CN110511174A - A kind of indolyl piperazine compounds and its application - Google Patents

A kind of indolyl piperazine compounds and its application Download PDF

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CN110511174A
CN110511174A CN201810496729.0A CN201810496729A CN110511174A CN 110511174 A CN110511174 A CN 110511174A CN 201810496729 A CN201810496729 A CN 201810496729A CN 110511174 A CN110511174 A CN 110511174A
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propyl
piperazinyl
indoles
amyl
salt
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CN110511174B (en
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付伟
彭伟青
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Fudan University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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

Abstract

The invention belongs to pharmaceutical technology fields, are related to indolyl piperazine compounds and its application, and in particular to indolyl piperazine derivative is to 5-HT1AThe affinity and action characteristic of receptor and its nervous system disease agent is being prepared, especially and 5-HT1AThe application in the relevant nervous system disease agent field of receptor.The indolyl piperazine compounds have the structure of logical formula (I):Wherein R1、R2、R3, m, n definition referring to specification.Such compound can be used as selective 5-HT1AReceptor stimulating agent is used to prepare treatment nerve related with brain and psychotic disorder, such as the drug of anxiety disorder, depression, schizophrenia and parkinsonism.

Description

A kind of indolyl piperazine compounds and its application
Technical field
Present specification pharmaceutical technology field is related to indolyl piperazine compounds and its application, and in particular to indoles alkane Base piperazine derivative is to 5-HT1AThe affinity and action characteristic of receptor and its nervous system disease agent is being prepared, especially With 5-HT1AThe application in the relevant nervous system disease agent field of receptor.
Background technique
Researches show that serotonins (5-hydroxytrptamine, 5-HT) as a kind of important neurotransmitter, passes through At least 16 different receptor subtypes participate in adjusting and mediate a variety of physiological effects.It is different from profile according to pharmacology, These receptor subtypes are divided into 7 different subfamily (5-HT1-7), wherein 5-HT1AReceptor is first and is completely sequenced simultaneously The receptor studied extensively.Studies have shown that 5-HT1AReceptor participation has adjusted a variety of physiological effects, and its functional disturbance can be made At a variety of central nervous system diseases.
Anxiety is also known as anxious neuropathy, is one of the most common type in this major class disease of neurosis, with anxiety Experience is main feature.Different according to external symptom, anxiety disorder can be divided into chronic anxiety (generalized anxiety disorder) and acute anxiety (panic disorder) two kinds of forms.The representative drugs for the treatment of anxiety are mainly with 5-HT at present1ABased on receptor stimulating agent, such as fourth loop coil Ketone etc..Although specific mechanism of action is not yet clear, common belief is that, in addition to presynaptic membrane 5-HT1ABy external, distribution In the 5-HT of marginal zone (hippocampus, amygdaloid nucleus, side interval) postsynaptic membrane1AReceptor plays crucial work during adjusting anxiety With.Hippocampus and amygdaloid nucleus area are the main control zones for adjusting mood and relieving stress, and side interval can be incited somebody to action as terminal Nerve impulse from marginal zone is transmitted to hypothalamus, to regulate and control various physiological responses.5-HT1AReceptor stimulating agent is considered It is the neuron that hippocampus and side interval are inhibited by the inward rectification potassium-channel (GIRK) of activation G- albumen gate Activity, to alleviate the symptom of anxiety.
Depression is also referred to as depressive disorder, low for main clinic symptoms with significant and lasting mood.According to the state of an illness Severity, clinical manifestation, again to the depression or even pessimistic and worldweary of feeling oneself inferior, are finally resulted in from depressed to depressed Suicide, and part patient is simultaneously also with mental symptoms such as anxiety, illusion, vain hopes.Clinical primary treatment medicine at present Object includes 5-HT1AThe combination therapy of receptor stimulating agent, 5-HT reuptake inhibitor (SSRIs) and the two.Although for 5- HT1AThe specific mechanism of receptor agonist treatment depression is indefinite, but the viewpoint for comparing approval is presynaptic membrane 5-HT1AReceptor is de- Quick or downward, it may be assumed that repetition receives 5-HT1AReceptor agonist treatment causes nuclei of median raphe presynaptic membrane 5-HT1AReceptor desensitization to It alleviates and the 5-HT neuron inhibited is adjusted by autoreceptor, eventually lead to 5-HT neuron and be activated, alleviate in anxiety symptom The shortage of 5-HT.Meanwhile 5-HT1AThe use in conjunction of receptor stimulating agent and SSRIs, which not only alleviate, is used alone SSRIs action slowly The problem of, while potential therapeutic effect is improved, accelerate the desensitization speed of autoreceptor.The treatment weight of the approval of FDA in 2011 The drug vilazodone of degree depression just has 5-HT1AReceptor stimulating agent and 5-HT reuptake inhibitor activity.
Schizophrenia be one of the most common type continue, chronic great mental disorder, clinical manifestation is positive symptom And negative symptoms, the former includes illusion, vain hope, chorea etc.；The latter refers mainly to Cognitive, learning memory disorder, work Make memory disorders etc..With the continuous increase of people's work and life pressure, psychic problems are serious not to entire society's generation Good influence.The first generation antipsychotic drug of early stage is very poor to the curative effect of negative symptoms to treat based on positive symptom, and The incidence of extrapyramidal symptom (Extrapyramidal Symptoms, EPS) is high, also known as classic antipsychotics.Rather than Classic antipsychotics not only work to positive symptom, also have good therapeutic effect to negative symptoms while can reduce cone In vitro is side reaction, but its in terms of treat cognitive impairment not apparent advantage.Some researches show that 5-HT1AReceptor agonism Agent can activate the 5-HT of corpus straitum and cerebral cortex prefrontal lobe postsynaptic membrane by non-dopaminergic pathway1AReceptor is anti-to reduce The EPS that schizophrenia drug is caused.Meanwhile 5-HT1AReceptor antagonist can be located inside by blocking and lie prostrate estrangement or oblique 5-HT of the angle with core postsynaptic membrane1AReceptor improves cognitive function to alleviate the level of acetylcholine or glutamic acid.Treatment at present In schizoid drug, the atypical antipsychotic agnets such as Aripiprazole, Ziprasidone etc. with multiple activities all have There is affectedly unconventional 5-HT1AReceptor active.
Parkinson's disease (Parkinson ' s Disease, PD) is also known as shaking plasy, is that a kind of most common nervous system is moved back One of row disease, clinic is based on static tremor, muscle rigidity, bradykinesia and attitudinal reflex obstacle.PD not only falls ill Rate is high, and is a kind of lifelong disease, and with the development of period of disease, patient gradually loses life and labour capacity, and generates The non-athletic complication such as cognitive impairment and amentia, seriously affects quality of life, and patient needs Long-term taking medicine, gives family and society Bring heavy burden.Currently, levodopa (L-DOPA) is the optimal PD therapeutic agent of curative effect, it is in vivo through DOP Adecarboxylase It is changed into dopamine and plays a role.But since it can cause motor fluctuations and dyskinesia, so left-handed it is generally desirable to postpone The application of DOPA.L-DOPA collocation 5-HT1AReceptor stimulating agent is believed to that the generation of movement syndrome is effectively relieved, although tool The mechanism of action of body need to be explored, but current pharmacological evaluation shows: 1) L-DOPA may by serotonin neuronal uptake, And then it is converted into dopamine and discharges into synaptic cleft.2) serotonin neuron release dopamine is very likely by negative anti- Feedback is adjusted by 5-HT1AReceptor stimulating agent is inhibited, to ensure that the normal contents of internal dopamine.
Status based on the prior art, the quasi- exploitation of present inventor have novel structural class, and effect is clear, and poison is secondary Act on small 5-HT1AReceptor stimulating agent, and in particular to a kind of indolyl piperazine compounds and its application, the compound will It is possible that being made for the drug of the central nervous system diseases such as treatment anxiety, depression, schizophrenia, parkinsonism.
Summary of the invention
There is 5-HT the purpose of the present invention is to provide a kind of structure novel1AThe affinity of receptor, can especially make For 5-HT1AThe indolyl piperazine compounds of receptor stimulating agent.
It is a further object of the present invention to provide the preparation methods of the indolyl piperazine compounds.
The object of the invention is also to provide above compounds to treat nerve related with brain and psychotic disorder, Such as the purposes in terms of anxiety disorder, depression, schizophrenia and parkinsonism.
