CN110627657A - Novel sertraline analogue and preparation method and application thereof - Google Patents

Novel sertraline analogue and preparation method and application thereof Download PDF

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Publication number
CN110627657A
CN110627657A CN201810661677.8A CN201810661677A CN110627657A CN 110627657 A CN110627657 A CN 110627657A CN 201810661677 A CN201810661677 A CN 201810661677A CN 110627657 A CN110627657 A CN 110627657A
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alkyl
radical
hydroxy
group
formula
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CN110627657B (en
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闫京波
李松
钟武
肖军海
王刚
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AMBER MOLTECH Co Ltd
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AMBER MOLTECH Co Ltd
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    • A61P13/00—Drugs for disorders of the urinary system
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Abstract

The invention belongs to the technical field of compounds and preparation methods and applications thereof, and particularly relates to a sertraline analogue or pharmaceutically acceptable salt thereof, which has a structure shown in the following formula (I). The compounds of the present invention have superior pharmaceutical activity to sertraline. The invention also provides a preparation method and application of the compound shown in the formula (I).

Description

Novel sertraline analogue and preparation method and application thereof
Technical Field
The invention relates to a novel sertraline analogue and a preparation method and application thereof, belonging to the technical field of compounds and preparation methods and applications thereof.
Background
Sertraline [ chemical name (1S-cis) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydro-N-methyl-1-naphthyridine amine (structural formula shown in formula (I-M) ] or sertraline hydrochloride (also abbreviated to sertraline) [ chemical name (1S-cis) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydro-N-methyl-1-naphthyridine amine hydrochloride (structural formula shown in formula (II-M) ]:
sertraline is used in the treatment of symptoms associated with depression, including depression with anxiety, with or without a history of mania; it is also used for treating obsessive-compulsive disorder.
However, the activity of sertraline remains to be further improved.
Disclosure of Invention
It is an object of the present invention to overcome the above-mentioned deficiencies of the prior art and to provide a novel sertraline analog having superior pharmaceutical activity over sertraline.
It is another object of the present invention to provide a process for the preparation of the above novel sertraline analogs.
The invention further aims to provide application of the novel sertraline analogue in preparing a medicine for treating depression and obsessive-compulsive disorder.
Based on this, the present invention provides a novel sertraline analog or a pharmaceutically acceptable salt thereof, which has a structure represented by the following formula (I):
wherein:
R1and R2Each independently selected from H, halogen, C1-6Alkyl radical, C3-8Cycloalkyl, hydroxy, C1-6Alkoxy radical, C1-6A haloalkyl group;
R3is selected from C3-8A cycloalkyl group;
R4selected from the following groups unsubstituted or optionally substituted with Rs: c1-6Alkyl, hydroxy C1-6Alkyl radical, C3-10Cycloalkyl radical, C1-6Alkyl radical C3-10Cycloalkyl, hydroxy, mercapto, C1-6Alkoxy, hydroxy C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkoxy radical, C1-6Alkylthio, mercapto C1-6Alkylthio radical, C1-6Alkylthio group C1-6Alkylthio, amino, C1-6Alkylamino, di (C)1-6Alkyl) amino, C3-8Cycloalkylamino, di (C)3-8Cycloalkyl) amino, hydroxy C1-6Alkylamino, 3-to 10-membered heterocycloalkyl, C1-6Alkyl 3-10 membered heterocycloalkyl, C1-6Alkoxy radical C1-6Alkyl, hydroxy C1-6Alkoxy radical C1-6Alkyl, mercapto C1-6Alkyl radical, C1-6Alkylthio group C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, di (C)1-6Alkyl) amino C1-6Alkyl, hydroxy C1-6Alkylamino radical C1-6Alkyl radical, C6-14Aryl, 5-14 membered heteroaryl;
rs is selected from halogen, C1-6Alkyl or C3-10A cycloalkyl group;
n is an integer of 0 to 4;
m is an integer of 0 to 5;
q is an integer of 0 to 3.
