阅读说明：本技术 芳基肟类化合物及其制备和应用 (Aryl oxime compound and preparation and application thereof ) 是由 叶娜 镇学初 李棒 杨慧翠 于 2019-04-29 设计创作，主要内容包括：本发明涉及一种通式I所示的芳基肟类化合物、其药剂学上可接受的盐、酯或水合物,及其制备和应用：<Image he="290" wi="494" file="DDA0002045194100000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,R<Sub>1</Sub>和R<Sub>2</Sub>独立地选自氢、C1-C8烷基、C1-C8氧烷基、芳基、取代芳基或芳烷基；或者R<Sub>1</Sub>和R<Sub>2</Sub>与它们连接的N原子形成3-8元环；或者R<Sub>1</Sub>和R<Sub>2</Sub>的其中之一、与它们连接的N原子以及与N原子连接的C原子形成3-8元环；R<Sub>3</Sub>和R<Sub>4</Sub>独立地选自氢、C1-C6烷基、芳基或取代芳基；n＝1-4中的任一整数。本发明的芳基肟类化合物可应用于制备多种治疗中枢神经系统的疾病的药物。(The invention relates to an aryl oxime compound shown as a general formula I, pharmaceutically acceptable salt, ester or hydrate thereof, and preparation and application thereof: wherein R is 1 And R 2 Independently selected from hydrogen, C1-C8 alkyl, C1-C8 oxyalkyl, aryl, substituted aryl or aralkyl; or R 1 And R 2 Form a 3-8 membered ring with the N atom to which they are attached; or R 1 And R 2 The N atom to which they are attached and the C atom to which the N atom is attached form a 3-8 membered ring; r 3 And R 4 Independently selected from hydrogen, C1-C6 alkyl, aryl or substituted aryl; n is an integer of 1 to 4. The aryl oxime compound can be applied to the preparation of various medicines for treating central nervous system diseases.)

1. An aryl oxime compound shown as a general formula I, and a pharmaceutically acceptable salt, ester or hydrate thereof:

R₁and R₂Independently selected from hydrogen, C1-C8 alkyl, cycloalkyl, C1-C8 oxyalkyl, C1-C6 aminoalkyl, aryl, substituted aryl or aralkyl; or

R₁And R₂Form a 3-8 membered ring with the N atom to which they are attached; or

R₁And R₂One of them andthe N atom to which they are attached and the C atom attached to the other side of the N atom form a 3-8 membered ring;

R₃and R₄Independently selected from hydrogen, C1-C6 alkyl, aryl, substituted aryl, heteroaromatic ring or substituted heteroaromatic ring;

n is an integer of 0 to 4.

2. The aryl oximes, pharmaceutically acceptable salts, esters, or hydrates thereof according to claim 1, wherein: the pharmaceutically acceptable salt is a salt formed by a compound shown in a formula (1) and an inorganic acid or an organic acid, the pharmaceutically acceptable ester is an ester formed by the compound shown in the formula (1) and an acid or an alcohol, and the pharmaceutically acceptable hydrate is an aqueous compound formed by the compound shown in the formula (1) and water through a coordination bond or a covalent bond.

3. The aryl oximes, pharmaceutically acceptable salts, esters, or hydrates thereof according to claim 1, wherein: r₁And R₂The N atom to which they are attached; or R₁And R₂With the N atom to which they are attached and the C atom to which the N atom is attached on the other side

A pyrrole ring, a substituted pyrrole ring, a piperidine ring, a substituted piperidine ring, a piperazine ring, an alkyl-substituted piperazine ring, a heteroazacyclobutane ring, an aziridine ring, a homopiperazine ring, an alkyl-or aryl-substituted homopiperazine ring, a morpholine ring, a substituted morpholine ring, an aryl piperazine ring, a tetrahydroisoquinoline ring, a substituted tetrahydroisoquinoline ring, a tetrahydroquinoline ring, a substituted tetrahydroquinoline ring, an indoline ring or a substituted indoline ring.

4. The aryl oximes, pharmaceutically acceptable salts, esters, or hydrates thereof according to claim 1, wherein: r₄Is aryl, substituted aryl, aromatic heterocycle or substituted aromatic heterocycle.

