CN114456150A - NR2B receptor antagonist or pharmaceutically acceptable salt thereof, preparation method and application - Google Patents
NR2B receptor antagonist or pharmaceutically acceptable salt thereof, preparation method and application Download PDFInfo
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- CN114456150A CN114456150A CN202210035794.XA CN202210035794A CN114456150A CN 114456150 A CN114456150 A CN 114456150A CN 202210035794 A CN202210035794 A CN 202210035794A CN 114456150 A CN114456150 A CN 114456150A
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- oxoacetamide
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
The invention discloses an NR2B receptor antagonist or a pharmaceutically acceptable salt thereof, a preparation method and an application thereof, and the structure is shown as the following (general formula I). The invention discloses a compound with NR2B receptor antagonistic activity and application thereof in treating central nervous system diseases for the first timeSuch compounds have positive potential use in the treatment of depression. The compound 57 of the embodiment of the invention has a high protective effect on nerve cells, and can improve the cell survival rate from 75% to 94% at a concentration of 0.01 mu M. The compound 28 of the embodiment of the invention shows the same antidepressant effect as the positive medicine Trxoprodil in the tail suspension experiment of mice. The invention has simple synthetic route and strong practicability.
Description
Technical Field
The invention relates to chemical medicine, a preparation method and application thereof, in particular to an NR2B receptor antagonist or pharmaceutically acceptable salt thereof, a preparation method and application thereof.
Background
N-methyl-D-aspartate (NMDA) receptors are a class of ionotropic glutamate receptors that have high permeability to calcium ions, which makes NMDA receptors important for Synaptic plasticity (synthetic plasticity) and excitotoxicity. In addition, because NMDA receptors are involved in a variety of important physiological functions of the nervous system, and the abnormality thereof may cause dysfunction of the central nervous system, NMDA receptors themselves have become targets for the treatment of certain neuropsychiatric diseases, including depression, neuropathic pain, Alzheimer's disease, Parkinson's disease, and the like.
Functional NMDA receptors are composed of different subunits, of which there are 3, namely NR1, NR2, NR 3. NR1 comprises 8 different subunits (NR1-1a/b-4a/b), NR2 comprises 4 different subunits (NR2A-2D), and NR3 comprises 2 subunits (NR3A, NR 3B). NR1 is a basic subunit constituting an ion channel; NR2 is a regulatory subunit. It is presently believed that NMDA receptors are predominantly heterotetramers consisting of two NR1 subunits and two NR2 subunits, where the two NR1 and NR2 subunits may be the same or different.
Numerous studies have shown that NMDA receptors, especially channel antagonists or allosteric modulators containing the NR2B subunit, have been used as therapeutic agents for the treatment of major depressive disorder. The NR2B receptor contains an additional ligand binding site in addition to the ligand binding site for glutamate. Common non-selective NMDA inhibitors, such as Ketamine (Ketamine), are channel blockers that interfere with calcium ion transport through the channel. Ketamine has shown rapid and long-lasting antidepressant properties in human clinical trials as an intravenously administered drug. However, such agents are of limited therapeutic value due to side effects (including dissociative effects) of the central nervous system.
An allosteric, noncompetitive binding site has also been identified in the N-terminal domain of the NR2B subunit of the NMDA receptor. Agents that selectively bind at this site, such as tasoprodil (Traxoprodil), exhibit sustained antidepressant efficacy and improved side effect profiles in human clinical trials as intravenously administered drugs. However, the development of such drugs has been hampered by low bioavailability, poor pharmacokinetics, and lack of selectivity for other pharmacological targets, including hERG ion channels. Blocking the hERG ion channel can lead to arrhythmias, and selectivity for this channel is therefore critical. At present, the development of potent, highly selective NR2B receptor antagonists or negative allosteric modulators is a major focus of research by researchers in the treatment of major depressive disorder.
Disclosure of Invention
The purpose of the invention is as follows: the object of the present invention is to provide NR2B receptor antagonists or pharmaceutically acceptable salts thereof.
Another object of the present invention is to provide a process for the preparation and use of the NR2B receptor antagonist or a pharmaceutically acceptable salt thereof.
The technical scheme is as follows: the NR2B receptor antagonist or the pharmaceutically acceptable salt thereof has the following structure:
wherein the content of the first and second substances,
x is
Z is
Y is CO or CH2；
W is CH or N;
m is NH and OH;
R1、R2are respectively selected from hydrogen atoms and C1-6Alkyl of (C)1-6Haloalkyl, C1-6Alkoxy, halogen, nitro, cyano or hydroxy;
R3is a hydrogen atom, C1-6Alkyl of (C)1-6Alkoxy, halogen, hydroxy, amino or methanesulfonamido;
m and n are each independently selected from 0, 1 or 2.
Further, the salt is selected from hydrochloride, sulfate, acetate, trifluoroacetate, methanesulfonate, maleate or tartrate. The halogen is fluorine, chlorine, bromine or iodine.
