CN107793350B - Arylethylpiperidinyl derivatives and their use for the treatment of schizophrenia - Google Patents

Arylethylpiperidinyl derivatives and their use for the treatment of schizophrenia Download PDF

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CN107793350B
CN107793350B CN201610801210.XA CN201610801210A CN107793350B CN 107793350 B CN107793350 B CN 107793350B CN 201610801210 A CN201610801210 A CN 201610801210A CN 107793350 B CN107793350 B CN 107793350B
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ethyl
piperazin
piperidin
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dichlorophenyl
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CN107793350A (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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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 an arylethyl piperidyl derivative and application thereof in resisting schizophrenia. Pharmacological experiment results show that the arylethylpiperidine compound provided by the invention is dopamine D2、D3、5‑HT1A、5‑HT2AThe receptor has higher affinity and is to D3/D2The receptor selectivity is good. In vivo test results show that the preferred compound has good anti-schizophrenia effect, lower acute toxicity, higher safety and good pharmacokinetic property, and has development value as a novel high-efficiency low-toxicity anti-neuro-psychosis medicine. The aryl ethyl piperidine compound is a compound shown as a structural general formula (I) or a salt or hydrate of the salt thereof:

Description

Arylethylpiperidinyl derivatives and their use for the treatment of schizophrenia
Technical Field
The invention relates to an arylethylpiperidinyl derivative having an anti-schizophrenia activity or a pharmaceutically acceptable hydrate, salt or hydrate of salt thereof, a pharmaceutical composition containing the compound or the pharmaceutically acceptable hydrate, salt or hydrate of salt, a kit, and an application thereof in treating schizophrenia.
Background
Schizophrenia is a chronic persistent disease, is the most serious and most harmful one of mental diseases, affects the normal life of about 1% of the population in the world, and is the 7 th disease of the social burden, wherein the number of people in China exceeds 10,000,000. Schizophrenia is a complex disorder with symptoms often varying with the course of the disease. Schizophrenia symptoms mainly include positive symptoms such as delusions, hallucinations; negative symptoms, such as social withdrawal, apathy; cognitive dysfunction, such as three major symptoms of working memory loss.
The cause of schizophrenia is complex and is not clear up to now. There are several major hypotheses in academia, including the influence of neurodevelopmental hypothesis, neurobiochemical hypothesis, and genetic factor hypothesis, as well as social and environmental factors. The neurobiochemical hypothesis is accepted and approved by academia. Relevant basic research and clinical data of anti-schizophrenia medicines show that schizophrenia can have a plurality of neurotransmitter functional abnormalities, mainly Dopamine (DA) neuron hyperfunction, 5-hydroxytryptamine (5-HT) functional system loss and the like. The DA hypothesis states that schizophrenia symptoms result from an imbalance in dopamine activity in the mesocerebral-cortical pathway in schizophrenic patients. The 5-HT hypothesis states that alterations in the 5-HT energy mechanism of the patient's prefrontal cortex lead to an inability of the cerebral cortex to properly inhibit subcortical dopamine, leading to dopaminergic hyperactivity.
Currently, the commercially available and clinical anti-schizophrenia drugs are mainly atypical antipsychotics. The drugs mainly act on DA system and 5-HT system. Acting on dopamine D2Receptors are a common mechanism for antipsychotics. D2Receptors are widely distributed in the brain and are involved in numerous physiological functions and pathological conditions. D2Receptor antagonists are widely used as antipsychotics. However, a large number of antagonisms of D2D of receptors, especially of the nigro-striatal pathway2The receptor causes the patient to develop extrapyramidal side Effects (EPS), etc. While acting simultaneously on the 5-HT system, e.g. antagonising 5-HT2AReduced receptor capacity D2The excessive inhibition of the receptor can reduce the side reaction of EPS, hyperprolactinemia and the like. Thus, non-classical antipsychotics may further treat negative symptoms, such as the marketed drugs risperidone, aripiprazole, ziprasidone, etc., in addition to maintaining the activity of anti-positive symptoms similar to those of classical antipsychotics. However, with the deepening of clinical medication practices, the medicines have limited improvement on negative symptoms, cannot meet clinical requirements, interact with a plurality of receptors, and easily generate side effects such as obesity, akathisia, insomnia, anxiety and the like. Meanwhile, clinical test results show that the existing antipsychotic has no obvious effect of improving cognitive impairment. Therefore, the search for novel anti-schizophrenia drugs with high efficiency, low toxicity and wide treatment spectrum is a common challenge for global pharmaceutical enterprises, and is also a hot spot of research on the drugs.
Clinical and animal test results show that the selective antagonism of dopamine D3The receptors can reduce the occurrence of extrapyramidal side effects and improve the cognitive function of the patient. But with D2Receptor comparison, D3Receptor mRNA is less distributed in the brain, requiring the drug to act on D simultaneously2、D3And should have a certain D3Receptor selectivity, i.e. for D3Has a stronger affinity than for D2The affinity of the receptor is 10 times or more, so as to exert physiological effects such as cognitive improvement. The results of clinical and preclinical tests show that D is too high3Receptor selectivity, e.g. compound pair D3Receptor affinity greater than D2More than one hundred times of the receptor, or D3/D2At receptor selectivities greater than 100-fold or greater, the compounds fail to exhibit anti-schizophrenia activity, particularly against the positive symptoms of schizophrenia. In recent years, 5-HT1AThe improvement effect of the receptor on reducing the side effect of the schizophrenia drug and improving the cognitive function is more and more accepted by academia. It has been shown that 5-HT1ACan effectively reduce the cause D2EPS and the like due to excessive blockingSide effects, and improving cognitive impairment of schizophrenia patients. Thus, selectively act on D2、D3、5-HT1AAnd 5-HT2AThe research and development of novel multi-target anti-schizophrenia medicines of receptors have wide prospects, and a novel anti-schizophrenia medicine Cariprazine (Cariprazine) belonging to the action mechanism is marketed in the United states in 2015 and 9 months.
The inventor notices that the series of compounds disclosed in Chinese patents CN1829703A, CN102159557A, CN103130737A and CN104140421A have the activity of treating mental and neurological diseases. The structures of the compounds all contain arylethylcyclohexyl fragments, but slight changes in the structures, such as changes on aryl groups connected with piperazine, different substituents on amino groups and intermediate connecting chains, cause differences of physicochemical properties, pharmacokinetic parameters, in vitro receptor action characteristics, in vivo pharmacological activity and related side effects of the compounds to a great extent. The details are as follows.
1. Patent CN1829703A, which discloses the following structure as D2And D3Receptor dual modulators:
Figure BDA0001109288820000021
wherein
R1And R2Independently represents a substituent selected from hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aroyl, or R1And R2May form a heterocyclic ring with the adjacent nitrogen atom;
x represents an oxygen or sulfur atom;
n is an integer of 1 to 2,
and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof.
2. Patent CN102159557A, which discloses the following structure as an alternative 5-HT2AAnd D3Receptor modulators:
Figure BDA0001109288820000031
wherein:
x independently of one another is halogen or C1-6-an alkyl group;
n is 0, 1 or 2;
R1is-COR2or-SO2-C1-6-an alkyl group;
R2is C1-6Alkyl radical, C1-6-haloalkyl group, C1-6-hydroxyalkyl, C1-6-alkoxy, 3-to 10-membered cycloalkyl, 4-to 10-membered heterocycloalkyl or 5-to 10-membered heteroaryl, optionally substituted with one or more substituents selected from:
the halogen(s) are selected from the group consisting of,
a hydroxyl group(s),
C1-6-an alkyl group,
C1-6-a halogenated alkyl group,
C1-6-a hydroxyalkyl group,
C1-6-an alkoxy group,
optionally substituted by one or more RaSubstituted C1-6-alkoxy groups,
-S-C1-6-an alkyl group,
-SO2-C1-6-an alkyl group,
-CONH2，
CHO
optionally substituted by one or more RaA substituted 3 to 10-membered cycloalkyl group,
optionally substituted by one or more RaSubstituted 4 to 10 membered heterocycloalkyl and
optionally substituted by one or more RaSubstituted 5 to 10 membered heteroaryl;
wherein R isaSelected from:
halogen element
A hydroxyl group(s),
C1-6-an alkyl group,
C1-6-a hydroxyalkyl group,
C1-6-haloalkyl and
C1-6-alkoxy groups.
3. Patent CN 103130737A. It discloses the following structure as D2、D3、5-HT1AReceptor modulators:
Figure BDA0001109288820000041
wherein:
r is
Figure BDA0001109288820000042
R1，R2，R3Each represents hydrogen, trifluoromethyl, C1～C4Alkyl and substituted alkyl of (2), C3～C6Cycloalkyl and substituted cycloalkyl of (A), C5～C7The heterocycloalkyl and substituted heterocycloalkyl, phenyl and substituted phenyl, pyridyl and substituted pyridyl of (a);
R4and R5Independently represent hydrogen, C1～C4Alkyl and substituted alkyl of (2), C3～C6Cycloalkyl and substituted cycloalkyl of (A), C5～C7Heterocycloalkyl and substituted heterocycloalkyl of (A), R4And R5A pyrrolidine ring, unsubstituted or substituted piperazine, morpholine or unsubstituted or substituted piperidine formed with the adjacent nitrogen atom;
R6and R7Independently represent hydrogen, C1～C4Alkyl and substituted alkyl of (2), C3～C6Cycloalkyl and substituted cycloalkyl of (A), C5～C7Heterocycloalkyl and substituted heterocycloalkyl of (A), R4And R5A pyrrolidine ring, unsubstituted or substituted piperazine, morpholine or unsubstituted or substituted piperidine formed with the adjacent nitrogen atom;
R8and R9Independently represent hydrogen, C1～C4Alkyl and substituted alkyl of (2), C3～C6Cycloalkyl and substituted cycloalkyl of (A), C5～C7Heterocycloalkyl and substituted heterocycloalkyl of (A), R4And R5A pyrrolidine ring with an adjacent nitrogen atom, an unsubstituted or substituted piperazine, morpholine or an unsubstituted or substituted piperidine.
4. Patent CN104140421A, which discloses the following structure as D2、D3、5-HT1A、5-HT2AReceptor modulators:
Figure BDA0001109288820000043
wherein:
w is:
Figure BDA0001109288820000051
R1、R2each represents a heteroaryl group or a substituted heteroaryl group;
n is 0, 1, 2 or 3; m is 0, 1 or 2;
R3represents C1～C4Alkyl, substituted C1～C4Alkyl of (C)3～C6Cycloalkyl, substituted C3～C6Cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, heteroaryl, substituted heteroaryl, heteroarylmethyl or substituted heteroarylmethyl;
R4is a hydrogen atom or C1～C4Alkyl groups of (a);
R5is aryl or substituted aryl.
The differences in activity of the representative compounds in the above patents are exemplified by:
Figure BDA0001109288820000052
Figure BDA0001109288820000061
in conclusion, it is suggested that for the structure containing the arylethylcyclohexyl segment, the change of different acyl substituents on aryl and cyclohexyl amino groups connected to piperazine is completely different from the effect of in vitro receptors or has larger activity difference.
In addition, the compounds represented in the patents also have the defects of poor solubility, unsatisfactory in vivo bioavailability, poor brain targeting and other drug-forming defects.
In the existing anti-schizophrenia drugs, metabolic side effects (such as obesity) and arrhythmia, constipation, somnolence, Extrapyramidal (EPS) side effects (such as catalepsy) and serious side effects are easy to generate, so that the compliance of patients is poor, and the cognitive disorder of the schizophrenia patients is not obviously improved. Therefore, it is necessary to research compounds with different structures or new compounds with different structures but good physicochemical properties to overcome the above-mentioned defects of the existing compounds.
The literature (Journal of Medicinal Chemistry,2013,56,9199-2、D3The G protein-coupled receptor and the intermediate connecting chain of the compound, including the length, the flexibility, the configuration and the like of the G protein-coupled receptor and the intermediate connecting chain of the compound influence the binding force of the compound and the receptor and the pharmacological activity of the compound, such as agonism and partial agonism. In view of the specificity and specificity of central nervous system target, the change of the action of the receptor can lead the compound to show different pharmacological activities in vivo and larger difference of related side effects, and the influence of the compound on the action of the receptor and the activities in vitro and in vivo needs to be further proved by experiments.
The invention designs an arylethylpiperidine derivative, the structure of which contains 1, 4-disubstituted piperidyl, and compared with the 1, 4-disubstituted cyclohexyl in the prior art, the arylethylpiperidine derivative has no cis/trans isomer, and the flexibility and the space configuration of the arylethylpiperidine derivative are greatly different from those of the cyclohexyl; secondly, the "N" atom of the 1, 4-disubstituted piperidinyl group has a lone pair of electrons, with a greater difference in electron density from cyclohexyl. Thus, compounds having a1, 4-disubstituted piperidinyl linker may differ significantly in the mode of binding to the receptor, the magnitude of the binding force, water solubility and pharmacological activity and safety compared to compounds containing a1, 4-disubstituted cyclohexyl linker, but need to be confirmed experimentally.
Brief description of the invention
Aiming at the defects in the prior art, the invention discloses an arylethylpiperidinyl derivative, which is used for overcoming the defects of side effects such as obesity, high blood sugar rise and the like, side effects such as arrhythmia, EPS (such as catalepsy) and the like, poor treatment effect on negative symptoms and cognitive disorder and the like of the existing medicines, and meeting the requirement of clinical medication.
Also disclosed are methods of using the above compounds in the treatment of schizophrenia. The invention also discloses the application of the compound in preparing broad-spectrum anti-schizophrenia and medicines for treating schizophrenia.
According to one aspect of the present application, there is provided an arylethylpiperidinyl derivative which is a compound having the general structural formula (I) or a pharmaceutically acceptable hydrate, salt or hydrate of salt thereof:
Figure BDA0001109288820000071
wherein:
r is
Figure BDA0001109288820000072
R3Is selected from C1～C3Alkyl of (C)1～C2Alkoxy group of (C)3～C6Cycloalkyl, phenyl, substituted phenyl or heteroaryl of (a);
R4、R5each independently represents hydrogen or C1～C3Alkyl of (C)3～C6Cycloalkyl, phenyl, benzyl or pyridyl;
or R4、R5Forms a morpholine ring with the attached N atom;
n is an integer of 0 to 1;
R1、R2each independently represents chlorine, methyl, methoxy, phenyl;
or R1、R2Together form a benzene ring, an oxazolone ring or a thiophene ring.