According to the invention, preferably R1And R2Each independently selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6A haloalkyl group.
According to the invention, preferably R3Selected from the group consisting of cyclopropane.
According to the invention, preferably R4Selected from H, C1-6Alkyl, hydroxy C1-6Alkyl radical, C3-8Cycloalkyl, hydroxy, mercapto, C1-6Alkoxy, hydroxy C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkoxy radical, C1-6Alkylthio, amino, C1-6Alkylamino, di (C)1-6Alkyl) amino, C3-8Cycloalkylamino, hydroxy C1-6Alkylamino radical, C1-6Alkoxy radical C1-6Alkyl, hydroxy C1-6Alkoxy radical C1-6Alkyl, mercapto C1-6Alkyl radical, C1-6Alkylthio group C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, di (C)1-6Alkyl) amino C1-6Alkyl, hydroxy C1-6Alkylamino radical C1-6Alkyl, and unsubstituted or substituted by halogen, C1-6Alkyl, substituted C3-8Heterocyclic group, C6-14Aryl radical, C6-14A heteroaryl group;
wherein C is3-8Heterocyclyl is more preferably morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl; c6-14More preferably, the heteroaryl group is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thienyl, furyl, thiazolyl, imidazolyl, oxazolyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, indolyl, quinolinyl, isoquinolinyl, benzopyrazinyl, benzopyrimidinyl, benzodioxanyl, 1, 3-benzodioxolyl, and
according to the invention, preferably n is 0, 1 or 2; more preferably n is 1.
According to the invention, preferably m is 1,2 or 3; more preferably m is 2.
According to the invention, preferably q is 0, 1 or 2; more preferably q is 1.
According to a preferred embodiment of the invention, the sertraline analogue is selected from the following compounds:
pharmaceutically acceptable salts of the compounds of the invention include acid addition salts of conventional inorganic acids, carboxylic and sulfonic acids, for example, salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
Pharmaceutically acceptable salts of the compounds of the invention also include salts of conventional bases, such as, for example and preferably, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and organic amines derived from ammonia or having 1 to 16 carbon atoms, such as, for example and preferably, ammonium salts of ethylamine, diethylamine, triethylamine, N-diisopropylethylamine, monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, diethylaminoethanol, procaine, dicyclohexylamine, dibenzylamine, N-methylpiperidine, N-methylmorpholine, arginine, lysine and 1, 2-ethylenediamine.
The compounds according to the invention may, depending on their structure, exist in different stereoisomeric forms, i.e. in the form of configurational isomers, or optionally as conformational isomers (enantiomers and/or diastereomers, including those diastereomers in the case of atropisomers). The present invention thus includes enantiomers and diastereomers and their respective mixtures. Stereoisomerically identical components can be separated from mixtures of such enantiomers and/or diastereomers in a known manner; preference is given to using chromatography, in particular HPLC chromatography on the achiral or chiral phase.
If the compounds according to the invention can exist in tautomeric forms, the invention encompasses all tautomeric forms.
In the context of the present invention, unless specifically stated otherwise, the substituents are defined as follows:
according to the invention, "alkyl", by itself or as part of a chemical group, is a straight or branched chain hydrocarbon, preferably having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1, 2-dimethylpropyl, 1-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 2-dimethylpropyl, 1, 3-dimethylbutyl, 1, 4-dimethylbutyl, 2, 3-dimethylbutyl, 1-dimethylbutyl, 2-dimethylbutyl, pentyl, 1-methylbutyl, 2-dimethylbutyl, pentyl, 1-methylbutyl, 1, 2-dimethylpropyl, 2-dimethylbutyl, 1, 2-dimethylp, 3, 3-dimethylbutyl, 1, 2-trimethylpropyl, 1,2, 2-trimethylpropyl, 1-ethylbutyl and 2-ethylbutyl. Preference is also given to alkyl having from 1 to 4 carbon atoms, such as, in particular, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
According to the invention, a "cycloalkyl group" (by itself or as part of a chemical group) is a monocyclic hydrocarbon, preferably having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. Preference is also given to cycloalkyl having 3,4, 5, 6 or 7 carbon atoms, such as, in particular, cyclopropyl or cyclobutyl.