The NR2B receptor antagonist or the pharmaceutically acceptable salt thereof is any one of the following:
2- (1H-indol-3-yl) -N- (1- (4-methylbenzyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-bromo-1H-indol-3-yl) -N- (1- (4-methylbenzyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-methoxy-1H-indol-3-yl) -N- (1- (4-methylbenzyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-hydroxy-1H-indol-3-yl) -N- (1- (4-methylbenzyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-amino-1H-indol-3-yl) -N- (1- (4-methylbenzyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-amino-1H-indol-3-yl) -N- (1- (4-fluorobenzyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-bromo-1H-indol-3-yl) -N- (1- (4-fluorobenzyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
N- (1-benzyl-2-oxopyrrolidin-3-yl) -2- (1H-indol-3-yl) -2-oxoacetamide,
N- (1- (4-methylbenzyl) -2-oxopyrrolidin-3-yl) -2- (5- (methylsulfonylamino) -1H-indol-3-yl) -2-oxoacetamide,
N- (1- (4-fluorobenzyl) -2-oxopyrrolidin-3-yl) -2- (5- (methylsulfonylamino) -1H-indol-3-yl) -2-oxoacetamide,
N- (1- (4-fluorobenzyl) -2-oxopyrrolidin-3-yl) -2- (5-hydroxy-1H-indol-3-yl) -2-oxoacetamide,
N- (1- (4-fluorobenzyl) -2-oxopyrrolidin-3-yl) -2- (5-methoxy-1H-indol-3-yl) -2-oxoacetamide,
N- (1- (4-fluorobenzyl) -2-oxopyrrolidin-3-yl) -2- (1H-indol-3-yl) -2-oxoacetamide,
3- ((2- (1H-indol-3-yl) -2-oxyethyl) amino) -1-benzyl-2-oxopyrrolidine,
3- ((2- (1H-indol-3-yl) -2-oxyethyl) amino) -1- (4-methylbenzyl) -2-oxopyrrolidine,
3- ((2- (1H-indol-3-yl) -2-oxyethyl) amino) -1- (4-fluorobenzyl) -2-oxopyrrolidine,
3- ((2- (5-bromo-1H-indol-3-yl) -2-oxyethyl) amino) -1- (4-methylbenzyl) -2-oxopyrrolidine,
3- ((2- (5-bromo-1H-indol-3-yl) -2-oxyethyl) amino) -1- (4-fluorobenzyl) -2-oxopyrrolidine,
3- ((2- (5-methoxy-1H-indol-3-yl) -2-oxoethyl) amino) -1- (4-methylbenzyl) -2-oxopyrrolidine,
3- ((2- (5-hydroxy-1H-indol-3-yl) -2-oxoethyl) amino) -1- (4-methylbenzyl) -2-oxopyrrolidine,
3- ((2- (5-amino-1H-indol-3-yl) -2-oxoethyl) amino) -1- (4-methylbenzyl) -2-oxopyrrolidine,
3- ((2- (5-amino-1H-indol-3-yl) -2-oxoethyl) amino) -1- (4-fluorobenzyl) -2-oxopyrrolidine,
1- (4-fluorobenzyl) -3- ((2- (5-hydroxy-1H-indol-3-yl) -2-oxyethyl) amino) -2-oxopyrrolidine,
1- (4-fluorobenzyl) -3- ((2- (5-methoxy-1H-indol-3-yl) -2-oxyethyl) amino) -2-oxopyrrolidine,
N- (3- ((1- (4-fluorobenzyl) -2-oxopyrrolidin-3-yl) glycyl) -1H-indol-5-yl) methanesulfonamide,
N- (3- ((1- (4-methylbenzyl) -2-oxopyrrolidin-3-yl) glycyl) -1H-indol-5-yl) methanesulfonamide,
2- (1H-indol-3-yl) -2-oxo-N- (2-oxo-1-phenylpyrrolidin-3-yl) acetamide,
2- (1H-indol-3-yl) -2-oxo-N- (2-oxo-1- (4-methyl) phenylpyrrolidin-3-yl) acetamide,
2- (5-amino-1H-indol-3-yl) -2-oxo-N- (2-oxo-1-phenylpyrrolidin-3-yl) acetamide,
2- (5-bromo-1H-indol-3-yl) -2-oxo-N- (2-oxo-1-phenylpyrrolidin-3-yl) acetamide,
2- (5-hydroxy-1H-indol-3-yl) -2-oxo-N- (2-oxo-1-phenylpyrrolidin-3-yl) acetamide,
2- (5-methoxy-1H-indol-3-yl) -2-oxo-N- (2-oxo-1-phenylpyrrolidin-3-yl) acetamide,
2- (5-amino-1H-indol-3-yl) -2-oxo-N- (2-oxo-1- (4-methyl) phenylpyrrolidin-3-yl) acetamide,
2- (5-bromo-1H-indol-3-yl) -2-oxo-N- (2-oxo-1- (4-methyl) phenylpyrrolidin-3-yl) acetamide,
2- (5-methoxy-1H-indol-3-yl) -2-oxo-N- (2-oxo-1- (4-methyl) phenylpyrrolidin-3-yl) acetamide,
N- (1- (4-fluorophenyl) -2-oxopyrrolidin-3-yl) -2- (1H-indol-3-yl) -2-oxoacetamide,
N- (1- (4-fluorophenyl) -2-oxopyrrolidin-3-yl) -2- (5-methoxy-1H-indol-3-yl) -2-oxoacetamide,
N- (1- (4-fluorophenyl) -2-oxopyrrolidin-3-yl) -2- (5-hydroxy-1H-indol-3-yl) -2-oxoacetamide,
2- (5-amino-1H-indol-3-yl) -N- (1- (4-fluorophenyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-bromo-1H-indol-3-yl) -N- (1- (4-fluorophenyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (1H-indol-3-yl) -2-oxo-N- (2-oxo-1- (4- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) acetamide,
2- (5-amino-1H-indol-3-yl) -2-oxo-N- (2-oxo-1- (4- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) acetamide,
2- (5-bromo-1H-indol-3-yl) -2-oxo-N- (2-oxo-1- (4- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) acetamide,
2- (5-methoxy-1H-indol-3-yl) -2-oxo-N- (2-oxo-1- (4- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) acetamide,
2- (5-bromo-1H-indol-3-yl) -N- (1- (2-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-bromo-1H-indol-3-yl) -N- (1- (3-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-amino-1H-indol-3-yl) -N- (1- (2-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-amino-1H-indol-3-yl) -N- (1- (3-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