Indolyl piperazine compounds shown in the following logical formula (I) of present invention offer (or " indolyl piperazines are spread out Biology ") and its pharmacologically acceptable inorganic or organic salt, crystalline hydrate:
Wherein:
M, n are independently optionally from 0,1,2,3 or 4；Preferably, m is selected from 1 or 2；N is selected from 3；
Substituent R1Selected from hydrogen, halogen, C1-C6Substituted or unsubstituted alkyl, C1-C6Substituted or unsubstituted alkoxy, Hydroxyl, cyano preferably are selected from F, Cl, hydroxyl, methoxyl group, cyano；
Substituent R2Be not present or at least one position in 2,3,4,5,6, be it is unsubstituted, mono-substituted, It is disubstituted or polysubstituted, substituent R2Selected from one of following groups, two or more: hydrogen, halogen, nitro, hydroxyl, Carboxyl, cyano, amino, C1-C6Substituted or unsubstituted alkyl, C1-C6Substituted or unsubstituted alkoxy ,-SO2CH3Group；When R2For when double or three replace, substituent group can be identical or different；Preferably, substituent R2It is not present or positioned at 4 methoxies Base, F, mesyl；
Substituent R3Selected from H, C1-C6Substituted or unsubstituted alkyl, C3-C7Substituted or unsubstituted naphthenic base or HetAr1 preferably is selected from C5-C6Alkyl, 4- methoxycyclohexyl, 4- tetrahydro -2-H- pyranose, 4- oxocyclohexyl, 4- piperidyl, Ethoxy, hydroxypropyl, 1- methoxyl group -2- propyl, 1,2- Dimethoxy-ethyl；
Unless otherwise indicated, C of the present invention1-C6Alkyl (C1-C6Unsubstituted alkyl) it is C1-C6Linear chain or branched chain Alkyl, refers to the alkyl containing 1-6 carbon atom, including but not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, different Butyl, sec-butyl, tert-butyl, amyl, hexyl, heptyl or octyl.C1-C6Alkyl is replaced to refer to C1-C6Alkyl can be selected from hydroxyl Base, halogen, C1-C31-2 identical or different groups of alkoxy replace.
Unless otherwise indicated, C of the present invention1-C6Alkoxy (C1-C6Unsubstituted alkoxy) it is C1-C6Straight chain or Branched alkoxy, refers to the alkoxy containing 1-6 carbon atom, including but not limited to methoxyl group, ethyoxyl, positive propoxy, different Propoxyl group, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, amoxy, hexyloxy, oxygroup in heptan or octyloxy.C1-C6 Substituted alkoxy refers to C1-C6Alkoxy can be selected from hydroxyl and C1-C31-2 identical or different groups of alkoxy replace.
Unless otherwise indicated, C of the present invention3-C7Naphthenic base (C3-C7Unsubstituted naphthenic base) refer to containing 3-7 The naphthenic base of carbon atom, including but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclopropyl and cyclopenta, ring Third and cyclohexyl.C3-C7Substituted cycloalkyl refers to C3-C7Naphthenic base can be selected from halogen, carbonyl, hydroxyl and C1-C3Alkoxy 1-2 identical or different groups replace.
Unless otherwise indicated, C of the present invention1-C3Alkoxy refers to C1-C3Straight or branched alkoxyl, refer to containing The alkoxy of 1-3 carbon atom, including but not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy.
Unless otherwise indicated, HetAr1 of the present invention indicates to have the full of 1,2 or 3 N and/or O and/or S atom With the circle heterocyclic ring of unsubstituted 4,5,6,7,8,9 or 10.
Unless otherwise indicated, term halogen is halogen substituent group, including but not limited to fluorine, chlorine, bromine or iodine.
Wherein, the term " polysubstituted " in the present invention and " a variety of " refer to three kinds or more, and what is appeared below is also phase Same meaning.
As one of optimal embodiment, indolyl piperazine derivative of the present invention is following specific chemical combination Object:
N- (3- amyl) -2- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (3- hexyl) -2- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- amyl) -3- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- amyl) -3- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (2- hexyl) -3- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- hexyl) -3- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (4- methoxycyclohexyl) -3- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- phenylpropionyl Amine,
N- (2- amyl) -2- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- (5- fluorophenyl) acetyl Amine,
N- (2- amyl) -2- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- (5- methoxyphenyl) second Amide,
N- (2- amyl) -2- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- (5- methanesulfonylphenYl) Acetamide,
N- (2- amyl) -2- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (3- amyl) -2- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- hexyl) -2- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (3- hexyl) -2- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (4- methoxycyclohexyl) -2- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- phenylacetyl Amine,
N- (2- amyl) -3- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- amyl) -3- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (2- hexyl) -3- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- hexyl) -3- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (4- methoxycyclohexyl) -3- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- phenylpropionyl Amine,
N- (3- amyl) -2- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- hexyl) -2- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (3- hexyl) -2- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- amyl) -3- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- amyl) -3- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (2- hexyl) -3- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- hexyl) -3- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (4- methoxycyclohexyl) -3- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl)-N- phenyl Propionamide,
N- (3- amyl) -2- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- hexyl) -2- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (3- hexyl) -2- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- amyl) -3- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- amyl) -3- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (2- hexyl) -3- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- hexyl) -3- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (4- methoxycyclohexyl) -3- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-N- phenyl third Amide,
N- (2- amyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (3- amyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- hexyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (3- hexyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (4- methoxycyclohexyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- phenyl second Amide,
N- (2- amyl) -3- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- amyl) -3- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (2- hexyl) -3- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- hexyl) -3- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (4- methoxycyclohexyl) -3- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- phenyl third Amide,
N- (2- amyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- (5- fluorophenyl) acetyl Amine,
N- (2- amyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- (5- methoxyphenyl) Acetamide,
N- (2- amyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- (5- mesyl benzene Base) acetamide,
N- (4- tetrahydro -2-H- pyranose) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- benzene Yl acetamide,
N- (4- oxocyclohexyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- phenylacetyl Amine,
N- (4- piperidyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- ethyl alcohol base) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- propyl alcohol base) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (1- methoxyl group -2- propyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- phenyl Acetamide,
N- (1,2- Dimethoxy-ethyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- benzene Yl acetamide,
The indolyl piperazine derivative further includes its pharmaceutically acceptable salt, solvate, precursor chemical combination Object or polymorph.
In the present invention, pharmaceutically acceptable salt, solvate, pro-drug or polymorph, which is characterized in that described Pharmaceutically acceptable salt is inorganic salts, organic salt or amino-acid salt；
Wherein inorganic salts can are as follows: sodium salt, hydrochloride, trifluoroacetate, sulfate, phosphate, diphosphate, hydrobromate Or nitrate；
Wherein organic salt can are as follows: maleate, acetate, fumarate, tartrate, succinate, lactate, to first Benzene sulfonate, salicylate or oxalates；
Wherein amino-acid salt are as follows: arginine salt, ornithine salt, lysine salt, leucine salt, isoleucine salt, glycine Salt, cystine salt, cysteine salt, tyrosine salt, alanine salt, phenylalanine salt, histidine salt, serine salt, threonine Salt, methionine salt, tryptophan salt, glutamate, aspartate, valine salt, methionine salt, proline salt or hydroxyl dried meat ammonia Hydrochlorate.
To realize above-mentioned second purpose, the technical solution adopted by the present invention is that:
The indolyl piperazine derivative preparation method can synthesize to obtain, include the following steps: by following below scheme
Prepare intermediate 2
Compound 1 is anti-by Fisher indole synthesis at 150 DEG C in lower and 3, the 4- dihydropyran of 4% sulfuric acid condition Compound 2 should be generated.Wherein, compound 2d and cuprous cyanide react generationization in 80 DEG C, n,N-Dimethylformamide solvent Close object 2e.
Prepare intermediate 3
Compound 2 reacts in dichloromethane solvent with carbon tetrabromide, triphenylphosphine generates compound 3.Wherein, compound 3b, which reacts in dichloromethane solvent at -78 DEG C with Boron tribromide, generates compound 3c.
Prepare intermediate 5
Compound 4 under the conditions of acetic acid with R3The zinc powder of the corresponding ketone compound of group and hydrochloric acid activation is 75 DEG C, reaction generates compound 5 in water.
Prepare intermediate 6
Compound 5, which reacts in dichloromethane solvent under triethylamine alkaline condition with corresponding chloro acyl chlorides, generates chemical combination Object 7.
