CN110511174B - Indolylalkyl piperazine compound and application thereof - Google Patents
Indolylalkyl piperazine compound and application thereof Download PDFInfo
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- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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- 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
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention belongs to the technical field of medicines, relates to an indolyl alkyl piperazine compound and application thereof, and particularly relates to indolyl alkyl piperazine derivative p-5-HT 1A Affinity and action characteristics of receptor and its application in preparing medicine for treating nervous system diseases, especially 5-HT 1A The application in the field of medicines for treating receptor-related nervous system diseases. The indole alkyl piperazine compound has a structure shown in a general formula (I):
wherein R is 1 、R 2 、R 3 The definitions of m and n are shown in the specification. The compounds can be used as selective 5-HT 1A Receptor agonists are used for the preparation of medicaments for the treatment of neurological and psychiatric disorders associated with the brain, such as anxiety, depression, schizophrenia and parkinson's disease.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to an indolyl alkyl piperazine compound and application thereof, and particularly relates to an indolyl alkyl piperazine derivative p-5-HT 1A Affinity and action characteristics of receptor and its application in preparing medicine for treating nervous system diseases, especially 5-HT 1A The application in the field of medicines for treating receptor-related nervous system diseases.
Background
Studies have shown that 5-hydroxytryptamine (5-HT), an important neurotransmitter, is involved in the regulation and mediation of a variety of physiological effects via at least 16 different receptor subtypes. These receptor subtypes are divided into 7 distinct subfamilies (5-HT) according to pharmacological and functional criteria 1-7 ) In which 5-HT 1A The receptor was the first receptor to be completely sequenced and studied extensively. Studies have shown that 5-HT 1A Receptors are involved in the modulation of a variety of physiological effects, and functional disorders thereof can contribute to a variety of central nervous system disorders.
Anxiety, also known as anxious neuropathy, is the most common of the large group of neurological disorders and is primarily characterized by an anxious emotional experience. Anxiety disorders can be divided into two forms, chronic anxiety (generalized anxiety disorder) and acute anxiety disorder (panic disorder), depending on the extrinsic symptoms. The current representative drugs for treating anxiety are mainly 5-HT 1A Receptor agonists are mainly, such as buspirone and the like. Although the specific mechanism of action is not clear, the general view is that 5-HT is present in addition to the presynaptic membrane 1A Receptor in vitro, 5-HT distributed in the postsynaptic membrane of the marginal zone (hippocampal, amygdala, lateral compartment) 1A Receptors play a key role in the regulation of anxiety processes. The hippocampal and amygdala regions are the main control regions for mood regulation and stress relief, while the lateral compartment acts as a relay station to transmit nerve impulses from the limbic region to the hypothalamus, thereby regulating various physiological responses. 5-HT 1A Receptor agonists are believed to suppress neuronal activity in the hippocampus and lateral compartments by activating G-protein gated inward rectifying potassium channels (GIRK), thereby alleviating the symptoms of anxiety.
Depression is also known as depressive disorder, with a marked and persistent depression as the major clinical symptom. According to the severity of the disease condition, the clinical manifestations of the disease mainly range from sultriness, depression, and pessimism, and finally lead to suicide behavior, while some patients are accompanied by mental symptoms such as anxiety, hallucination, and delusion. The current clinical major therapeutic drug includes 5-HT 1A Receptor agonists, 5-HT reuptake inhibitors (SSRIs), and combinations thereof. Although for 5-HT 1A The specific mechanism of receptor agonists for the treatment of depression is not clear, but the more accepted view is that of presynaptic membrane 5-HT 1A Receptor desensitization or downregulation, i.e.: repeated acceptance of 5-HT 1A Receptor agonist treatment of the suprasynaptic membrane of the raphe nucleus 5-HT 1A Receptor desensitization thus relieves the 5-HT neurons that are inhibited by autoreceptor modulation, ultimately resulting in activation of the 5-HT neurons, relieving the deficiency of 5-HT in the symptoms of anxiety. At the same time, 5-HT 1A The combined use of receptor agonists and SSRIs not only alleviates the slow onset of action of SSRIs when applied alone, but also improves the potential therapeutic effectThe rate of desensitization from the receptor is accelerated. The drug vilazodone approved by FDA for treating major depression in 2011 has 5-HT 1A Receptor agonist and 5-HT reuptake inhibitor activity.
Schizophrenia is the most common serious continuous and chronic mental disease, and clinical manifestations are positive symptoms and negative symptoms, wherein the former symptoms comprise hallucinations, delusions, chorea and the like; the latter mainly refers to defective recognition function, learning and memory disorder, working and memory disorder, etc. With the increasing work and life pressure of people, mental problems have serious adverse effects on the whole society. Early first generation anti-schizophrenia drugs, also known as classical antipsychotics, were primarily responsible for positive Symptoms, poorly effective for negative Symptoms, and have a high incidence of Extrapyramidal Symptoms (EPS). While the atypical antipsychotic not only has the effect on positive symptoms, but also has good treatment effect on negative symptoms and can reduce extrapyramidal side effects, but has no obvious advantage in the aspect of treating cognitive impairment. It has been shown that 5-HT 1A Receptor agonists activate the postsynaptic membrane of the striatum and prefrontal lobe of the cerebral cortex via a non-dopaminergic pathway 1A The receptors reduce EPS induced by anti-schizophrenia drugs. At the same time, 5-HT 1A Receptor antagonists may block 5-HT of the nuclear postsynaptic membrane located inside the subtertian septum or the limbic septum 1A The receptor relieves acetylcholine or glutamate levels and improves cognitive function. Of the current drugs for schizophrenia, the non-classical antipsychotics with multiple activities, such as aripiprazole, ziprasidone, etc., all have corrected 5-HT 1A Receptor activity.
Parkinson's Disease (PD), also known as paralysis agitans, is one of the most common degenerative diseases of the nervous system, and clinically, resting tremor, muscular rigidity, bradykinesia and postural reflex disorder are the main causes. PD is not only high in morbidity, but also is a lifelong disease, and with the development of the disease period, patients gradually lose life and labor capacity and produce non-motor complications such as cognitive impairment and mental confusion, so that the life quality is seriously affected, and the patients need to take medicines for a long time to give families and societyA heavy burden is imposed. At present, levodopa (L-DOPA) is the most effective PD therapeutic drug, and it acts by being converted into dopamine in vivo by DOPA decarboxylase. But because it causes fluctuation of symptoms and dyskinesias, it is generally desirable to delay the use of levodopa. L-DOPA with 5-HT 1A Receptor agonists are believed to be effective in alleviating the onset of motor syndrome, and although specific mechanisms of action remain to be explored, current pharmacological experiments suggest: 1) L-DOPA may be taken up by serotonin neurons, converted to dopamine and released into the synaptic cleft. 2) Dopamine release from serotonin neurons is highly likely to be regulated by 5-HT through negative feedback 1A The receptor agonist is inhibited, thereby ensuring the normal content of dopamine in the body.
Based on the current situation of the prior art, the inventor of the application plans to develop the 5-HT with novel structure type, definite effect and small toxic and side effect 1A The receptor stimulant specifically relates to an indolealkylpiperazine compound and application thereof, and the compound can be prepared into a medicament for treating central nervous system diseases such as anxiety, depression, schizophrenia, parkinson disease and the like.
Disclosure of Invention
The invention aims to provide a novel structure of the compound with 5-HT 1A Of receptor affinity, especially as 5-HT 1A Indolealkylpiperazines as receptor agonists.
The invention also aims to provide a preparation method of the indolealkylpiperazine compound.
The invention also aims to provide the application of the compound in treating neurological and psychiatric diseases related to the brain, such as anxiety, depression, schizophrenia and Parkinson's disease.