N- (1- (2-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2- (1H-indol-3-yl) -2-oxoacetamide,
N- (1- (3-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2- (1H-indol-3-yl) -2-oxoacetamide,
N- (1- (2-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2- (5-methoxy-1H-indol-3-yl) -2-oxoacetamide,
N- (1- (3-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2- (5-methoxy-1H-indol-3-yl) -2-oxoacetamide,
N- (1- (2-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2- (5-hydroxy-1H-indol-3-yl) -2-oxoacetamide,
N- (1- (3-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2- (5-hydroxy-1H-indol-3-yl) -2-oxoacetamide,
3- ((2- (5-methoxy-1H-indol-3-yl) -2-oxoethyl) amino) -1- (4-phenyl) -2-oxopyrrolidine,
1- (4-fluorophenyl) -3- ((2- (5-methoxy-1H-indol-3-yl) -2-oxoethyl) -2-oxopyrrolidine,
3- ((2- (5-methoxy-1H-indol-3-yl) -2-oxoethyl) amino) -1-phenyl-2-oxopyrrolidine,
3- ((2- (1H-indol-3-yl) -2-oxyethyl) amino) -1-phenyl-2-oxopyrrolidine.
A pharmaceutical composition comprising a therapeutically effective amount of one or more NR2B receptor antagonists according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant.
A process for the preparation of an NR2B receptor antagonist of claim 1 or a pharmaceutically acceptable salt thereof comprising the steps of:
or
Wherein the content of the first and second substances,
step 1: reacting lactone with phosphorus tribromide and liquid bromine to generate Int-1;
step 2: acylating Int-1 with thionyl chloride in N, N-dimethylformamide to obtain Int-2;
and step 3: int-2 and X-NH2Condensing under the conditions of triethylamine and anhydrous ether to obtain Int-3;
and 4, step 4: in anhydrous tetrahydrofuran, Int-3 is subjected to ring closing under the condition of sodium hydride to obtain Int-4;
and 5: reaction of Int-4 with ammonia water to produce Int-5;
step 6: nucleophilic substitution of Int-5 and Int-6 to obtain the compound;
and 7: and carrying out nucleophilic substitution on Int-4 and Int-9 to obtain the compound.
The NR2B receptor antagonist or the medicinal salt thereof is applied to the preparation of medicaments for treating central nervous system diseases. Further, the central nervous system disease is depression, major depression, alzheimer's disease, neuropathic pain or parkinson's disease.
Forms of the compounds of the present invention include salts, solvates and N-oxides of the compounds having the general formula I, including but not limited to acid addition salts and/or base addition salts.
The invention also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound having the general formula I or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms are within the scope of the present invention.
Has the advantages that: the invention discloses a compound with NR2B receptor antagonistic activity and application thereof in treating central nervous system diseases for the first time, and the compound has positive potential application in treating depression. The compound 57 of the embodiment of the present invention exhibits a high protective effect on nerve cells, and can increase the cell survival rate from 75% to 94% at a concentration of 0.01. mu.M. The compound 28 of the embodiment of the invention shows the same antidepressant effect as the positive medicine Traxoprodil in the tail suspension experiment of mice. The invention has simple synthetic route and strong practicability.
Drawings
FIG. 1 shows the results of the bioactivity test.
Detailed Description
In the examples below, "room temperature" generally means about 10 ℃ to about 35 ℃. The proportions indicated by the mixed solvents are volume mixing proportions unless otherwise specified.
Determination by Fourier transform type NMR1H-NMR (proton nuclear magnetic resonance spectrum). For the analysis, ACD/SpecMarager, etc. were used. Peaks of active hydrogen (e.g., hydroxyl, amino, etc.) are not described.
MS (Mass Spectrometry) was determined by LC/MS (liquid chromatography Mass Spectrometry). As the ionization method, an ESI (electrospray ionization) method or the like is used. The data represent those measured values. Typically, molecular ion peaks are observed. In the case of salts, a molecular ion peak or fragment ion peak is usually observed in free form.
In the following examples and experimental examples, the following abbreviations are used:
DMF: the concentration of N, N-dimethylformamide,
THF: the reaction mixture of tetrahydrofuran and water is taken as a reaction mixture,
DCM: the reaction mixture of methylene chloride and water is distilled,
r.t.: and (4) room temperature.