Prepare intermediate 7
Compound 6 reacts generation compound 7 under the conditions of potassium alkaline with N-Boc- piperazine at 85 DEG C, in acetonitrile solvent
Prepare intermediate 8
Compound 7 reacts in dichloromethane solvent with trifluoroacetic acid generates compound 8.
Prepare compound I
Under the conditions of potassium alkaline, reaction generates chemical compounds I in acetonitrile solvent for compound 3 and compound 8.
It should be understood that the specific R listed in above-mentioned reaction process1It is the R as an example, in structural formula1It is without being limited thereto, also Including all R1 mentioned hereinabove.
Wherein, the preparation method of indolyl piperazine derivative pharmaceutically acceptable salt can be according to this field routine Prepared by method, the compound of the present invention is usually separated as former state, or in the form of its pharmaceutically acceptable salt, such as with Inorganic salts, organic salt or amino-acid salt are reacted under normal conditions and are obtained.
Bioactivity of the compound by the invention on Serotonin receptor is illustrated below by the pharmacological results:
1, compound affinity experimental method: Radioligand binding assay
Compound functional experiment method: [35S]GTPγS binding assay
2, experimental result is as shown in table 1,2:
1 compound affinity experimental result of table
In table 1, on the column " inhibiting rate %/Ki nM ", the data for being expressed as percentage refer to inhibiting rate %, in addition to this Each mean Ki nM.
In table 1, two substituent groups on Cis finger ring hexane are in ipsilateral, on Trans finger ring hexane two substituent groups In heteropleural.
In table 1 ,-refer to it is inactive.
2 part of compounds contractile studies of table
The results show that all noval chemical compounds all show a degree of displacement 5-HT1AThe ability of receptor isotope ligand, And 5-HT with higher1AReceptor-selective, part of compounds show high 5-HT1AThe complete agonist activity of receptor.
These above-mentioned compounds of the present invention can be used as lead compound and further develop the high 5-HT of the good activity of selectivity1ABy Body compound, and be used to prepare as 5-HT1AReceptor agonist treatment anxiety disorder, depression, schizophrenia and parkinsonism Etc. diseases potential drug.
Specific embodiment
The present invention is further elaborated combined with specific embodiments below, but does not limit the present invention.
1H-NMR is measured with Varian Mercury Plus 400Hz type instrument；MS Agilent 6120Quadrupole LC/MS measurement, all solvents are passing through re-distillation using preceding, and used anhydrous solvent presses standard method drying process It obtains；In addition to explanation, all reactions are tracked with TLC, and post-processing is through saturated sodium-chloride water solution washing and anhydrous sodium sulfate Drying process；The purifying of product uses silica gel (200~300 mesh) column chromatography in addition to explanation；Wherein silica gel (200~300 Mesh) it is Haiyang Chemical Plant, Qingdao's production, TLC is Qingdao Haiyang 0.2mm GF245 High Performance Thin Layer Chromatography silica gel plate with plate.
Embodiment 1: preparation N- (2- amyl) -3- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- phenyl Propionamide (FW I -01)
Step 1: preparation 3- (5- fluoro indole) propyl alcohol (intermediate 2a)
At room temperature, in single-necked flask by 4- fluorophenyl hydrazine hydrochloride (5g, 3.07 × 10-2Mol) be dissolved in acetonitrile (50ml) with In the mixed liquor of 4% sulfuric acid (50ml), be slowly added dropwise under stirring conditions 3,4- dihydropyran (3.36ml, 3.7 × 10- 2Mol), reaction is heated to 150 DEG C after being added dropwise, maintains reaction 3h.To which after reaction, reaction solution is cooled to room temperature, It is evaporated under reduced pressure out excessive acetonitrile, 50ml ethyl acetate is then added into remaining mixed liquor and is extracted three times.Merge organic Phase, anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (PE:EA=20:1) obtains rufous grease 4.56g, yield 76%.
Step 2: preparation 3- (3- bromopropyl) -1-H-5- fluoro indole (intermediate 3a)
At 0 DEG C, with 100ml in dry three-necked flask by intermediate 2a (1g, 3.73 × 10-3), mol be dissolved in 30ml without In water methylene chloride, then sequentially add carbon tetrabromide (1.08ml, 1.11 × 10-2Mol), triphenylphosphine (2.91g, 1.11 × 10-2mol).It continues thereafter with plus water 20ml three times with the extraction of 20ml methylene chloride merges organic phase, uses nothing after saturated common salt washing Aqueous sodium persulfate is dry, and concentration rear pillar chromatography (PE:EA=20:1) obtains grey black oily liquids 0.72g, yield 76%.
Step 3: preparation N- (2- amyl) aniline (intermediate 5a)
By aniline (1ml, 1.09 × 10-2Mol), 2 pentanone (0.94g, 1.09 × 10-2Mol), acetic acid (25ml) and water (2.5ml) is added in 100ml single-necked flask, is added portionwise under stirring condition by the zinc powder of hydrochloric acid activation, is then transferred into 75 DEG C, Flow back 12h at this temperature.After the reaction was completed, after reaction solution is cooled to room temperature, weak base ring is adjusted to ammonium hydroxide under ice bath Border, pH ≈ 10 three times with the extraction of 50ml methylene chloride merge organic phase, and anhydrous sodium sulfate is dry, and concentration rear pillar chromatographs (PE:EA =50:1) obtain yellow oil 1.65g, yield 92.2%.
Step 4: preparation N- (2- amyl)-N- phenyl -3- chlorine propionamide (intermediate 6a)
With in single-necked flask by intermediate 5a (2.5g, 1.5 × 10-2Mol), triethylamine (2.54ml, 1.83 × 10-2mol) Be dissolved in 50ml anhydrous methylene chloride, under condition of ice bath be added dropwise dissolved with 3- chlorpromazine chloride (1.79ml, 1.83 × 10-2Mol) two Chloromethanes solution, is gradually increased to room temperature after being added dropwise, the reaction was continued under the conditions of stirring was transferred to 75 DEG C after 30 minutes 8h.To After reaction, methylene chloride 30ml is added, and three times with 30ml saturated common salt water washing, merges organic phase, anhydrous sodium sulfate Dry, concentration rear pillar chromatography (PE:EA=30:1) obtains white solid 2.91g, yield 76.4%.
Step 5: preparation N- (2- amyl) -3- (4-Boc-1- piperazinyl)-N- Phenylpropionamide (intermediate 7a)
By intermediate 6a (5g, 1.97 × 10-2Mol), N-Boc- piperazine (3.67g, 1.97 × 10-2Mol) it is dissolved in acetonitrile In, then be added potassium carbonate (3.27g, 2.36 × 10-2Mol), 85 DEG C are warming up to, reaction 8h is maintained.To after reaction, depressurize Acetonitrile is removed, then plus water 30ml, three times with the extraction of 30ml methylene chloride.Merge organic phase, anhydrous sodium sulfate is dry, after concentration Column chromatography (DCM:MeOH=50:1) obtains light yellow solid 7.01g, yield 88.1%.
Step 6: preparation N- (2- amyl) -3- (1- piperazinyl)-N- Phenylpropionamide trifluoroacetate (intermediate 8a)
In single-necked flask by intermediate 7a (5g, 1.24 × 10-2Mol it) is dissolved in 50ml methylene chloride, stirs lower be added dropwise 30ml trifluoroacetic acid, after room temperature the reaction was continued 3h.To removed under reduced pressure excess of solvent after the reaction was completed, 30ml petroleum is used respectively Ether, 30ml ether respectively wash three times, and white solid 4.12g, yield 91.3% are obtained after filtration drying.
Step 7: preparation N- (2- amyl) -3- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- phenyl third Amide
At room temperature, in the single-necked flask containing 50ml acetonitrile solution be added intermediate 8a (1g, 2.75 × 10-3Mol) and Intermediate 3a (0.96g, 2.75 × 10-3Mol) and potassium carbonate (0.76g, 5.54 × 10-3Mol), reaction is heated to 75 DEG C, stirs Mix reflux 12h.To after reaction, remove extra acetonitrile quilt, 30ml water is added, 30ml methylene chloride extracts three times, merges Organic phase, anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (DCM:MeOH=10:1) obtains white solid 1.05g, yield 79.5%.
Embodiment 2-8: compound FW I -02-FW I -08
Embodiment 1 is repeated, difference is: using different raw materials in step 3, use different raw materials in step 5, from And I -02-FW I -08 of compound FW is made.Compound FW I -02 and FW I -03 is a pair of of cis-trans-isomer, in step 4 through column Chromatography (PE:EA=30:1) obtains its corresponding intermediate.