5. The aryl oximes, pharmaceutically acceptable salts, esters, or hydrates thereof according to claim 1, wherein: the aryl group is selected from C6-C10 aromatic rings; the aralkyl group includes a substituted or unsubstituted benzyl group, a substituted or unsubstituted phenethyl group, or a substituted or unsubstituted phenylpropyl group; the aromatic heterocyclic ring is a 5-8-membered aromatic heterocyclic ring containing 1-3 atoms selected from N, O and S.

6. The aryl oximes, pharmaceutically acceptable salts, esters, or hydrates thereof according to claim 1, wherein: the substituent on the substituted aryl or substituted aromatic heterocycle is one or more of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, cyano, nitro, hydroxyl, carboxyl, alkoxy acyl, amino, amido, acyloxy, acyl, sulfonyl, sulfonamido, urea, thiourea or carbamoyl, halogen and C1-C6 haloalkyl.

7. A process for the preparation of aryl oximes of general formula I according to any one of claims 1 to 6, comprising the following steps:

(1) reacting a compound shown as a formula LB-1 in an organic solvent at 85-100 ℃ in the presence of hydroxylamine hydrochloride and acetate to obtain a compound shown as a formula LB-2 after the reaction is completed;

(2) reacting a compound shown as a formula LB-2 with halogenated hydrocarbon containing 1-5 carbon atoms in an organic solvent at 40-60 ℃ under the action of alkali and quaternary ammonium salt, and obtaining a compound shown as a formula LB-3 after the reaction is completed;

(3) reacting a compound shown as a formula LB-3 with an amine compound in an organic solvent at 80-100 ℃ under the action of carbonate to obtain an aryl oxime compound shown as a general formula I after the reaction is completed; the structural formula of the amine compound is shown as The reaction route is as follows:

or

(4) Reacting a compound shown as a formula LB-2 with haloalkylamine in an organic solvent at 80-100 ℃ under the action of alkali to obtain an aryl oxime compound shown as a general formula I after the reaction is completed; the structural formula of the haloalkylamine is shown as

wherein R is₁、R₂、R₃、R₄And n is as defined in any one of claims 1 to 6;

x is halogen.

8. The method of claim 7, wherein: in the step (2), the molar ratio of the compound shown as the formula LB-2 to the halogenated hydrocarbon is 1:3 to 1: 5; in the step (3), the molar ratio of the compound shown as the formula LB-3 to the amine compound is 1:1.2 to 1: 3; in the step (4), the molar ratio of the compound represented by the formula LB-2 to the haloalkylamine is 1:1.5 to 1: 3.

9. Use of aryl oximes compound of general formula I, pharmaceutically acceptable salts, esters or hydrates thereof as Sigma-1 ligand in the preparation of medicaments for the prevention and/or treatment of diseases related to Sigma-1 as claimed in any one of claims 1 to 6.

Technical Field

The invention relates to the field of medicinal chemistry, in particular to an aryl oxime compound and preparation and application thereof.

Background

The Sigma receptor was first proposed in 1976 and was classified in the opioid receptor family as specific agonists (+) SKF10047 and pentazocine, but later, Sigma receptors were distinguished from opioid receptors because the effects caused by Sigma receptor ligands could not be reversed by opioid receptor antagonists (e.g., naloxone, naltrexone, etc.). It is presently believed that the Sigma receptor has no homology to opioid receptors or other mammalian proteins, is an independent receptor family, and exists in 2 subtypes: sigma-1 and Sigma-2 receptors. Although this receptor was first cloned 20 years ago, the molecular structure of proteins and the mechanism underlying their interaction with small drug-like molecules was not slowly understood until recently. The Sigma-1 receptor consists of 223 amino acids, is located primarily on the surface of the endoplasmic reticulum-mitochondria interface, and is also commonly referred to as the "mitochondrially-associated endoplasmic reticulum membrane (MAM).