In part
The structural formula and the preparation method are as follows:
example 1
2- (1H-indol-3-yl) -2-oxoacetyl chloride
Indole (1.17g) and 40mL of dehydrated ether were added to a single 100mL port, oxalyl chloride (0.22mL) was slowly added dropwise at 0 ℃ and, after completion of the addition, the reaction was continued at 0 ℃ for about 1.5 hours. TLC monitored the progress of the reaction, after completion of the reaction, it was filtered with suction and washed with ice dry ether to give 1.82g of a yellow powder, the title compound. The product was used in the next reaction without further purification.
Example 2
2- (5-bromo-1H-indol-3-yl) -2-oxoacetyl chloride
The title compound was obtained from 5-bromo-1H-indole by reaction with oxalyl chloride using the same method as in example 1.
Example 3
2- (5-methoxy-1H-indol-3-yl) -2-oxoacetyl chloride
The title compound was obtained by reacting 5-methoxy-1H-indole with oxalyl chloride using the same method as in example 1.
Example 4
2-amino-1- (1H-indol-3-yl) ethan-1-one acetate
(A)2- (1H-indol-3-yl) -2-oxyacetamides
In a 100mL single-necked flask, 2- (1H-indol-3-yl) -2-oxoacetyl chloride (1.04g) and 30mL of anhydrous diethyl ether were added, followed by dropwise addition of a concentrated aqueous ammonia solution (10mL) and stirring at room temperature for 5 minutes. TLC monitored the progress of the reaction, after completion of the reaction, suction filtered, washed with water, and washed with cold anhydrous ether to give 0.80g of a pale yellow solid, i.e., the title compound.1H NMR(300MHz， DMSO)δppm 12.18(s，1H)，8.73(s，1H)，8.26(dd，J＝6.2，2.8Hz，1H)，8.08(s，1H)，7.72(s， 1H)，7.61-7.48(m，1H)，7.33-7.15(m，2H).MS(ESI)：[M-H]-187.1 m/z。
(B) 1H-indole-3-carbonyl cyanide
Adding 2- (1H-indol-3-yl) -2-oxyacetamide (0.75g) and 15mL of DMF into a 50mL gem-bikou bottle, vacuumizing for 3 times, argon protection and dropwise adding SOCl under the ice bath condition2(0.71 mL). TLC monitors the reaction progress, the reaction is carried out for about 30 minutes, ice water is dripped to quench under the ice bath condition after the reaction is completed, ethyl acetate is used for extraction, and anhydrous Na2SO4Drying, filtering and concentrating to obtain light yellow solid 0.56g, namely the title compound.1H NMR(300 MHz，DMSO)δ ppm 12.90(s，1H)，8.63(s，1H)，8.05(d，J＝7.6Hz，1H)，7.60(d，J＝7.6Hz，1H)，7.36(m， 2H).MS(ESI)：[M-H]-169.1 m/z。
(C) 2-amino-1- (1H-indol-3-yl) ethan-1-one acetate
1H-indole-3-carbonyl cyanide (0.34g) and 30mL of acetic acid were added to a 100mL single-neck flask, followed by Pd/C (0.05g, 10%), followed by purging with hydrogen balloon at room temperature. TLC monitored the progress of the reaction, after completion of the reaction, the reaction mixture was filtered through celite, desolventized, recrystallized from ether and filtered with suction to give 0.27g of a brown powder as the title compound.1H NMR(300MHz，DMSO)δppm 8.33(s，1H)，8.21-8.12(m，1H)，7.56- 7.42(m，1H)，7.24-7.16(m，1H)，4.05(s，2H)，1.84(s，3H).MS(ESI)：[M+H]+175.1 m/z。
Example 5
2-amino-1- (5-methoxy-1H-indol-3-yl) ethan-1-one acetate
In the same manner as in example 4, 5-methoxy-1H-indole was substituted for the indole in (4) and the reaction equivalent was not changed to obtain the title compound.
The following are some of the methods for preparing the compounds of the present invention:
example 6
Preparation of N- (1-benzyl-2-oxopyrrolidin-3-yl) -2- (1H-indol-3-yl) -2-oxoacetamide
(A)2, 4-dibromobutyric acid
Butyrolactone (20.00g) and PBr were added to a 100mL three-necked flask under argon3(0.40mL), the mixture was warmed to 110 ℃ and Br was added slowly below the surface of the reaction mixture2(11.00mL), after the completion of the dropwise addition, the reaction temperature was maintained at 100 ℃ and 110 ℃ for further 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, and excess bromine was removed by introducing air to obtain 53.33g of a pale yellow oily liquid, which was the title compound.1H NMR(300MHz， CDCl3)δppm 10.27(s，1H)，4.57(dd，J＝8.5，5.7Hz，1H)，3.69-3.47(m，2H)，2.63-2.48 (m，2H).MS(ESI)：[M+Na]+265.9 m/z。
(B)2, 4-dibromobutyryl chloride
2, 4-dibromobutyric acid (2.40g), 15mL thionyl chloride and 1 drop of DMF were added to a 50mL one-necked flask, and the reaction was heated to reflux and stirred for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and excess thionyl chloride, i.e., the title compound, was removed under reduced pressure as a colorless oily liquid and used in the next reaction without further purification.