Shown in table specific as follows:
Step 3:
Step 5:
Embodiment 9-11: compound FW I -09-FW I -11
Embodiment 1 is repeated, difference is: using different raw materials in step 3, so that I -09-FW of compound FW be made Ⅰ-11.Table specific as follows:
Embodiment 12: preparation N- (2- amyl) -2- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- benzene Yl acetamide (FW I -12)
Step 1: preparation 3- (5- chloro-indole) propyl alcohol (intermediate 2c)
At room temperature, in single-necked flask by 4- chlorophenylhydxazine hydrochloride (5g, 2.79 × 10-2Mol) be dissolved in acetonitrile (50ml) with In the mixed liquor of 4% sulfuric acid (50ml), be slowly added dropwise under stirring conditions 3,4- dihydropyran (4.46ml, 2.79 × 10- 2Mol), reaction is heated to 150 DEG C after being added dropwise, maintains reaction 3h.To which after reaction, reaction solution is cooled to room temperature, It is evaporated under reduced pressure out excessive acetonitrile, 50ml ethyl acetate is then added into remaining mixed liquor and is extracted three times.Merge organic Phase, anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (PE:EA=20:1) obtains grease 4.20g, yield 72%.
Step 2: preparation 3- (3- bromopropyl) -1-H-5- chloro-indole (intermediate 3d)
At 0 DEG C, with 100ml in dry three-necked flask by intermediate 2c (1g, 4.78 × 10-3), mol be dissolved in 30ml without In water methylene chloride, then sequentially add carbon tetrabromide (0.84ml, 1.43 × 10-2Mol), triphenylphosphine (2.26g, 1.43 × 10-2mol).It continues thereafter with plus water 20ml three times with the extraction of 20ml methylene chloride merges organic phase, uses nothing after saturated common salt washing Aqueous sodium persulfate is dry, and concentration rear pillar chromatography (PE:EA=20:1) obtains grey black oily liquids 1.00g, yield 77%.
Step 3: preparation N- (2- amyl) aniline (intermediate 5a)
By aniline (2.94g, 0.03mol), 2 pentanone (2.58g, 0.03mol), acetic acid (25ml) and water (2.5ml) are added It is added portionwise in 100ml single-necked flask, under stirring condition by the zinc powder of hydrochloric acid activation, is then transferred into 75 DEG C, at this temperature Flow back 12h.After the reaction was completed, after reaction solution is cooled to room temperature, mild alkaline conditions are adjusted to ammonium hydroxide under ice bath, pH ≈ 10, Three times with the extraction of 50ml methylene chloride, merging organic phase, anhydrous sodium sulfate is dry, concentration rear pillar chromatography (PE:EA=50:1) Yellow oil 3.06g, yield 62.6%.
Step 4: preparation N- (2- amyl)-N- phenyl -2- chloroacetamide (intermediate 6a)
With in single-necked flask by intermediate 5a (5g, 3.07 × 10-2Mol), triethylamine (4.74ml, 3.42 × 10-2mol) Be dissolved in 50ml anhydrous methylene chloride, under condition of ice bath be added dropwise dissolved with chloracetyl chloride (2.72ml, 3.42 × 10-2Mol dichloro) Dichloromethane, is gradually increased to room temperature after being added dropwise, the reaction was continued under the conditions of stirring was transferred to 75 DEG C after 30 minutes 8h.To anti- After answering, methylene chloride 30ml is added, and three times with 30ml saturated common salt water washing, merges organic phase, anhydrous sodium sulfate is dry Dry, concentration rear pillar chromatography (PE:EA=30:1) obtains white solid 6.6g, yield 90.3%.
Step 5: preparation N- (2- amyl) -2- (4-Boc-1- piperazinyl)-phenyl acetanilide,Phenacetylaniline (intermediate 7a)
By intermediate 6a (6g, 2.51 × 10-2Mol), N-Boc- piperazine (4.20g, 2.51 × 10-2Mol) it is dissolved in acetonitrile In, then be added potassium carbonate (4.68g, 3.76 × 10-2Mol), 85 DEG C are warming up to, reaction 8h is maintained.To after reaction, depressurize Acetonitrile is removed, then plus water 30ml, three times with the extraction of 30ml methylene chloride.Merge organic phase, anhydrous sodium sulfate is dry, after concentration Column chromatography (DCM:MeOH=50:1) obtains light yellow solid 7.5g, yield 77%.
Step 6: preparation N- (2- amyl) -2- (1- piperazinyl)-phenyl acetanilide,Phenacetylaniline trifluoroacetate (intermediate 8a)
In single-necked flask by intermediate 7a (6g, 1.54 × 10-2Mol it) is dissolved in 50ml methylene chloride, stirs lower be added dropwise 30ml trifluoroacetic acid, after room temperature the reaction was continued 3h.To removed under reduced pressure excess of solvent after the reaction was completed, 30ml petroleum is used respectively Ether, 30ml ether respectively wash three times, and white solid 6.08g, yield 98.0% are obtained after filtration drying.
Step 7: preparation N- (2- amyl) -2- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- phenyl second Amide
At room temperature, in the single-necked flask containing 50ml acetonitrile solution be added intermediate 8a (1g, 2.48 × 10-3Mol) and Intermediate 3d (0.93g, 2.85 × 10-3Mol) and potassium carbonate (0.85g, 4.96 × 10-3Mol), reaction is heated to 75 DEG C, stirs Mix reflux 12h.To after reaction, remove extra acetonitrile quilt, 30ml water is added, 30ml methylene chloride extracts three times, merges Organic phase, anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (DCM:MeOH=10:1) obtains white solid 1.13g, yield 82.8%.
Embodiment 13-23: compound FW I -13-FW I -23
Repeat embodiment 12, difference is: using different raw materials in step 3, in step 5 using different raw materials from And I -13-FW I -23 of compound FW is made.Compound FW I -20 and FW I -21, FW I -22 and FW I -23 are a pair of of cis-trans isomerisms Body obtains its corresponding intermediate through column chromatography (PE:EA=30:1) in step 4.
Table specific as follows:
Step 3:
Step 5
Embodiment 24: preparation N- (2- amyl) -3- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl) - N- Phenylpropionamide (FW I -24)
Step 1: preparation 3- (5- methoxy-Indole) propyl alcohol (intermediate 2b)
At room temperature, in single-necked flask by 4- methoxyphenyl hydrazine hydrochloride (5g, 2.86 × 10-2Mol) it is dissolved in acetonitrile In the mixed liquor of (50ml) and 4% sulfuric acid (50ml), be slowly added dropwise under stirring conditions 3,4- dihydropyran (4.35ml, 2.86×10-2Mol), reaction is heated to 150 DEG C after being added dropwise, maintains reaction 3h.To which after reaction, liquid cooling will be reacted But to room temperature, it is evaporated under reduced pressure out excessive acetonitrile, 50ml ethyl acetate is then added into remaining mixed liquor and is extracted three times. Merge organic phase, anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (PE:EA=20:1) obtains grease 4.63g, yield 79%.
Step 2: preparation 3- (3- bromopropyl) -1-H-5- methoxy-Indole (intermediate 3b)
At 0 DEG C, with 100ml in dry three-necked flask by intermediate 2b (1g, 4.88 × 10-3), mol be dissolved in 30ml without In water methylene chloride, then sequentially add carbon tetrabromide (0.82ml, 1.46 × 10-2Mol), triphenylphosphine (2.21g, 1.46 × 10-2mol).It continues thereafter with plus water 20ml three times with the extraction of 20ml methylene chloride merges organic phase, uses nothing after saturated common salt washing Aqueous sodium persulfate is dry, and concentration rear pillar chromatography (PE:EA=20:1) obtains grey black oily liquids 0.93g, yield 71%.
Step 3: preparation N- (2- amyl) aniline (intermediate 5a)
By aniline (1ml, 1.09 × 10-2Mol), 2 pentanone (0.94g, 1.09 × 10-2Mol), acetic acid (25ml) and water (2.5ml) is added in 100ml single-necked flask, is added portionwise under stirring condition by the zinc powder of hydrochloric acid activation, is then transferred into 75 DEG C, Flow back 12h at this temperature.After the reaction was completed, after reaction solution is cooled to room temperature, weak base ring is adjusted to ammonium hydroxide under ice bath Border, pH ≈ 10 three times with the extraction of 50ml methylene chloride merge organic phase, and anhydrous sodium sulfate is dry, and concentration rear pillar chromatographs (PE:EA =50:1) obtain yellow oil 1.65g, yield 92.2%.
