReceptor binding assays, so as to detect institute of the present invention State compound and 5-HT1AThe affinity of acceptor.
1st, experiment material
5-HT1AAcceptor isotope part [3H] 8-OH-DPAT (0.3nM), 8-OH-DPAT (10 μM), fat-soluble scintillation solution, Express people source restructuring 5-HT1AThe HEK-293 cells of RECEPTOR FUNCTIONAL albumen.Cariliprazine is as positive drug control.
2nd, experimental method
(1994) such as reference literature Mulheron, J.G., J.Biol.Chem., 269:12954-12962. operation side Method, use [3H] 8-OH-DPAT (0.3nM) is used as 5-HT1AAcceptor isotope part, in expression people source restructuring 5-HT1AAcceptor egg 5-HT is carried out on white HEK-293 cells1AReceptor binding assay.Non-specific knot is determined in the presence of 10 μM of 8-OH-DPAT Close.
Inhibiting rate carries out a series of receptor binding assays of concentration higher than 95% compound, determines half amount of suppression (IC50, Suppression 50% [3H] 8-OH-DPAT and 5-HT1AAcceptor compound concentration with reference to needed for).Per the looped pipeline of concentration mensuration two, each chemical combination Thing carries out independent experiment twice.
The affinity of medicine and acceptor is calculated by following formula：
Ki=IC50/(1+[L]KD)
(Ki：The affinity of medicine and acceptor, L：The concentration of radioligand, KD：The affinity of radioligand and acceptor Value)
The compounds of this invention and 5-HT1AReceptor binding assays the results are shown in Table 1.Table 1 test result indicates that, it is of the present invention Compound is to 5-HT1AAcceptor has strong affinity, suitable with positive drug Cariliprazine.
Embodiment 52：5-HT2AReceptor binding assays
All compounds of the present invention are subjected to 5-HT in the present embodiment2AReceptor binding assays, so as to detect institute of the present invention State compound and 5-HT2AThe affinity of acceptor.
1st, experiment material
5-HT2AAcceptor isotope part [3H] ketanserin (ketanserin) (0.5nM), ketanserin (ketanserin) (1 μM), fat-soluble scintillation solution, expression people source restructuring 5-HT2AThe HEK-293 cells of RECEPTOR FUNCTIONAL albumen.Cariliprazine is as sun Property medicine control.
2nd, experimental method
(1995) such as reference literature Bonhaus, D.W., Brit.J.Pharmacol., 115:622-628. operation side Method, use [3H] ketanserin (0.5nM) is used as 5-HT2AAcceptor isotope part, in expression people source restructuring 5-HT2AReceptor protein 5-HT is carried out on HEK-293 cells2AReceptor binding assay.Non-specific binding is determined in the presence of 1 μM of ketanserin.
Inhibiting rate carries out a series of receptor binding assays of concentration higher than 95% compound, determines half amount of suppression (IC50, Suppression 50% [3H] ketanserin and 5-HT2AAcceptor compound concentration with reference to needed for).Per the looped pipeline of concentration mensuration two, each compound Carry out independent experiment twice.
The affinity of medicine and acceptor is calculated by following formula：
Ki=IC50/(1+[L]KD)
(Ki：The affinity of medicine and acceptor, L：The concentration of radioligand, KD：The affinity of radioligand and acceptor Value)
The compounds of this invention and 5-HT2AReceptor binding assays the results are shown in Table 1.The result of the test of table 1 shows, of the present invention Compound is to 5-HT2AAcceptor has strong affinity, and majority of compounds is to 5-HT2AAffinity be better than positive drug Cariliprazine.
Table 1：Affinity (Ki value) of the compound to each acceptor
Therefore, the compound of the invention it can be seen from the result of table 1 is to D2、D3、5-HT1A、5-HT2AAcceptor is equal Has strong or moderate strength affinity, majority of compounds is to D in addition2/D3The suitable selectivity of acceptor tool, selectivity is 10~60 Between times, better than Cariliprazine (selectivity is less than 10 times).Majority of compounds is to 5-HT2AReceptor affinity is significantly better than the positive Comparison medicine.Thus such compound has the function that potential while improves cognitive disorder and low EPS side effects etc..