(C) N-benzyl-2, 4-dibromobutanamide
In a 100mL one-neck flask were added benzylamine (0.96g), triethylamine (1.11g) and 30mL anhydrous diethyl ether, followed by dropwise addition of 10mL of the above anhydrous diethyl ether solution of 2, 4-dibromobutyryl chloride. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. TLC monitored the progress of the reaction, and after completion of the reaction, concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2.42g of a white solid, which was the title compound.1H NMR(300MHz，CDCl3)δppm 9.13(s，1H)，7.20-6.91(m， 5H)，4.54(dd，J＝8.9，4.8Hz，1H)，4.42(d，J＝5.5Hz，2H)，3.63-3.46(m，2H)，2.61-2.46 (m，2H).MS(ESI)：[M+Na]+355.9 m/z。
(D) N-benzyl-3-bromopyrrolidin-butan-2-one
In a 100mL single-necked flask were added N-benzyl-2, 4-dibromobutyramide (1.66g) and 30mL of anhydrous THF, followed by addition of NaH (0.24g) in portions, and stirring was carried out at room temperature for 12 hours. TLC monitors the reaction progress, and after the reaction is complete, water is added for quenching. Separating the organic layer, and subjecting the obtained organic layer to anhydrous Na2SO4Drying, filtering and concentrating. The residue was purified by column chromatography on silica gel to give 1.12g of a pale yellow oily liquid as the title compound.1H NMR(300MHz， CDCl3)δppm 7.35-7.25(m，5H)，4.58-4.41(m，3H)，3.42(dt，J＝10.0，7.2Hz，1H)，3.20 (ddd，J＝10.1，8.0，2.4Hz，1H)，2.56(dq，J＝15.0，7.6Hz，1H)，2.38-2.26(m，1H).MS(ESI)： [M+H]+254.0 m/z。
(E) 3-amino-1-benzylpyrrolidin-butan-2-one
In a 100mL single-necked flask were added N-benzyl-3-bromopyrrolidin-butan-2-one (0.76g) and 20mL CH3CN, then aqueous ammonia (10mL) was added and the reaction was stirred at 40 ℃ overnight. TLC monitors the reaction progress, and after the reaction is completed, CH is removed under reduced pressure3CN, the remaining aqueous solution was extracted with dichloromethane (20mL twice). Separating the organic layer, and subjecting the obtained organic layer to anhydrous Na2SO4Drying, filtration and concentration gave 0.56g of a colorless oily liquid, i.e. the title compound.1H NMR(300MHz，CDCl3)δppm 7.38-7.15(m，5H)，4.45(s，2H)，3.57(t，J＝9.0Hz，1H)， 3.22-3.13(m，2H)，2.46-2.31(m，1H)，2.09(s，2H)，1.70(dq，J＝12.5，9.3Hz， 1H).MS(ESI)：[M+H]+205.0 m/z。
(F) N- (1-benzyl-2-oxopyrrolidin-3-yl) -2- (1H-indol-3-yl) -2-oxoacetamide
Compound 9(0.21g) and 10mL of anhydrous DCM were added dropwise to a 50mL single-neck flask under nitrogen, followed by 5mL of compound 7(0.19g) in anhydrous DCM. After the addition, the mixture was stirred at room temperature. TLC monitors the reaction progress, after the reaction is completed, the mixture is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography to obtain0.27g of white solid, the title compound.1H NMR(300MHz，DMSO)δppm 12.26(s，1H)，9.08(d，J＝8.6Hz，1H)， 8.78(d，J＝2.2Hz，1H)，8.31-8.20(m，1H)，7.59-7.49(m，1H)，7.41-7.20(m，7H)，4.64 (q，J＝9.2Hz，1H)，4.43(dd，J＝37.5，15.1Hz，2H)，3.25(dd，J＝9.1，3.7Hz，2H)，2.31(dd，J ＝8.9，3.4Hz，1H)，2.17-1.96(m，1H).MS(ESI)：[M+H]+362.2 m/z。
Example 7
3- ((1H-indol-3-yl) -2-oxyethyl) amino) -1-benzyl-2-oxopyrrolidine
In a 50mL single neck flask were added N-benzyl-3-bromopyrrolidin-butan-2-one (Int-4, 0.25g), 2-amino-1- (5-methoxy-1H-indol-3-yl) ethan-1-one acetate (Int-9, 0.22g), potassium carbonate and 20mL CH3And CN, heating to reflux reaction. TLC monitored progress of the reaction, after completion of the reaction, concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 0.16g of a white solid, i.e. the title compound.1H NMR(300MHz，DMSO)δppm 12.03(s，1H)， 8.40(s，1H)，8.21(d，J＝5.6Hz，1H)，7.49(d，J＝6.0Hz，1H)，7.28-7.18(m，3H)，7.13(d，J ＝3.8Hz，4H)，4.35(s，2H)，4.17-3.93(m，2H)，3.44(s，1H)，3.14(dd，J＝15.7，8.1Hz，2H)， 2.77(s，1H)，2.28(s，4H)，1.86-1.67(m，1H).MS(ESI)：[M+H]+348.2 m/z。
The present invention can be illustrated by the compounds shown in Table 1, but is not limited to Table 1.