According to certain embodiments of the invention, the substituted phenyl is selected from halogen, cyano, methoxy or C1～C2Alkyl-substituted phenyl of (a).
According to certain embodiments of the invention, the heteroaryl group is selected from furyl, pyrrolyl, thienyl, pyridyl, 2-benzothienyl, 2-benzofuryl or 2-indolyl.
According to certain embodiments of the invention, the salt is a salt comprising a pharmaceutically acceptable anion.
According to certain embodiments of the invention, the salt of the pharmaceutically acceptable anion is preferably a hydrochloride, hydrobromide, sulfate, acetate, trifluoroacetate, citrate, tartrate, maleate, fumarate, mesylate, p-toluenesulfonate or oxalate salt.
According to certain embodiments of the present invention, the hydrate of the salt of the compound contains 0.5 to 3 molecules of water of crystallization.
According to certain embodiments of the invention, the salt in the hydrate of the salt of the compound is preferably an oxalate, mesylate, hydrobromide or trifluoroacetate salt.
According to certain embodiments of the present invention, the arylethylpiperidinyl derivatives of the present invention may include, but are not limited to, the following preferred compounds:
I-1N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) acetamide,
I-2N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) butanamide,
I-3N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -2-methoxyacetamide,
I-4N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -2-ethoxyacetamide,
I-5N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) cyclopropylcarboxamide,
I-6N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) cyclohexylcarboxamide,
I-7N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) benzamide,
I-8N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-fluorobenzamide,
I-9N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-cyanobenzamide,
I-10N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-methylbenzamide,
I-11N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) nicotinamide,
I-12N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) furan-2-carboxamide,
I-13N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) pyrrole-2-carboxamide,
I-14N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) thiophene-2-carboxamide,
I-15N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) indole-2-carboxamide,
II-11- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-methylurea,
II-23- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -1, 1-dimethylurea,
II-31- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-propylurea,
II-41-cyclopropyl-3- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) urea,
II-51-cyclohexyl-3- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) urea,
II-61- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-phenylurea,
II-71-benzyl-3- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) urea,
II-81- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -3- (pyridin-3-yl) urea,
II-9N- (4- (2- (4- (2,3- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) morpholine-4-carboxamide,
III-1N- (4- (2- (4- (2, 3-dimethylphenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-methoxybenzamide,
III-2N- (4- (2- (4- (2, 3-dimethylphenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-ethylbenzamide,
III-31-Ethyl-3- (4- (2- (4- (2-methoxyphenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -1-methylurea,
III-43- (4- (2- (4- (2-methoxyphenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -1-methyl-1-phenylurea,
III-5N- (4- (2- (4- ([1,1' -diphenyl ] -3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -2-methoxyacetamide,
III-63- (4- (2- (4- ([1,1' -diphenyl ] -3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -1, 1-dimethylurea,
III-7N- (4- (2- (4- (naphthalen-1-yl) piperazin-1-yl) ethyl) piperidin-1-yl) furan-2-carboxamide,
III-81, 1-dimethyl-3- (4- (2- (4- (naphthalen-1-yl) piperazin-1-yl) ethyl) piperidin-1-yl) urea,
III-9N- (4- (2- (4- (2(3H) H-benzoxazolon-7-yl) piperazin-1-yl) ethyl) piperidin-1-yl) furan-2-carboxamide,
III-101, 1-dimethyl-3- (4- (2- (4- (2(3H) H-benzoxazolon-7-yl) piperazin-1-yl) ethyl) piperidin-1-yl) urea,
IV-1N- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) pentanamide,
IV-2N- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -2-methoxyacetamide,
IV-3N- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) benzamide,
IV-4N- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) cyclopropylcarboxamide,
IV-5N- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) nicotinamide,
IV-6N- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) furan-2-carboxamide,
IV-73- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -1, 1-dimethylurea,
IV-81- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-phenylurea,
IV-91- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -3- (pyridin-3-yl) urea,
IV-103- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -1-methyl-1-phenylurea,
IV-111- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-cyclopropylurea,
IV-12N- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) morpholine-4-carboxamide.
The structures of the preferred compounds are shown in the following table:
Figure BDA0001109288820000091
Figure BDA0001109288820000101
Figure BDA0001109288820000111
according to one aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of the arylethylpiperidinyl derivative or a pharmaceutically acceptable hydrate, salt or hydrate of salt thereof, and a pharmaceutically acceptable carrier.
According to one aspect of the present invention there is provided a kit comprising said arylethylpiperidinyl derivative or a pharmaceutically acceptable hydrate, salt or hydrate of salt thereof.
According to one aspect of the present invention, there is provided a method of treating schizophrenia by administering to a patient the arylethylpiperidinyl derivative or a pharmaceutically acceptable hydrate, salt or hydrate of salt thereof.
According to one aspect of the invention, there is provided the use of the arylethylpiperidinyl derivative or a pharmaceutically acceptable hydrate, salt or hydrate of a salt thereof in the preparation of a medicament for the treatment of schizophrenia.
Detailed Description
Definition of
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The term "halogen" or "halogen atom" refers to a fluorine (F) atom, a chlorine (Cl) atom, a bromine (Br) atom, or an iodine (I) atom. The term "halo" when used in front of a chemical group means that the substituent is substituted with one or more halo substituents. The term "haloalkyl" refers to an alkyl group as defined above wherein the hydrogen atom at one or more arbitrary positions is replaced by one or more halogen atoms which may be the same or different.
The term "cycloalkyl" refers to a monocyclic or polycyclic ring formed from carbon atoms, which may be saturated or partially saturated. In certain embodiments of the present application, the cycloalkyl group comprises a 3-6 membered (e.g., 3, 4, 5, or 6 membered) cycloalkyl, such as a 3 membered monocyclic ring, or a 5 membered monocyclic ring. Examples of cycloalkyl groups include cyclobutyl, cyclopentyl, and the like.
The term "aryl" refers to a carbocyclic aromatic ring comprising a single ring or multiple rings (e.g., 2,3, or 4 fused rings). In certain embodiments herein, examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, indenyl, and the like. In certain embodiments of the present application, the aryl group comprises a 5-9 membered (e.g., 5, 6, 7, 8, or 9 membered) aryl group.
The term "heteroaryl" means that one or more of the ring-forming carbon atoms in the above-mentioned aryl group is replaced by a heteroatom such as S, O or an N atom. The "heteroaryl" may be a monocyclic or polycyclic heteroaryl. Examples of such "heteroaryl" include, but are not limited to, furyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, pyrrolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, purinyl, benzimidazolyl, and the like. In certain embodiments of the present application, the heterocycloalkyl group has 4 to 8 (e.g., 4, 5, 6, 7, or 8) carbon atoms.
The term "arylethyl" refers to
Figure BDA0001109288820000121
Wherein R1 and R2 are as defined above.
In certain embodiments of the present application, the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl groups described above may be substituted or unsubstituted. In certain embodiments herein, the substituents may be one or more, independently selected from halogen, cyano, alkoxy, alkyl, and the like.
The compounds described herein include the anhydrate and hydrate forms of the compound. The hydrate may contain, for example, 0.5 to 3 water molecules, for example, 0.5, 1, 1.5, 2, 2.5 or 3 water molecules.
According to certain embodiments of the present application, the hydrate of the salt of the compound contains 0.5 to 3 molecules of water of crystallization, for example, 0.5, 1, 2,3 molecules of water of crystallization. According to certain embodiments of the present application, the salt of the compound is an oxalate, mesylate, hydrobromide or trifluoroacetate salt.
The term "pharmaceutical composition" means a mixture containing a therapeutically effective amount of one or more of the compounds and pharmaceutically acceptable hydrates or salts thereof, in admixture with other pharmaceutically acceptable carriers. The compounds are formulated into pharmaceutical compositions for more convenient administration to a subject.
The compounds of the present invention can be prepared into conventional pharmaceutical preparations by methods known in the art. For example, it may be a tablet, a capsule, an injection, etc.
According to some embodiments of the invention, the active ingredient is present in the formulation in an amount of 0.1% to 100% (by weight).
The compounds or pharmaceutical compositions described herein can be administered alone or in combination with other suitable agents.
The term "pharmaceutically acceptable carrier" is a pharmaceutically acceptable ingredient or vehicle, including but not limited to solvents, excipients, diluents, adjuvants, fillers, and the like.
The term "pharmaceutically acceptable salts" refers to acid addition salts formed by the compounds. The acid forming the acid addition salt may be an inorganic acid including, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like, or an organic acid including, for example, acetic acid, oxalic acid, methanesulfonic acid, citric acid, and the like.
According to certain embodiments of the invention, the salt of the compound is a salt comprising a pharmaceutically acceptable anion.
According to certain embodiments of the invention, the salt of the pharmaceutically acceptable anion is preferably a hydrochloride, hydrobromide, sulfate, acetate, trifluoroacetate, citrate, tartrate, maleate, fumarate, mesylate, p-toluenesulfonate or oxalate salt.
The term "semi-Inhibitory Concentration (IC)50) "or" half-inhibition "refers to the concentration of inhibitor when the activity of the target substance is half-inhibited during the inhibition of the target substance. Generally, the stronger the inhibitory potency of the inhibitor, the IC50The lower. According to certain embodiments of the present application, the IC of the compounds described herein50Is when D2、D3、5-HT1A、5-HT2AThe concentration of the compound at which the receptor is 50% inhibited.
When "about" is used in this application to modify a numerical value, it is meant that the numerical value may fluctuate within a range of ± 5%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2% or ± 1%.
General method of synthesis
The compounds of the present invention can be synthesized by the following two general synthetic methods.
The general method I comprises the following steps:
Figure BDA0001109288820000141
the method comprises the step of reacting raw material 1 and triethyl phosphonoacetate in tetrahydrofuran solution under the condition of potassium tert-butoxide to prepare an intermediate 2.2, carrying out palladium carbon hydrogenation reduction, ethyl ester reduction and mesylation, and condensing with an aryl piperazine fragment under an alkaline condition to obtain an important intermediate 6.6 removing protective group under the conditions of trifluoroacetic acid and dichloromethane, and preparing a compound 8 under the conditions of sodium nitrite and acetic acid. 8, reducing by zinc powder, and reacting with different acylating reagents to obtain the compounds I-1-I-15, III-1-III-2, III-5, III-7, III-9 and IV-1-IV-6. The specific description is as follows:
adding potassium tert-butoxide (360mmol)) into THF (300mL), dropwise adding a solution of triethyl phosphonoacetate (300mmol) in THF (60mL) at 5-10 ℃, stirring for 2h after addition, dropwise adding a solution of raw material 1(270mmol) in THF (100mL) at 5-10 ℃, reacting at room temperature for 2h after addition, stopping the reaction, dropwise adding water (50mL) to quench the reaction, extracting the reaction solution with ethyl acetate (100mL × 3), combining ethyl acetate layers, washing with water (50mL × 2) and saturated saline (50mL × 2) in sequence, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain 70g of white solid (intermediate 2) with a yield of 96%.
Adding the intermediate 2(250mmol) and 5% Pd/C, THF (500mL) into a 1L hydrogenation kettle, reacting at the external temperature of 60 ℃ under the pressure of 2.0MPa for 10h, stopping the reaction, and filtering to obtain a THF solution of an intermediate 3. Adding lithium borohydride (500mmol), carrying out reflux reaction for 20h, stopping the reaction, cooling to 5-10 ℃, sequentially adding 30% HCl aqueous solution (100mL) and 20% HCl aqueous solution (100mL), stirring for 1h, extracting with ethyl acetate (100mL × 3), combining ethyl acetate layers, sequentially washing with water (50mL × 2) and saturated saline (50mL × 2), drying with anhydrous sodium sulfate, filtering, and concentrating to obtain 53g of white solid (intermediate 4), wherein the yield of the two steps is 92% in total.
Adding the intermediate 4(240mmol), dichloromethane (200mL) and triethylamine (480mmol) into a 500mL three-necked flask, dropwise adding a dichloromethane (50mL) solution of methanesulfonyl chloride (260mmol) at 0-5 ℃, reacting at room temperature for 2h, stopping the reaction, washing with a sodium carbonate aqueous solution (20mL multiplied by 2) and a saturated saline solution (50mL multiplied by 2) in sequence, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain 61.5g of a light yellow solid (intermediate 5) with the yield of 83%.
Adding the intermediate 5(180mmol), potassium carbonate (540mmol), potassium iodide (1mmol), acetonitrile (1000mL) and aryl piperazine (162mmol) into a 2000mL single-neck bottle, carrying out reflux reaction for 24h, cooling to room temperature, stirring for 1h, filtering, washing a filter cake with acetonitrile (50mL multiplied by 2), and drying for 5h in an air drying oven (60 ℃) to obtain a white solid intermediate 6 with the yield of 70-81%.
Adding the intermediate 6(100mmol), trifluoroacetic acid (300mmol) and dichloromethane (500mL) into a 1000mL single-neck bottle, reacting at room temperature for 12h, adjusting the pH of the reaction solution to 10 with 20% sodium hydroxide, separating, washing the dichloromethane layer with water (100mL multiplied by 2) and saturated saline (60mL multiplied by 2) in sequence, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain an off-white semisolid (intermediate 7) with the yield of 90-95%.
Adding the intermediate 7(80mmol), acetic acid (100mL), sodium nitrite (160mL) and water (50mL) into a 500mL single-neck bottle, reacting for 5h at room temperature, concentrating the reaction solution, adding water (200mL), extracting with dichloromethane (100mL multiplied by 2), and concentrating the organic layer to obtain an off-white solid (intermediate 8) with the yield of 86-90%.
Adding the intermediate 8(50mmol), acetic acid (100mL) and zinc powder (150mmol (10mL) into a 250mL single-neck bottle, reacting at room temperature for 8h, filtering, concentrating the filtrate, adding water (200mL), extracting with dichloromethane (100mL multiplied by 2), and concentrating the organic layer to obtain a white solid (intermediate 9) with the yield of 70-80%.
Adding the intermediate 9(30mmol), dichloromethane (100mL) and triethylamine (45mmol) into a 250mL three-necked bottle, dropwise adding different acylating reagents (33mmol) at 0-5 ℃, reacting for 3h at room temperature, washing with water (100mL multiplied by 2) and saturated saline (60mL multiplied by 2) in sequence, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a white solid, and crystallizing by using a 95% ethanol solution to obtain the white solid, namely the compounds I-1-I-15, III-1-III-2, III-5, III-7, III-9 and IV-1-IV-6, wherein the yield is 82-95%.