Embodiment 53：For dopamine D2In acceptor agonist activity [3H] adenosine uptake examination face
All compounds of the present invention are subjected to dopamine D in the present embodiment2In acceptor agonist activity [3H] adenosine takes the photograph Take examination face.Aripiprazole is positive control drug.
Experimental method
Washed twice by using culture mediums of the 200 μ L without serum and serum deprivation is removed to cell, by 90 μ L without serum Culture medium is added in each hole and flat board is incubated into 2-3h.10 μ as positive control are contained into the culture medium of serum, carrier (no Culture medium containing serum), negative control (antagonist, haloperole) or test compound in the culture medium without serum and Standard items (Quinpirole, final concentration of 1 μM of 10 μ L 10 μM of solution) are added in each hole.Flat board is set to return in incubator.
After 18h, add [3H] adenosine (0.5 μ Ci/ holes) in culture mediums of the 10 μ L without serum, and returns to flat board In incubator.After 4h, membrane proteolytic enzyme (0.25%) (100 μ L/ holes) is added.Flat board is set to return in incubator again.After 1h, lead to Cross and carry out fast filtering termination test through Whatman GF/B glass fibre filters.Such as use Brandel MLR-96T cells Collector, with the buffer solution washing nozzles of 500mL 50mM Tris-HCl pH 7.0.For example, use Wallac 1205 Betaplate liquid scintillation counters assess the radioactivity (50% effective dose) of the reservation on filter.Intrinsic activity is defined as Total intake (l μM of Quinpirole) subtracts the culture medium without serum, by test compound and the l μ for being categorized as 100% intrinsic activity M Quinpiroles (complete DA receptor stimulating agents) compare.All experiments are preferably carried out according to triplicate, wherein every kind of medicine is every A complete row are accounted in individual flat board.
Table 2：It is of the present invention that there is D2The compound results of acceptor portion agonism
Compound Intrinsic activity (%) Compound Intrinsic activity (%)
Kui pyrrole sieve 100 II-9 38
Aripiprazole 26 III-6 20
I-4 23 III-9 17
I-14 28 IV-6 40
II-2 25 IV-7 29
Result of the test shows：The compounds of this invention I-4, I-14, II-2, II-9, III-6, III-9, IV-6, IV-7 have D2 Acceptor portion agonism.
Embodiment 54：Anti- schizophrenia activity test in compound body of the present invention
D is selected in the present embodiment2/D3Receptor-selective is between 10~60 times, tool D2/D3/5-HT1A/5-HT2AAcceptor is strong The compound of affinity carries out anti-schizophrenia activity test.
1st, apomorphine model
(1) test method
The experiment uses acute administration pattern.
Experiment mice is grouped at random, gavage gives control or test compound 30 minutes pneumoretroperitoneum injection apomorphines (5mg/kg), induce stereotyped movement model.Observe and record and give after mouse apomorphine solution in 70 minutes, every 10 minutes (0- 10 minutes, 11-20 minutes, 21-30 minutes, 31-40 minutes, 41-50 minutes, 51-60 minutes, 61-70 minutes) go out within first 30 seconds Existing following symptoms, and scored according to following standards：
1) 4 points, persistently bait；
2) 3 points, cage lid is at least stung once during observation；
3) 2 points, cage bottom disk or cage wall are at least licked during observation once；
4) 1 point, there is mandatory smell and activity of bowing；
5) 0 point, do not occur above-mentioned activity.
Calculate mouse in 70 minutes and the total score of above-mentioned behavior occur, calculate improvement rate according to the following formula.Data are with average Value ± standard error (Mean ± SEM) is represented, is mapped with GraphPad Prism softwares, and data analysis is examined using t, P< It is believed that significant difference be present when 0.05.
(2) experiment packet and administration design
C57BL/6 mouse are randomly divided into 6 groups, and every group at least 9, respectively model control group (apomorphine, is dissolved in physiology Salt solution), Cariliprazine (positive control drug) and compound of the present invention (I-4, I-14, II-2, II-9, III-6, III-9, IV-1, IV-7 and IV-12).