The research finds that the Sigma-1 receptor is a binding protein of various specific psychotropic drugs, and plays the physiological functions as a receptor type molecular chaperone, including: modulation of ion channels (K)⁺、Ca²⁺、Na⁺Channels, etc.) and downstream receptors [ inositol triphosphate (IP3) receptor, NMDAR, etc]Thereby regulating mitochondrial function, neurotransmitter release, and the like. The physiological functions of Sigma-1 receptors in the central nervous system mainly include improving drug addiction and dyskinesia, protecting nerves, regulating cognition and the like, while peripheral Sigma-1 receptors are mainly distributed in lymphatic tissues and mainly play a role in regulating the immune function of the body. In a stable state, the Sigma-1 receptor is predominantly localized to MAM, forming Ca with another chaperone glucose regulatory protein 78(GRP78), also known as immunoglobulin heavy chain binding protein (BiP)²⁺Sensitive Complex, Ca in ER²⁺When the concentration is reduced or the specific agonist acts on a Sigma-1 receptor, the Sigma-1 receptor is separated from BiP and activated, and is redistributed to a cell membrane lipid raft to regulate an ion channel, a protein kinase and a G Protein Coupled Receptor (GPCR), so that a plurality of downstream signal transduction paths are started.

With the application of Sigma-1 receptor specific ligands and the discovery of Sigma-1 receptor subtypes in central nervous systems, particularly in limbic cortex and motor-related regions, physiological mechanisms of Sigma-1 receptors are widely excavated, Sigma-1 receptors are widely distributed in the central nervous systems, and play important roles in nervous systems such as cholinergic, gamma-aminobutyric acid (GABA) energy and dopaminergic energy by regulating ion channels, neurotransmitter functions, mitochondrial functions and the like, so that the effects of analgesia, memory disorder improvement, epilepsy resistance, depression resistance, neuroprotection and the like are exerted.

Initially, the structure of the co-crystal between Sigma-1 receptor and ligand was unknown, and Glennon et al, 1994 summarized the Sigma-1 receptor ligand as a pharmacophore model by summarizing the Sigma-1 receptor small molecule ligand, and proposed that the Sigma-1 receptor ligand is composed of three parts, a basic nitrogen atom center in the middle, and a hydrophobic feature on the nitrogen side, which is located at a distance from the nitrogen atom center

On the other side is a second hydrophobic feature, located away from the center of the nitrogen atomThe distance of (c).

To date, many marketed neuropsychiatric disease therapeutics have been reported to act non-selectively on Sigma-1 receptors, with SA4503, (+) -Pentazocine, (+) -SKD-10047, PER-084, Fluvoxamine, fluxetine, etc. acting as Sigma-1 receptor agonists; BD-1047, BD-1063, Halpperidol, E-52862, NE-100, etc., may act as Sigma-1 antagonists. However, to date, no drug that selectively acts on the Sigma-1 receptor has been successfully marketed, and only two drug candidates SIRA and Cutamesine have been introduced into clinical trials.

Therefore, the development of a small molecule ligand which selectively acts on Sigma-1 receptor is urgently needed, which has important significance for deeply recognizing and treating neuropsychiatric diseases such as epilepsy, alzheimer disease, parkinson disease, ischemic stroke, neuropathic pain and drug addiction.

Disclosure of Invention

In order to solve the technical problems, the invention aims to provide an aryl oxime compound, a pharmaceutically acceptable salt, an ester or a hydrate thereof, and preparation and application thereof.

The first purpose of the invention is to provide an aryl oxime compound shown as a general formula I, and a pharmaceutically acceptable salt, ester or hydrate thereof:

wherein the content of the first and second substances,

R₁and R₂Independently selected from hydrogen, C1-C8 alkyl, C1-C8 oxyalkyl, C1-C6 aminoalkyl, aryl, substituted aryl or aralkyl; or

R₁And R₂Form a 3-8 membered ring with the N atom to which they are attached;

or

R₁Or R₂The N atom to which they are attached and the C atom to which the other side of the N atom is attached form a 3-8 membered ring;

R₃and R₄Independently selected from hydrogen, C1-C6 alkyl, aryl, substituted aryl, heteroaromatic ring or substituted heteroaromatic ring; n is an integer of 0 to 4.

Preferably, n is 1 or 2.