Step 4: preparation N- (2- amyl)-N- phenyl -3- chlorine propionamide (intermediate 6a)
With in single-necked flask by intermediate 5a (2.5g, 1.5 × 10-2Mol), triethylamine (2.54ml, 1.83 × 10-2mol) Be dissolved in 50ml anhydrous methylene chloride, under condition of ice bath be added dropwise dissolved with 3- chlorpromazine chloride (1.79ml, 1.83 × 10-2Mol) two Chloromethanes solution, is gradually increased to room temperature after being added dropwise, the reaction was continued under the conditions of stirring was transferred to 75 DEG C after 30 minutes 8h.To After reaction, methylene chloride 30ml is added, and three times with 30ml saturated common salt water washing, merges organic phase, anhydrous sodium sulfate Dry, concentration rear pillar chromatography (PE:EA=30:1) obtains white solid 2.91g, yield 76.4%.
Step 5: preparation N- (2- amyl) -3- (4-Boc-1- piperazinyl)-N- Phenylpropionamide (intermediate 7a)
By intermediate 6a (5g, 1.97 × 10-2Mol), N-Boc- piperazine (3.67g, 1.97 × 10-2Mol) it is dissolved in acetonitrile In, then be added potassium carbonate (3.27g, 2.36 × 10-2Mol), 85 DEG C are warming up to, reaction 8h is maintained.To after reaction, depressurize Acetonitrile is removed, then plus water 30ml, three times with the extraction of 30ml methylene chloride.Merge organic phase, anhydrous sodium sulfate is dry, after concentration Column chromatography (DCM:MeOH=50:1) obtains light yellow solid 7.01g, yield 88.1%.
Step 6: preparation N- (2- amyl) -3- (1- piperazinyl)-N- Phenylpropionamide trifluoroacetate (intermediate 8a)
In single-necked flask by intermediate 7a (5g, 1.24 × 10-2Mol it) is dissolved in 50ml methylene chloride, stirs lower be added dropwise 30ml trifluoroacetic acid, after room temperature the reaction was continued 3h.To removed under reduced pressure excess of solvent after the reaction was completed, 30ml petroleum is used respectively Ether, 30ml ether respectively wash three times, and white solid 4.12g, yield 91.3% are obtained after filtration drying.
Step 7: preparation N- (2- amyl) -3- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl)-N- benzene Base propionamide
At room temperature, in the single-necked flask containing 50ml acetonitrile solution be added intermediate 8a (1g, 2.75 × 10-3Mol) and Intermediate 3b (0.99g, 2.75 × 10-3Mol) and potassium carbonate (0.76g, 5.54 × 10-3Mol), reaction is heated to 75 DEG C, stirs Mix reflux 12h.To after reaction, remove extra acetonitrile quilt, 30ml water is added, 30ml methylene chloride extracts three times, merges Organic phase, anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (DCM:MeOH=10:1) obtains white solid 1.12g, yield 82.9%.
Embodiment 25-32: compound FW I -25-FW I -32
Repeat embodiment 24, difference is: using different raw materials in step 3, in step 5 using different raw materials from And I -25-FW I -32 of compound FW is made.Compound FW I -31 and FW I -32 is a pair of of cis-trans-isomer, in step 4 through column Chromatography (PE:EA=30:1) obtains its corresponding intermediate.
Table specific as follows:
Step 3:
Step 5:
Embodiment 33: preparation N- (2- amyl) -3- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide (FW I -33)
Step 1: preparation 3- (5- methoxy-Indole) propyl alcohol (intermediate 2b)
At room temperature, in single-necked flask by 4- methoxyphenyl hydrazine hydrochloride (5g, 2.86 × 10-2Mol) it is dissolved in acetonitrile In the mixed liquor of (50ml) and 4% sulfuric acid (50ml), be slowly added dropwise under stirring conditions 3,4- dihydropyran (4.35ml, 2.86×10-2Mol), reaction is heated to 150 DEG C after being added dropwise, maintains reaction 3h.To which after reaction, liquid cooling will be reacted But to room temperature, it is evaporated under reduced pressure out excessive acetonitrile, 50ml ethyl acetate is then added into remaining mixed liquor and is extracted three times. Merge organic phase, anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (PE:EA=20:1) obtains grease 4.63g, yield 79%.
Step 2: preparation 3- (3- bromopropyl) -1-H-5- oxyindole (intermediate 3c)
[step a] at 0 DEG C, with 100ml in dry three-necked flask by intermediate 2b (1g, 4.88 × 10-3), mol molten In 30ml anhydrous methylene chloride, then sequentially add carbon tetrabromide (0.82ml, 1.46 × 10-2Mol), triphenylphosphine (2.21g,1.46×10-2mol).It continues thereafter with plus water 20ml three times with the extraction of 20ml methylene chloride merges organic phase, saturation Dry with anhydrous sodium sulfate after salt washing, concentration rear pillar chromatography (PE:EA=20:1) obtains grey black oily liquids 0.93g, Yield 71%.
[step b] under nitrogen protection, with 100ml in dry three-necked flask by upper step grease (1g, 3.75 × 10- 3Mol), it is dissolved in 30ml anhydrous methylene chloride, is cooled to -40 DEG C with dry ice-ethyl acetate system, then uses glass syringe 3ml Boron tribromide dichloromethane solution is added, is slowly increased to 0 DEG C, the reaction was continued 2 hours.After reaction, be cooled to again- 40 DEG C, water quenching reaction is slowly added dropwise.It continues thereafter with plus water 20ml three times with the extraction of 20ml methylene chloride merges organic phase, satisfies Dry with anhydrous sodium sulfate after washing with salt, concentration rear pillar chromatography (PE:EA=20:1) obtains oily liquids 0.77g, yield 81%.
Step 3: preparation N- (2- amyl) aniline (intermediate 5a)
By aniline (1ml, 1.09 × 10-2Mol), 2 pentanone (0.94g, 1.09 × 10-2Mol), acetic acid (25ml) and water (2.5ml) is added in 100ml single-necked flask, is added portionwise under stirring condition by the zinc powder of hydrochloric acid activation, is then transferred into 75 DEG C, Flow back 12h at this temperature.After the reaction was completed, after reaction solution is cooled to room temperature, weak base ring is adjusted to ammonium hydroxide under ice bath Border, pH ≈ 10 three times with the extraction of 50ml methylene chloride merge organic phase, and anhydrous sodium sulfate is dry, and concentration rear pillar chromatographs (PE:EA =50:1) obtain yellow oil 1.65g, yield 92.2%.
Step 4: preparation N- (2- amyl)-N- phenyl -3- chlorine propionamide (intermediate 6a)
With in single-necked flask by intermediate 5a (2.5g, 1.5 × 10-2Mol), triethylamine (2.54ml, 1.83 × 10-2mol) Be dissolved in 50ml anhydrous methylene chloride, under condition of ice bath be added dropwise dissolved with 3- chlorpromazine chloride (1.79ml, 1.83 × 10-2Mol) two Chloromethanes solution, is gradually increased to room temperature after being added dropwise, the reaction was continued under the conditions of stirring was transferred to 75 DEG C after 30 minutes 8h.To After reaction, methylene chloride 30ml is added, and three times with 30ml saturated common salt water washing, merges organic phase, anhydrous sodium sulfate Dry, concentration rear pillar chromatography (PE:EA=30:1) obtains white solid 2.91g, yield 76.4%.
Step 5: preparation N- (2- amyl) -3- (4-Boc-1- piperazinyl)-N- Phenylpropionamide (intermediate 7a)
By intermediate 6a (5g, 1.97 × 10-2Mol), N-Boc- piperazine (3.67g, 1.97 × 10-2Mol) it is dissolved in acetonitrile In, then be added potassium carbonate (3.27g, 2.36 × 10-2Mol), 85 DEG C are warming up to, reaction 8h is maintained.To after reaction, depressurize Acetonitrile is removed, then plus water 30ml, three times with the extraction of 30ml methylene chloride.Merge organic phase, anhydrous sodium sulfate is dry, after concentration Column chromatography (DCM:MeOH=50:1) obtains light yellow solid 7.01g, yield 88.1%.