(3) it is administered and to observation post administration
Compound and positive drug Cariliprazine (oral administration gavage) of the present invention administration graded doses are 0.05,0.10, 0.40、0.60、1.20mg·kg-1.In experimentation, the clinical response symptom of animal is recorded.
(4) statistical method
Total data withRepresent, handled with 11.5 software statistics bags, carry out the t inspections that two sample averages compare Test and one-way analysis of variance, with P<0.05 is significant difference.
(5) experimental result
Specific experimental result is shown in Table 3.
Table 3：Single oral gives suppression of the compounds such as I-1 to the total stereotyped movement of Apo. inducing mouse schizophrenia models (ED50)
This result of the test shows：Compared to positive control drug Cariliprazine, compound of the present invention can significantly improve small Mouse stereotypic behavior, and apomorphine induction schizophrenia model is schizoid classical model, thus present invention series Compound has good antipsychotic effect.Compound I-14, II-2, II-9, III-6, IV-1, IV-7 are to the mechanical row of mouse For improvement result (ED50) it is better than positive control drug Cariliprazine.
2nd, the mouse autogenic movement experiment of MK-801 inductions
(1) test method
The experiment uses acute administration pattern.Experiment mice is grouped at random, and is put into before experiment in spontaneous activity box Adapt to 5-10 minutes.Animal receives 10 minutes pneumoretroperitoneum injection MK-801 (0.5mg/kg) of gastric infusion, and puts back to spontaneous activity Case starts infrared monitor control, the video of continuous acquisition animal activity 90 minutes.Experiment uses the software statistics bags of SPSS 11.5 after terminating Video file is analyzed, obtains activity total distance in 90 minutes.Data are represented with average value ± standard error (Mean ± SEM), are used GraphPad Prism softwares are mapped, and data analysis is examined using t, P<It is believed that significant difference be present when 0.05.
(2) experiment packet and administration design
57BL/6 mouse are randomly divided into 6 groups, every group at least 12, respectively blank control group, model control group (MK- 801, be dissolved in physiological saline), Cariliprazine group and preferred compounds of the invention group.Cariliprazine as positive drug control, MK-801 is the tool drug of modeling.
(3) experimental result
Concrete outcome is shown in Table 4.
Table 4：The influence of total distance is moved in single oral administration to MK-801 inducing mouse schizophrenia models spacious field (ED50)
This result of the test shows：The spacious field motion that Cariliprazine group, the compound of the present invention can be obviously improved mouse is total Distance.Due to the common model that the spacious field motion model of MK-801 inductions is negative symptoms of schizophrenia, so institute of the present invention State series compound and have good antipsychotic negative symptoms effect.Compound I-14, II-9, III-6, IV-1, IV-7 couple The improvement rate of mouse spacious field motion is better than positive drug control Cariliprazine, illustrates I-14, II-9, III-6, IV- under the model 1st, IV-7 activity is better than Cariliprazine.
Embodiment 55：The measure of compound water soluble
The present embodiment choose 14 kinds of compounds of the present invention (compound I-4, I-5, I-8, I-14, II-2, II-5, II-9, III-2, III-6, III-9, IV-1, IV-6, IV-7 and IV-12), and 4 kinds of compound (PR-1 of the prior art: CN1829703A, the compound 1 of the specification embodiment 3 of page 17；PR-2：CN102159557A, specification embodiment of page 86 84 compound 84；PR-3：The compound IV-2 of the CN103130737A specifications embodiment 44 of page 41；PR-4： CN104140421A, the compound I-1 of the specification embodiment 1 of page 15) carry out soluble test measure.
1st, instrument：Waters e2695 high performance liquid chromatographs, SHA-B water-bath constant temperature oscillators.
2nd, method：Excessive bulk drug is added in the water of certain volume, is configured to its saturated solution, in constant temperature (37 DEG C) Vibrated 2 hours in shaker, supernatant is taken after standing, with 0.45 μm of filtering membrane filtration to sample introduction bottle, sample introduction measure.
3rd, the determining instrument of dissolution rate
ZRD-14 intelligence digestion instruments, Waters e2695 high performance liquid chromatographs.
4th, dissolution medium：Dissolution medium is used as using 900mL pH1.0 hydrochloric acid solutions and water respectively.