The invention provides an indolealkylpiperazine compound (or called 'indolealkylpiperazine derivative') shown as a general formula (I) and a pharmacologically acceptable inorganic or organic salt and a crystal hydrate thereof:
wherein:
m and n are independently 0,1,2,3 or 4 respectively; preferably, m is selected from 1 or 2; n is selected from 3;
substituent R 1 Selected from hydrogen, halogen, C 1 -C 6 Substituted or unsubstituted alkyl, C 1 -C 6 Substituted or unsubstituted alkoxy, hydroxy, cyano, preferably from F, cl, hydroxy, methoxy, cyano;
substituent R 2 Absent or in at least one of the 2,3, 4,5, 6 positions, being unsubstituted, mono-, di-or poly-substituted, the substituent R 2 One, two or more selected from the following groups: hydrogen, halogen, nitro, hydroxy, carboxyl, cyano, amino, C 1 -C 6 Substituted or unsubstituted alkyl, C 1 -C 6 Substituted or unsubstituted alkoxy, -SO 2 CH 3 A group; when R is 2 When di-or tri-substituted, the substituents may be the same or different; preferably, the substituent R 2 Methoxy, F, methanesulfonyl, absent or at position 4;
substituent R 3 Selected from H, C 1 -C 6 Substituted or unsubstituted alkyl, C 3 -C 7 Substituted or unsubstituted cycloalkyl or HetAr1, preferably from C 5 -C 6 Alkyl, 4-methoxycyclohexyl, 4-tetrahydro-2-H-pyranyl, 4-oxocyclohexyl, 4-piperidinyl, hydroxyethyl, hydroxypropyl, 1-methoxy-2-propyl, 1,2-dimethoxy-ethyl;
unless otherwise indicated, C is defined herein 1 -C 6 Alkyl radical (C) 1 -C 6 Unsubstituted alkyl) is C 1 -C 6 Straight or branched alkyl refers to alkyl groups containing 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, or octyl. C 1 -C 6 Substituted alkyl is C 1 -C 6 The alkyl group may be selected from hydroxy, halogen, C 1 -C 3 1-2 of the alkoxy groups are the sameOr different groups.
Unless otherwise indicated, C is defined herein 1 -C 6 Alkoxy (C) 1 -C 6 Unsubstituted alkoxy) is C 1 -C 6 Straight-chain or branched alkoxy means alkoxy containing 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy or octyloxy. C 1 -C 6 Substituted alkoxy means C 1 -C 6 Alkoxy groups may be selected from hydroxy and C 1 -C 3 1-2 identical or different substituents of the alkoxy radical.
Unless otherwise indicated, C is defined herein 3 -C 7 Cycloalkyl (C) 3 -C 7 Unsubstituted cycloalkyl) refers to cycloalkyl groups containing 3 to 7 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl. C 3 -C 7 Substituted cycloalkyl means C 3 -C 7 Cycloalkyl groups may be selected from halogen, carbonyl, hydroxy and C 1 -C 3 1-2 identical or different substituents of the alkoxy radical.
Unless otherwise indicated, C in the present invention 1 -C 3 Alkoxy means C 1 -C 3 Straight or branched alkoxy refers to alkoxy groups containing 1 to 3 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy.
HetAr1 as described herein represents a saturated unsubstituted 4,5, 6, 7, 8, 9 or 10 membered heterocyclic ring having 1,2 or 3N and/or O and/or S atoms, unless otherwise specified.
Unless otherwise indicated, the term halogen is a halogen substituent, including but not limited to fluorine, chlorine, bromine, or iodine.
In the present invention, the terms "polysubstituted" and "plural" mean three or more, and the same meanings are given below.
In a preferred embodiment, the indolealkylpiperazine derivatives of the invention are the following specific compounds:
n- (3-pentyl) -2- (4- (3- (5-fluoro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (3-hexyl) -2- (4- (3- (5-fluoro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (2-pentyl) -3- (4- (3- (5-fluoro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide,
n- (3-pentyl) -3- (4- (3- (5-fluoro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide,
n- (2-hexyl) -3- (4- (3- (5-fluoro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide,
n- (3-hexyl) -3- (4- (3- (5-fluoro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide,
n- (4-methoxycyclohexyl) -3- (4- (3- (5-fluoro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide,
n- (2-pentyl) -2- (4- (3- (5-fluoro-1H-3-indole) propyl) -1-piperazinyl) -N- (5-fluorophenyl) acetamide,
n- (2-pentyl) -2- (4- (3- (5-fluoro-1H-3-indole) propyl) -1-piperazinyl) -N- (5-methoxyphenyl) acetamide,
n- (2-pentyl) -2- (4- (3- (5-fluoro-1H-3-indole) propyl) -1-piperazinyl) -N- (5-methanesulfonylphenyl) acetamide,
n- (2-pentyl) -2- (4- (3- (5-chloro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (3-pentyl) -2- (4- (3- (5-chloro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (2-hexyl) -2- (4- (3- (5-chloro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (3-hexyl) -2- (4- (3- (5-chloro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (4-methoxycyclohexyl) -2- (4- (3- (5-chloro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (2-pentyl) -3- (4- (3- (5-chloro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropionamide,
n- (3-pentyl) -3- (4- (3- (5-chloro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropionamide,
n- (2-hexyl) -3- (4- (3- (5-chloro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropionamide,
n- (3-hexyl) -3- (4- (3- (5-chloro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropionamide,
n- (4-methoxycyclohexyl) -3- (4- (3- (5-chloro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide,
n- (3-pentyl) -2- (4- (3- (5-methoxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (2-hexyl) -2- (4- (3- (5-methoxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (3-hexyl) -2- (4- (3- (5-methoxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (2-pentyl) -3- (4- (3- (5-methoxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide,
n- (3-pentyl) -3- (4- (3- (5-methoxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide,
n- (2-hexyl) -3- (4- (3- (5-methoxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide,
n- (3-hexyl) -3- (4- (3- (5-methoxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropionamide,
n- (4-methoxycyclohexyl) -3- (4- (3- (5-methoxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide,
n- (3-pentyl) -2- (4- (3- (5-hydroxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (2-hexyl) -2- (4- (3- (5-hydroxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (3-hexyl) -2- (4- (3- (5-hydroxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (2-pentyl) -3- (4- (3- (5-hydroxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide,
n- (3-pentyl) -3- (4- (3- (5-hydroxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide,
n- (2-hexyl) -3- (4- (3- (5-hydroxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropionamide,
n- (3-hexyl) -3- (4- (3- (5-hydroxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide,
n- (4-methoxycyclohexyl) -3- (4- (3- (5-hydroxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide,
n- (2-pentyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (3-pentyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (2-hexyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (3-hexyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (4-methoxycyclohexyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (2-pentyl) -3- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropionamide,
n- (3-pentyl) -3- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropionamide,
n- (2-hexyl) -3- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropionamide,
n- (3-hexyl) -3- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropionamide,
n- (4-methoxycyclohexyl) -3- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide,
n- (2-pentyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N- (5-fluorophenyl) acetamide,
n- (2-pentyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N- (5-methoxyphenyl) acetamide,
n- (2-pentyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N- (5-methanesulfonylphenyl) acetamide,
n- (4-tetrahydro-2-H-pyranyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (4-oxocyclohexyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (4-piperidinyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (2-ethanolyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (2-propanolyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (1-methoxy-2-propyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
n- (1,2-dimethoxy-ethyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide,
the indole alkyl piperazine derivative also comprises pharmaceutically acceptable salts, solvates, precursor compounds or polymorphs thereof.
In the present invention, a pharmaceutically acceptable salt, solvate, prodrug or polymorph is characterized in that the pharmaceutically acceptable salt is an inorganic salt, an organic salt or an amino acid salt;
wherein the inorganic salt may be: sodium salts, hydrochlorides, trifluoroacetates, sulfates, phosphates, diphosphates, hydrobromides or nitrates;
wherein the organic salt may be: maleate, acetate, fumarate, tartrate, succinate, lactate, p-toluenesulfonate, salicylate, or oxalate;
wherein the amino acid salt is: arginine salt, ornithine salt, lysine salt, leucine salt, isoleucine salt, glycine salt, cystine salt, cysteine salt, caseinate, alanine salt, phenylalanine salt, histidine salt, serine salt, threonine salt, methionine salt, tryptophan salt, glutamate, aspartate salt, valine salt, methionine salt, proline salt, or hydroxyproline salt.