Further, R₁And R₂The N atom to which they are attached; or R₁And R₂With the N atom to which they are attached and the C atom to which the N atom is attached on the other side

A pyrrole ring, a substituted pyrrole ring, a piperidine ring, a substituted piperidine ring, a piperazine ring, an alkyl-substituted piperazine ring, a azetidine ring, an aziridine ring, a homopiperazine ring, an alkyl-or aryl-substituted homopiperazine ring, a morpholine ring, a substituted morpholine ring, an aryl piperazine ring, a tetrahydroisoquinoline ring, a substituted tetrahydroisoquinoline ring, a tetrahydroquinoline ring, a substituted tetrahydroquinoline ring, an indoline ring, a substituted indoline ring.

Further, the pharmaceutically acceptable salt is a salt formed by the compound shown in the formula (1) and an inorganic acid or an organic acid, the pharmaceutically acceptable ester is an ester formed by the compound shown in the formula (1) and an acid (carboxylic acid or inorganic oxygen acid) or an alcohol, and the pharmaceutically acceptable hydrate is an aqueous compound formed by the compound shown in the formula (1) and water through a coordination bond or a covalent bond.

Preferably, R₄Is aryl, aromatic heterocycle, substituted aryl or substituted aromatic heterocycle.

Preferably, the aryl group is selected from C6-C10 aromatic rings, including, but not limited to, phenyl, naphthyl, or a biphenyl ring. The substitution site on the naphthyl group is 1, 2 or 3.

Preferably, aralkyl includes, but is not limited to, substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl or substituted or unsubstituted phenylpropyl.

Preferably, the aromatic heterocyclic ring is a 5-8 membered aromatic heterocyclic ring containing 1-3 atoms selected from N, O and S, including without limitation, a quinoline, isoquinoline, indole, benzofuran, furan, benzothiophene, thiophene, pyridine or pyrrole ring.

Preferably, the substituent on the substituted aryl substituted aromatic heterocyclic ring is one or more of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, cyano, nitro, hydroxyl, carboxyl, alkoxy acyl, amino, amido, acyloxy, acyl, sulfonyl, sulfonamido, urea, thiourea or carbamoyl, halogen and C1-C6 haloalkyl.

Preferably, the substituted aryl group is 2, 3 or 4-trifluoromethylphenyl, 2, 3 or 4-chlorophenyl, 2, 3 or 4-bromophenyl, 2, 3 or 4-methylphenyl, 2, 3 or 4-methoxyphenyl, 2, 3-dimethylphenyl, 2, 4-dimethylphenyl, 3, 5-dimethylphenyl, 2, 3-dichlorophenyl, 2, 4-dichlorophenyl, 3, 5-dichlorophenyl, 2-chloro-4-trifluoromethylphenyl, 3-chloro-4-trifluoromethylphenyl, 2-chloro-4-methylphenyl, 3-chloro-4-methylphenyl.

More preferably, the aryl oximes of the present invention have the following structural formula:

the second purpose of the invention is to provide a preparation method of aryl oxime compounds shown in the general formula I, which comprises the following steps:

(1) reacting a compound shown as a formula LB-1 in an organic solvent at 85-100 ℃ in the presence of hydroxylamine hydrochloride and acetate to obtain a compound shown as a formula LB-2 after the reaction is completed;

(2) reacting a compound shown as a formula LB-2 with halogenated hydrocarbon containing 1-5 carbon atoms in an organic solvent at 40-60 ℃ under the action of alkali and quaternary ammonium salt, and obtaining a compound shown as a formula LB-3 after the reaction is completed;

(3) reacting a compound shown as a formula LB-3 with an amine compound in an organic solvent at 80-100 ℃ under the action of carbonate to obtain an aryl oxime compound shown as a general formula I after the reaction is completed; the structural formula of the amine compound is The reaction route is as follows:

or

(4) Reacting a compound shown as a formula LB-2 with haloalkylamine in an organic solvent at 80-100 ℃ under the action of strong alkali to obtain an aryl oxime compound shown as a general formula I after the reaction is completed; the structural formula of the haloalkylamine is

The reaction route is as follows:

wherein R is₁、R₂、R₃、R₄And n is as defined hereinbefore;

x is halogen.

Further, in the step (2), the molar ratio of the compound represented by the formula LB-2 to the halogenated hydrocarbon is 1:3 to 1: 5.