Method：The Chinese Pharmacopoeia dissolution rate of version rules of preparations 0931 in 2015 and drug release determination method the second method paddle method.
Rotating speed：75 revs/min.
Sample point：Respectively through 5,10,15,20,30,45,60min, take dissolution fluid 10mL, through 0.45 μm of membrane filtration, enter Sample determines.
5th, experimental result
Choose 14 kinds of compound (compound I-4, I-5, I-8, I-14, II-2, II-5, II-9, III- of the present invention 2nd, III-6, III-9, IV-1, IV-6, IV-7 and IV-12), and 4 kinds of compound (PR-1 of the prior art: CN1829703A, the compound 1 of the specification embodiment 3 of page 17；PR-2：CN102159557A, specification embodiment of page 86 84 compound 84；PR-3：The compound IV-2 of the CN103130737A specifications embodiment 44 of page 41；PR-4： CN104140421A, the compound I-1 of the specification embodiment 1 of page 15) soluble test measure is carried out as described above.It is specific real Test and the results are shown in Table 5.
Table 5：Compound water soluble
This result of the test shows：The compound water soluble of the present invention is significantly better than the representation compound in patent document.Cause This compound of the present invention is more conducive to the preparation and research of preparation and prescription.
Embodiment 56：Medicine generation experiment in compound rats body
The present embodiment choose 12 kinds of compounds of the present invention (compound I-4, I-5, I-8, II-2, II-5, II-9, III-2, III-6, III-9, IV-1, IV-6 and IV-7), and 4 kinds of compound (PR-1 of the prior art:CN1829703A, The compound 1 of the specification embodiment 3 of page 17；PR-2：CN102159557A, the compound of the specification embodiment 84 of page 86 84；PR-3：The compound IV-2 of the CN103130737A specifications embodiment 44 of page 41；PR-4：CN104140421A, specification The compound I-1 of the embodiment 1 of page 15) and positive drug control Cariliprazine carry out rat body in medicine generation experiment.
1st, testing program
1.1 experimental animal
Healthy male SD rat 48, it is divided into two groups, every group 24.The week old of all rats was at 10-12 weeks, weight range For 250-290g.
1.2 medication
Difference group rat uses different administering modes.It is 0.5mg/kg that vein, which gives the compounds of this invention dosage, administration Volume is 5mL/kg.Qf oral administration dosage is 2mg/kg, administered volume 10mL/kg.Punctured by tail vein and orally filled respectively Stomach is administered.Overnight fasting before administration, four hours feedings after administration.
1.3 sample collection
0.083 after administration, 0.25,0.5,1,2,4,8 and 24 hours respectively at each time point CO2Suction euthanasia 3 Rat, through in heart puncture blood collecting (about 1mL) to EDTA-K2 anticoagulant tubes (Bo Feimei sections, production number CLS-11131), and take brain Weighed after tissue, supernatant i.e. blood plasma taken with 6000rpm centrifugations 8min (centrifugation preposition in wet on ice) in blood sample 1 hour, Blood plasma and brain tissue are in -20 DEG C of Cord bloods, in case LC-MS/MS is analyzed.
1.4 analysis methods and detection
This experiment determines the sheet in P of Rats K experiments in plasma sample and brain tissue sample using LC-MS method respectively Invention compounds content.Each analysis batch establishes two standard curves, calculates the concentration of determinand in the analysis batch sample, and Retinue quality-control sample.The degree of accuracy of 3/4 concentrations above point is within 80%~120% in standard curve.Each analysis batch is set There is a quality-control sample (QC) of high, medium and low various concentrations, the parallel double sample of each concentration.Quality-control sample quantity is more than or equal to every batch The 5% of sample size, the concentration of quality-control sample is calculated according to the standard curve of each analysis batch.
The preparation of 1.5 quality-control samples
The μ L of rat blank plasma 95 are taken, it is 40,20,10,2,1,0.2,0.04 and 0.02 μ g/mL to be separately added into 5 μ L concentration Tested material standard aqueous solution of the present invention, mix, obtain concentration be respectively 2000,1000,500,100,50,10,2,1ng/mL Standard curve sample.The μ L of rat blank plasma 95 are taken, it is 32,16,0.8,0.06 μ g/mL tested materials to be separately added into 5 μ L concentration Standard aqueous solution, mix, it is respectively 1600,800,40 and 3ng/mL Quality Controls (QC) sample to obtain concentration.