In order to achieve the second purpose, the invention adopts the technical scheme that:
the preparation method of the indole alkyl piperazine derivative can be synthesized by the following steps:
preparation of intermediate 2
The compound 1 and 3,4-dihydropyran are subjected to Fisher indole synthesis reaction at 150 ℃ under the acidic condition of 4% sulfuric acid to generate a compound 2. Wherein the compound 2d reacts with cuprous cyanide in an N, N-dimethylformamide solvent at 80 ℃ to generate a compound 2e.
Preparation of intermediate 3
And reacting the compound 2 with carbon tetrabromide and triphenylphosphine in a dichloromethane solvent to generate a compound 3. Wherein the compound 3b reacts with boron tribromide in a dichloromethane solvent at-78 ℃ to produce a compound 3c.
Preparation of intermediate 5
Reaction of Compound 4 with R under acidic conditions of acetic acid 3 The ketone compound corresponding to the group and hydrochloric acid activated zinc powder react in water at 75 ℃ to generate a compound 5.
Preparation of intermediate 6
The compound 5 reacts with corresponding chloro-acyl chloride in dichloromethane solvent under the basic condition of triethylamine to generate a compound 7.
Preparation of intermediate 7
Reacting the compound 6 with N-Boc-piperazine at 85 ℃ in acetonitrile solvent under the alkaline condition of potassium carbonate to generate a compound 7
Preparation of intermediate 8
Compound 7 is reacted with trifluoroacetic acid in dichloromethane solvent to produce compound 8.
Preparation of Compound I
And reacting the compound 3 with the compound 8 in an acetonitrile solvent under the alkaline condition of potassium carbonate to generate a compound I.
It is understood that the specific R's listed in the above reaction schemes 1 Is exemplified by R in the formula 1 Not limited thereto, but also includeAll R1 mentioned herein.
Among them, the process for preparing pharmaceutically acceptable salts of indolealkylpiperazine derivatives can be carried out according to the conventional methods in the art, and the compounds of the present invention are usually isolated as such or obtained by reacting with inorganic salts, organic salts or amino acid salts in the form of pharmaceutically acceptable salts thereof under conventional conditions.
The biological activity of the compounds encompassed by the present invention at the serotonin receptor is illustrated by the results of pharmacological experiments as follows:
1. compound affinity assay methods: radioligadand binding assay
Compound functional test method: [ 35 S]GTPγS binding assay
2. The experimental results are shown in tables 1 and 2:
table 1 affinity test results for compounds
In table 1, the data expressed as percentage in the column "inhibition%/Ki nM" means inhibition%, and the other data means Ki nM.
In Table 1, cis indicates that the two substituents on cyclohexane are on the same side, and Trans indicates that the two substituents on cyclohexane are on opposite sides.
In Table 1, — means no activity.
Table 2 functional test results of some compounds
The results show that all the novel compounds show a certain degree of replacement of 5-HT 1A Receptor isotope ligand capacity and higher 5-HT 1A Receptor selectivity, some compounds show high 5-HT 1A Full agonist activity of the receptor.
The compounds can be used as lead compounds to further develop 5-HT with good selectivity and high activity 1A Receptor compounds and their use in the preparation of compounds as 5-HT 1A The receptor stimulant is a potential drug for treating anxiety, depression, schizophrenia, parkinson's disease and other diseases.
Detailed Description
The invention will now be further illustrated, but not limited, by the following examples.
1 H-NMR was measured using a Varian Mercury Plus 400Hz model instrument; MS was determined by Agilent 6120Quadrupole LC/MS, incRedistilling the solvent before use, and drying the anhydrous solvent according to a standard method to obtain the anhydrous solvent; all reactions were followed by TLC, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, except as indicated; purifying the product by silica gel (200-300 meshes) column chromatography except for the specification; wherein the silica gel (200-300 meshes) is produced by Qingdao ocean chemical plants, and the TLC plate is a Qingdao ocean 0.2mm GF245 high-efficiency thin-layer chromatography silica gel plate.
Example 1: preparation of N- (2-pentyl) -3- (4- (3- (5-fluoro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide (FW I-01)
Step 1: preparation of 3- (5-Fluoroindole) propanol (intermediate 2 a)
4-Fluorophenylhydrazine hydrochloride (5 g, 3.07X 10) was added to a single-neck flask at room temperature -2 mol) was dissolved in a mixture of acetonitrile (50 ml) and 4% sulfuric acid (50 ml), and 3,4-dihydropyran (3.36ml, 3.7 × 10) was slowly added dropwise with stirring - 2 mol), heating the reaction to 150 ℃ after the dropwise addition is finished, and maintaining the reaction for 3h. After the reaction was completed, the reaction solution was cooled to room temperature, excess acetonitrile was distilled off under reduced pressure, and then 50ml of ethyl acetate was added to the remaining mixture and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column chromatographed (PE: EA = 20) to give 4.56g of a reddish brown oil in 76% yield.
Step 2: preparation of 3- (3-bromopropyl) -1-H-5-fluoroindole (intermediate 3 a)
Intermediate 2a (1g, 3.73X 10) was placed in a 100ml dry three-necked flask at 0 deg.C -3 mol) ofTo 30ml of anhydrous dichloromethane were added carbon tetrabromide (1.08ml, 1.11X 10 in that order -2 mol), triphenylphosphine (2.91g, 1.11X 10 -2 mol). Subsequently, 20ml of water was further added, extraction was carried out three times with 20ml of dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and column chromatography was carried out after concentration (PE: EA = 20) to obtain 0.72g of a dark gray oily liquid in a yield of 76%.
And 3, step 3: preparation of N- (2-pentyl) aniline (intermediate 5 a)
Aniline (1ml, 1.09X 10) -2 mol), 2-pentanone (0.94g, 1.09X 10 -2 mol), acetic acid (25 ml) and water (2.5 ml) were charged into a 100ml single-neck flask, and zinc powder activated with hydrochloric acid was added in portions with stirring, followed by transferring to 75 ℃ and refluxing at this temperature for 12 hours. After the reaction is completed, after the reaction solution is cooled to room temperature, ammonia water is used for adjusting to a weak base environment under an ice bath, the pH value is approximately equal to 10, 50ml dichloromethane is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is dried, column chromatography is carried out after concentration (PE: EA = 50.
And 4, step 4: preparation of N- (2-pentyl) -N-phenyl-3-chloropropylamide (intermediate 6 a)
In a single-neck flask, intermediate 5a (2.5g -2 mol), triethylamine (2.54ml, 1.83X 10 -2 mol) is dissolved in 50ml of anhydrous dichloromethane, and 3-chloropropionyl chloride (1.79ml, 1.83X 10 is added dropwise under ice bath conditions -2 mol) of dichloromethane solution, gradually increasing to room temperature after the dropwise addition, stirring for 30 minutes, transferring to the condition of 75 ℃ and continuing the reaction for 8 hours. After the reaction was completed, 30ml of dichloromethane was added, and the mixture was washed three times with 30ml of saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA = 30) to obtain 2.91g of a white solid, yield 76.4%.
And 5: preparation of N- (2-pentyl) -3- (4-Boc-1-piperazinyl) -N-phenylpropionamide (intermediate 7 a)
Intermediate 6a (5g, 1.97X 10) -2 mol), N-Boc-piperazine (3.67g, 1.97X 10 -2 mol) was dissolved in acetonitrile, and potassium carbonate (3.27g, 2.36X 10 was added -2 mol), heating to 85 ℃, and maintaining the reaction for 8h. After completion of the reaction, acetonitrile was removed under reduced pressure, 30ml of water was added, and the mixture was extracted three times with 30ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column chromatographed (DCM: meOH = 50).