Table 1: compounds of the invention partially represented by formula I
Example 62: examples of biological Activity test (cell protection Activity test)
Purpose of the experiment: evaluation of Compounds for neuronal protection Activity
The experimental principle is as follows:
the glutamate induced cytotoxicity assay can measure the cytoprotective activity of selective NR2B antagonists. In a glutamate-induced cytotoxicity model, selective NR2B antagonists can protect cells and increase cell survival.
The CCK-8 reagent (Cell Counting Kit-8 Cell Counting reagent) contains WST-8, the chemical name of which is 2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfonic acid benzene) -2H-tetrazole monosodium salt, which is reduced into a yellow Formazan product (Formazan) with high water solubility by dehydrogenase in Cell mitochondria under the action of an electron carrier 1-methoxy-5-methylphenazinium dimethyl sulfate (1-MethoxPMS), and the amount of generated Formazan is in direct proportion to the amount of living cells. The light absorption value of the compound is measured at the wavelength of 450nm by an enzyme-linked immunosorbent assay detector, so that the number of living cells can be indirectly reflected, and the affinity of the compound to a receptor can be reflected.
The experimental method comprises the following steps:
1. HT-22 cells in logarithmic growth phase are taken, the culture solution is discarded, and the cells are digested by 0.25% Trypsin containing EDTA to prepare cell suspension.
2. DMEM/F12 medium (containing 10% FBS, 1% double antibody) was used to adjust the cell density to 50000/mL, and the cells were inoculated into a 96-well plate at 100. mu.L/well, the number of cells per well was about 50000, and the plate was incubated at 37 ℃ in a 5% CO2 cell incubator for 24 hours.
NMDA solution (100mM), DMEM/F12 medium (10% FBS, 1% double antibody) was diluted with NMDA solution (1: 16.6) to prepare a cell culture medium containing 10. mu.M NMDA.
4. Preparing a drug-containing culture medium: the test compound and the positive drug were diluted to final concentrations of 10. mu.M, 1. mu.M, 0.1. mu.M, and 0.01. mu.M, respectively, using a cell culture medium containing 10. mu.M NMDA as a diluent.
5. The cell culture medium in the cell culture plate was changed to 90. mu.L of cell culture medium containing 10. mu.M NMDA, and the blank was changed to 90. mu.L of cell culture medium containing no NMDA.
The Control group was added with 10. mu.L of normal DMEM/F12 medium, the model group was added with 10. mu.L of cell culture medium containing 10. mu.M NMDA, and the other wells were added with test compound and positive drug at different concentrations, respectively, to give concentrations of 10. mu.M, 1. mu.M, 0.1. mu.M, and 0.01. mu.M.
After 7.24 hours, 20. mu.L of CCK-8 solution was added to each well and incubation continued in the incubator for 4 hours. After the incubation, the supernatant was discarded, 150. mu.L of DMSO was added to each well, and the wells were incubated in an oven at 37 ℃ for 10 minutes, and then the absorbance (OD) was measured at a wavelength of 450nm using a microplate reader. Meanwhile, the cell survival rate was calculated using SPSS statistical software.
The cell survival rate is [ (As-Ab)/(Ac-Ab) ]. times.100%
As: absorbance of the assay well (containing cells, medium, CCK-8 solution and drug solution);
ac: control wells absorbance (cells, medium, CCK-8 solution, no drug);
ab: blank wells absorbance (medium, CCK-8 solution, no cells, drug).
The experimental results are as follows:
table 2 results of experiments at 1. mu.M dose concentration for examples 15, 30-39, 41-47, 49-56, 58-60:
table 3 experimental results for examples 28, 40, 48, 52, 54, 57 at dose concentrations of 10 μ M, 1 μ M, 0.1 μ M, 0.01 μ M:
the results show that: several compounds exhibit protective effects on NMDA-damaged HT-22 cells; example 57 was able to increase cell viability from 75% to 94% at 0.01 μ M; example 28 cell viability was increased from 75% to 88% at 10 μ M; this indicates that examples 57, 28 show significant protective activity against NMDA-damaged HT-22 cells.
Example 63: biological Activity test example (mouse tail suspension experiment)
Purpose of the experiment: evaluation of the antidepressant Activity of Compounds
The experimental principle is as follows: in the experiment, the tail-suspended mouse struggles to overcome abnormal postures, but keeps a static state after struggling for a certain time, and shows a 'despair' state, the static time of the mouse reflects the depression degree of the mouse, and the longer the static time is, the more serious the depression degree is; after the antidepressant is given, the immobility time of the antidepressant is effectively reduced.
The experimental method comprises the following steps:
compounds example 28 solution was prepared in DMSO at a concentration of 10mg/kg and administered by gavage 2 hours prior to the behavioral test. All solutions were prepared immediately before the experiment and given in a constant volume of 20ml/kg, and the positive controls were Traxoprodil and Duloxetine (Duloxetine) at a dose of 10 mg/kg.