Step 6: preparation N- (2- amyl) -3- (1- piperazinyl)-N- Phenylpropionamide trifluoroacetate (intermediate 8a)
In single-necked flask by intermediate 7a (5g, 1.24 × 10-2Mol it) is dissolved in 50ml methylene chloride, stirs lower be added dropwise 30ml trifluoroacetic acid, after room temperature the reaction was continued 3h.To removed under reduced pressure excess of solvent after the reaction was completed, 30ml petroleum is used respectively Ether, 30ml ether respectively wash three times, and white solid 4.12g, yield 91.3% are obtained after filtration drying.
Step 7: preparation N- (2- amyl) -3- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-N- phenyl Propionamide
At room temperature, in the single-necked flask containing 50ml acetonitrile solution be added intermediate 8a (1g, 2.75 × 10-3Mol) and Intermediate 3c (0.95g, 2.75 × 10-3Mol) and potassium carbonate (0.76g, 5.54 × 10-3Mol), reaction is heated to 75 DEG C, stirs Mix reflux 12h.To after reaction, remove extra acetonitrile quilt, 30ml water is added, 30ml methylene chloride extracts three times, merges Organic phase, anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (DCM:MeOH=10:1) obtains white solid 1.08g, yield 82.4%.
Embodiment 34-41: compound FW I -34-FW I -41
Repeat embodiment 33, difference is: using different raw materials in step 3, in step 5 using different raw materials from And I -34-FW I -41 of compound FW is made.Compound FW I -40 and FW I -41 is a pair of of cis-trans-isomer, in step 4 through column Chromatography (PE:EA=30:1) obtains its corresponding intermediate.
Table specific as follows:
Step 3:
Step 5:
Embodiment 42: preparation N- (2- amyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenyl-acetamides (FW I -42)
Step 1: preparation 3- (5- cyanoindole) propyl alcohol (intermediate 2e)
[step a] at room temperature, in single-necked flask by 4- bromobenzene hydrazine hydrochloride (5g, 2.24 × 10-2Mol) it is dissolved in acetonitrile In the mixed liquor of (50ml) and 4% sulfuric acid (50ml), be slowly added dropwise under stirring conditions 3,4- dihydropyran (5.55ml, 2.86×10-2Mol), reaction is heated to 150 DEG C after being added dropwise, maintains reaction 3h.To which after reaction, liquid cooling will be reacted But to room temperature, it is evaporated under reduced pressure out excessive acetonitrile, 50ml ethyl acetate is then added into remaining mixed liquor and is extracted three times. Merge organic phase, anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (PE:EA=20:1) obtains grease 4.36g, yield 77%.
[step b] at room temperature, in single-necked flask by upper step grease (1g, 3.94 × 10-3Mol) it is dissolved in N, N- dimethyl Formamide (50ml), and addition cuprous cyanide (1.10g, 1.18 × 10-2Mol), reaction is heated to 130 DEG C, maintains reaction 6h.To anti- After answering, reaction solution is poured into 100ml water, 20ml ethyl acetate extracts 5 times.Merging organic phase, anhydrous sodium sulfate is dry, Concentration rear pillar chromatography (PE:EA=20:1) obtains grease 0.71g, yield 90%.
Step 2: preparation 3- (3- bromopropyl) -1-H-5- cyanoindole (intermediate 3e)
At 0 DEG C, with 100ml in dry three-necked flask by intermediate 2 (1g, 5.00 × 10-3), mol be dissolved in 30ml without In water methylene chloride, then sequentially add carbon tetrabromide (0.80ml, 1.50 × 10-2Mol), triphenylphosphine (2.15g, 1.50 × 10-2mol).It continues thereafter with plus water 20ml three times with the extraction of 20ml methylene chloride merges organic phase, uses nothing after saturated common salt washing Aqueous sodium persulfate is dry, and concentration rear pillar chromatography (PE:EA=20:1) obtains grey black oily liquids 0.93g, yield 71%.
Step 3: preparation N- (2- amyl) aniline (intermediate 5a)
By aniline (2.94g, 0.03mol), 2 pentanone (2.58g, 0.03mol), acetic acid (25ml) and water (2.5ml) are added It is added portionwise in 100ml single-necked flask, under stirring condition by the zinc powder of hydrochloric acid activation, is then transferred into 75 DEG C, at this temperature Flow back 12h.After the reaction was completed, after reaction solution is cooled to room temperature, mild alkaline conditions are adjusted to ammonium hydroxide under ice bath, pH ≈ 10, Three times with the extraction of 50ml methylene chloride, merging organic phase, anhydrous sodium sulfate is dry, concentration rear pillar chromatography (PE:EA=50:1) Yellow oil 3.06g, yield 62.6%.
Step 4: preparation N- (2- amyl)-N- phenyl -2- chloroacetamide (intermediate 6a)
With in single-necked flask by intermediate 5a (5g, 3.07 × 10-2Mol), triethylamine (4.74ml, 3.42 × 10-2mol) Be dissolved in 50ml anhydrous methylene chloride, under condition of ice bath be added dropwise dissolved with chloracetyl chloride (2.72ml, 3.42 × 10-2Mol dichloro) Dichloromethane, is gradually increased to room temperature after being added dropwise, the reaction was continued under the conditions of stirring was transferred to 75 DEG C after 30 minutes 8h.To anti- After answering, methylene chloride 30ml is added, and three times with 30ml saturated common salt water washing, merges organic phase, anhydrous sodium sulfate is dry Dry, concentration rear pillar chromatography (PE:EA=30:1) obtains white solid 6.6g, yield 90.3%.
Step 5: preparation N- (2- amyl) -2- (4-Boc-1- piperazinyl)-phenyl acetanilide,Phenacetylaniline (intermediate 7a)
By intermediate 6a (6g, 2.51 × 10-2Mol), N-Boc- piperazine (4.20g, 2.51 × 10-2Mol) it is dissolved in acetonitrile In, then be added potassium carbonate (4.68g, 3.76 × 10-2Mol), 85 DEG C are warming up to, reaction 8h is maintained.To after reaction, depressurize Acetonitrile is removed, then plus water 30ml, three times with the extraction of 30ml methylene chloride.Merge organic phase, anhydrous sodium sulfate is dry, after concentration Column chromatography (DCM:MeOH=50:1) obtains light yellow solid 7.5g, yield 77%.
Step 6: preparation N- (2- amyl) -2- (1- piperazinyl)-phenyl acetanilide,Phenacetylaniline trifluoroacetate (intermediate 8a)
In single-necked flask by intermediate 7a (6g, 1.54 × 10-2Mol it) is dissolved in 50ml methylene chloride, stirs lower be added dropwise 30ml trifluoroacetic acid, after room temperature the reaction was continued 3h.To removed under reduced pressure excess of solvent after the reaction was completed, 30ml petroleum is used respectively Ether, 30ml ether respectively wash three times, and white solid 6.08g, yield 98.0% are obtained after filtration drying.
Step 7: preparation N- (2- amyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- phenyl Acetamide
At room temperature, in the single-necked flask containing 50ml acetonitrile solution be added intermediate 8a (1g, 2.48 × 10-3Mol) and Intermediate 3e (0.75g, 2.85 × 10-3Mol) and potassium carbonate (0.85g, 4.96 × 10-3Mol), reaction is heated to 75 DEG C, stirs Mix reflux 12h.To after reaction, remove extra acetonitrile quilt, 30ml water is added, 30ml methylene chloride extracts three times, merges Organic phase, anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (DCM:MeOH=10:1) obtains white solid 0.97g, yield 82.7%.
Embodiment 43-55,58,60,61: compound FW I -43-FW I -55, FW I -58, FW I -60, FW I -61
Repeat embodiment 42, difference is: using different raw materials in step 3, in step 5 using different raw materials from And I -43-FW I -55 of compound FW, FW I -58, FW I -60, FW I -61 is made.Compound FW I -50 and FW I -51, FW I -52 with FW I -53 is a pair of of cis-trans-isomer, obtains its corresponding intermediate through column chromatography (PE:EA=30:1) in step 4.