And 6: preparation of N- (2-pentyl) -3- (1-piperazinyl) -N-phenylpropionamide trifluoroacetate (intermediate 8 a)
Intermediate 7a (5g, 1.24X 10) was placed in a single-neck flask -2 mol) is dissolved in 50ml dichloromethane, 30ml trifluoroacetic acid is added dropwise with stirring, and after completion, the reaction is continued for 3h at room temperature. After the reaction is finished, the excess solvent is removed under reduced pressure, and the mixture is washed three times by 30ml of petroleum ether and 30ml of diethyl ether respectively, filtered and dried to obtain 4.12g of white solid with the yield of 91.3 percent.
And 7: preparation of N- (2-pentyl) -3- (4- (3- (5-fluoro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide
Intermediate 8a (1g, 2.75X 10) was added to a single-neck flask containing 50ml of acetonitrile solution at room temperature -3 mol) and intermediate 3a (0.96g, 2.75X 10 -3 mol) and potassium carbonate (0.76g, 5.54X 10 -3 mol), heating the reaction to 75 ℃, and stirring and refluxing for 12h. After the reaction was complete, the excess acetonitrile was removed, 30ml of water, 30ml dichloromethane three times, the organic phases are combined, dried over anhydrous sodium sulfate, concentrated and column chromatographed (DCM: meOH = 10).
Examples 2 to 8: compound FW I-02-FW I-08
Example 1 was repeated, with the difference that: different starting materials are used in step 3 and different starting materials are used in step 5, thereby producing compounds FW I-02-FW I-08. Compounds FW i-02 and FW i-03 are a pair of cis-trans isomers, and their corresponding intermediates are obtained in step 4 via column chromatography (PE: EA = 30.
The details are shown in the following table:
and step 3:
and 5:
examples 9 to 11: compound FW I-09-FW I-11
Example 1 was repeated, with the difference that: in step 3, different starting materials are used to produce compounds FW I-09-FW I-11. The concrete is as follows:
example 12: preparation of N- (2-pentyl) -2- (4- (3- (5-chloro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide (FW I-12)
Step 1: preparation of 3- (5-Chloroindole) propanol (intermediate 2 c)
4-Chlorophenylhydrazine hydrochloride (5 g, 2.79X 10) was added to a single-neck flask at room temperature -2 mol) was dissolved in a mixture of acetonitrile (50 ml) and 4% sulfuric acid (50 ml), and 3,4-dihydropyran (4.46ml, 2.79X 10) was slowly added dropwise with stirring - 2 mol), heating the reaction to 150 ℃ after the dropwise addition is finished, and maintaining the reaction for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, excess acetonitrile was distilled off under reduced pressure, and then 50ml of ethyl acetate was added to the remaining mixture and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column chromatographed (PE: EA = 20) to give 4.20g of oil in 72% yield.
And 2, step: preparation of 3- (3-bromopropyl) -1-H-5-chloroindole (intermediate 3 d)
Intermediate 2c (1g, 4.78X 10) was reacted at 0 ℃ with 100ml of a dry three-necked flask -3 mol), dissolved in 30ml of anhydrous dichloromethane, followed by the sequential addition of carbon tetrabromide (0.84ml, 1.43X 10 -2 mol), triphenylphosphine (2.26g, 1.43X 10 -2 mol). Subsequently, 20ml of water was further added, extraction was carried out three times with 20ml of dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography (PE: EA = 20) to obtain 1.00g of a dark gray oily liquid in a yield of 77%.
And step 3: preparation of N- (2-pentyl) aniline (intermediate 5 a)
Aniline (2.94g, 0.03mol), 2-pentanone (2.58g, 0.03mol), acetic acid (25 ml) and water (2.5 ml) were charged into a 100ml single-neck flask, and zinc powder activated with hydrochloric acid was added in portions with stirring, followed by transferring to 75 ℃ and refluxing at this temperature for 12 hours. After the reaction is completed, after the reaction solution is cooled to room temperature, ammonia water is used for adjusting to a weak base environment under an ice bath, the pH value is approximately equal to 10, 50ml dichloromethane is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is used for drying, column chromatography is carried out after concentration (PE: EA = 50.
And 4, step 4: preparation of N- (2-pentyl) -N-phenyl-2-chloroacetamide (intermediate 6 a)
In a single-neck flask, intermediate 5a (5g, 3.07X 10) -2 mol), triethylamine (4.74ml, 3.42X 10 -2 mol) was dissolved in 50ml of anhydrous dichloromethane and the chloroacetyl chloride (2.72ml, 3.42X 10) was added dropwise under ice-bath conditions -2 mol) of dichloromethane solution, gradually increasing to room temperature after the dropwise addition, stirring for 30 minutes, transferring to the condition of 75 ℃ and continuing the reaction for 8 hours. After the reaction was completed, 30ml of dichloromethane was added, and the mixture was washed three times with 30ml of saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA = 30) to obtain 6.6g of a white solid with a yield of 90.3%.
And 5: preparation of N- (2-pentyl) -2- (4-Boc-1-piperazinyl) -N-phenylacetamide (intermediate 7 a)
Intermediate 6a (6 g, 2.51X 10) -2 mol), N-Boc-piperazine (4.20g, 2.51X 10 -2 mol) was dissolved in acetonitrile, and potassium carbonate (4.68g, 3.76X 10 was added -2 mol), heating to 85 ℃, and maintaining the reaction for 8h. After completion of the reaction, acetonitrile was removed under reduced pressure, 30ml of water was added, and the mixture was extracted three times with 30ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column chromatographed (DCM: meOH = 50) to give 7.5g of a pale yellow solid in 77% yield.
Step 6: preparation of N- (2-pentyl) -2- (1-piperazinyl) -N-phenylacetamide trifluoroacetate (intermediate 8 a)
Intermediate 7a (6 g, 1.54X 10) was placed in a single-neck flask -2 mol) is dissolved in 50ml dichloromethane, 30ml trifluoroacetic acid is added dropwise with stirring, and after completion, the reaction is continued for 3h at room temperature. After the reaction is finished, the excess solvent is removed under reduced pressure, and the mixture is washed three times by 30ml of petroleum ether and 30ml of diethyl ether respectively, filtered and dried to obtain 6.08g of white solid with the yield of 98.0 percent.
And 7: preparation of N- (2-pentyl) -2- (4- (3- (5-chloro-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide
Intermediate 8a (1g, 2.48X 10) was added to a single-neck flask containing 50ml of acetonitrile solution at room temperature -3 mol) and intermediate 3d (0.93g, 2.85X 10 -3 mol) and potassium carbonate (0.85g, 4.96X 10 -3 mol), heating the reaction to 75 ℃, and stirring and refluxing for 12h. After the reaction was finished, the excess acetonitrile was removed, 30ml of water was added, 30ml of dichloromethane was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column-chromatographed (DCM: meOH = 10) to give 1.13g of white solid with a yield of 82.8%.
Examples 13 to 23: compound FW I-13-FW I-23
Example 12 was repeated, with the difference that: different starting materials are used in step 3 and different starting materials are used in step 5 to produce compounds FWI-13-FWI-23. Compounds FW I-20 and FW I-21, FW I-22 and FW I-23 are a pair of cis-trans isomers, which are purified by column chromatography (PE: EA = 30) in step 4 to give the corresponding intermediates.