40 mice were divided into 4 groups (blank control group, Traxoprodil positive drug group, Duloxetine positive drug group, test drug group) at random according to body mass, and each group had 10 mice. The test animals were gavaged 2 hours before the start of the experiment with placebo, test and positive control drugs, respectively. The animal tail is connected with the fixed rod when the experiment begins, so that the mouse is kept in an inverted suspension state, and the motion condition of the mouse in the tail suspension state in the next 6 minutes is recorded by the camera. After the experiment is finished, the video of the mouse in the tail suspension state is analyzed by using computer software, the standing time of the mouse in the tail suspension state is recorded, and the experimental result is shown in figure 1.
The results show that: by carrying out the tail suspension experiment after a single gavage administration of 10mg/kg of example 28, test compound 28 showed the same antidepressant effect as that of the positive drug Traxoprodil, compared to the control group.
Claims (8)
1. An NR2B receptor antagonist having the structure:
wherein the content of the first and second substances,
x is
Z is
Y is CO or CH2；
W is CH or N;
m is NH and OH;
R1、R2are respectively selected from hydrogen atoms and C1-6Alkyl of (C)1-6Haloalkyl, C1-6Alkoxy, halogen, nitro, cyano or hydroxy;
R3is a hydrogen atom, C1-6Alkyl of (C)1-6Alkoxy, halogen, hydroxy, amino or methanesulfonamido;
m and n are each independently selected from 0, 1 or 2.
2. The NR2B receptor antagonist according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: the salt is selected from hydrochloride, sulfate, acetate, trifluoroacetate, methanesulfonate, maleate, citrate or tartrate, etc.
3. The NR2B receptor antagonist according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: the halogen is fluorine, chlorine, bromine or iodine.
4. The NR2B receptor antagonist according to claim 1, or a pharmaceutically acceptable salt thereof, being any one of:
2- (1H-indol-3-yl) -N- (1- (4-methylbenzyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-bromo-1H-indol-3-yl) -N- (1- (4-methylbenzyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-methoxy-1H-indol-3-yl) -N- (1- (4-methylbenzyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-hydroxy-1H-indol-3-yl) -N- (1- (4-methylbenzyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-amino-1H-indol-3-yl) -N- (1- (4-methylbenzyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-amino-1H-indol-3-yl) -N- (1- (4-fluorobenzyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-bromo-1H-indol-3-yl) -N- (1- (4-fluorobenzyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
N- (1-benzyl-2-oxopyrrolidin-3-yl) -2- (1H-indol-3-yl) -2-oxoacetamide,
N- (1- (4-methylbenzyl) -2-oxopyrrolidin-3-yl) -2- (5- (methylsulfonylamino) -1H-indol-3-yl) -2-oxoacetamide,
N- (1- (4-fluorobenzyl) -2-oxopyrrolidin-3-yl) -2- (5- (methylsulfonylamino) -1H-indol-3-yl) -2-oxoacetamide,
N- (1- (4-fluorobenzyl) -2-oxopyrrolidin-3-yl) -2- (5-hydroxy-1H-indol-3-yl) -2-oxoacetamide,
N- (1- (4-fluorobenzyl) -2-oxopyrrolidin-3-yl) -2- (5-methoxy-1H-indol-3-yl) -2-oxoacetamide,
N- (1- (4-fluorobenzyl) -2-oxopyrrolidin-3-yl) -2- (1H-indol-3-yl) -2-oxoacetamide,
3- ((2- (1H-indol-3-yl) -2-oxyethyl) amino) -1-benzyl-2-oxopyrrolidine,
3- ((2- (1H-indol-3-yl) -2-oxyethyl) amino) -1- (4-methylbenzyl) -2-oxopyrrolidine,
3- ((2- (1H-indol-3-yl) -2-oxyethyl) amino) -1- (4-fluorobenzyl) -2-oxopyrrolidine,
3- ((2- (5-bromo-1H-indol-3-yl) -2-oxyethyl) amino) -1- (4-methylbenzyl) -2-oxopyrrolidine,
3- ((2- (5-bromo-1H-indol-3-yl) -2-oxoethyl) amino) -1- (4-fluorobenzyl) -2-oxopyrrolidine,
3- ((2- (5-methoxy-1H-indol-3-yl) -2-oxoethyl) amino) -1- (4-methylbenzyl) -2-oxopyrrolidine,
3- ((2- (5-hydroxy-1H-indol-3-yl) -2-oxoethyl) amino) -1- (4-methylbenzyl) -2-oxopyrrolidine,
3- ((2- (5-amino-1H-indol-3-yl) -2-oxoethyl) amino) -1- (4-methylbenzyl) -2-oxopyrrolidine,
3- ((2- (5-amino-1H-indol-3-yl) -2-oxoethyl) amino) -1- (4-fluorobenzyl) 2-oxopyrrolidine,
1- (4-fluorobenzyl) -3- ((2- (5-hydroxy-1H-indol-3-yl) -2-oxyethyl) amino) -2-oxopyrrolidine,
1- (4-fluorobenzyl) -3- ((2- (5-methoxy-1H-indol-3-yl) -2-oxyethyl) amino) -2-oxopyrrolidine,
N- (3- ((1- (4-fluorobenzyl) -2-oxopyrrolidin-3-yl) glycyl) -1H-indol-5-yl) methanesulfonamide,
N- (3- ((1- (4-methylbenzyl) -2-oxopyrrolidin-3-yl) glycyl) -1H-indol-5-yl) methanesulfonamide,