2nd, chromatographic condition
Efficient liquid phase system：Shimadzu LC-30AD chromatographic columns：Thermo, C18,2.1 × 50mm, 5 μm
Flow velocity：0.4mL/min
3rd, Mass Spectrometer Method pattern
ESI, MRM (+)
4th, data are calculated and handled
Initial data is gathered and calculated by AB Sciex companies mass spectrograph software Analyst 1.6.1 in experiment, and standard is bent Line linear regression, weight coefficient 1/X2.
Use (MS) processing datas of computer program Microsoft Office Excel 2007 and system Figure.Pharmacokinetic parameters are calculated using DAS (version 2 .1.1) processing software statistics Moment Methods.
5th, result of the test
Choose 12 kinds of compounds of the present invention (compound I-4, I-5, I-8, II-2, II-5, II-9, III-2, III-6, III-9, IV-1, IV-6 and IV-7), and 4 kinds of compound (PR-1 of the prior art:CN1829703A, specification The compound 1 of the embodiment 3 of page 17；PR-2：CN102159557A, the compound 84 of the specification embodiment 84 of page 86；PR-3： The compound IV-2 of the CN103130737A specifications embodiment 44 of page 41；PR-4：CN104140421A, specification reality of page 15 Apply the compound I-1 of example 1) and Cariliprazine (positive control drug) carry out in rat body medicine generation experiment as described above.Specific experiment It the results are shown in Table shown in 6.
Table 6：Male SD rat gives saturating the brain rate and bioavilability after the compounds of this invention
This result of the test shows：The saturating brain rate of the compounds of this invention is high, meets maincenter class medicine medicine for feature.
In addition, the oral absolute bioavailability of test-compound is good (being more than 30%), illustrate that the compounds of this invention tool is good Good potential druggability.
Embodiment 57：Experiment is investigated in the side effect of compound catalepsy
The present embodiment choose 6 kinds of compounds of the present invention (compound I-14, II-2, III-6, III-9, IV-6 and IV-7), and Cariliprazine (positive control drug) and Risperidone (positive control drug) carry out the side effect of compound catalepsy and investigated Experiment.
1st, experimental animal
SD rats, male, this experimental animal Co., Ltd of Changzhou Cavan provide.
2nd, laboratory apparatus
9mm diameter wooden sticks, horizontal positioned, height 11cm.
3rd, experimental design
Rat forelimb performance is positioned on wooden stick and starts timing, when its Body Position Change timing stops.When Catalepsy is tested Between be 60 seconds, if it exceeds being then still designated as 60 seconds.Compound dose design is with the ED of apomorphine test50It is worth for standard, gives 10th, 50 and 200 multiple dose.Oral administration of compounds, catalepsy was tested after 30,60 and 120 minutes.
3rd, experimental result
6 kinds of compounds of the present invention are chosen, and Cariliprazine and Risperidone carry out compound catalepsy as described above Experiment is investigated in side effect.Specific experimental result is shown in Table 7.
Table 7：Compound causes catalepsy, and a situation arises
Test result indicates that the compound such as I-14 of the invention causes, catalepsy incidence is low, and EPS side effects are low, more sharp training Ketone is excellent.
Embodiment 58：The acute toxicity testing of compound
The present embodiment choose 10 kinds of compounds of the present invention (I-4, I-14, II-2, II-9, III-2, III-6, III-9, IV-1, IV-7 and IV12), and Cariliprazine (positive control drug) progress acute toxicity testing.
(1) experimental program
1., observe its oral poison given animal after the compounds such as ICR mouse Cariliprazine, I-4 of the present invention and occurred Sex character shape and death condition, compare its acute toxicity.
2., solvent prepare：Appropriate Tween-80 is weighed, it is 5% (g/v) Tween-80 to be diluted to concentration with deionized water.
3., drug-delivery preparation：Weigh required test sample respectively, with 5% Tween 80 solution be configured to concentration for 6.25, 12.50th, 25.00,50.00 and 100.00mg/mL (be respectively equivalent to 125,250,500,1000,2000mg/kg) suspension.