Putting the compounds I-1-I-15, III-1-III-2, III-5, III-7, III-9 and IV-1-IV-6 into 5% acid/ethanol for reflux dissolution, cooling and precipitating salts of the compounds I-1-I-15, III-1-III-2, III-5, III-7, III-9 and IV-1-IV-6, wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid or oxalic acid.
R in the above general method I1、R2、R3The definitions of (a) are consistent with those in the aforementioned compounds, i.e.,
R3is selected from C1～C3Alkyl of (C)1～C2Alkoxy group of (C)3～C6Cycloalkyl, phenyl, substituted phenyl or heteroaryl of (a);
n is an integer of 0 to 1;
R1、R2each independently represents chlorine, methyl, methoxy, phenyl;
or R1、R2Together form a benzene ring, an oxazolone ring or a thiophene ring.
The general method II comprises the following steps:
Figure BDA0001109288820000161
adding the compound 9 (prepared by a general method I), substituted amine and triethylamine into a solvent dissolved with triphosgene to react to obtain the compounds II-1-II-9, III-3-III-4, III-6, III-8, III-10 and IV-7-IV-12. The specific description is as follows:
dissolving triphosgene (10mmol) in dichloromethane (50mL), dropwise adding a solution of compound 9(0.9mmol) and triethylamine (10mmol) in dichloromethane (50mL) at-0 ℃, stirring at the constant temperature for 3h, dropwise adding the reaction solution into a solution of substituted amine (50mmol) in isopropanol (100mL) at-5-0 ℃, reacting at the constant temperature for 5h, stopping the reaction, adding a saturated ammonium chloride solution (50mL), distributing, washing with water (50mL × 2) and saturated saline (50mL × 2) in turn, and drying with anhydrous sodium sulfate. Filtering, taking filtrate, concentrating under reduced pressure to obtain off-white or white solid, and recrystallizing or separating by a Flash column to obtain the compounds II-1-II-9, III-3-III-4, III-6, III-8, III-10 and IV-7-IV-12 of the invention with the yield of 73-90%. The preparation method of the salts of the compounds II-1 to II-9, III-3 to III-4, III-6, III-8, III-10 and IV-7 to IV-12 and the acid and the salt form obtained by the method are the same as the one of the common method.
R in the above general formula II1、R2、R4、R5The definitions of (a) are consistent with those in the aforementioned compounds, i.e.,
R1、R2each independently represents chlorine, methyl, methoxy, phenyl;
or R1、R2Together form a benzene ring, an oxazolone ring or a thiophene ring;
R4、R5each independently represents hydrogen or C1～C3Alkyl of (C)3～C6Cycloalkyl, phenyl, benzyl or pyridyl;
or R4、R5Form a morpholine ring with the attached N atom.
In addition, the invention synthesizes a representative compound 1 by referring to a method reported by a patent CN1829703A, synthesizes a compound cariprazine (hydrochloride of the compound 1 reported by CN 1829703A) reported by a literature by referring to methods reported by patents WO2010070370 and WO2011073705, and synthesizes a representative compound 84 by referring to a method reported by a patent CN 102159557A; representative compound 84 was synthesized according to the method reported in patent CN102159557A, representative compound IV-2 was synthesized according to the method reported in patent CN103130737A, and representative compound I-1 was synthesized according to the method reported in patent CN 104140421A. The synthesized patent represents a compound, and is used as a control sample for in vivo and in vitro pharmacological screening and physicochemical property research of the compound.
Pharmaceutical composition and kit
According to one aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of the arylethylpiperidinyl derivative or a pharmaceutically acceptable hydrate, salt or hydrate of salt thereof, and a pharmaceutically acceptable carrier.
According to one aspect of the present invention, there is provided a process for preparing the pharmaceutical composition, characterized in that the process comprises mixing the arylethylpiperidinyl derivative or a pharmaceutically acceptable hydrate, salt or hydrate of salt thereof with a pharmaceutically acceptable carrier.
According to one aspect of the present invention there is provided a kit comprising said arylethylpiperidinyl derivative or a pharmaceutically acceptable hydrate, salt or hydrate of salt thereof.
Pharmacological research
Acting on dopamine D2Receptors are a common mechanism for classical and non-classical antipsychotic drugs. Antagonism of D2The receptor can significantly treat the positive symptoms of patients with schizophrenia. At the same time, antagonize serotonin 5-HT2AReduced receptor capacity D2The excessive inhibition of the receptor can reduce the side reaction of EPS, hyperprolactinemia and the like. Selective antagonism of dopamine D3The receptor can reduce the occurrence of extrapyramidal side effects and significantly improve cognitive deficits in schizophrenic patients. But with D2Receptor comparison, D3Receptor mRNA is less distributed in the brain, requiring that the drug have a certain D3Receptor selectivity, i.e. for D3Has a stronger affinity than for D2The affinity of the receptor is 10 times or more, so as to exert physiological effects such as cognitive improvement. However, too high D3Receptor selectivity, e.g. compound pair D3Receptor affinity greater than D2More than one hundred times of the receptor, or D3/D2At receptor selectivities greater than 100-fold or greater, the compounds fail to exhibit anti-schizophrenia activity, particularly against the positive symptoms of schizophrenia. 5-HT1AThe improvement effect of the receptor on reducing the side effect of the schizophrenia drug and improving the cognitive function is more and more accepted by academia. Thus, selectively act on D2、D3、5-HT1AAnd 5-HT2AThe research and development of novel multi-target anti-schizophrenia medicaments of the receptor have wide applicationAnd (5) landscape.
The results of in vitro pharmacological studies show that:
1. the aryl ethyl piperidyl derivative (I) has strong affinity to the drug effect target of schizophrenia, such as dopamine D2、D3Receptor, serotonin 5-HT1A、5-HT2AReceptors, most of which are directed to 5-HT2AThe receptor affinity is superior to that of the representative compound 1 in the patent CN 1829703A; most of the compounds of the pair D2The receptor affinity is significantly better than that of the compounds in patents CN102159557A (representing compound 84) and CN103130737A (representing compound IV-2).
2. The compounds of the invention have suitable dopamine D3/D2Receptor-selective, largely compound D3/D2The receptor selectivity is in the range of 5-60 fold, compared with CN1829703A (D)3/D2Receptor selectivity 5-200 times), CN102159557A (most of the compounds D)3/D2Receptor selectivity greater than 100-fold) and CN103130737A (majority of compound D)3/D2Receptor selectivity is more than 100 times) further proves that the compound has good cognitive impairment improving effect and is not easy to generate side effects such as extrapyramidal system (EPS) and the like.
3. Further receptor function test results show that part of compounds show certain D2Partial receptor agonism, 5-HT1AThe receptor agonism (partial) agonism is in line with the characteristics of the in vitro pharmacological model of the anti-schizophrenia drug on the market.
The animal body internal model experiment result shows that:
the compound of the invention can obviously improve the relevant symptoms of a mouse apomorphine model and an MK-801 model, and the activity of part of the compound is better than that of the marketed drug Carilazine (see example 54). The action target and the animal model are closely related to nervous system diseases, particularly schizophrenia, caused by disorders of dopaminergic system and the like, so that the compound has a treatment effect on the schizophrenia.
The compound in vitro physicochemical experiment shows that:
the water solubility of the compound of the invention is obviously superior to that of the representative compounds in patents CN1829703A, CN102159557A, CN103130737A and CN104140421A (see example 55), so that the compound of the invention is more beneficial to preparation and research of preparations and prescriptions.
The pharmacokinetics experiment in the compound body shows that:
the compound has high brain penetration rate (brain AUC/plasma AUC >8), good oral absolute bioavailability (more than 30%), and brain penetration rate and oral bioavailability superior to those of representative compounds in patents CN1829703A, CN102159557A, CN103130737A and CN104140421A (see example 56), which are related to good physicochemical properties of the compound, so the compound has good potential drug properties.
In summary, compared with the prior art, the compound of the invention has the following advantages and characteristics:
1. the compounds of the invention are not only p-D2The receptor has partial agonism, 5-HT1AThe receptor has agonistic (partial) agonistic action, compared with the prior art, on D3/D2The selectivity of the receptor is more appropriate, and the action mechanism of the receptor is characterized remarkably.
2. The compound of the invention has good anti-schizophrenia effect on various animal in vivo models, has broad-spectrum anti-schizophrenia effect, and is preferably stronger than a positive drug or a drug on the market.
3. The compound of the invention has low toxicity and low side effect.
4. The compound of the invention has stronger brain targeting property and higher oral bioavailability, and the drug generation parameters conform to the characteristics of central drugs, thereby having good drug forming property.
5. Compared with the prior art, the compound of the invention has better water solubility and is more beneficial to the research of preparations and prescriptions.
Therefore, the compound has good effect characteristics on the drug effect target of schizophrenia, has definite anti-schizophrenia activity in animals, better water solubility and good pharmacokinetic property, and can be used for treating schizophrenia.
The invention relates to the arylethylpiperidinyl derivative which is likely to have an improving and treating effect on schizophrenia and can be used for treating schizophrenia. The schizophrenia refers to serious psychological disorder, and the mental activities of the patients, such as cognition, emotion, will, action and behavior, can all have lasting obvious abnormality; the normal study, work and life can not be realized; the action behavior is difficult to be understood by the ordinary people; under the control of pathological psychology, there are actions of suicide or attack, and harm to others.
According to one aspect of the present invention, there is provided a method of treating schizophrenia by administering to a patient the arylethylpiperidinyl derivative or a pharmaceutically acceptable hydrate, salt or hydrate of salt thereof.
According to one aspect of the invention, there is provided the use of the arylethylpiperidinyl derivative or a pharmaceutically acceptable hydrate, salt or hydrate of a salt thereof in the preparation of a medicament for the treatment of schizophrenia.
In conclusion, compared with the arylethylcyclohexyl structure in the prior art, the compound is an arylethylpiperidinyl structure, and the piperidyl and cyclohexyl have essential differences in the aspects of physicochemical properties, such as water solubility, flexibility, configuration, electron density and the like, so that the compound not only has novelty in chemical structure, but also has more advantages in the aspects of physicochemical properties, pharmacokinetic properties, in vivo and in vitro pharmacological activity, safety and the like, and embodies creative and substantial scientific progress.
All patents, patent applications, and references cited in this application are incorporated by reference into this application in their entirety to the same extent as if each individual reference were individually incorporated by reference. In the event of a conflict between the present application and the references provided herein, the present application shall control.
Detailed Description
The present invention will be further illustrated with reference to specific examples, but the scope of the present invention is not limited to these examples.
Example 1: n- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) acetamide (Compound No.) Preparation of the substances I-1) and salts thereof
4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-amine (9) (prepared according to general method one) (1.0g,2.8mmol) and triethylamine (4.2mmol) were added to dichloromethane (10mL), a solution of acetyl chloride (0.24g,3.1mmol) in dichloromethane (5mL) was added dropwise, reacted for 3h, washed with water (20 mL. times.2) and saturated brine (10 mL. times.2) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid, which was crystallized from a 95% ethanol solution to give 1.1g of a white solid in 95% yield.
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+].
Preparation of Compound I-1 hydrochloride
Compound I-1(0.3g,0.8mmol) and 5% aqueous hydrochloric acid (0.8mmol) were added to ethanol (10mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 0.3g of a white solid with a yield of 88%.
Elemental analysis: c19H28Cl2N4O.HCl (theoretical values: C52.36, H6.71, N12.86; experimental values: C52.32, H6.79, N12.88).
The difference between the theoretical and experimental values is within. + -. 0.3%, indicating that the salt or hydrate of the salt is obtained in this experiment. The theoretical values and experimental values in the following experiments have the same meaning.
Preparation of Compound I-1 mesylate hemihydrate
Compound I-1(0.3g,0.8mmol) and methanesulfonic acid aqueous solution (0.8mmol) were added to ethanol (10mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 0.28g of a white solid with a yield of 69%.
Elemental analysis: c19H28Cl2N4O·CH4O3S·1/2H2O (theoretical values: C47.62, H6.59, N11.11; experimental values: C47.51, H6.48, N11.23).
Preparation of Compound I-1 hydrobromic acid salt trihydrate
Compound I-1(0.3g,0.8mmol) and a 5% aqueous hydrobromic acid solution (0.8mmol) were added to ethanol (10mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, which was filtered to obtain 0.34g of a white solid with a yield of 80%.
Elemental analysis: c19H28Cl2N4O·HBr·3H2O (theoretical value%: C42.71, H6.60, N10.49; experimental value%: C42.80, H6.66, N10.42).
Preparation of Compound I-1 oxalate dihydrate
Compound I-1(0.3g,0.8mmol) and oxalic acid dihydrate (0.8mmol) were added to ethanol (10mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 0.35g of a white solid with a yield of 83%.
Elemental analysis: c19H28Cl2N4O·C2H2O4·2H2O (theoretical value%: C48.00, H6.52, N10.66; experimental value%: C47.89, H6.61, N10.54).
Example 2: n- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) butanamide (Compound Preparation of the substances I-2) and salts thereof
By using intermediate 9(2.8mmol) and butyryl chloride (3.1mmol) as raw materials and following the method for preparing compound I-1, 1.14g of the objective compound I-2 as a white solid was obtained with a yield of 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+].
Preparation of Compound I-2 hydrobromic acid salt
Using compound I-2(2.0mmol) and 5% aqueous hydrobromic acid (2.1mmol) as starting materials, the procedure for the preparation of the hydrobromide salt of compound I-1 was used to give 0.9g of a white solid with a yield of 88%.
Elemental analysis: c21H32Cl2N4O.HBr (% of theory: C49.62, H6.54, N11.02; and% of experiment: C49.51, H6.67, N11.28).
Example 3: n- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -2-methoxyethyl Preparation of amide (Compound I-3) and salts thereof
The intermediate 9(2.8mmol) and 2-methoxyacetyl chloride (3.1mmol) were used as raw materials to obtain 1.1g of the objective compound I-3 as a white solid in 92% yield according to the method for preparing the compound I-1.
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+].
Preparation of Compound I-3 fumarate
Using compound I-3(2.3mmol) and fumaric acid (2.4mmol) as starting materials, 1.0g of a white solid was obtained in a yield of 72% by the method for producing the compound I-1 hydrobromide.
Elemental analysis: c20H30Cl2N4O·C4H4O4(theoretical values: C52.85, H6.28, N10.27; experimental values: C52.72, H6.34, N10.14).