Table specific as follows:
Step 3:
Step 5:
Embodiment 56,57,59: compound FW I -56, FW I -57, FW I -59
Embodiment 42 is repeated, difference is: using different raw materials to which compound FW I -56, FW be made in step 3 Ⅰ-57,FWⅠ-59.Table specific as follows:
Step 3
Embodiment 62: preparation N- (2- ethyl alcohol base) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl) - Phenyl acetanilide,Phenacetylaniline (FW I -62)
Step 1: preparation 3- (5- cyanoindole) propyl alcohol (intermediate 2e)
[step a] at room temperature, in single-necked flask by 4- bromobenzene hydrazine hydrochloride (5g, 2.24 × 10-2Mol) it is dissolved in acetonitrile In the mixed liquor of (50ml) and 4% sulfuric acid (50ml), be slowly added dropwise under stirring conditions 3,4- dihydropyran (5.55ml, 2.86×10-2Mol), reaction is heated to 150 DEG C after being added dropwise, maintains reaction 3h.To which after reaction, liquid cooling will be reacted But to room temperature, it is evaporated under reduced pressure out excessive acetonitrile, 50ml ethyl acetate is then added into remaining mixed liquor and is extracted three times. Merge organic phase, anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (PE:EA=20:1) obtains grease 4.36g, yield 77%.
[step b] at room temperature, in single-necked flask by upper step grease (1g, 3.94 × 10-3Mol) it is dissolved in N, N- dimethyl Formamide (50ml), and addition cuprous cyanide (1.10g, 1.18 × 10-2Mol), reaction is heated to 130 DEG C, maintains reaction 6h.To anti- After answering, reaction solution is poured into 100ml water, 20ml ethyl acetate extracts 5 times.Merging organic phase, anhydrous sodium sulfate is dry, Concentration rear pillar chromatography (PE:EA=20:1) obtains grease 0.71g, yield 90%.
Step 2: preparation 3- (3- bromopropyl) -1-H-5- cyanoindole (intermediate 3e)
At 0 DEG C, with 100ml in dry three-necked flask by intermediate 2e (1g, 5.00 × 10-3), mol be dissolved in 30ml without In water methylene chloride, then sequentially add carbon tetrabromide (0.80ml, 1.50 × 10-2Mol), triphenylphosphine (2.15g, 1.50 × 10-2mol).It continues thereafter with plus water 20ml three times with the extraction of 20ml methylene chloride merges organic phase, uses nothing after saturated common salt washing Aqueous sodium persulfate is dry, and concentration rear pillar chromatography (PE:EA=20:1) obtains grey black oily liquids 0.93g, yield 71%.
Step 3: preparation N- [2- (tertiary butyl dimethyl Si base) ethyl] aniline (intermediate 5b)
[step a] is separately added into iodobenzene (1.11ml, 0.01mol) in tube sealing, ethylaminoethanol (0.93ml, 0.012mol) Potassium hydroxide (1.12g, 0.02mol), and iodate Asia ketone (0.19g, 1 × 10-3Mol) and water, then reaction solution is heated to 100 DEG C. After reaction, 50ml water is added, ethyl acetate extracts three times, merges organic phase, and anhydrous slufuric acid is dry, and column layer is carried out after concentration Analysis (PE:EA=10:1) obtains colorless oil 0.85g, yield 62%.
[step b] at room temperature, in single-necked flask by the colorless oil compound (1.5g, 1.09 × 10-2Mol) it is dissolved in two In chloromethanes (20ml), be slowly added under stirring condition imidazoles (0.89g, 1.3 × 10-2Mol), continue stirring 10 minutes, then Into reaction solution be added tert-butyl chloro-silicane (1.96g, 1.3 × 10-2Mol), 10h is reacted at room temperature.After the reaction was completed, 30ml water is added, and then ethyl acetate extraction three times, merges organic phase, and anhydrous sodium sulfate is dry, and concentration rear pillar chromatographs (PE:EA =20:1) obtain colorless oil intermediate 4,2.32g, yield 84.6%.
Step 4: preparation N- [2- (tertiary butyl dimethyl Si base) ethyl]-N- phenyl -2- chloroacetamide (intermediate 6b)
With in single-necked flask by intermediate 5b (5g, 1.99 × 10-2Mol), triethylamine (5.42ml, 2.99 × 10-2mol) Be dissolved in 50ml anhydrous methylene chloride, under condition of ice bath be added dropwise dissolved with chloracetyl chloride (3.11ml, 2.99 × 10-2Mol dichloro) Dichloromethane, is gradually increased to room temperature after being added dropwise, the reaction was continued under the conditions of stirring was transferred to 75 DEG C after 30 minutes 8h.To anti- After answering, methylene chloride 30ml is added, and three times with 30ml saturated common salt water washing, merges organic phase, anhydrous sodium sulfate is dry Dry, concentration rear pillar chromatography (PE:EA=30:1) obtains white solid 5.5g, yield 85.3%.
Step 5: preparation N- (2- amyl) -2- (4-Boc-1- piperazinyl)-phenyl acetanilide,Phenacetylaniline (intermediate 7b)
By intermediate 6b (6g, 1.83 × 10-2Mol), N-Boc- piperazine (5.74g, 1.83 × 10-2Mol) it is dissolved in acetonitrile In, then be added potassium carbonate (6.40g, 2.75 × 10-2Mol), 85 DEG C are warming up to, reaction 8h is maintained.To after reaction, depressurize Acetonitrile is removed, then plus water 30ml, three times with the extraction of 30ml methylene chloride.Merge organic phase, anhydrous sodium sulfate is dry, after concentration Column chromatography (DCM:MeOH=50:1) obtains light yellow solid 6.1g, yield 70%.
Step 6: preparation N- (2- amyl) -2- (1- piperazinyl)-phenyl acetanilide,Phenacetylaniline trifluoroacetate (intermediate 8b)
In single-necked flask by intermediate 7b (6g, 1.26 × 10-2Mol it) is dissolved in 50ml methylene chloride, stirs lower be added dropwise 30ml trifluoroacetic acid, after room temperature the reaction was continued 3h.To removed under reduced pressure excess of solvent after the reaction was completed, 30ml petroleum is used respectively Ether, 30ml ether respectively wash three times, and white solid 3.13g, yield 94.1% are obtained after filtration drying.
Step 7: preparation N- (2- ethyl alcohol base) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- benzene Yl acetamide
At room temperature, in the single-necked flask containing 50ml acetonitrile solution be added intermediate 8b (1g, 2.65 × 10-3Mol) and Intermediate 3e (0.59g, 2.65 × 10-3Mol) and potassium carbonate (1.05g, 5.68 × 10-3Mol), reaction is heated to 75 DEG C, stirs Mix reflux 12h.To after reaction, remove extra acetonitrile quilt, 30ml water is added, 30ml methylene chloride extracts three times, merges Organic phase, anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (DCM:MeOH=10:1) obtains white solid 0.95g, yield 80.8%.
Embodiment 63: compound FW I -63
Embodiment 62 is repeated, difference is: using different raw materials to which compound FW I -63 be made in step 3.Tool Body is as follows:
The chemical structure for the target product that the present invention has synthesized is shown in Table 3.Nucleus magnetic hydrogen spectrum, mass spectrometer system characterize target product Chemical structure.
The chemical structure and nucleus magnetic hydrogen spectrum, mass spectrometric data of 3 target product of table
Embodiment 64: pharmacology embodiment
Affinity experiment:
1. medicine ordinance
Test-compound, 5-HT1AReceptor positive drug 5-hydroxytryptamine, 5-HT2AReceptor positive drug Butaclmol is dissolved to 0.01mol/L with DMSO, is then diluted to 100 μm of ol/L with deionized water.
2. Receptor Binding Assay material
5-HT1AReceptor isotope aglucon [3H] 8-OH-DPAT, 5-HT2AReceptor isotope aglucon [3H] Ketanserin (purchase From PE company), (+) 5-hydroxytrptamine, (+)-Butaclamol hydrochloride (are purchased from Sigma company), GF/B glass fiber filter paper (is purchased from Whatman company), fat-soluble scintillation solution: PPO, POPOP (are purchased from Shanghai Reagent One Plant), first Benzene (is purchased from Sinopharm Chemical Reagent Co., Ltd.), and Tris is dispensed by Ji Tai Science and Technology Ltd..Cell: steady with genetic recombination Surely 5-HT is expressed1AReceptor, 5-HT2AThe HEK-293 cell of receptor, after the cell culture fluid culture 3-5 of DMEM+10% serum, Cell is received with PBS, cell is abandoned into supernatant with the 3000 turns of centrifugations of -4 degree after ten minutes, receives cell space, -80 degree refrigerators is stored in and saves.It is real It is resuspended when testing with Tris-Cl (pH 7.4).