4., method of administration：The method of administration of test sample and vehicle control group (0.5% Tween-80) is to be administered orally.
5., administration frequency：Single-dose, fasting overnight before administration.
6., administration capacity：20mL/Kg.
General symptom observation：The administration same day is observed 1 time for about 0.5,1,2,4,6 hour respectively after being administered in first time；Observation The 2nd~6 day phase, daily observation 2 times, each 1 time of upper and lower noon.
Observed content includes but is not limited to：General status, behavioral activity, gait posture, eye, mouth, nose, intestines and stomach, skin Skin hair, urogenital tract.
(2) statistical analysis
Weight data is represented with mean ± standard deviation, and is examined and single factor test variance using Levene`s using comparing between group Analysis, if display is variant, then examined using Dunnet t.
(3) experimental result
10 kinds of compounds of the present invention are chosen, and Cariliprazine (positive control drug) carries out acute toxicity as described above Experiment.Experimental result is shown in Table 8.
In MTD experiments, tolerance situation of the animal to medicine is investigated, dosage reaches animal frequency when dying on one's deathbed, is most Big dosis tolerata.
Table 8：The compounds such as I-4 and Cariliprazine positive drug single oral administration acute toxicity testing result
Note：MTD：Maximal tolerance dose.
As a result show：The compounds of this invention II-2, II-9, III-9, IV-7 MTD (maximum tolerances in above-mentioned tested material Amount) 2000mg/kg is all higher than, acute toxicity is well below Cariliprazine；Compound I-4, I-14, II-9, III-2, III-6, IV-1, IV-12 MTD values are all higher than 900mg/kg, and security is better than Cariliprazine.
Embodiment 59：The reverse mutation experiment of compound
Salmonella reversion test full name is pollutant mutagenicity detection.The histidine auxotroph bacterium of salmonella typhimurium Strain, in the culture medium containing micro histidine, except only a few spontaneous recovery mutation it is extracellular, can only typically divide several times, shape Into the microcolony that can just see under the microscope.After being acted on by mutagens, back mutation occurs for a large amount of cells, voluntarily synthesis group ammonia Acid, develop into macroscopic bacterium colony.In view of chemical substance has potential mutagenesis, and mutagenesis and carcinogenic work It is closely related between, so method is now widely used in carcinogenic screening.
The present embodiment choose 10 kinds of compounds of the present invention (I-4, I-14, II-2, II-9, III-2, III-6, III-9, IV-1, IV-7 and IV12), and Cariliprazine (positive control drug) progress histidine auxotroph mouse typhus sramana Salmonella reverse mutation test, to check whether to cause gene mutation, to evaluate its potential mutagenicity.
(1) compound method
0.0303g test samples are accurately weighed before use, it is dissolved completely in certain capacity under conditions of sterile, ultrasonic Solvent DMSO in, be configured to the solution of 10000.0 μ g/mL maximum concentration, then by 1:2 (v/v) dilution proportion into 3333.3rd, the solution of 1111.1,370.4,123.5,41.2,13.7,4.6 and 1.5 μ g/mL totally 8 concentration.
(2) test strain
Salmonella typhimurium histidine auxotroph mutant strain TA98 and TA100, purchased from MolTox companies (lot number point Wei 4367D and 4370D).
(3) reference substance
Negative controls dimethyl sulfoxide (DMSO) (DMSO)
Positive reference substance 2- nitrofluorenes (Aldrich, 09213BA)
Sodium azide (Sigma, 043K0056)
(4) formal test
Formal test by metabolism activation or without the two groups of parallel laboratory tests of metabolism activation system by forming.Mixed using standard plate Method, 500 μ L are contained to the melt and dissolved top layer culture medium of 0.6% agar, 0.5%NaCl, 0.5mM biotin and 0.5mM histidines With following material mixing：
20 μ L need testing solutions (or Yin/Yang tester)
25 μ L are incubated overnight bacterium solution
100μL S9(metabolism activation system) mixed liquor or 0.2M sodium phosphate buffers (pH=7.4)
It is laid in after mixture is shaken up on V-B bottom culture mediums well prepared in advance, room temperature solidification, puts 37 DEG C of incubators Result is observed after being inverted culture 72 hours.Each bacterial strain is all provided with negative and positive controls, the parallel training of each group in formal test Support 2 holes/group.