Example 4: n- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -2-ethoxyethane Preparation of amide (Compound I-4) and salts thereof
The intermediate 9(2.8mmol) and 2-ethoxyacetyl chloride (3.1mmol) were used as raw materials to obtain the target compound I-4 as a white solid in an amount of 1.0g with a yield of 81% according to the method for producing the compound I-1.
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+].
Preparation of Compound I-4 succinate
By using the compound I-4(2.2mmol) and succinic acid (2.4mmol) as raw materials and adopting the preparation method of the compound I-1 hydrobromide, 1.1g of white solid is obtained with the yield of 89%.
Elemental analysis: c21H32Cl2N4O·C4H6O4(theoretical values: C53.68, H6.82, N9.98; experimental values: C53.79, H6.70, N10.07).
Example 5: n- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) cyclopropylformyl Preparation of amine (Compound I-5) and salts thereof
By using the intermediate 9(2.8mmol) and cyclopropylcarbonyl chloride (3.1mmol) as raw materials and following the preparation method of the compound I-1, the target compound I-5 was obtained as a white solid in an amount of 1.0g, with a yield of 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+].
Preparation of Compound I-5 tartrate salt
Using compound I-5(2.0mmol) and tartaric acid (2.1mmol) as starting materials, 1.0g of a white solid was obtained in a yield of 91% by the method for producing the compound I-1 hydrobromide.
Elemental analysis: c21H30Cl2N4O·C4H6O6(theoretical values: C52.18, H6.31, N9.74; experimental values: C52.26, H6.38, N9.88).
Example 6: n- (4- (2- (4- (2, 3-dichloro) -N-methyl-4-methyl-2-methyl-4-methyl-ethyl-4-methyl-2-methyl-4-methyl-ethyl)Phenyl) piperazin-1-yl) ethyl) piperidin-1-yl) cyclohexanecarboxyl Preparation of amine (Compound I-6) and salts thereof
By using the intermediate 9(2.8mmol) and cyclohexyl carbonyl chloride (3.1mmol) as raw materials and according to the preparation method of the compound I-1, 1.1g of the target compound I-6 white solid is obtained with the yield of 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+].
Preparation of Compound I-6 hydrochloride
Using compound I-6(1.8mmol) and 5% aqueous hydrochloric acid (1.9mmol) as starting materials, 0.85g of a white solid was obtained in a yield of 93% by the method for producing the compound I-1 hydrobromide.
Elemental analysis: c24H36Cl2N4O.HCl (theoretical values: C57.20, H7.40, N11.12; experimental values: C57.32, H7.58, N11.01).
Example 7: n- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) benzamide (amide) Preparation of Compound I-7) and salts thereof
By using intermediate 9(2.8mmol) and benzoyl chloride (3.1mmol) as raw materials and following the preparation method of compound I-1, 0.9g of the target compound I-7 as a white solid was obtained with a yield of 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+].
Preparation of Compound I-7 hydrobromide
Using compound I-7(1.9mmol) and 5% aqueous hydrobromic acid (2.0mmol) as starting materials, the procedure for the preparation of the hydrobromide salt of compound I-1 was used to give 0.93g of a white solid with a yield of 90%.
Elemental analysis: c24H30Cl2N4O.HBr (% of theory: C53.15, H5.76, N10.33; and% of experiment: C53.28, H5.59, N10.56).
Example 8: n- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-fluorobenzoyl Preparation of amine (Compound I-8) and salts thereof
By using the intermediate 9(2.8mmol) and 4-fluorobenzoyl chloride (3.1mmol) as raw materials and according to the preparation method of the compound I-1, 1.2g of the target compound I-8 white solid is obtained, and the yield is 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+].
Preparation of Compound I-8 oxalate salt
1.2g of a white solid was obtained in a yield of 85% by a method for producing a hydrobromide of the compound I-1 using the compound I-8(2.4mmol) and oxalic acid dihydrate (2.5mmol) as raw materials.
Elemental analysis: c24H29Cl2FN4O·C2H2O4(theoretical values: C56.28, H5.90, N9.38; experimental values: C56.42, H5.79, N9.51).
Example 9: n- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-cyanobenz-yl Preparation of amide (Compound I-9) and salts thereof
The intermediate 9(2.8mmol) and 4-cyanobenzoyl chloride (3.1mmol) were used as raw materials to obtain the target compound I-9 as a white solid in an amount of 1.1g with a yield of 80% according to the method for preparing the compound I-1.
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+].
Preparation of acetate salt of Compound I-9
1.1g of white solid was obtained with a yield of 92% by a method for producing a hydrobromide of the compound I-1 using the compound I-9(2.2mmol) and glacial acetic acid (2.3mmol) as raw materials.
Elemental analysis: c25H29Cl2N5O·C2H4O2(theoretical values: C59.34, H6.09, N12.82; experimental values: C59.18, H6.21, N12.93).
Example 10: n- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-methylbenzene Preparation of formamide (Compound I-10) and salts thereof
By using the intermediate 9(2.8mmol) and 4-methylbenzoyl chloride (3.1mmol) as raw materials and following the preparation method of the compound I-1, the target compound I-10 was obtained as a white solid (1.18 g), with a yield of 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+].
Preparation of Compound I-10 hydrochloride
Using compound I-10(2.3mmol) and 5% aqueous hydrochloric acid (2.4mmol) as starting materials, 0.9g of a white solid was obtained in a yield of 79% by the method for producing the compound I-1 hydrobromide.
Elemental analysis: c25H32Cl2N4O.HCl (theoretical%: C58.66, H)6.50, N10.94; experimental value%: c58.51, H6.68, N10.78).
Example 11: n- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) nicotinamide (amide) Preparation of Compound I-11) and salts thereof
By using the intermediate 9(2.8mmol) and nicotinoyl chloride (3.1mmol) as raw materials and following the preparation method of the compound I-1, 1.05g of the target compound I-11 as a white solid was obtained with a yield of 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+].
Preparation of compound I-11 maleate salt
Using compound I-11(2.1mmol) and maleic acid (2.2mmol) as starting materials, 1.06g of a white solid was obtained in 88% yield by the method for producing the compound I-1 hydrobromide.
Elemental analysis: c23H29Cl2N5O·C4H4O4(theoretical values: C56.06, H5.75, N12.11; experimental values: C56.18, H5.89, N12.19).
Example 12: n- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) furan-2-carboxylic acid Preparation of amine (Compound I-12) and salts thereof
The intermediate 9(2.8mmol) and furan-2 carbonyl chloride (3.1mmol) were used as raw materials to obtain the target compound I-12 as a white solid 1.06g with a yield of 84% according to the preparation method of the compound I-1.
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+].
Preparation of Compound I-12 mesylate
Using compound I-12(2.2mmol) and methanesulfonic acid (2.3mmol) as starting materials, 1.12g of a white solid was obtained in a yield of 93% by the method for producing the compound I-1 hydrobromide.
Elemental analysis: c22H28Cl2N4O·CH4O3S (theoretical values: C50.46, H5.89, N10.23; experimental values: C50.60, H5.74, N10.11).
Example 13: n- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) pyrrole-2-carboxylic acid Preparation of amine (Compound I-13) and salts thereof
By using the intermediate 9(2.8mmol) and pyrrole-2 carbonyl chloride (3.1mmol) as raw materials and according to the preparation method of the compound I-1, 1.13g of the target compound I-13 white solid is obtained with the yield of 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+].
Preparation of Compound I-13 p-toluenesulfonate
Using compound I-13(2.4mmol) and p-toluenesulfonic acid (2.5mmol) as starting materials, 1.35g of a white solid was obtained in a yield of 91% by the method for producing the compound I-1 hydrobromide.
Elemental analysis: c22H29Cl2N5O·C7H8O3S (theoretical values: C55.94, H5.99, N11.25; experimental values: C55.81, H5.76, N11.39).
Example 14: n- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) thiophene-2-carboxylic acid Amine (Compound)I-14) preparation of salts thereof
The intermediate 9(2.8mmol) and thiophene-2 formyl chloride (3.1mmol) are used as raw materials, and the preparation method of the compound I-1 is adopted to obtain 1.02g of the target compound I-14 as a white solid with the yield of 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+].
Preparation of Compound I-14 citrate salt
Using compound I-14(1.8mmol) and citric acid (1.85mmol) as starting materials, 1.1g of a white solid was obtained in a yield of 81% by the method for producing the compound I-1 hydrobromide.
Elemental analysis: c22H28Cl2N4OS·C6H8O7(theoretical values: C50.99, H5.50, N8.49; experimental values: C56.21, H5.63, N8.32).
Example 15: n- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) indole-2-carboxylic acid Preparation of amine (Compound I-15) and salts thereof
By using the intermediate 9(2.8mmol) and indole-2 formyl chloride (3.1mmol) as raw materials and according to the preparation method of the compound I-1, 1.2g of a white solid of the target compound I-15 is obtained, and the yield is 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+].
Preparation of Compound I-15 hydrobromide
Using compound I-15(2.1mmol) and 5% aqueous hydrobromic acid (2.2mmol) as starting materials, the procedure for the preparation of compound I-1 hydrobromide gave 1.07g of a white solid in 88% yield.
Elemental analysis: c26H31Cl2N5O.HCl (theoretical values: C53.71, H5.55, N12.05; experimental values: C53.88, H5.36, N12.21).
Example 16: 1- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-methylurea (Compound II-1) and preparation of salts thereof
Triphosgene (6.2mmol) is dissolved in dichloromethane (10mL), 4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-amine (9) (prepared according to the general method I) (2.0g,5.6mmol) and triethylamine (6.2mmol) are added dropwise to a dichloromethane (20mL) solution at-0 ℃, stirred for 3h under heat preservation, the reaction solution is added dropwise to an isopropanol (60mL) solution of a methylamine water solution (31mmol) under the condition of-5 to 0 ℃, the reaction is stopped under heat preservation for 5h, a saturated ammonium chloride solution (30mL) is added, the mixture is distributed, the organic phase is washed by water (30mL x 2) and saturated salt water (30mL x 2) in turn, and dried by anhydrous sodium sulfate. Filtering, taking the filtrate, concentrating under reduced pressure to obtain an off-white solid, and separating by using a Flash column (dichloromethane: methanol is 50: 1) to obtain 2.0g of the white solid with the yield of 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+].
Preparation of Compound II-1 sulfate
Compound II-1(0.5g,1.21mmol) and a 5% aqueous solution of sulfuric acid (1.33mmol) were added to ethanol (10mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 0.49g of a white solid with a yield of 87%.
Elemental analysis: c19H29Cl2N5O (theoretical%: C49.24, H6.53, N15.11; experimental%)：C 49.30，H 6.61，N 15.01)。
Preparation of compound II-1 trifluoroacetate monohydrate
Compound II-1(0.5g,1.21mmol) and a 5% aqueous trifluoroacetic acid solution (1.33mmol) were added to ethanol (10mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 0.58g of a white solid with a yield of 90%.
Elemental analysis: c19H29Cl2N5O·CF3COOH·H2O (theoretical value%: C47.64, H5.90, N13.23; experimental value%: C47.58, H5.99, N13.41).
Preparation of Compound II-1 maleate salt
Compound II-1(0.5g,1.21mmol) and maleic acid (1.33mmol) were added to ethanol (10mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 0.55g of a white solid with a yield of 85%.
Elemental analysis: c19H29Cl2N5O·C4H4O4(theoretical values%: C52.08, H6.27, N13.20; experimental values%: C52.16, H6.39, N13.31).
Example 17: 3- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -1, 1-dimethyl Preparation of ureide (Compound II-2) and salts thereof
Using intermediate 9(2.8mmol) and dimethylamine (15.4mmol) as starting materials, 1.1g of the objective compound II-2 as a white solid was obtained in a yield of 91% according to the method for producing the compound II-1.
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+].
Preparation of Compound II-2 hydrochloride
Using compound II-2(2.5mmol) and 5% hydrochloric acid aqueous solution (2.6mmol) as raw materials, 0.95g of white solid was obtained in a yield of 82% by the method for producing sulfate of compound II-1.
Elemental analysis: c20H31Cl2N5O.HCl (theoretical values: C51.67, H6.94, N15.07; experimental values: C51.83, H6.86, N15.19).
Example 18: 1- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-propylurea (Compound II-3) and preparation of salt thereof
By using intermediate 9(2.8mmol) and n-propylamine (15.4mmol) as raw materials and according to the preparation method of the compound II-1, 1.04g of a white solid of the target compound II-3 is obtained with a yield of 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+].
Preparation of Compound II-3 hydrobromide
Using compound II-3(2.2mmol) and 5% hydrobromic acid aqueous solution (2.3mmol) as starting materials, 1.04g of a white solid was obtained in a yield of 90% by a method for producing sulfate of compound II-1.
Elemental analysis: c21H33Cl2N5O.HBr (theoretical values: C48.20, H6.55, N13.38; experimental values: C48.01, H6.71, N13.52).
Example 19: 1-cyclopropyl-3- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) Preparation of Urea (Compound II-4) and salts thereof
By using the intermediate 9(2.8mmol) and cyclopropylamine (15.4mmol) as raw materials and following the method for the preparation of the compound II-1, 1.06g of the objective compound II-4 as a white solid was obtained with a yield of 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+].
Preparation of Compound II-4 hydrochloride
Using compound II-4(2.2mmol) and 5% aqueous hydrochloric acid (2.3mmol) as starting materials, 0.87g of a white solid was obtained in 83% yield by the method for producing sulfate of compound II-1.
Elemental analysis: c21H31Cl2N5O & HCl (theoretical values: C52.89, H6.76, N14.69; experimental values: C52.76, H6.90, N14.55).
Example 20: 1-cyclohexyl-3- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) Preparation of Urea (Compound II-5) and salts thereof
By using the intermediate 9(2.8mmol) and cyclohexylamine (15.4mmol) as raw materials and following the method for producing the compound II-1, 1.09g of the objective compound II-5 as a white solid was obtained with a yield of 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+].
Preparation of Compound II-5 hydrobromide
Using compound II-5(2.2mmol) and 5% hydrobromic acid aqueous solution (2.3mmol) as starting materials, 1.14g of a white solid was obtained in 92% yield by a method for preparing compound II-1 sulfate.
Elemental analysis: c24H37Cl2N5O.HBr (% of theory: C51.16, H6.80, N12.43; and% of experiment: C51.31, H6.88, N12.51).