The following table specifically shows:
and step 3:
step 5
Example 24: preparation of N- (2-pentyl) -3- (4- (3- (5-methoxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropionamide (FW I-24)
Step 1: preparation of 3- (5-methoxyindole) propanol (intermediate 2 b)
4-Methoxyphenylhydrazine hydrochloride (5 g, 2.86X 10) was added to a single-neck flask at room temperature -2 mol) was dissolved in a mixture of acetonitrile (50 ml) and 4% sulfuric acid (50 ml), and 3,4-dihydropyran (4.35ml, 2.86 × 10) was slowly added dropwise with stirring -2 mol), heating the reaction to 150 ℃ after the dropwise addition is finished, and maintaining the reaction for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, excess acetonitrile was distilled off under reduced pressure, and then 50ml of ethyl acetate was added to the remaining mixture and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column chromatographed (PE: EA = 20) to give 4.63g of oil in 79% yield.
Step 2: preparation of 3- (3-bromopropyl) -1-H-5-methoxyindole (intermediate 3 b)
Intermediate 2b (1g, 4.88X 10) was placed in a 100ml dry three-necked flask at 0 deg.C -3 mol), dissolved in 30ml of anhydrous dichloromethane, followed by the sequential addition of carbon tetrabromide (0.82ml, 1.46X 10) -2 mol), triphenylphosphine (2.21g, 1.46X 10 -2 mol). Then, 20ml of water is added, and 20ml of water is usedThe organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA = 20) to obtain 0.93g of a dark gray oily liquid with a yield of 71%.
And step 3: preparation of N- (2-pentyl) aniline (intermediate 5 a)
Aniline (1ml, 1.09X 10) -2 mol), 2-pentanone (0.94g, 1.09X 10 -2 mol), acetic acid (25 ml) and water (2.5 ml) were charged into a 100ml single-neck flask, and zinc powder activated with hydrochloric acid was added in portions with stirring, followed by transferring to 75 ℃ and refluxing at this temperature for 12 hours. After the reaction is completed, after the reaction solution is cooled to room temperature, ammonia water is used for adjusting to a weak base environment under an ice bath, the pH value is approximately equal to 10, 50ml dichloromethane is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is dried, column chromatography is carried out after concentration (PE: EA = 50.
And 4, step 4: preparation of N- (2-pentyl) -N-phenyl-3-chloropropylamide (intermediate 6 a)
In a single-neck flask, intermediate 5a (2.5g -2 mol), triethylamine (2.54ml, 1.83X 10 -2 mol) is dissolved in 50ml of anhydrous dichloromethane, and 3-chloropropionyl chloride (1.79ml, 1.83X 10 is added dropwise under ice bath conditions -2 mol) of dichloromethane, gradually increasing to room temperature after the dropwise addition is finished, stirring for 30 minutes, and then transferring to the 75 ℃ condition for continuous reaction for 8 hours. After the reaction was completed, dichloromethane 30ml was added and washed three times with 30ml of saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography (PE: EA = 30) to obtain 2.91g of a white solid with a yield of 76.4%.
And 5: preparation of N- (2-pentyl) -3- (4-Boc-1-piperazinyl) -N-phenylpropionamide (intermediate 7 a)
Intermediate 6a (5g, 1.97X 10) -2 mol), N-Boc-piperazine (3.67g, 1.97X 10 -2 mol) was dissolved in acetonitrile, and potassium carbonate (3.27g, 2.36X 10) was added -2 mol), heating to 85 ℃, and maintaining the reaction for 8h. After completion of the reaction, acetonitrile was removed under reduced pressure, 30ml of water was added, and the mixture was extracted three times with 30ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column chromatographed (DCM: meOH = 50).
Step 6: preparation of N- (2-pentyl) -3- (1-piperazinyl) -N-phenylpropionamide trifluoroacetate (intermediate 8 a)
Intermediate 7a (5g, 1.24X 10) was placed in a single-neck flask -2 mol) is dissolved in 50ml dichloromethane, 30ml trifluoroacetic acid is added dropwise with stirring, and after completion, the reaction is continued for 3h at room temperature. After the reaction is finished, the excess solvent is removed under reduced pressure, and the mixture is washed three times by 30ml of petroleum ether and 30ml of diethyl ether respectively, filtered and dried to obtain 4.12g of white solid with the yield of 91.3 percent.
And 7: preparation of N- (2-pentyl) -3- (4- (3- (5-methoxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide
Intermediate 8a (1g, 2.75X 10) was added to a single-neck flask containing 50ml of acetonitrile solution at room temperature -3 mol) and intermediate 3b (0.99g, 2.75X 10 -3 mol) and potassium carbonate (0.76g, 5.54X 10 -3 mol), heating the reaction to 75 ℃, and stirring and refluxing for 12h. After the reaction was finished, the excess acetonitrile was removed, 30ml of water was added, 30ml of dichloromethane was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column-chromatographed (DCM: meOH = 10) to give 1.12g of a white solid with a yield of 82.9%.
Examples 25 to 32: compound FW I-25-FW I-32
Example 24 was repeated, with the difference that: different starting materials are used in step 3 and different starting materials are used in step 5 to produce compounds FW I-25-FW I-32. Compounds FW i-31 and FW i-32 are a pair of cis-trans isomers, and their corresponding intermediates were obtained in step 4 via column chromatography (PE: EA = 30.
The following table specifically shows:
and step 3:
and 5:
example 33: preparation of N- (2-pentyl) -3- (4- (3- (5-hydroxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropionamide (FW I-33)
Step 1: preparation of 3- (5-methoxyindole) propanol (intermediate 2 b)
4-Methoxyphenylhydrazine hydrochloride (5 g, 2.86X 10) was added to a single-neck flask at room temperature -2 mol) was dissolved in a mixture of acetonitrile (50 ml) and 4% sulfuric acid (50 ml), and 3,4-dihydropyran (4.35ml, 2.86 × 10) was slowly added dropwise with stirring -2 mol), heating the reaction to 150 ℃ after the dropwise addition is finished, and maintaining the reaction for 3 hours. After the reaction is finished, the reaction solution is addedAfter cooling to room temperature, excess acetonitrile was distilled off under reduced pressure, and then 50ml of ethyl acetate was added to the remaining mixture and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column chromatographed (PE: EA = 20) to give 4.63g of oil in 79% yield.
Step 2: preparation of 3- (3-bromopropyl) -1-H-5-hydroxyindole (intermediate 3 c)
[ step a)]Intermediate 2b (1g, 4.88X 10) was reacted at 0 ℃ with 100ml of a dry three-necked flask -3 mol), dissolved in 30ml of anhydrous dichloromethane, followed by the sequential addition of carbon tetrabromide (0.82ml, 1.46X 10) -2 mol), triphenylphosphine (2.21g, 1.46X 10 -2 mol). Subsequently, 20ml of water was further added, extraction was carried out three times with 20ml of dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and column chromatography was carried out after concentration (PE: EA = 20) to obtain 0.93g of a dark gray oily liquid with a yield of 71%.
[ step b]The oil obtained above (1g, 3.75X 10) was placed in a 100ml dry three-necked flask under nitrogen protection - 3 mol), dissolving in 30ml of anhydrous dichloromethane, cooling to-40 ℃ by a dry ice-ethyl acetate system, then adding 3ml of boron tribromide dichloromethane solution by using a glass syringe, slowly raising the temperature to 0 ℃, and continuing the reaction for 2 hours. After the reaction is finished, cooling to-40 ℃ again, and slowly dropwise adding water to quench the reaction. Subsequently, 20ml of water was further added, extraction was carried out three times with 20ml of dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and after concentration, column chromatography (PE: EA = 20).
And 3, step 3: preparation of N- (2-pentyl) aniline (intermediate 5 a)
Aniline (1ml, 1.09X 10) -2 mol), 2-pentanone (0.94g, 1.09X 10 -2 mol), acetic acid (25 ml) and water (2.5 ml) were addedA100 ml single-neck flask was charged with zinc powder activated with hydrochloric acid in portions with stirring, then transferred to 75 ℃ and refluxed at this temperature for 12 hours. After the reaction is completed, after the reaction solution is cooled to room temperature, ammonia water is used for adjusting to a weak base environment under an ice bath, the pH value is approximately equal to 10, 50ml dichloromethane is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is dried, column chromatography is carried out after concentration (PE: EA = 50.