2- (1H-indol-3-yl) -2-oxo-N- (2-oxo-1-phenylpyrrolidin-3-yl) acetamide,
2- (1H-indol-3-yl) -2-oxo-N- (2-oxo-1- (4-methyl) phenylpyrrolidin-3-yl) acetamide,
2- (5-amino-1H-indol-3-yl) -2-oxo-N- (2-oxo-1-phenylpyrrolidin-3-yl) acetamide,
2- (5-bromo-1H-indol-3-yl) -2-oxo-N- (2-oxo-1-phenylpyrrolidin-3-yl) acetamide,
2- (5-hydroxy-1H-indol-3-yl) -2-oxo-N- (2-oxo-1-phenylpyrrolidin-3-yl) acetamide,
2- (5-methoxy-1H-indol-3-yl) -2-oxo-N- (2-oxo-1-phenylpyrrolidin-3-yl) acetamide,
2- (5-amino-1H-indol-3-yl) -2-oxo-N- (2-oxo-1- (4-methyl) phenylpyrrolidin-3-yl) acetamide,
2- (5-bromo-1H-indol-3-yl) -2-oxo-N- (2-oxo-1- (4-methyl) phenylpyrrolidin-3-yl) acetamide,
2- (5-methoxy-1H-indol-3-yl) -2-oxo-N- (2-oxo-1- (4-methyl) phenylpyrrolidin-3-yl) acetamide,
N- (1- (4-fluorophenyl) -2-oxopyrrolidin-3-yl) -2- (1H-indol-3-yl) -2-oxoacetamide,
N- (1- (4-fluorophenyl) -2-oxopyrrolidin-3-yl) -2- (5-methoxy-1H-indol-3-yl) -2-oxoacetamide,
N- (1- (4-fluorophenyl) -2-oxopyrrolidin-3-yl) -2- (5-hydroxy-1H-indol-3-yl) -2-oxoacetamide,
2- (5-amino-1H-indol-3-yl) -N- (1- (4-fluorophenyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-bromo-1H-indol-3-yl) -N- (1- (4-fluorophenyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (1H-indol-3-yl) -2-oxo-N- (2-oxo-1- (4- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) acetamide,
2- (5-amino-1H-indol-3-yl) -2-oxo-N- (2-oxo-1- (4- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) acetamide,
2- (5-bromo-1H-indol-3-yl) -2-oxo-N- (2-oxo-1- (4- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) acetamide,
2- (5-methoxy-1H-indol-3-yl) -2-oxo-N- (2-oxo-1- (4- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) acetamide,
2- (5-bromo-1H-indol-3-yl) -N- (1- (2-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-bromo-1H-indol-3-yl) -N- (1- (3-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-amino-1H-indol-3-yl) -N- (1- (2-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
2- (5-amino-1H-indol-3-yl) -N- (1- (3-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2-oxoacetamide,
N- (1- (2-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2- (iH-indol-3-yl) -2-oxoacetamide,
N- (1- (3-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2- (1H-indol-3-yl) -2-oxoacetamide,
N- (1- (2-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2- (5-methoxy-1H-indol-3-yl) -2-oxoacetamide,
N- (1- (3-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2- (5-methoxy-1H-indol-3-yl) -2-oxoacetamide,
N- (1- (2-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2- (5-hydroxy-1H-indol-3-yl) -2-oxoacetamide,
N- (1- (3-chloro-4-methylphenyl) -2-oxopyrrolidin-3-yl) -2- (5-hydroxy-1H-indol-3-yl) -2-oxoacetamide,
3- ((2- (5-methoxy-1H-indol-3-yl) -2-oxoethyl) amino) -1- (4-phenyl) -2-oxopyrrolidine,
1- (4-fluorophenyl) -3- ((2- (5-methoxy-1H-indol-3-yl) -2-oxoethyl) -2-oxopyrrolidine,
3- ((2- (5-methoxy-1H-indol-3-yl) -2-oxoethyl) amino) -1-phenyl-2-oxopyrrolidine,
3- ((2- (1H-indol-3-yl) -2-oxoethyl) amino) -1-phenyl-2-oxopyrrolidine.
5. A pharmaceutical composition comprising a therapeutically effective amount of one or more NR2B receptor antagonists according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant.
6. A process for the preparation of an NR2B receptor antagonist according to claim 1, wherein: the method comprises the following steps:
wherein the content of the first and second substances,
step 1: reacting lactone with phosphorus tribromide and liquid bromine to generate Int-1;
step 2: acylating Int-1 with thionyl chloride in N, N-dimethylformamide to obtain Int-2;
and step 3: int-2 and X-NH2Condensing under the conditions of triethylamine and anhydrous ether to obtain Int-3;
and 4, step 4: in anhydrous tetrahydrofuran, Int-3 is subjected to ring closing under the condition of sodium hydride to obtain Int-4;
and 5: reaction of Int-4 with ammonia water to produce Int-5;
step 6: nucleophilic substitution of Int-5 and Int-6 to obtain the compound;
and 7: and carrying out nucleophilic substitution on Int-4 and Int-9 to obtain the compound.
7. Use of an NR2B receptor antagonist according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a central nervous system disorder.
8. The use according to claim 7, wherein the central nervous system disorder is depression, major depression, Alzheimer's disease, neuropathic pain or Parkinson's disease.
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