Example 21: 1- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-phenylurea (Compound II-6) and preparation of salt thereof
By using intermediate 9(2.8mmol) and aniline (15.4mmol) as raw materials and following the preparation method of compound II-1, 1.23g of the target compound II-6 as a white solid was obtained with a yield of 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+].
Preparation of Compound II-6 hydrochloride
1.11g of a white solid was obtained in a yield of 90% by a method for producing a sulfate salt of the compound II-1 using the compound II-6(2.4mmol) and a 5% aqueous hydrochloric acid solution (2.5mmol) as raw materials.
Elemental analysis: c24H31Cl2N5O.HCl (% of theory: C56.20, H6.29, N13.65; and% of experiment: C56.29, H6.12, N13.83).
Example 22: 1-benzyl-3- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) urea (Compound II-7) and preparation of salt thereof
1.3g of a white solid of the objective compound II-7 was obtained in a yield of 95% by the method for producing the compound II-1 using the intermediate 9(2.8mmol) and benzylamine (15.4mmol) as starting materials.
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+].
Preparation of Compound II-7 hydrobromide
1.27g of a white solid was obtained in 89% yield by the method for producing a sulfate of compound II-1 using compound II-7(2.5mmol) and 5% aqueous hydrochloric acid (2.6mmol) as raw materials.
Elemental analysis: c25H33Cl2N5O.HBr (% of theory: C52.55, H6.00, N12.26; and% of experiment: C52.71, H6.18, N12.13).
Example 23: 1- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -3- (pyridine- Preparation of 3-yl) urea (Compound II-8) and salts thereof
1.06g of the objective compound II-8 as a white solid was obtained in 79% yield according to the preparation method of the compound II-1 using the intermediate 9(2.8mmol) and pyridin-3-amine (15.4mmol) as raw materials.
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+].
Preparation of Compound II-8 hydrochloride
Using compound II-8(2.1mmol) and 5% hydrochloric acid aqueous solution (2.2mmol) as raw materials, 0.88g of white solid was obtained in a yield of 82% by the method for producing sulfate of compound II-1.
Elemental analysis: c23H30Cl2N6O.HCl (% of theory: C53.76, H6.08, N16.35; and% of experiment: C53.54, H6.19, N16.27).
Example 24: n- (4- (2- (4- (2,3- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) morpholine- Preparation of 4-carboxamide (Compound II-9) and salts thereof
By using intermediate 9(2.8mmol) and morpholine (15.4mmol) as raw materials and following the preparation method of compound II-1, 1.14g of the target compound II-9 as a white solid was obtained with a yield of 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+].
Preparation of Compound II-9 hydrobromide
Using compound II-9(2.3mmol) and 5% hydrobromic acid aqueous solution (2.4mmol) as starting materials, 1.15g of a white solid was obtained in a yield of 91% by a method for producing sulfate of compound II-1.
Elemental analysis: c22H33Cl2N5O2HBr (% of theory: C47.93, H6.22, N12.70; and% of experiment: C47.80, H6.36, N12.55).
Example 25: n- (4- (2- (4- (2, 3-dimethylphenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-methoxylpiperidine Preparation of phenylbenzamides (Compound III-1) and salts thereof
4- (2- (4- (2, 3-dimethylphenyl) piperazin-1-yl) ethyl) piperidin-1-amine (9-1) (prepared according to general method one) (1.0g,2.8mmol) and triethylamine (4.2mmol) were added to dichloromethane (10mL), a solution of 4-methoxybenzoyl chloride (0.53g,3.1mmol) in dichloromethane (5mL) was added dropwise, reacted for 3h, washed with water (20 mL. times.2) and saturated brine (10 mL. times.2) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid, which was crystallized from a 95% ethanol solution to give 1.14g of a white solid in 90% yield.
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+].
Preparation of compound III-1 hydrochloride
Compound III-1(2.5mmol) and 5% aqueous hydrochloric acid (2.6mmol) were added to ethanol (20mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 1.04g of a white solid with a yield of 85%.
Elemental analysis: c27H38N4O2HCl (% of theory: C66.58, H8.07, N11.50; and% of experiment: C66.71, H7.86, N11.69).
Example 26: n- (4- (2- (4- (2, 3-dimethylphenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-ethyl Preparation of benzamide (Compound III-2) and salts thereof
1.19g of a white solid of the objective compound III-2 was obtained in a yield of 94% by the preparation method of the compound III-1 using the intermediate 9-1(2.8mmol) and 4-ethylbenzoyl chloride (3.1mmol) as raw materials.
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+].
Preparation of Compound III-2 hydrobromide
Compound III-2(2.5mmol) and 5% hydrobromic acid aqueous solution (2.6mmol) were added to ethanol (20mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 1.18g of a white solid with a yield of 89%.
Elemental analysis: c28H40N4O.HBr (% of theory: C63.51, H7.80, N10.58; and% of experiment: C63.64, H7.89, N10.40).
Example 27: 1-ethyl-3- (4- (2- (4- (2-methoxyphenyl) piperazin-1-yl) ethyl) piperidine-1-yl) -1- Preparation of methylurea (Compound III-3) and salts thereof
Triphosgene (6.2mmol) is dissolved in dichloromethane (10mL), 4- (2- (4- (2-methoxyphenyl) piperazin-1-yl) ethyl) piperidin-1-amine (9-2) (prepared according to the general method I) (2.0g,5.6mmol) and triethylamine (6.2mmol) are added dropwise at-0 ℃ to a dichloromethane (20mL), the mixture is stirred for 3h under heat preservation, the reaction solution is added dropwise into an isopropanol (60mL) solution of a methylamine water solution (31mmol) under the conditions of-5 to 0 ℃, the reaction is stopped under heat preservation for 5h, a saturated ammonium chloride solution (30mL) is added, the mixture is distributed, the organic phase is washed with water (30mL x 2) and a saturated common salt solution (30mL x 2) in turn, and dried over anhydrous sodium sulfate. Filtering, taking the filtrate, concentrating under reduced pressure to obtain an off-white solid, and separating by using a Flash column (dichloromethane: methanol: 50: 1) to obtain 1.83g of the white solid with the yield of 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+].
Preparation of compound III-3 hydrochloride
Compound III-3(2.5mmol) and 5% aqueous hydrochloric acid (2.6mmol) were added to ethanol (20mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 0.92g of a white solid with a yield of 84%.
Elemental analysis: c22H37N5O2HBr (% of theory: C60.05, H8.70, N15.92; in the experiment%: C60.18, H8.82, N15.76).
Example 28: 3- (4- (2- (4- (2-methoxyphenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -1-methyl-1- Preparation of phenylurea (Compound III-4) and salts thereof
The intermediate 9-2(2.8mmol) and N-methylaniline (15.4mmol) were used as raw materials to obtain the target compound III-4 as a white solid in an amount of 1.11g with a yield of 88% according to the method for producing the compound III-3.
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+].
Preparation of Compound III-4 hydrobromide
Compound III-4(2.5mmol) and 5% aqueous hydrobromic acid (2.6mmol) were added to ethanol (20mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 1.07g of a white solid with a yield of 80%.
Elemental analysis: c26H37N5O2HBr (% of theory: C58.64, H7.19, N13.15; and% of experiment: C58.77, H7.31, N13.30).
Example 29: n- (4- (2- (4- ([1,1' -diphenyl group))]-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -2- Preparation of methoxyacetamide (Compound III-5) and salts thereof
4- (2- (4- ([1,1' -diphenyl ] -3-yl) piperazin-1-yl) ethyl) piperidin-1-amine (9-3) (prepared according to general method one) (1.0g,2.8mmol), triethylamine (4.2mmol) were added to dichloromethane (10mL), a solution of methoxyacetyl chloride (0.34g,3.1mmol) in dichloromethane (5mL) was added dropwise, reacted for 3h, washed with water (20 mL. times.2) and saturated brine (10 mL. times.2) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid, which was crystallized from a 95% ethanol solution to give 1.08g of a white solid in 88% yield.
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+].
Preparation of compound III-5 hydrochloride
Compound III-5(2.5mmol) and 5% aqueous hydrochloric acid (2.6mmol) were added to ethanol (20mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 1.08g of a white solid with a yield of 91%.
Elemental analysis: c26H36N4O2HCl (% of theory: C66.01, H7.88, N11.84; and% of experiment: C66.23, H7.69, N11.60).
Example 30: 3- (4- (2- (4- ([1,1' -diphenyl group))]-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -1, preparation of 1-dimethylurea (Compound III-6) and salts thereof
The intermediate 9-3(2.8mmol) and N, N-dimethylamine (15.4mmol) were used as raw materials to obtain the target compound III-6 as a white solid (1.12 g, yield 92%) by the method for producing the compound III-3.
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+].
Preparation of Compound III-6 hydrobromide
Using compound III-6(2.5mmol) and 5% hydrobromic acid aqueous solution (2.6mmol) as starting materials, the preparation of hydrochloride of compound III-5 was carried out to give 1.07g of a white solid with a yield of 83%.
Elemental analysis: c26H37N5O.HBr (% of theory: C60.46, H7.42, N13.56; and% of experiment: C60.59, H7.30, N13.78).
Example 31: n- (4- (2- (4- (naphthalen-1-yl) piperazin-1-yl) ethyl) piperidin-1-yl) furan-2-carboxamide (Compound III-7) and preparation of salt thereof
Starting from intermediate 4- (2- (4- (naphthalen-1-yl) piperazin-1-yl) ethyl) piperidin-1-amine (9-4) (2.8mmol, prepared according to general procedure one) and furan-2-carbonyl chloride (3.1mmol), the preparation of compound III-5 gave 1.16g of the title compound III-7 as a white solid in 96% yield.
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+].
Preparation of compound III-7 hydrochloride
Using compound III-7(2.5mmol) and 5% aqueous hydrochloric acid (2.6mmol) as starting materials, 1.09g of a white solid was obtained in a yield of 93% by the method for producing hydrochloride of compound III-5.
Elemental analysis: c26H32N4O2HBr (% of theory: C66.58, H7.09, N11.95; and% of experiment: C66.73, H7.28, N11.84).
Example 32: 1, 1-dimethyl-3- (4- (2- (4- (naphthalen-1-yl) piperazin-1-yl) ethyl) piperidin-1-yl) urea (Compound III-8) and preparation of salts thereof
Using intermediate 9-4(2.8mmol) and N, N-dimethylamine (15.4mmol) as starting materials, 0.99g of the objective compound III-8 as a white solid was obtained in 86% yield according to the method for producing the compound III-3.
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+].
Preparation of Compound III-8 hydrobromide
Using compound III-8(2.4mmol) and 5% hydrobromic acid aqueous solution (2.5mmol) as starting materials, the preparation of hydrochloride of compound III-5 was carried out to give 1.07g of a white solid with a yield of 91%.
Elemental analysis: c24H35N5O & HBr (theoretical values: C58.77, H7.40, N14.28; experimental values: C58.89, H7.61, N14.11).
Example 33: n- (4- (2- (4- (2(3H) H-benzoxazolon-7-yl) piperazin-1-yl) ethyl) piperidin-1-yl) Preparation of furan-2-carboxamide (Compound III-9) and salts thereof
Using intermediate 7- (4- (2- (1-aminopiperidin-4-yl) ethyl) piperazin-1-yl) benzo [ d ] oxazol-2 (3H) -one (9-5) (2.8mmol, prepared according to general procedure one) and furan-2-carbonyl chloride (3.1mmol) as starting materials, according to the method for preparing compound III-5, the objective compound III-9 was obtained as a white solid in an amount of 1.11g with a yield of 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+].
Preparation of compound III-9 hydrochloride
Using compound III-9(2.5mmol) and 5% aqueous hydrochloric acid (2.6mmol) as starting materials, 1.04g of a white solid was obtained in 87% yield by the method for producing hydrochloride of compound III-5.
Elemental analysis: c23H29N5O4HCl (% of theory: C58.04, H6.35, N14.71; and% of experiment: C58.19, H6.48, N14.54).
Example 34: 1, 1-dimethyl-3- (4- (2- (4- (2(3H) H-benzoxazolon-7-yl) piperazin-1-yl) ethyl) acetate Preparation of yl) piperidin-1-yl) urea (Compound III-10) and salts thereof
The intermediate 9-5(2.8mmol) and N, N-dimethylamine (15.4mmol) were used as raw materials to obtain the target compound III-10 as a white solid (1.06 g, 91% yield) according to the method for producing the compound III-3.
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+].
Preparation of Compound III-10 hydrobromide
Using compound III-10(2.5mmol) and 5% hydrobromic acid aqueous solution (2.6mmol) as starting materials, the procedure for the preparation of hydrochloride salt of compound III-5 was carried out to give 1.16g of a white solid in 93% yield.
Elemental analysis: c21H32N6O3HBr (% of theory: C50.71, H6.69, N16.89; and% of experiment: C50.58, H6.81, N16.62).
Example 35: n- (4- (2- (4- (benzo [ b ]))]Thien-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) pentanamide (Compound IV-1) and preparation of salts thereof
Using intermediate 4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl-amine 9-6(2.8mmol, prepared according to general method one), valeryl chloride (3.1mmol) as a starting material, according to the preparation method of compound I-1, the target compound IV-1 was obtained as a white solid in 1.17g with a yield of 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+].
Preparation of Compound IV-1 hydrochloride
Using compound IV-1(2.7mmol) and 5% aqueous hydrochloric acid (2.8mmol) as starting materials, 1.13g of a white solid was obtained in a yield of 90% by the method for producing hydrochloride of compound I-1.
Elemental analysis: c24H36N4OS & HCl (theoretical%: C61.98, H8.02, N12.05; experimental%: C61.75, H8.22, N12.18).
Example 36: n- (4- (2- (4- (benzo [ b ]))]Thien-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -2-methyl Preparation of oxyacetamide (Compound IV-2) and salts thereof
The intermediate 9-6(2.8mmol) and methoxy hexanoyl chloride (3.1mmol) were used as raw materials to obtain the target compound IV-2 as a white solid 1.04g with a yield of 89% according to the preparation method of the compound I-1.
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+].
Preparation of Compound IV-2 hydrobromide
Using compound IV-2(2.7mmol) and 5% hydrobromic acid aqueous solution (2.8mmol) as starting materials, the preparation of hydrochloride of compound I-1 was carried out to give 1.14g of a white solid with a yield of 85%.