And 4, step 4: preparation of N- (2-pentyl) -N-phenyl-3-chloropropylamide (intermediate 6 a)
In a single-neck flask, intermediate 5a (2.5g, 1.5X 10 -2 mol), triethylamine (2.54ml, 1.83X 10 -2 mol) is dissolved in 50ml of anhydrous dichloromethane, and 3-chloropropionyl chloride (1.79ml, 1.83X 10) is added dropwise under ice bath conditions -2 mol) of dichloromethane solution, gradually increasing to room temperature after the dropwise addition, stirring for 30 minutes, transferring to the condition of 75 ℃ and continuing the reaction for 8 hours. After the reaction was completed, dichloromethane 30ml was added and washed three times with 30ml of saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography (PE: EA = 30) to obtain 2.91g of a white solid with a yield of 76.4%.
And 5: preparation of N- (2-pentyl) -3- (4-Boc-1-piperazinyl) -N-phenylpropionamide (intermediate 7 a)
Intermediate 6a (5g, 1.97X 10) -2 mol), N-Boc-piperazine (3.67g, 1.97X 10 -2 mol) was dissolved in acetonitrile, and potassium carbonate (3.27g, 2.36X 10) was added -2 mol), heating to 85 ℃, and maintaining the reaction for 8h. After completion of the reaction, acetonitrile was removed under reduced pressure, 30ml of water was added, and the mixture was extracted three times with 30ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column chromatographed (DCM: meOH = 50).
Step 6: preparation of N- (2-pentyl) -3- (1-piperazinyl) -N-phenylpropionamide trifluoroacetate (intermediate 8 a)
Intermediate 7a (5g, 1.24X 10) was placed in a single-neck flask -2 mol) are dissolved in 50ml of dichloromethane, 30ml of trifluoroacetic acid are added dropwise with stirring, and after completion, the reaction is continued for 3h at room temperature. After the reaction is finished, removing excessive solvent under reduced pressure, washing with 30ml of petroleum ether and 30ml of diethyl ether respectively for three times, filtering and drying to obtain 4.12g of white solid with the yield of 91.3%.
And 7: preparation of N- (2-pentyl) -3- (4- (3- (5-hydroxy-1H-3-indole) propyl) -1-piperazinyl) -N-phenylpropanamide
Intermediate 8a (1g, 2.75X 10) was added to a single-neck flask containing 50ml of acetonitrile solution at room temperature -3 mol) and intermediate 3c (0.95g, 2.75X 10 -3 mol) and potassium carbonate (0.76g, 5.54X 10 -3 mol), heating the reaction to 75 ℃, and stirring and refluxing for 12h. After the reaction was finished, the excess acetonitrile was removed, 30ml of water was added, 30ml of dichloromethane was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column chromatographed (DCM: meOH = 10) to give 1.08g of white solid with 82.4% yield.
Examples 34 to 41: compound FW I-34-FW I-41
Example 33 was repeated, except that: different starting materials are used in step 3 and different starting materials are used in step 5 to produce compounds FW I-34-FW I-41. Compounds FW i-40 and FW i-41 are a pair of cis-trans isomers, and their corresponding intermediates were obtained in step 4 via column chromatography (PE: EA = 30.
The concrete is as follows:
and 3, step 3:
and 5:
example 42: preparation of N- (2-pentyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide (FW I-42)
Step 1: preparation of 3- (5-Cyanoindole) propanol (intermediate 2 e)
[ step a ]]4-bromophenylhydrazine hydrochloride (5g, 2.24X 10) was placed in a single-neck flask at room temperature -2 mol) was dissolved in a mixture of acetonitrile (50 ml) and 4% sulfuric acid (50 ml), and 3,4-dihydropyran (5.55ml, 2.86 × 10) was slowly added dropwise with stirring -2 mol), heating the reaction to 150 ℃ after the dropwise addition is finished, and maintaining the reaction for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, excess acetonitrile was distilled off under reduced pressure, and then 50ml of ethyl acetate was added to the remaining mixture and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column chromatographed (PE: EA = 20) to give 4.36g of oil in 77% yield.
[ step b]The oil obtained above (1g, 3.94X 10) was combined with a single-neck flask at room temperature -3 mol) was dissolved in N, N-dimethylformamide (50 ml), and cuprous cyanide (1.10 g, 1.18X 10) was added -2 mol) and the reaction is heated to 130 ℃ and kept for 6h. After the reaction was completed, the reaction mixture was poured into 100ml of water and extracted 5 times with 20ml of ethyl acetate. Combining the organic phases, anhydrousDried over sodium sulfate, concentrated and column chromatographed (PE: EA = 20).
Step 2: preparation of 3- (3-bromopropyl) -1-H-5-cyanoindole (intermediate 3 e)
Intermediate 2 (1g, 5.00X 10) was placed in a 100ml dry three-necked flask at 0 deg.C -3 mol), dissolved in 30ml of anhydrous dichloromethane, followed by the sequential addition of carbon tetrabromide (0.80ml, 1.50X 10 -2 mol), triphenylphosphine (2.15g, 1.50X 10 -2 mol). Subsequently, 20ml of water was further added, extraction was carried out three times with 20ml of dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and column chromatography was carried out after concentration (PE: EA = 20) to obtain 0.93g of a dark gray oily liquid with a yield of 71%.
And 3, step 3: preparation of N- (2-pentyl) aniline (intermediate 5 a)
Aniline (2.94g, 0.03mol), 2-pentanone (2.58g, 0.03mol), acetic acid (25 ml) and water (2.5 ml) were charged into a 100ml single-neck flask, and zinc powder activated with hydrochloric acid was added in portions with stirring, followed by transferring to 75 ℃ and refluxing at this temperature for 12 hours. After the reaction is completed, after the reaction solution is cooled to room temperature, the reaction solution is adjusted to a weak base environment with ammonia water under ice bath, the pH is approximately equal to 10, the reaction solution is extracted with 50ml of dichloromethane three times, organic phases are combined, dried by anhydrous sodium sulfate, and after concentration, column chromatography (PE: EA = 50) is carried out to obtain 3.06g of yellow oily matter, and the yield is 62.6%.
And 4, step 4: preparation of N- (2-pentyl) -N-phenyl-2-chloroacetamide (intermediate 6 a)
In a single-neck flask, intermediate 5a (5g, 3.07X 10) -2 mol), triethylamine (4.74ml, 3.42X 10 -2 mol) was dissolved in 50ml of anhydrous dichloromethane and the chloroacetyl chloride (2.72ml, 3.42X 10) was added dropwise under ice-bath conditions -2 mol) of dichloromethane solution, gradually increasing to room temperature after the dropwise addition, stirring for 30 minutes, transferring to the condition of 75 ℃ and continuing the reaction for 8 hours. After the reaction was completed, dichloromethane 30ml was added and washed three times with 30ml of saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography (PE: EA = 30) to obtain 6.6g of a white solid with a yield of 90.3%.
And 5: preparation of N- (2-pentyl) -2- (4-Boc-1-piperazinyl) -N-phenylacetamide (intermediate 7 a)
Intermediate 6a (6 g, 2.51X 10) -2 mol), N-Boc-piperazine (4.20g, 2.51X 10 -2 mol) was dissolved in acetonitrile, and potassium carbonate (4.68g, 3.76X 10 was added -2 mol), heating to 85 ℃, and maintaining the reaction for 8h. After completion of the reaction, acetonitrile was removed under reduced pressure, 30ml of water was added, and the mixture was extracted three times with 30ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column chromatographed (DCM: meOH = 50) to give 7.5g of a pale yellow solid in 77% yield.