After culture terminates, whether observation test sample has the growing state of precipitation and background bacterial plaque, counts returning per hole and becomes bacterium Fall number, the returning for each concentration group for calculating every plant of bacterium becomes bacterium colony mean, is as a result represented with mean.
Returning for negative control group becomes clump count in the range of history negative control data, and returning for positive controls becomes clump count Higher than 2 times of negative control group, show that pilot system is effective.
What test sample was induced returns the notable rise for becoming that clump count is in dose dependent, and/or test sample is in certain dose Returning for group becomes 2 times that clump count is higher than negative control group, as a result can determine whether as the positive.
(4) experimental result
Experimental result is shown in table 9 and table 10.
Table 9：The bacterium colony back mutation number of the compound effects salmonella typhimurium TA98 bacterial strains such as I-4
Table 10：The bacterium colony back mutation number of the compound effects salmonella typhimurium TA100 bacterial strains such as I-4
Table 9 and table 10 test result indicates that compound I-4, I-14, II-2, II-9, III-2, III-6, III-9, IV- 1st, no matter IV-7, IV12 and all proof loads of Cariliprazine are without S9Or add S9Do not cause Salmonella typhimurium in experimental system Bacterium TA98 and TA100 bacterial strain bacterium colony, which returns parameter, substantially to be increased, i.e., compound is without mutagenesis.
Therefore, the effect of Compounds in Salmonella typhimurium TA98 and TA100 bacterial strains without Mutation induction of the present invention, All test-compound Salmonella reversion tests are negative.

Claims (10)

1. fragrant ethyl piperidine base
Derivative, it is characterised in that be with the compound as shown in general structure (I) or its pharmaceutically acceptable hydration The hydrate of thing, salt or salt：
Wherein：
R is
R3Selected from C1~C3Alkyl, C1~C2Alkoxy, C3~C6Cycloalkyl, phenyl, substituted-phenyl or heteroaryl；
R4、R5Separately represent hydrogen, C1~C3Alkyl, C3~C6Cycloalkyl, phenyl, benzyl or pyridine radicals；
Or R4、R5Morpholine ring is formed with the N atoms being connected；
N is 0~1 integer；
R1、R2Separately represent chlorine, methyl, methoxyl group, phenyl；
Or R1、R2It is collectively forming phenyl ring, azolactones ring or thiphene ring.
2. fragrant ethyl piperidine radical derivative according to claim 1, it is characterised in that the substituted-phenyl be selected from halogen, Cyano group, methoxyl group or C1~C2Alkyl-substituted substituted-phenyl.
3. fragrant ethyl piperidine radical derivative according to claim 1, it is characterised in that the heteroaryl be selected from furyl, Pyrrole radicals, thienyl, pyridine radicals, 2- benzothienyls, 2- benzofuranyls or 2- indyls.
4. fragrant ethyl piperidine radical derivative according to claims 1 to 3, it is characterised in that the salt of the compound be containing There are the salt of pharmaceutically acceptable anion, preferably hydrochloride, hydrobromate, sulfate, acetate, trifluoroacetate, lemon Hydrochlorate, tartrate, maleate, fumarate, mesylate, tosilate, oxalates.
5. fragrant ethyl piperidine radical derivative according to claim 4, it is characterised in that the hydrate of the salt of the compound contains The crystallization water of 0.5~3 molecule, wherein it is preferred that the salt of the compound is oxalates, mesylate, hydrobromic acid hydrochlorate or trifluoro vinegar Hydrochlorate.