Elemental analysis: c22H32N4O2S & HBr (% of theory: C53.11, H6.69, N11.26; and% of experiment: C53.34, H6.86, N11.04).
Example 37: n- (4- (2- (4- (benzo [ b ]))]Thien-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) benzoyl Preparation of amine (Compound IV-3) and salts thereof
The intermediate 9-6(2.8mmol) and benzoyl chloride (3.1mmol) were used as raw materials to obtain the target compound IV-3 as a white solid in an amount of 1.16g and a yield of 92% according to the preparation method of the compound I-1.
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+].
Preparation of Compound IV-3 hydrochloride
Using compound IV-3(2.6mmol) and 5% aqueous hydrochloric acid (2.7mmol) as starting materials, 1.0g of a white solid was obtained in 79% yield by the method for producing hydrochloride of compound I-1.
Elemental analysis: c26H32N4OS & HCl (theoretical values: C64.38, H6.86, N11.55; experimental values: C64.51, H6.61, N11.78).
Example 38: n- (4- (2- (4- (benzo [ b ]))]Thien-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) cyclopropyl Preparation of formamide (compound IV-4) and salts thereof
The intermediate 9-6(2.8mmol) and cyclopropylcarbonyl chloride (3.1mmol) were used as raw materials to obtain the target compound IV-4 as a white solid in an amount of 1.1g with a yield of 95% according to the preparation method of the compound I-1.
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+].
Preparation of Compound IV-4 hydrobromide
Using compound IV-4(2.5mmol) and 5% hydrobromic acid aqueous solution (2.6mmol) as starting materials, the preparation of hydrochloride of compound I-1 was carried out to give 1.04g of a white solid with a yield of 84%.
Elemental analysis: c23H32N4OS & HBr (% of theory: C55.98, H6.74, N11.35; and% of experiment: C55.72, H6.89, N11.17).
Example 39: n- (4- (2- (4- (benzo [ b ]))]Thien-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) nicotinamide (Compound IV-5) and preparation of salts thereof
The intermediate 9-6(2.8mmol) and nicotinoyl chloride (3.1mmol) were used as raw materials to obtain the target compound IV-5 as a white solid 1.08g with a yield of 86% according to the preparation method of the compound I-1.
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+].
Preparation of Compound IV-5 hydrochloride
Using compound IV-5(2.2mmol) and 5% hydrochloric acid aqueous solution (2.3mmol) as raw materials, 0.98g of white solid was obtained in a yield of 92% by the method for producing hydrochloride of compound I-1.
Elemental analysis: c25H31N5OS & HCl (theoretical values: C61.77, H6.64, N14.41; experimental values: C61.50, H6.83, N14.25).
Example 40: n- (4- (2- (4- (benzo [ b ]))]Thien-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) furan- Preparation of 2-carboxamide (Compound IV-6) and salts thereof
The intermediate 9-6(2.8mmol) and furan-2-carbonyl chloride (3.1mmol) are used as raw materials, and the preparation method of the compound I-1 is adopted to obtain 1.08g of the target compound IV-6 as a white solid with the yield of 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+].
Preparation of Compound IV-6 hydrobromide
Using compound IV-6(2.3mmol) and 5% hydrobromic acid aqueous solution (2.4mmol) as starting materials, the preparation of hydrochloride of compound I-1 was carried out to give 1.05g of a white solid with a yield of 88%.
Elemental analysis: c24H30N4O2S & HBr (% of theory: C55.49, H6.01, N10.78; and% of experiment: C55.33, H6.24, N10.54).
Example 41: 3- (4- (2- (4- (benzo [ b ]))]Thien-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -1,1- Preparation of dimethylurea (Compound IV-7) and salts thereof
Using intermediate 9-6(2.8mmol) and N, N-dimethylamine (15.4mmol) as starting materials, the process for the preparation of compound II-1 gave the target compound IV-7 as a white solid (0.94 g), in a yield of 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+].
Preparation of Compound IV-7 hydrochloride
Using compound IV-7(2.3mmol) and 5% aqueous hydrochloric acid (2.4mmol) as starting materials, the preparation of hydrochloride of compound I-1 gave 0.83g of a white solid with a yield of 80%.
Elemental analysis: c22H33N5OS · HCl (theoretical%:c58.45, H7.58, N15.49; experimental value%: c58.61, H7.33, N15.67).
Example 42: 1- (4- (2- (4- (benzo [ b ]))]Thien-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-benzene Preparation of ureide (Compound IV-8) and salts thereof
By using the intermediate 9-6(2.8mmol) and aniline (15.4mmol) as raw materials and according to the preparation method of the compound II-1, 1.22g of the target compound IV-8 white solid is obtained with the yield of 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+].
Preparation of Compound IV-8 hydrobromide
Using compound IV-8(2.5mmol) and 5% hydrobromic acid aqueous solution (2.6mmol) as starting materials, the preparation of hydrochloride of compound I-1 was carried out to give 1.16g of a white solid with a yield of 85%.
Elemental analysis: c26H33N5OS & HBr (% of theory: C57.35, H6.29, N12.86; and% of experiment: C57.49, H6.14, N12.61).
Example 43: 1- (4- (2- (4- (benzo [ b ]))]Thien-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -3- (pir-yl Preparation of pyridin-3-yl) urea (Compound IV-9) and salts thereof
The intermediate 9-6(2.8mmol) and pyridin-3-amine (15.4mmol) were used as starting materials to obtain the target compound IV-9 as a white solid in an amount of 1.18g with a yield of 91% according to the method for producing the compound II-1.
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+].
Preparation of Compound IV-9 hydrochloride
Using compound IV-9(2.5mmol) and 5% aqueous hydrochloric acid (2.6mmol) as starting materials, the preparation of hydrochloride of compound I-1 gave 1.09g of a white solid with a yield of 87%.
Elemental analysis: c25H32N6OS & HCl (theoretical values: C59.92, H6.64, N16.77; experimental values: C59.71, H6.44, N16.62).
Example 44: 3- (4- (2- (4- (benzo [ b ]))]Thien-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -1-methyl Preparation of 1-phenylurea (Compound IV-10) and salts thereof
The intermediate 9-6(2.8mmol) and N-methylaniline (15.4mmol) were used as raw materials to obtain the target compound IV-10 as a white solid in an amount of 1.04g with a yield of 78% according to the method for producing the compound II-1.
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+].
Preparation of Compound IV-10 hydrobromide
Using compound IV-10(2.0mmol) and 5% hydrobromic acid aqueous solution (2.1mmol) as starting materials, the preparation of hydrochloride of compound I-1 was carried out to give 1.01g of a white solid with a yield of 90%.
Elemental analysis: c27H35N5OS & HBr (% of theory: C58.06, H6.50, N12.54; and% of experiment: C58.22, H6.40, N12.37).
Example 45: 1- (4- (2- (4- (benzo [ b ]))]Thien-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-ring Preparation of propylurea (Compound IV-11) and salts thereof
The intermediate 9-6(2.8mmol) and cyclopropylamine (15.4mmol) were used as raw materials to obtain the target compound IV-11 as a white solid in an amount of 0.94g with a yield of 88% according to the method for producing the compound II-1.
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+].
Preparation of Compound IV-11 hydrochloride
Using compound IV-11(2.3mmol) and 5% aqueous hydrochloric acid (2.4mmol) as starting materials, the preparation of hydrochloride of compound I-1 gave 0.90g of a white solid with a yield of 84%.
Elemental analysis: c23H33N5OS & HCl (theoretical values: C59.53, H7.38, N15.09; experimental values: C59.41, H7.21, N15.31).
Example 46: n- (4- (2- (4- (benzo [ b ]))]Thien-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) morpholine- Preparation of 4-carboxamide (Compound IV-12) and salts thereof
By using intermediate 9-6(2.8mmol) and morpholine (15.4mmol) as raw materials and following the preparation method of compound II-1, the target compound IV-12 was obtained as a white solid 1.09g with a yield of 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+].
Preparation of Compound IV-12 hydrobromide
Using compound IV-12(2.3mmol) and 5% hydrobromic acid aqueous solution (2.4mmol) as starting materials, the preparation of hydrochloride of compound I-1 was carried out to give 1.13g of a white solid with a yield of 91%.
Elemental analysis: c24H35N5O2S.HBr (% of theory: C53.53, H6.74, N13.00; and% of experiment: C53.27, H6.87, N13.25).
Example 47: preparation of tablets
This example is a tablet formulation of a compound of the present invention. In this example all compounds of the invention were prepared as tablets.
The components of the tablet are as follows:
Figure BDA0001109288820000431
the preparation method comprises the following steps: mixing the active ingredients with sucrose and corn starch, moistening with water, stirring, drying, pulverizing, sieving, adding magnesium stearate, mixing, and tabletting. Each tablet weighs 200mg, and the content of active ingredients is 5 mg.
Example 48: preparation of injection
This example illustrates the preparation of an injection containing the compound of the present invention. In this example, all compounds of the present invention were prepared as injections.
The injection comprises the following components:
compound of the invention 10mg
90mg of water for injection
The preparation method comprises the following steps: dissolving active ingredient in water for injection, mixing, filtering, and subpackaging the obtained solution in ampoule bottle under aseptic condition, wherein each bottle contains 10mg of active ingredient and 1.0mg of active ingredient.
2Example 49: dopamine D receptor binding assay
In this example all compounds of the invention were subjected to dopamine D2Receptor binding assays to detect the Compounds of the invention with dopamine D2The affinity of the receptor.
1. Experimental Material
D2Receptor isotope ligand [ alpha ], [ alpha3H]methyl-Spiperone (0.3nM), butalamol (10. mu.M), liposoluble scintillant, and recombinant (human recombiant) D2HEK-293 cells that receive functional proteins. Carilazine was used as a positive drug control.
2. Experimental methods
Reference is made to the methods of operation of Hall, D.A. and Strange, P.G (1997), Brit.J.Pharmacol, 121:731-736, using3H]methyl-Spiperone (0.3nM) as D2Receptor isotope ligands in the expression of recombinant D of human origin2Receptor protein on HEK-293 cells2A receptor binding assay. Nonspecific binding was determined in the presence of 10 μ M butalamol (butaclad).
The inhibition rate was calculated by the following formula:
the inhibition (I%) (total bound tube cpm-compound cpm)/(total bound tube cpm-non-specific bound tube cpm) × 100%.
Compounds with inhibition rates higher than 95% were subjected to a series of receptor binding assays at concentrations to determine the median inhibitory amount (IC)50Inhibiting the expression of 50%3H]Methyl-spiroperimidezene and D2Concentration of compound required for receptor binding). Two secondary tubes were measured per concentration and two independent experiments were performed for each compound.
The affinity of the drug for the receptor was calculated by the following formula:
Ki＝IC50/(1+[L]KD)
(Ki: affinity of drug to receptor, L: concentration of radioligand, KD: affinity value of radioligand with receptor
Compounds of the invention and D2The results of the receptor binding assay are shown in the table1. The test results in table 1 show that: the compound of the invention is p-dopamine D2The receptor has a strong or moderate affinity.
3Example 50: dopamine D receptor binding assay
In this example all compounds of the invention were subjected to dopamine D3Receptor binding assays to detect the Compounds of the invention with dopamine D3The affinity of the receptor.
1. Experimental Material
D3Receptor isotope ligand [ alpha ], [ alpha3H]Methyl-spiro-piperdine (0.3nM), (+) butalamol (10. mu.M), liposoluble scintillation fluid, expression of human recombinant D3CHO cells that receive functional proteins. Carilazine was used as a positive drug control.
2. Experimental methods
Reference is made to Mackenzie, R.G. et al (1994), Eur.J.Pharmacol, 266:79-85, methods of operation, using3H]methyl-Spirospiroperidine (0.3nM) as D3Receptor isotope ligands in the expression of recombinant D of human origin3CHO cell for receptor protein D3A receptor binding assay. Nonspecific binding was determined in the presence of 10 μ M (+) butalamol.
The inhibition rate was calculated by the following formula:
the inhibition (I%) (total bound tube cpm-compound cpm)/(total bound tube cpm-non-specific bound tube cpm) × 100%.
Compounds with inhibition rates higher than 95% were subjected to a series of receptor binding assays at concentrations to determine the median inhibitory amount (IC)50Inhibiting the expression of 50%3H]Methyl-spiroperimidezene and D3Concentration of compound required for receptor binding). Two secondary tubes were measured per concentration and two independent experiments were performed for each compound.
The affinity of the drug for the receptor was calculated by the following formula:
Ki＝IC50/(1+[L]KD)
(Ki: affinity of drug to receptor, L: concentration of radioligand, KD: affinity of radioligand to receptorValue)
Compounds of the invention and D3The results of the receptor binding assay are shown in table 1. From Table 1, it can be seen that the compound pair D of the present invention3The receptors have strong affinity and are equivalent to the positive drug Carilazine, and the compounds in the series have the results of example 493/D2The acceptor is also suitably selective, i.e. between 10 and 60 fold selective.
1AExample 51: 5-HT receptor binding assays
In this example all compounds of the invention were subjected to 5-HT1AReceptor binding assays to detect the Compounds of the invention and 5-HT1AThe affinity of the receptor.
1. Experimental Material
5-HT1AReceptor isotope ligand [ alpha ], [ alpha3H]8-OH-DPAT (0.3nM), 8-OH-DPAT (10. mu.M), fat-soluble scintillation fluid and expression human recombinant 5-HT1AHEK-293 cells that receive functional proteins. Carilazine was used as a positive drug control.
2. Experimental methods
Reference is made to the method of operation of Mulheron, J.G. et al (1994), J.biol.chem.,269:12954-3H]8-OH-DPAT (0.3nM) as 5-HT1AReceptor isotope ligands in the expression of recombinant 5-HT of human origin1A5-HT on HEK-293 cells of receptor proteins1AA receptor binding assay. Nonspecific binding was determined in the presence of 10. mu.M 8-OH-DPAT.
Compounds with inhibition rates higher than 95% were subjected to a series of receptor binding assays at concentrations to determine the median inhibitory amount (IC)50Inhibiting the expression of 50%3H]8-OH-DPAT and 5-HT1AConcentration of compound required for receptor binding). Two secondary tubes were measured per concentration and two independent experiments were performed for each compound.
The affinity of the drug for the receptor was calculated by the following formula:
Ki＝IC50/(1+[L]KD)
(Ki: affinity of drug to receptor, L: concentration of radioligand, KD: affinity of radioligand to receptorHarmony value)
Compounds of the invention and 5-HT1AThe results of the receptor binding assay are shown in table 1. The experimental results in Table 1 show that the compounds of the present invention are resistant to 5-HT1AThe receptors all have strong affinity and are equivalent to the positive drug Carilazine.