Step 6: preparation of N- (2-pentyl) -2- (1-piperazinyl) -N-phenylacetamide trifluoroacetate (intermediate 8 a)
Intermediate 7a (6 g, 1.54X 10) was placed in a single-neck flask -2 mol) is dissolved in 50ml dichloromethane, 30ml trifluoroacetic acid is added dropwise with stirring, and after completion, the reaction is continued for 3h at room temperature. After the reaction is finished, the excess solvent is removed under reduced pressure, and the mixture is washed three times by 30ml of petroleum ether and 30ml of diethyl ether respectively, filtered and dried to obtain 6.08g of white solid with the yield of 98.0 percent.
And 7: preparation of N- (2-pentyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide
Intermediate 8a (1g, 2.48X 10) was added to a single-neck flask containing 50ml of acetonitrile solution at room temperature -3 mol) and intermediate 3e (0.75g, 2.85X 10 -3 mol) and potassium carbonate (0.85g, 4.96X 10 -3 mol), heating the reaction to 75 ℃, and stirring and refluxing for 12h. After the reaction was finished, the excess acetonitrile was removed, 30ml of water was added, 30ml of dichloromethane was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column-chromatographed (DCM: meOH = 10) to obtain 0.97g of a white solid with a yield of 82.7%.
Examples 43-55, 58, 60, 61: the compounds FW I-43-FWI-55, FW I-58, FW I-60, FW I-61
Example 42 was repeated, except that: the different starting materials are used in step 3 and the different starting materials are used in step 5 to produce compounds FW I-43-FW I-55, FW I-58, FW I-60 and FW I-61. Compounds FW I-50 and FW I-51, FW I-52 and FW I-53 are a pair of cis-trans isomers, which are purified by column chromatography (PE: EA = 30) in step 4 to give their corresponding intermediates.
The following table specifically shows:
and step 3:
and 5:
examples 56, 57, 59: compounds FW I-56, FW I-57, FW I-59
Example 42 was repeated, except that: in step 3, different starting materials are used to produce compounds FW I-56, FW I-57 and FW I-59. The following table specifically shows:
step 3
Example 62: preparation of N- (2-Ethanol) -2- (4- (3- (5-cyano-1H-3-indol) propyl) -1-piperazinyl) -N-phenylacetamide (FW I-62)
Step 1: preparation of 3- (5-Cyanoindole) propanol (intermediate 2 e)
[ step a ]]4-bromophenylhydrazine hydrochloride (5g, 2.24X 10) was reacted with a single-neck flask at room temperature -2 mol) was dissolved in a mixture of acetonitrile (50 ml) and 4% sulfuric acid (50 ml), and 3,4-dihydropyran (5.55ml, 2.86 × 10) was slowly added dropwise with stirring -2 mol), heating the reaction to 150 ℃ after the dropwise addition is finished, and maintaining the reaction for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, excess acetonitrile was distilled off under reduced pressure, and then 50ml of ethyl acetate was added to the remaining mixture and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column chromatographed (PE: EA = 20) to give 4.36g of oil in 77% yield.
[ step b]The oil obtained in the previous step (1g, 3.94X 10) was combined with a single-neck flask at room temperature -3 mol) was dissolved in N, N-dimethylformamide (50 ml), and cuprous cyanide (1.10 g, 1.18X 10) was added -2 mol) and the reaction is heated to 130 ℃ and kept for 6h. After the reaction was completed, the reaction mixture was poured into 100ml of water, and extracted 5 times with 20ml of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column chromatographed (PE: EA = 20) to give 0.71g of oil in 90% yield.
Step 2: preparation of 3- (3-bromopropyl) -1-H-5-cyanoindole (intermediate 3 e)
Intermediate 2e (1g, 5.00X 10) was placed in a 100ml dry three-necked flask at 0 deg.C -3 mol), dissolved in 30ml of anhydrous dichloromethane, followed by the sequential addition of carbon tetrabromide (0.80ml, 1.50X 10) -2 mol), triphenylphosphine (2.15g, 1.50X 10 -2 mol). Subsequently, 20ml of water was further added, extraction was carried out three times with 20ml of dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and column chromatography was carried out after concentration (PE: EA = 20) to obtain 0.93g of a dark gray oily liquid with a yield of 71%.
And 3, step 3: preparation of N- [2- (tert-butyldimethylsilyloxy) ethyl ] aniline (intermediate 5 b)
[ step a)]Iodobenzene (1.11ml, 0.01mol), aminoethanol (0.93ml, 0.012mol), potassium hydroxide (1.12g, 0.02mol), and methylidene iodide (0.19g, 1X 10 mol) were added to the sealed tube respectively -3 mol) and water, then the reaction solution is heated to 100 ℃. After the reaction was completed, 50ml of water was added, extraction was performed three times with ethyl acetate, the organic phases were combined, dried with anhydrous sulfuric acid, and after concentration, column chromatography was performed (PE: EA = 10).
[ step b ]]The colorless oily compound (1.5g, 1.09X 10) was placed in a single-neck flask at room temperature -2 mol) was dissolved in methylene chloride (20 ml), and imidazole (0.89g, 1.3X 10g, was slowly added with stirring -2 mol), stirring was continued for 10 minutes, and then tert-butyldimethylsilyl chloride (1.96g, 1.3X 10, g) was added to the reaction solution -2 mol) and reacting for 10h at room temperature. After completion of the reaction, 30ml of water was added, followed by extraction three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated followed by column chromatography (PE: EA = 20).
And 4, step 4: preparation of N- [2- (tert-butyldimethylsilyloxy) ethyl ] -N-phenyl-2-chloroacetamide (intermediate 6 b)
In a single-neck flask, intermediate 5b (5g, 1.99X 10) -2 mol), triethylamine (5.42ml, 2.99X 10 -2 mol) was dissolved in 50ml of anhydrous dichloromethane and chloroacetyl chloride (3.11ml, 2.99X 10) was added dropwise under ice-bath conditions -2 mol) of dichloromethane solution, gradually increasing to room temperature after the dropwise addition, stirring for 30 minutes, transferring to the condition of 75 ℃ and continuing the reaction for 8 hours. After the reaction was completed, dichloromethane 30ml was added and washed three times with 30ml of saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography (PE: EA = 30) to obtain 5.5g of a white solid with a yield of 85.3%.
And 5: preparation of N- (2-pentyl) -2- (4-Boc-1-piperazinyl) -N-phenylacetamide (intermediate 7 b)
Intermediate 6b (6 g, 1.83X 10) -2 mol), N-Boc-piperazine (5.74g, 1.83X 10 -2 mol) was dissolved in acetonitrile, and potassium carbonate (6.40g, 2.75X 10 was added -2 mol), heating to 85 ℃, and maintaining the reaction for 8h. After completion of the reaction, acetonitrile was removed under reduced pressure, 30ml of water was added, and the mixture was extracted three times with 30ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column chromatographed (DCM: meOH = 50) to give 6.1g of a pale yellow solid in 70% yield.
Step 6: preparation of N- (2-pentyl) -2- (1-piperazinyl) -N-phenylacetamide trifluoroacetate (intermediate 8 b)
Intermediate 7b (6 g, 1.26X 10) was placed in a single-neck flask -2 mol) is dissolved in 50ml dichloromethane, 30ml trifluoroacetic acid is added dropwise with stirring, and after completion, the reaction is continued for 3h at room temperature. Removing much by reducing pressure after the reaction is finishedThe remaining solvent was washed three times with 30ml of petroleum ether and 30ml of diethyl ether, respectively, and filtered and dried to obtain 3.13g of a white solid with a yield of 94.1%.
And 7: preparation of N- (2-ethanolyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide
Intermediate 8b (1g, 2.65X 10) was added to a single-neck flask containing 50ml of acetonitrile solution at room temperature -3 mol) and intermediate 3e (0.59g, 2.65X 10 -3 mol) and potassium carbonate (1.05g, 5.68X 10 -3 mol), heating the reaction to 75 ℃, and stirring and refluxing for 12h. After the reaction was finished, the excess acetonitrile was removed, 30ml of water was added, 30ml of dichloromethane was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and column-chromatographed (DCM: meOH = 10) to obtain 0.95g of a white solid with a yield of 80.8%.