Further, in the step (3), the molar ratio of the compound represented by the formula LB-3 to the amine compound is 1:1.2 to 1: 3.

Further, in the step (4), the molar ratio of the compound represented by the formula LB-2 to the haloalkylamine is 1:1.5 to 1: 3.

The third purpose of the invention is to provide a pharmaceutical composition, which comprises the aryl oxime compound shown in the general formula I, and pharmaceutically acceptable salts, esters or hydrates thereof.

The fourth purpose of the invention is to disclose application of aryl oxime compounds shown in the general formula I and pharmaceutically acceptable salts, esters or hydrates thereof as Sigma-1 ligands in preparation of medicines for preventing and/or treating diseases related to Sigma-1.

Further, diseases associated with Sigma-1 include neuropsychiatric diseases.

Preferably, the neuropsychiatric disease comprises epilepsy, depression, alzheimer's disease, parkinson's disease, ischemic stroke, neuropathic pain or drug addiction, and the like.

By the scheme, the invention at least has the following advantages:

the invention starts from aryl oxime compounds such as fluvoxamine, utilizes a Sigma-1 receptor ligand pharmacophore model, and obtains a high-selectivity Sigma-1 ligand with a novel aryl oxime skeleton through reasonable structure modification, and therefore, the invention can be applied to the preparation of various medicines for treating diseases of the central nervous system.

The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to implement them in accordance with the contents of the description, the following detailed description is given with reference to the preferred embodiments of the present invention and the accompanying drawings.

Drawings

FIG. 1 is a scheme showing the preparation scheme of aryl oximes represented by general formula I.

Detailed Description

The following detailed description of embodiments of the present invention is provided in connection with the accompanying drawings and examples. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.

In the following examples of the present invention, the preparation route of aryl oximes compound represented by general formula I is shown in FIG. 1; the method comprises the following specific steps:

(1) Hydroxylamine hydrochloride (556mg, 8.0mmol) and sodium acetate (1360mg, 10mmol) were weighed out and dissolved in 10mL of 80% ethanol, followed by stirring at room temperature for 30 minutes. A compound (5mmol) shown as LB-1 was added thereto and reacted at 100 ℃ under reflux for 1 hour. After the reaction, the solvent was dried by spinning, water (15mL) was added, and the mixture was extracted with dichloromethane (20 mL. times.2), and then the organic phase was washed with brine (15mL), dried, filtered, and evaporated to give a crude white solid, i.e., a compound represented by LB-2.

Route 1: (2) LB-2(4mmol) was dissolved in 20mL of dichloromethane, 5N NaOH (5mL) was added, followed by 20mmol of 1, 2-dibromoethane (1724. mu.L) or 1-bromo-3-chloropropane (1963. mu.L), CTMAB (584mg, 1.6mmol), respectively, and reacted at 50 ℃ for 12 h. After completion of the reaction, water (15mL) was added for dilution, and extraction was performed with methylene chloride (20 mL. times.2), then the organic phase was washed with brine (15mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and finally purified by silica gel column chromatography to obtain LB-3.

(3) When n in LB-3 is 1, the appropriate amount of LB-3(0.25mmol) is weighed out and dissolved in acetonitrile (10mL), potassium carbonate (69mg, 0.5mmol) and the corresponding amine (0.5mmol) are added and the mixture is refluxed at 85 ℃ for 2 h. After the reaction was completed, the solvent was dried by spinning, diluted with water (15mL), and then extracted with dichloromethane (15 mL. times.2), the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by a silica gel column to obtain an aryl oxime compound represented by the general formula (I).

When n in LB-3 was 2, sodium iodide (75mg, 0.5mmol) was also added to the reaction system.

Route 2: (4) LB-2(4mmol) was dissolved in 15ml DMF and haloalkylamine (6mmol) and potassium carbonate (12mmol) were added and reacted at 80 ℃ for 12 h. After completion of the reaction, the reaction mixture was diluted with water (15mL), extracted with dichloromethane (15 mL. times.2), the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified with a silica gel column to obtain an aryl oxime compound represented by the general formula (I).

In the following implementation, the structural formulas of the compounds A1-A12, C1-C8, D1-D8, E1-E8 and B1-B3 are shown as the specification above.