2AExample 52: 5-HT receptor binding assays
In this example all compounds of the invention were subjected to 5-HT2AReceptor binding assays to detect the Compounds of the invention and 5-HT2AThe affinity of the receptor.
1. Experimental Material
5-HT2AReceptor isotope ligand [ alpha ], [ alpha3H]Ketanserin (0.5nM), Ketanserin (1 muM), liposoluble scintillant, and recombinant 5-HT expressed from human2AHEK-293 cells that receive functional proteins. Carilazine was used as a positive drug control.
2. Experimental methods
Reference is made to Bonhaus, D.W. et al (1995), Brit.J.Pharmacol, 115:622-3H]Ketanserin (0.5nM) as 5-HT2AReceptor isotope ligands in the expression of recombinant 5-HT of human origin2A5-HT on HEK-293 cells of receptor proteins2AA receptor binding assay. Nonspecific binding was determined in the presence of 1 μ M ketanserin.
Compounds with inhibition rates higher than 95% were subjected to a series of receptor binding assays at concentrations to determine the median inhibitory amount (IC)50Inhibiting the expression of 50%3H]Ketanserin and 5-HT2AConcentration of compound required for receptor binding). Two secondary tubes were measured per concentration and two independent experiments were performed for each compound.
The affinity of the drug for the receptor was calculated by the following formula:
Ki＝IC50/(1+[L]KD)
(Ki: affinity of drug to receptor, L: concentration of radioligand, KD: affinity value of radioligand with receptor
Compounds of the invention and 5-HT2AReceptor binding assaysThe results are shown in Table 1. The results of the experiments in Table 1 show that the compounds of the present invention are active against 5-HT2AThe receptors have strong affinity, and most of the compounds are resistant to 5-HT2AThe affinity of the compound is stronger than that of the positive drug Carlinazine.
Table 1: affinity of Compounds for Each receptor (Ki values)
Figure BDA0001109288820000461
Figure BDA0001109288820000471
Thus, as can be seen from the results of Table 1, the compound pair D of the present invention2、D3、5-HT1A、5-HT2AThe receptors all have strong or moderate affinity, and in addition most compounds have a strong or moderate affinity for D2/D3The receptor has proper selectivity, the selectivity is between 10 and 60 times, and is better than that of the Carilazine (the selectivity is lower than 10 times). Most of the compounds are p-5-HT2AThe receptor affinity is significantly better than that of the positive control drug. Therefore, the compounds have the potential effect of simultaneously improving cognitive impairment, low EPS side effect and the like.
2 3Example 53: [ H ] for intrinsic agonistic activity of dopamine D receptor]Adenosine uptake test face
In this example all compounds of the invention were subjected to dopamine D2Of intrinsic agonistic activity of a receptor3H]Adenosine was taken to test the face. Aripiprazole is a positive control drug.
Experimental methods
Cells were serum removed by washing twice with 200 μ Ι _ of serum free medium, 90 μ Ι _ of serum free medium was added to each well, plates were incubated for 2-3 h. 10 μ of serum-containing medium as a positive control, vehicle (serum-free medium), negative control (antagonist, haloperidol) or test compound and standard (quinpirole, 10 μ L of 10 μ M solution at a final concentration of 1 μ M) in serum-free medium were added to each well. The plate is returned to the incubator.
After 18h, add [ 2 ]3H]Adenosine (0.5. mu. Ci/well) was in 10. mu.L serum free medium and the plates were returned to the incubator. After 4h, membrane protease (0.25%) (100. mu.L/well) was added. The plate is again returned to the incubator. After 1h, a rapid filtration termination test was performed by passing through a Whatman GF/B glass fiber filter. For example, using a Brandel MLR-96T cell harvester, the filter is washed with 500mL of 50mM Tris-HCl pH 7.0 buffer. For example, retained radioactivity (50% effective amount) on the filter was assessed using a Wallac 1205 Betaplate liquid scintillation counter. Intrinsic activity was defined as total uptake (l μ M quinpirole) minus serum free medium and test compounds were compared to l μ M quinpirole (full DA receptor agonist) classified as 100% intrinsic activity. All assays are preferably performed in triplicate, with each drug in a complete column in each plate.
Table 2: according to the invention having D2Compound results of partial receptor agonism
Compound (I) Intrinsic Activity (%) Compound (I) Intrinsic Activity (%)
Quinpirole 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
The test result shows that: the compounds I-4, I-14, II-2, II-9, III-6, III-9, IV-6 and IV-7 of the present invention have the meaning of D2Partial receptor agonism.
Example 54: in vivo anti-schizophrenic activity assay of the compounds of the invention
In this example, option D2/D3Receptor selectivity of 10-60 times, and D2/D3/5-HT1A/5-HT2ACompounds with strong receptor affinity were tested for anti-schizophrenic activity.
1. Apomorphine model
(1) Test method
The experiment used an acute dosing mode.
Experimental mice were randomized into groups, and the stereotypic motor model was induced by intraperitoneal injection of apomorphine (5mg/kg) 30 minutes after gavage of either control or test compound. Observations record that within 70 minutes after administration of the apomorphine solution to the mice, the following symptoms appear every first 30 seconds of 10 minutes (0-10 minutes, 11-20 minutes, 21-30 minutes, 31-40 minutes, 41-50 minutes, 51-60 minutes, 61-70 minutes) and are scored according to the following criteria:
1)4 min, continuously biting;
2)3 min, biting the cage cover at least once during observation;
3)2 min, licking the cage bottom plate or the cage wall at least once during observation;
4)1 minute, compulsive sniffing and head lowering activities occur;
5) score 0, no such activity occurred.
The total score of the mice showing the above behavior within 70 minutes was calculated, and the improvement rate was calculated according to the following formula. Data are expressed as Mean ± SEM, plotted using GraphPad Prism software, and analyzed using the t-test, with significant differences being considered when P < 0.05.
Figure BDA0001109288820000491
(2) Experimental grouping and drug administration design
C57BL/6 mice were randomly divided into 6 groups of at least 9 mice, each of which was a model control group (apomorphine, in saline), Carilazine (positive control drug) and the compounds of the invention (I-4, I-14, II-2, II-9, III-6, III-9, IV-1, IV-7 and IV-12).
(3) Administration and post-administration observation
The compound and the positive drug Carilazine (oral gavage) are administered in gradient dosage of 0.05, 0.10, 0.40, 0.60 and 1.20 mg/kg-1. During the experiment, the clinical response symptoms of the animals were recorded.
(4) Statistical method
All data to
Figure BDA0001109288820000492
Show that the two samples were compared in mean t-test and one-way anova with P, processed with 11.5 software statistical package<0.05 is a significant difference.
(5) Results of the experiment
The specific experimental results are shown in table 3.
Table 3: inhibition of apo. induced gross stereotypical motor in mouse schizophrenia model (ED) by a single oral administration of compounds such as I-150)
Figure BDA0001109288820000493
Figure BDA0001109288820000501
The test result shows that: compared with the positive control drug Carilazine, the compounds of the invention can obviously improve the stereotypy of mice, and the apomorphine-induced schizophrenia model is a classic model of schizophrenia, so the series of compounds of the invention have good anti-schizophrenia effect. Improvement of stereotypy behavior (ED) of mouse by Compounds I-14, II-2, II-9, III-6, IV-1, IV-750) Is superior to the positive control drug Carilazine.
2. MK-801 induced spontaneous locomotion experiment in mice
(1) Test method
The experiment used an acute dosing mode. Experimental mice were randomly grouped and acclimated in a spontaneous activity box for 5-10 minutes prior to the experiment. After the animals receive the intragastric administration for 10 minutes, MK-801(0.5mg/kg) is injected into the abdominal cavity, the animals are placed back to the spontaneous activity box to start infrared monitoring, and videos of the animal activities are continuously collected for 90 minutes. And (4) analyzing the video file by using an SPSS 11.5 software statistical package after the experiment is finished to obtain the total activity distance within 90 minutes. Data are expressed as Mean ± SEM, plotted using GraphPad Prism software, and analyzed using the t-test, with significant differences being considered when P < 0.05.
(2) Experimental grouping and drug administration design
57BL/6 mice were randomly divided into 6 groups of at least 12 mice each, a placebo control group, a model control group (MK-801, in physiological saline), a cariprazine group, and a preferred compound group of the invention. Carilazine as a positive drug control, MK-801 as a molding tool drug.
(3) Results of the experiment
The specific results are shown in Table 4.
Table 4: effect of a Single oral administration on MK-801 induced Total distance to open field movement in a mouse model of schizophrenia (ED)50)
Figure BDA0001109288820000502
The test result shows that: both the kalilazine group and the compound of the invention can obviously improve the total distance of the mouse moving in the open field. As an open-field movement model induced by MK-801 is a common model of schizophrenia negative symptoms, the series of compounds have good anti-schizophrenia negative symptom effects. The improvement rate of the compounds I-14, II-9, III-6, IV-1 and IV-7 on the mouse open field movement is better than that of positive drug control Carlinazine, which indicates that the activity of the compounds I-14, II-9, III-6, IV-1 and IV-7 in the model is better than that of Carlinazine.
Example 55: determination of Water solubility of Compounds
This example selects 14 compounds according to the invention (compounds 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 compounds according to the prior art (PR-1: CN1829703A, page 17 of the description, compound 1 of example 3; PR-2: CN102159557A, page 86 of the description, compound 84 of example 84; PR-3: CN103130737A, page 41 of the description, compound IV-2 of example 44; PR-4: CN104140421A, page 15 of the description, compound I-1 of example 1) for the determination of the water solubility test.
1. The instrument comprises the following steps: waters e2695 high performance liquid chromatograph, SHA-B water bath constant temperature oscillator.
2. The method comprises the following steps: adding excessive raw materials into water of certain volume to obtain saturated solution, shaking in a constant temperature (37 deg.C) shaking instrument for 2 hr, standing, collecting supernatant, filtering with 0.45 μm filter membrane to sample injection vial, and sampling for determination.
3. Dissolution rate measuring instrument
ZRD-14 intelligent dissolution instrument, Waters e2695 high performance liquid chromatograph.
4. Dissolution medium: 900mL of a hydrochloric acid solution having a pH of 1.0 and water were used as dissolution media, respectively.
The method comprises the following steps: method for measuring dissolution rate and release rate of 0931 general rule of preparation in Chinese pharmacopoeia 2015 year edition by a second method.
Rotating speed: 75 revolutions per minute.
Sampling points are as follows: respectively passing through 5, 10, 15, 20, 30, 45, and 60min, collecting 10mL of eluate, filtering with 0.45 μm filter membrane, and measuring by sample injection.
5. Results of the experiment
The water solubility test was carried out as described above using 14 compounds according to the invention (compounds 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 compounds according to the prior art (PR-1: CN1829703A, Compound 1 according to example 3 on page 17 of the description; PR-2: CN102159557A, Compound 84 according to example 84 on page 86 of the description; PR-3: CN103130737A, Compound IV-2 according to example 44 on page 41 of the description; PR-4: CN104140421A, Compound I-1 according to example 1 on page 15 of the description). The specific experimental results are shown in table 5.
Table 5: water solubility of compounds
Figure BDA0001109288820000511
Figure BDA0001109288820000521
The test result shows that: the water solubility of the compounds of the present invention is significantly superior to that of representative compounds in the patent literature. Therefore, the compound of the invention is more beneficial to the preparation and research of preparations and prescriptions.
Example 56: compound rat in vivo drug test
In this example 12 compounds according to the invention (compounds 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) were selected as well as 4 prior art compounds (PR-1: CN1829703A, Compound 1 of example 3 on page 17 of the description; PR-2: CN102159557A, Compound 84 of example 84 on page 86 of the description; PR-3: CN103130737A, Compound IV-2 of example 44 on page 41 of the description; PR-4: CN104140421A, Compound I-1 of example 1 on page 15 of the description) and the positive drug control Carilazine for the in vivo drug tests in rats.
1. Test protocol
1.1 test animals
Healthy male SD rats were 48, divided into two groups of 24 rats each. All rats were aged 10-12 weeks in the week and weighed 250-290 g.
1.2 methods of administration
Different groups of rats used different modes of administration. The compound of the present invention was administered intravenously at a dose of 0.5mg/kg and in a volume of 5 mL/kg. The dose for oral administration was 2mg/kg, and the volume for administration was 10 mL/kg. The drug is respectively administered by tail vein puncture and oral gavage. Fasting was overnight before dosing and four hours after dosing.
1.3 sample Collection
CO at each time point 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours post-administration23 rats were inhaled euthanasia, blood was collected by cardiac puncture (about 1mL) into an EDTA-K2 anticoagulation tube (Bofeimei, product No. CLS-11131), brain tissue was taken and weighed, blood samples were centrifuged at 6000rpm for 8min (wet ice before centrifugation) within 1 hour, and supernatant, i.e., plasma, was taken, and the plasma and brain tissue were cryopreserved at-20 ℃ for LC-MS/MS analysis.
1.4 analytical methods and assays
In the experiment, the contents of the compound of the invention in a plasma sample and a brain tissue sample in a rat PK experiment are respectively measured by adopting a liquid chromatography-mass spectrometry method. And (3) establishing two standard curves for each analysis batch, calculating the concentration of the substance to be detected in the samples of the analysis batch, and controlling the samples along with the quality. The accuracy of the concentration points above 3/4 in the standard curve is within 80% -120%. Each analysis batch was set with quality control samples (QC) at different concentrations, high, medium, and low, each concentration being in parallel with a double sample. And (3) calculating the concentration of the quality control samples according to the standard curve of each analysis batch, wherein the quantity of the quality control samples is more than or equal to 5% of the quantity of each batch of samples.
1.5 preparation of quality control samples
Taking 95 mu L of rat blank plasma, respectively adding 5 mu L of the standard aqueous solution of the test object with the concentration of 40, 20, 10, 2, 1, 0.2, 0.04 and 0.02 mu g/mL, and uniformly mixing to obtain standard curve samples with the concentrations of 2000, 1000, 500, 100, 50, 10, 2 and 1 ng/mL. Taking 95 mu L of rat blank plasma, respectively adding 5 mu L of standard aqueous solution of the test object with the concentration of 32, 16, 0.8 and 0.06 mu g/mL, and uniformly mixing to obtain Quality Control (QC) samples with the concentrations of 1600, 800, 40 and 3 ng/mL.