Example 63: compound FW I-63
Example 62 was repeated, except that: in step 3, various starting materials are used to produce compound FW I-63. The concrete is as follows:
the chemical structure of the synthesized target product of the invention is shown in Table 3. The nuclear magnetic hydrogen spectrum and mass spectrum system characterize the chemical structure of the target product.
TABLE 3 chemical structure of target product, nuclear magnetic hydrogen spectrum, mass spectrum data
Example 64: example of pharmacological practice
Affinity experiments:
1. drug configuration
Test Compound, 5-HT 1A Receptor positive drug 5-hydroxyryptamine, 5-HT 2A The receptor positive drugs butalcol are dissolved to 0.01mol/L by DMSO and then diluted to 100 mu mol/L by deionized water.
2. Receptor binding assay materials
5-HT 1A Receptor isotopes ligand [2 ] 3 H]8-OH-DPAT，5-HT 2A Receptor isotopic ligand [3H]Ketanserin (from PE), (+) 5-hydroxyyttramine, (+) -Butalcalamol hydrochloride (from Sigma), GF/B glass fiber filter paper (from Whatman), liposoluble scintillant: PPO, POPOPOP (from Shanghai reagent Co., ltd.), toluene (from national drug group chemical Co., ltd.), and Tris were dispensed from Gittie technology Co., ltd. Cell: stable expression of 5-HT by genetic recombination 1A Receptor, 5-HT 2A Recipient HEK-293 cells were cultured in DMEM +10% serum cell culture medium for 3-5 hours, harvested with PBS, centrifuged at-4 ℃ for 10 minutes, discarded, harvested and stored in-80 ℃ freezer. For the experiments, the suspension was resuspended in Tris-Cl (pH 7.4).
3. Competitive receptor binding assay
Adding 10 mu L and 80 mu L of receptor protein of a compound to be tested and radioactive ligand into a reaction test tube respectively to ensure that the final concentrations of the compound to be tested and the positive drug are both 10 mu mol/L, and immediately moving the reaction tube to an ice bath to stop the reaction after incubating the mixture in a water bath at 37 ℃ for 15 min; on a Millipore cell sample collector, the mixture is rapidly filtered by GF/B glass fiber filter paper, and is washed 3 times by 3mL of eluent (50 mM Tris-HCl, pH 7.7), dried by a microwave oven for 8-9 min, the filter paper is moved into a 0.5mL centrifuge tube, and 500 mu L of fat-soluble scintillation fluid is added. Standing in dark for more than 30min, and counting to determine radioactivity. The percentage inhibition of the binding of the isotopic ligand by each compound was calculated and compounds with an inhibition of more than 80% were subjected to a series of receptor binding assays to determine the median inhibitory amount (IC 50, the concentration of compound required to inhibit the binding of 50% of the positive control drug to the receptor). Two secondary tubes were measured per concentration and two independent experiments were performed for each compound.
The inhibition rate calculation formula is as follows:
functional experiments are carried out:
1. experimental Material
[ 35 S]GTP gamma S; GF/C glass fiber filter paper; fat-soluble scintillation liquid; gpp (NH) p (10-2); GDP (4 x 10-3); RB buffer solution. Cell: 5-HT expressed by HEK293 cells 1A A recipient egg. Positive drugs: 5-HT
2. Experimental method
1) The cells were then centrifuged at 50mM Tris, pH 7.4, 1000 Xg, 4 ℃ for 10 minutes, the supernatant was centrifuged at 36000 Xg and 4 ℃ for 30 minutes, the pellet, i.e., the cell membrane, was retained, and the cell membrane was suspended in 50mM Tris, pH 7.4, and the protein concentration was measured by BCA.
2) GTP γ S binding experiments were performed in 200. Mu.l buffer system, 30. Mu.g protein per tube, reaction buffer 50mM Tris, ph 7.4,5mM MgCl2,1mM EDTA,100mM NaCl,1mM DTT, ph 7.5. The reaction system contains 40 mu M GDP, 100 mu M Gpp (NH) p is added into a non-specific tube, and test drugs with different concentrations are added into a test tube. Detecting the antagonistic function, adding different concentrations of the test drug and 5-HT (5-HT) into the test tube 1A ). 0.1nM [2 ] was added to each tube 35 S]GTP gamma S is put in a water bath at 30 ℃ for reaction for 20min. Taking out, placing on ice to stop reaction, filtering by a GF/C membrane, drying, placing in a 0.5ml EP tube, adding 500 μ l fat-soluble scintillation liquid, and measuring the radiation intensity by a Microbeta liquid scintillation instrument. Each concentration was triplicated and at least 2 independent experiments were performed.
The calculation formula is as follows: [ 35 S]GTP γ S Bound (% above basal) =100 × (sample dpm-basal dpm)/(basal dpm-nonspecific dpm)%
Software fitting of concentration-Effect curves and EC 50 Or IC 50 The value is obtained.
Claims (6)
1. Compounds of formula (I)
The compound is selected from:
n- (4-tetrahydro-2-H-pyranyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide
N- (1-methoxy-2-propyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide
N- (1,2-dimethoxy-ethyl) -2- (4- (3- (5-cyano-1H-3-indole) propyl) -1-piperazinyl) -N-phenylacetamide.
2. A pharmaceutically acceptable salt of the compound of claim 1.
3. The pharmaceutically acceptable salt according to claim 2, wherein the pharmaceutically acceptable salt is an inorganic salt, an organic salt or an amino acid salt;
wherein the inorganic salt is: sodium salts, hydrochlorides, trifluoroacetates, sulfates, phosphates, diphosphates, hydrobromides or nitrates;
wherein the organic salt is: maleate, acetate, fumarate, tartrate, succinate, lactate, p-toluenesulfonate, salicylate, or oxalate;
wherein the amino acid salt is: arginine salt, ornithine salt, lysine salt, leucine salt, isoleucine salt, glycine salt, cystine salt, cysteine salt, caseinate, alanine salt, phenylalanine salt, histidine salt, serine salt, threonine salt, methionine salt, tryptophan salt, glutamate, aspartate salt, valine salt, methionine salt, proline salt, or hydroxyproline salt.
4. A compound as claimed in claim 1 or a compound as claimed in claim 2Use of pharmaceutically acceptable salts for the manufacture of a medicament for the treatment of 5-HT 1A The use of a medicament for treating a receptor-related disease.
5. Use according to claim 4, characterized in that the diseases are neurological and psychiatric diseases associated with the brain.
6. Use according to claim 5, characterized in that the disorders are anxiety, depression, schizophrenia and Parkinson's disease.
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| US6486153B1 (en) * | 1997-09-04 | 2002-11-26 | Merck Sharp & Dohme Ltd. | Phenylindole derivatives as 5-HT2A receptor ligands |
| CN103977004A (en) * | 2013-02-08 | 2014-08-13 | 复旦大学 | Medicinal use of indole piperazine derivative |
| CN105367565A (en) * | 2014-08-20 | 2016-03-02 | 上海医药工业研究院 | Piperazine (piperidine) cyclohexyl derivative and applications of piperazine (piperidine) cyclohexyl derivative in treatment of neuropsychiatric diseases |
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| US6486153B1 (en) * | 1997-09-04 | 2002-11-26 | Merck Sharp & Dohme Ltd. | Phenylindole derivatives as 5-HT2A receptor ligands |
| CN103977004A (en) * | 2013-02-08 | 2014-08-13 | 复旦大学 | Medicinal use of indole piperazine derivative |
| CN105367565A (en) * | 2014-08-20 | 2016-03-02 | 上海医药工业研究院 | Piperazine (piperidine) cyclohexyl derivative and applications of piperazine (piperidine) cyclohexyl derivative in treatment of neuropsychiatric diseases |
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