3. Receptor Competition Binding experiment
Untested compound and each 10 μ L of radioactive ligand and 80 μ L receptor proteins are added in reaction tube, tested chemical combination is made Object and positive drug final concentration are that 10 μm of ol/L move to ice bath at once and terminate its reaction after 37 DEG C of water-baths are incubated for 15min；In On Millipore cell sample collection device, by GF/B glass fiber filter paper rapid filtration under suction, and with eluent (50mM Tris- HCl, pH 7.7) 3ml washing 3 times, it is dried with 8~9min of micro-wave oven, filter paper is moved into 0.5mL centrifuge tube, 500 μ L rouge are added Dissolubility scintillation solution.It is protected from light and stands 30min or more, count measurement radioactive intensity.Each compound is calculated to combine isotope aglucon Inhibition percentage, compound of the inhibiting rate higher than 80% carry out the receptor binding assays of concentration a series of, determine that half inhibits Amount (IC50 inhibits 50% positive control medicine required compound concentration in conjunction with receptor).Every two looped pipeline of concentration mensuration, Mei Gehua It closes object and carries out independent experiment twice.
Inhibiting rate calculation formula is as follows:
Functional experiment:
1. experimental material
[35S]GTPγS；GF/C glass fiber filter paper；Fat-soluble scintillation solution；Gpp(NH)p(10-2)；GDP(4*10-3)； RB buffer.Cell: the 5-HT of HEK293 cell expression1AReceptor egg.Positive drug: 5-HT
2. experimental method
1) cell 50mM Tris, pH 7.4, broken cell, 1000 × g, 4 DEG C are centrifuged 10 minutes, supernatant 36000 × g again, 4 DEG C are centrifuged 30 minutes, and retaining precipitating is cell membrane, is suspended with 50mM Tris, pH 7.4, and BCA method surveys protein concentration.
2) GTP γ S Binding experiment carries out in 200 μ l buffer systems, every 30 μ g albumen of pipe, reaction buffer 50mM Tris,Ph 7.4,5mM MgCl2,1mM EDTA,100mM NaCl,1mM DTT,Ph 7.5.Reaction system contains 40 μM of GDP, 100 μM of Gpp (NH) p are added in non-specific pipe, and various concentration test medicine is added in testing tube.Antagonism function person is detected, testing tube adds Enter various concentration test medicine and 5-HT (5-HT1A).Each pipe be added 0.1nM [35S] GTP γ S, it is placed in 30 DEG C of water-baths 20min.Stopped reaction on ice is set in taking-up, is filtered through GF/C film, and drying is placed in 0.5ml EP pipe, and it is fat-soluble that 500 μ l are added Scintillation solution surveys activity with MicroBeta liquid scintillation instrument.Each concentration three is managed again, carries out at least 2 independent experiments.
Calculation formula are as follows: [35S] GTP γ S Bound (%above basal)=100 × (sample dpm- basis dpm)/ (the basic non-specific dpm of dpm-) %
Concentration effect curve is fitted with software and obtains EC50Or IC50Value.

Claims (6)

1. the indolyl piperazine compounds of general formula (I),
Wherein:
M, n are independently optionally from 0,1,2,3 or 4；Preferably, m is selected from 1 or 2；N is selected from 3；
Substituent R1Selected from hydrogen, halogen, C1-C6Substituted or unsubstituted alkyl, C1-C6Substituted or unsubstituted alkoxy, hydroxyl, Cyano；
Substituent R2It is not present or at least one position in 2,3,4,5,6, is unsubstituted, mono-substituted, disubstituted Or polysubstituted, substituent R2Selected from one of following groups, two or more: hydrogen, halogen, nitro, hydroxyl, carboxyl, Cyano, amino, C1-C6Substituted or unsubstituted alkyl, C1-C6Substituted or unsubstituted alkoxy ,-SO2CH3Group；Work as R2For When double or three substitution, substituent group can be identical or different；
Substituent R3Selected from H, C1-C6Substituted or unsubstituted alkyl, C3-C7Substituted or unsubstituted naphthenic base or HetAr1；
The HetAr1 indicates the saturation unsubstituted 4,5,6,7,8,9 or 10 with 1,2 or 3 N and/or O and/or S atom Circle heterocyclic ring.
2. indolyl piperazine compounds according to claim 1, which is characterized in that the compound is selected from:
N- (3- amyl) -2- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (3- hexyl) -2- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- amyl) -3- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- amyl) -3- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (2- hexyl) -3- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- hexyl) -3- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (4- methoxycyclohexyl) -3- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (2- amyl) -2- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- (5- fluorophenyl) acetamide,
N- (2- amyl) -2- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- (5- methoxyphenyl) acetyl Amine,
N- (2- amyl) -2- (4- (3- (the fluoro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- (5- methanesulfonylphenYl) acetyl Amine,
N- (2- amyl) -2- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (3- amyl) -2- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- hexyl) -2- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (3- hexyl) -2- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (4- methoxycyclohexyl) -2- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- amyl) -3- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- amyl) -3- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (2- hexyl) -3- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- hexyl) -3- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (4- methoxycyclohexyl) -3- (4- (3- (the chloro- 1H-3- indoles of 5-) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- amyl) -2- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- hexyl) -2- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (3- hexyl) -2- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- amyl) -3- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- amyl) -3- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (2- hexyl) -3- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- hexyl) -3- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (4- methoxycyclohexyl) -3- (4- (3- (5- methoxyl group -1H-3- indoles) propyl) -1- piperazinyl)-N- phenylpropionyl Amine,
N- (3- amyl) -2- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- hexyl) -2- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (3- hexyl) -2- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- amyl) -3- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- amyl) -3- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (2- hexyl) -3- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- hexyl) -3- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (4- methoxycyclohexyl) -3- (4- (3- (5- hydroxyl -1H-3- indoles) propyl) -1- piperazinyl)-N- phenylpropionyl Amine,
N- (2- amyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (3- amyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- hexyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (3- hexyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (4- methoxycyclohexyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- phenylacetyl Amine,
N- (2- amyl) -3- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- amyl) -3- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (2- hexyl) -3- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (3- hexyl) -3- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- Phenylpropionamide,
N- (4- methoxycyclohexyl) -3- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- phenylpropionyl Amine,
N- (2- amyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- (5- fluorophenyl) acetamide,
N- (2- amyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- (5- methoxyphenyl) acetyl Amine,
N- (2- amyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- (5- methanesulfonylphenYl) second Amide,
N- (4- tetrahydro -2-H- pyranose) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- phenyl second Amide,
N- (4- oxocyclohexyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (4- piperidyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- ethyl alcohol base) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (2- propyl alcohol base) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-phenyl acetanilide,Phenacetylaniline,
N- (1- methoxyl group -2- propyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- phenylacetyl Amine,
N- (1,2- Dimethoxy-ethyl) -2- (4- (3- (5- cyano -1H-3- indoles) propyl) -1- piperazinyl)-N- phenyl second Amide.
3. the pharmaceutically acceptable salt of indolyl piperazine compounds described in claim 1, solvate, precursor chemical combination Object or polymorph.
4. pharmaceutically acceptable salt, solvate, the precursor of indolyl piperazine compounds according to claim 3 Compound or polymorph, which is characterized in that the pharmaceutically acceptable salt is inorganic salts, organic salt or amino-acid salt；
Wherein inorganic salts are as follows: sodium salt, hydrochloride, trifluoroacetate, sulfate, phosphate, diphosphate, hydrobromate or nitric acid Salt；
Wherein organic salt are as follows: maleate, acetate, fumarate, tartrate, succinate, lactate, p-methyl benzenesulfonic acid Salt, salicylate or oxalates；
Wherein amino-acid salt are as follows: arginine salt, ornithine salt, lysine salt, leucine salt, isoleucine salt, glycinate, Guang Propylhomoserin salt, cysteine salt, tyrosine salt, alanine salt, phenylalanine salt, histidine salt, serine salt, threonine salt, egg Propylhomoserin salt, tryptophan salt, glutamate, aspartate, valine salt, methionine salt, proline salt or hydroxyproline salt.
5. indolyl piperazine compounds described in claim 1 or indolyl piperazines chemical combination as claimed in claim 3 Pharmaceutically acceptable salt, solvate, pro-drug or the polymorph of object are in preparation treatment and 5-HT1AReceptor associated diseases Drug in purposes.
6. purposes according to claim 5, which is characterized in that the disease is nerve related with brain and spirituality Disease is anxiety disorder, depression, schizophrenia and/or parkinsonism.
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