2. Chromatographic conditions
High-performance liquid phase system: shimadzu LC-30AD column: thermo, C18, 2.1X 50mm, 5 μm
Flow rate: 0.4mL/min
3. Mass spectrometric detection mode
ESI，MRM(+)
4. Data computation and processing
The raw data in the experiment were collected and calculated by AB Sciex Mass spectrometer software Analyst 1.6.1, the standard curve was linear regression, and the weight coefficient was 1/X2.
The data and charting were processed using the computer program Microsoft Office Excel 2007 (Microsoft corporation, usa). Pharmacokinetic parameters were calculated using DAS (version 2.1.1) processing software statistical moment method.
5. Test results
The in vivo pharmacological test in rats was carried out as described above, selecting 12 compounds of the invention (compounds 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 compounds of the prior art (PR-1: CN1829703A, Compound 1 of example 3 on page 17 of the description, PR-2: CN102159557A, Compound 84 of example 84 on page 86 of the description, PR-3: CN103130737A, Compound IV-2 of example 44 on page 41 of the description, PR-4: CN104140421A, Compound I-1 of example 1 on page 15 of the description, and Carilazine (positive control). The specific experimental results are shown in table 6.
Table 6: brain penetration rate and bioavailability of the compound of the invention in male SD rats
Figure BDA0001109288820000541
The test result shows that: the compound of the invention has high brain penetration rate and conforms to the pharmacological characteristics of central drugs.
In addition, the tested compounds have good absolute bioavailability (greater than 30%) when orally taken, which indicates that the compounds of the invention have good potential druggability.
Example 57: examination of side effects of catalepsy in Compounds
In this example, 6 compounds (compounds I-14, II-2, III-6, III-9, IV-6 and IV-7) of the present invention, as well as cariprazine (positive control drug) and risperidone (positive control drug) were selected to perform a test for examining the side effects of catalepsy.
1. Laboratory animal
SD rats, male, available from chengzhou kavens laboratory animals llc.
2. Laboratory apparatus
A 9mm diameter wooden stick, placed horizontally, and 11cm high.
3. Design of experiments
The rat forelimb was placed on a wooden stick to start timing and stopped when its posture was changed. The Catalepsy test time was 60 seconds and if exceeded, was recorded as 60 seconds. Compound dose design ED tested with apomorphine50Values are standard, and 10, 50 and 200 times doses are given. Compounds were administered orally and tested for catallepsy after 30, 60 and 120 minutes, respectively.
3. Results of the experiment
6 compounds of the invention, as well as cariprazine and risperidone were selected to perform compound catalepsy side effect investigation experiments as described above. The specific experimental results are shown in Table 7.
Table 7: the compound causes catalepsy
Figure BDA0001109288820000551
Experimental results show that the compounds such as I-14 and the like have low incidence rate of catalepsy and low EPS side effect, and are superior to risperidone.
Example 58: acute toxicity test of Compounds
In this example, 10 compounds (I-4, I-14, II-2, II-9, III-2, III-6, III-9, IV-1, IV-7 and IV12) according to the present invention and Carlinazine (positive control drug) were selected for acute toxicity test.
(1) Experimental protocol
Firstly, toxicity symptoms and death situations of animals are observed after the animals are orally administered with ICR mouse Carilazine and the compound such as I-4 of the invention, and the acute toxicity is compared.
Preparing a solvent: weighing a proper amount of Tween-80, and diluting with deionized water to a concentration of 5% (g/v) Tween-80.
③ administration preparation: the required test samples were weighed out separately and formulated with 5% Tween 80 solutions to 6.25, 12.50, 25.00, 50.00 and 100.00mg/mL (corresponding to 125, 250, 500, 1000, 2000mg/kg, respectively) suspensions.
Fourthly, the administration route: the test article and the vehicle control group (0.5% Tween-80) were administered orally.
Fifthly, administration frequency: single administration, with fasting overnight before dosing.
Sixthly, administration volume: 20 mL/Kg.
General symptom observation: the day of administration was observed 1 time about 0.5, 1, 2, 4, 6 hours after the first administration; the observation period is 2-6 days, 2 times per day, 1 time in the morning and afternoon.
Observations include, but are not limited to: general condition, behavioral activity, gait posture, eye, mouth, nose, gastrointestinal tract, dermal hair, urogenital tract.
(2) Statistical analysis
Body weight data are expressed as mean ± standard deviation and are compared between groups using the Levene's test and one-way analysis of variance, and if differences are indicated, the Dunnet test is followed.
(3) Results of the experiment
10 compounds of the invention were selected, and the acute toxicity test was performed as described above with cariprazine (positive control). The results are shown in Table 8.
In the MTD test, the tolerance of the animals to the drugs is considered, and the dosage is up to the time when the animals die frequently, namely the maximum tolerance.
Table 8: test results of acute toxicity of compounds such as I-4 and positive Carilazine by single oral administration
Figure BDA0001109288820000561
Note: MTD: maximum tolerated dose.
The results show that: the MTD (maximum tolerated dose) of the compounds II-2, II-9, III-9 and IV-7 in the test substance is more than 2000mg/kg, and the acute toxicity is far lower than that of the kalilazine; the MTD values of the compounds I-4, I-14, II-9, III-2, III-6, IV-1 and IV-12 are all larger than 900mg/kg, and the safety is better than that of the kalilazine.
Example 59: bacterial reverse mutation assay of Compounds
The Ames assay is collectively referred to as contaminant mutagenicity detection. The histidine auxotrophic strain of salmonella typhimurium, in a medium containing a trace amount of histidine, is generally capable of dividing only a few times, except for a few cells which spontaneously revert to mutation, to form microcolonies which can only be seen under a microscope. After the mutagenic agent acts, a large number of cells generate reversion, self-synthesize histidine and develop into macroscopic colonies. In view of the potential mutagenic effect of chemical substances and the close correlation between mutagenic and carcinogenic effects, the method is widely applied to screening carcinogens.
This example selects 10 compounds of the invention (I-4, I-14, II-2, II-9, III-2, III-6, III-9, IV-1, IV-7 and IV12) and Carlinazine (positive control) to perform a histidine auxotrophic Salmonella typhimurium back mutation test to examine whether a gene mutation is caused to evaluate their potential mutagenicity.
(1) Preparation method
0.0303g of test sample is accurately weighed before use, completely dissolved in DMSO (dimethylsulfoxide) with a certain volume under the aseptic and ultrasonic conditions to prepare a solution with the highest concentration of 10000.0 mu g/mL, and then the solution is diluted into 8 concentrations of 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6 and 1.5 mu g/mL according to the proportion of 1:2 (v/v).
(2) Test strains
Salmonella typhimurium histidine auxotrophic mutants TA98 and TA100, purchased from MolTox, Inc. (lots 4367D and 4370D, respectively).
(3) Reference substance
Negative control dimethyl sulfoxide (DMSO)
Positive control 2-nitrofluorene (Aldrich, 09213BA)
Sodium azide (Sigma, 043K0056)
(4) Official test
The formal test consists of two parallel experiments with or without metabolic activation system. Using standard plate incorporation methods, 500. mu.L of the solubilized top layer medium containing 0.6% agar, 0.5% NaCl, 0.5mM biotin and 0.5mM histidine were mixed with the following:
20 μ L of test solution (or negative/positive control)
25 μ L of overnight culture broth
100μL S9(metabolism activation system) mixture or 0.2M sodium phosphate buffer (pH 7.4)
Shaking the mixture evenly, spreading on a V-B bottom layer culture medium prepared in advance, solidifying at room temperature, placing in an incubator at 37 ℃ for inverted culture for 72 hours, and observing the result. In the official test, each strain is provided with a negative control group and a positive control group, and each group is cultured in 2 holes/group in parallel.
After the culture is finished, whether the test sample is precipitated or not and the growth condition of background bacterial plaque is observed, the number of the recurrent bacterial colonies in each hole is counted, the mean number of the recurrent bacterial colonies in each concentration group of each strain is calculated, and the result is expressed by the mean number.
The number of the retrogradation colonies of the negative control group is within the range of historical negative control data, and the number of the retrogradation colonies of the positive control group is 2 times higher than that of the negative control group, so that the test system is effective.
The number of the retrogradation colonies induced by the test article is obviously increased in a dose-dependent manner, and/or the number of the retrogradation colonies of the test article in a certain dose group is 2 times higher than that of the negative control group, and the result can be judged to be positive.
(4) Results of the experiment
The results are shown in tables 9 and 10.
Table 9: effect of Compounds such as I-4 on colony reversion number of Salmonella typhimurium TA98 Strain
Figure BDA0001109288820000571
Figure BDA0001109288820000581
Table 10: effect of Compounds such as I-4 on colony reversion number of Salmonella typhimurium TA100 Strain
Figure BDA0001109288820000582
The results of the experiments in tables 9 and 10 show that all tested doses of the compounds I-4, I-14, II-2, II-9, III-2, III-6, III-9, IV-1, IV-7, IV12 and Carilazine were tested in the absence of S9Or adding S9The colony inflection number of the salmonella typhimurium strain TA98 and TA100 is not obviously increased in the experimental system, namely the compound has no mutagenic effect.
Thus, the compounds of the invention have no mutagenic effect on the salmonella typhimurium strain TA98 and TA100, and all tested compounds Ames test are negative.

Claims (9)

1. A arylethylpiperidinyl derivative which is a compound represented by the general structural formula (I) below or a pharmaceutically acceptable salt thereof:
Figure FDA0003018668310000011
wherein:
r is
Figure FDA0003018668310000012
R3Is selected from C1～C3Alkyl of (C)1～C2Alkoxy group of (C)3～C6Cycloalkyl, phenyl, substituted phenyl or heteroaryl of (a);
R4、R5each independently represents hydrogen or C1～C3Alkyl of (C)3～C6Cycloalkyl, phenyl, benzyl or pyridyl;
or R4、R5Forms a morpholine ring with the attached N atom;
n is an integer of 0 to 1;
R1、R2each independently represents chlorine, methyl, methoxy, phenyl;
or R1、R2Together form a benzene ring, an oxazolone ring or a thiophene ring;
the substituted phenyl is selected from halogen, cyano, methoxy or C1～C2Alkyl-substituted phenyl of (a).
2. Arylethylpiperidinyl derivatives according to claim 1, characterized in that the heteroaryl is selected from furyl, pyrrolyl, thienyl, pyridyl, 2-benzothienyl, 2-benzofuryl or 2-indolyl.
3. Arylethylpiperidinyl derivatives according to any one of claims 1 to 2, characterized in that the salts of the compounds are salts containing pharmaceutically acceptable anions selected from the group consisting of hydrochloride, hydrobromide, sulfate, acetate, trifluoroacetate, citrate, tartrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate and oxalate.
4. Arylethylpiperidinyl derivatives according to claim 3, characterized in that the salt of said compound is an oxalate, a methanesulfonate, a hydrobromide or a trifluoroacetate.
5. Arylethylpiperidinyl derivatives, characterized in that they are:
I-1N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) acetamide,
I-2N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) butanamide,
I-3N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -2-methoxyacetamide,
I-4N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -2-ethoxyacetamide,
I-5N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) cyclopropylcarboxamide,
I-6N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) cyclohexylcarboxamide,
I-7N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) benzamide,
I-8N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-fluorobenzamide,
I-9N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-cyanobenzamide,
I-10N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-methylbenzamide,
I-11N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) nicotinamide,
I-12N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) furan-2-carboxamide,
I-13N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) pyrrole-2-carboxamide,
I-14N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) thiophene-2-carboxamide,
I-15N- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) indole-2-carboxamide,
II-11- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-methylurea,
II-23- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -1, 1-dimethylurea,
II-31- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-propylurea,
II-41-cyclopropyl-3- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) urea,
II-51-cyclohexyl-3- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) urea,
II-61- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-phenylurea,
II-71-benzyl-3- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) urea,
II-81- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -3- (pyridin-3-yl) urea,
II-9N- (4- (2- (4- (2,3- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) morpholine-4-carboxamide,
III-1N- (4- (2- (4- (2, 3-dimethylphenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-methoxybenzamide,
III-2N- (4- (2- (4- (2, 3-dimethylphenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-ethylbenzamide,
III-31-Ethyl-3- (4- (2- (4- (2-methoxyphenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -1-methylurea,
III-43- (4- (2- (4- (2-methoxyphenyl) piperazin-1-yl) ethyl) piperidin-1-yl) -1-methyl-1-phenylurea,
III-5N- (4- (2- (4- ([1,1' -diphenyl ] -3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -2-methoxyacetamide,
III-63- (4- (2- (4- ([1,1' -diphenyl ] -3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -1, 1-dimethylurea,
III-7N- (4- (2- (4- (naphthalen-1-yl) piperazin-1-yl) ethyl) piperidin-1-yl) furan-2-carboxamide,
III-81, 1-dimethyl-3- (4- (2- (4- (naphthalen-1-yl) piperazin-1-yl) ethyl) piperidin-1-yl) urea,
III-9N- (4- (2- (4- (2(3H) H-benzoxazolon-7-yl) piperazin-1-yl) ethyl) piperidin-1-yl) furan-2-carboxamide,
III-101, 1-dimethyl-3- (4- (2- (4- (2(3H) H-benzoxazolon-7-yl) piperazin-1-yl) ethyl) piperidin-1-yl) urea,
IV-1N- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) pentanamide,
IV-2N- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -2-methoxyacetamide,
IV-3N- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) benzamide,
IV-4N- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) cyclopropylcarboxamide,
IV-5N- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) nicotinamide,
IV-6N- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) furan-2-carboxamide,
IV-73- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -1, 1-dimethylurea,
IV-81- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-phenylurea,
IV-91- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -3- (pyridin-3-yl) urea,
IV-103- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -1-methyl-1-phenylurea,
IV-111- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-cyclopropylurea,
IV-12N- (4- (2- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) ethyl) piperidin-1-yl) morpholine-4-carboxamide.
6. A pharmaceutical composition comprising a therapeutically effective amount of a arylethylpiperidinyl derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
7. A process for preparing a pharmaceutical composition according to claim 6, wherein said process is carried out by mixing said arylethylpiperidinyl derivative or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.
8. A kit comprising a arylethylpiperidinyl derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.
9. Use of an arylethylpiperidinyl derivative or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5 for the preparation of a medicament for the treatment of schizophrenia.
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