6. according to the fragrant ethyl piperidine radical derivative described in one claim of any of the above, it is characterised in that the fragrant ethyl Acyclic derivatives are selected from：
I-1 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) acetamide,
I-2 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) butyramide,
I-3 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -2- methoxyl acetamides,
I-4 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -2- ethojqracetamides,
I-5 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) cyclopropyl carboxamide,
I-6 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) cyclohexyl formamide,
I-7 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) benzamide,
I-8 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -4- fluorobenzamides,
I-9 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -4- cyanobenzamides,
I-10 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -4- methyl benzamides,
I-11 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) niacinamide,
I-12 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) formamide of furans -2,
I-13 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) formamide of pyrroles -2,
I-14 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) formamide of thiophene -2,
I-15 N- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) formamide of indoles -2,
II-1 1- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -3- MUs,
II-2 3- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -1,1- dimethyl ureas,
II-3 1- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -3- propyl group urea,
II-4 1- cyclopropyl -3- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) urea,
II-5 1- cyclohexyl -3- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) urea,
II-6 1- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -3- phenylureas,
II-7 1- benzyls -3- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) urea,
II-8 1- (4- (2- (4- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -3- (pyridin-3-yl) urea,
II-9 N- (4- (2- (4- (2,3- (2,3- dichlorophenyls) piperazine -1- bases) ethyl) piperidin-1-yl) morpholine -4- formyls Amine,
III-1 N- (4- (2- (4- (2,3- 3,5-dimethylphenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -4- methoxybenzoyls Amine,
III-2 N- (4- (2- (4- (2,3- 3,5-dimethylphenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -4- ethylbenzoyls Amine,
III-3 1- ethyls -3- (4- (2- (4- (2- methoxyphenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -1- MUs,
III-4 3- (4- (2- (4- (2- methoxyphenyls) piperazine -1- bases) ethyl) piperidin-1-yl) -1- methyl isophthalic acids-phenylurea,
III-5 N- (4- (2- (4- ([1,1'- diphenyl] -3- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -2- methoxyl group second Acid amides,
III-6 3- (4- (2- (4- ([1,1'- diphenyl] -3- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -1,1- dimethyl Urea,
III-7 N- (4- (2- (4- (naphthalene -1- bases) piperazine -1- bases) ethyl) piperidin-1-yl) furans -2- formamides,
III-8 1,1- dimethyl -3- (4- (2- (4- (naphthalene -1- bases) piperazine -1- bases) ethyl) piperidin-1-yl) urea,
III-9 N- (4- (2- (4- (2 (3H) H- benzoxazolone -7- bases) piperazine -1- bases) ethyl) piperidin-1-yl) furans -2- Formamide,
III-10 1,1- dimethyl -3- (4- (2- (4- (2 (3H) H- benzoxazolone -7- bases) piperazine -1- bases) ethyl) piperidines - 1- yls) urea,
IV-1 N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) pentanamide,
IV-2 N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -2- methoxyl group acetyl Amine,
IV-3 N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) benzamide,
IV-4 N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) cyclopropyl carboxamide,
IV-5 N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) niacinamide,
IV-6 N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) furans -2- formamides,
IV-7 3- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -1,1- dimethyl ureas,
IV-8 1- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -3- phenylureas,
IV-9 1- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -3- (pyridin-3-yl) Urea,
IV-10 3- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -1- methyl isophthalic acids-benzene Base urea,
IV-11 1- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) -3- cyclopropyl urea,
IV-12 N- (4- (2- (4- (benzo [b] thiophene -4- bases) piperazine -1- bases) ethyl) piperidin-1-yl) morpholine -4- formyls Amine.
7. a kind of pharmaceutical composition, it is characterised in that described pharmaceutical composition is included in the claim 1~6 of therapeutically effective amount The hydrate of fragrant ethyl piperidine radical derivative or its pharmaceutically acceptable hydrate, salt or salt described in any one, and pharmacy Upper acceptable carrier.
A kind of 8. method for preparing pharmaceutical composition as claimed in claim 7, it is characterised in that methods described is by the fragrant second The hydrate of phenylpiperidines radical derivative or its pharmaceutically acceptable hydrate, salt or salt mixes with pharmaceutically acceptable carrier Prepare.
9. a kind of medicine box, it is characterised in that the medicine box includes the fragrant ethyl piperidine according to any one of claim 1-6 The hydrate of radical derivative or its pharmaceutically acceptable hydrate, salt or salt.
10. one kind treats schizoid method, methods described gives patient according to any one of claim 1~6 Fragrant ethyl piperidine radical derivative or its pharmaceutically acceptable hydrate, salt or salt hydrate.
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