According to the invention, "halogen" is fluorine, chlorine, bromine or iodine, in particular fluorine, chlorine or bromine.
According to the invention, "haloalkyl" is a halogen-substituted alkyl radical which preferably has 1 to 9 identical or different halogen atoms. Examples of haloalkyl are trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, chloromethyl, bromomethyl, 1-fluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2, 2, 2-trichloroethyl, 2-chloro-2, 2-difluoroethyl, pentafluoroethyl and pentafluoro-tert-butyl. Preference is given to haloalkyl having 1 to 4 carbon atoms and 1 to 9, preferably 1 to 5, identical or different halogen atoms from the group consisting of fluorine, chlorine or bromine. Particular preference is given to haloalkyl having 1 or 2 carbon atoms and having 1 to 5 identical or different halogen atoms from the group consisting of fluorine or chlorine, such as, in particular, difluoromethyl, trifluoromethyl or 2, 2-difluoroethyl.
According to the invention, "alkoxy" is a straight-chain or branched O-alkyl radical, preferably having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Alkoxy groups having 1 to 4 carbon atoms are also preferred.
According to the invention, "alkylthio" is a straight-chain or branched S-alkyl radical, preferably having 1 to 6 carbon atoms, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio and tert-butylthio. Alkylthio groups having 1 to 4 carbon atoms are also preferred.
According to the invention, "alkylamino" means that one hydrogen atom of the amino group is replaced by an alkyl group, being NH-alkyl. The alkyl group therein preferably has 1 to 6 carbon atoms, such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino and tert-butylamino. Preference is also given to alkylamino having from 1 to 4 carbon atoms.
According to the invention, "dialkylamino" means that both hydrogen atoms of the amino group are replaced by alkyl groups, being N- (alkyl)2. The alkyl group therein preferably has 1 to 6 carbon atoms, such as dimethylamino, diethylamino, methylethylamino, di-n-propylamino, and the like. Preference is also given to dialkylamino having 1 to 4 carbon atoms.
According to the invention, "alkylsulfinyl" is a linear or branched alkylsulfinyl group, preferably having 1 to 6 carbon atoms, such as methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl and tert-butylsulfinyl. Preference is also given to alkylsulfinyl having from 1 to 4 carbon atoms. The alkylsulfinyl groups according to the invention may be substituted by one or more identical or different radicals.
According to the invention, "alkylsulfonyl" is a straight-chain or branched alkylsulfonyl group, preferably having from 1 to 6 carbon atoms, such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl. Alkylsulfonyl groups having 1 to 4 carbon atoms are also preferred. The alkylsulfonyl groups according to the invention may be substituted by one or more groups which may be the same or different.
According to the invention, "alkylcarbonyl" is straight-chain or branched alkyl-C (═ O), preferably having 2 to 7 carbon atoms, such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, sec-butylcarbonyl and tert-butylcarbonyl. Also preferred are alkylcarbonyl groups having 1 to 4 carbon atoms. The alkylcarbonyl groups according to the invention may be substituted by one or more identical or different radicals.
According to the invention, "cycloalkylcarbonyl" is a straight-chain or branched cycloalkylcarbonyl group, preferably having 3 to 8 carbon atoms in the cycloalkyl moiety, such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl. Also preferred are cycloalkylcarbonyl groups having 3, 5, or 7 carbon atoms in the cycloalkyl moiety.
According to the invention, an "alkoxycarbonyl group", by itself or as part of a chemical group, is a linear or branched alkoxycarbonyl group, preferably having from 1 to 6 carbon atoms in the alkoxy moiety or from 1 to 4 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl.
According to the invention, "alkoxycarbonyl" is a linear or branched alkoxycarbonyl group, preferably having from 1 to 6 carbon atoms in the alkyl moiety or from 1 to 4 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl.
According to the invention, "alkylaminocarbonyl" is a straight-chain or branched alkylaminocarbonyl group, preferably having 1 to 6 carbon atoms or having 1 to 4 carbon atoms in the alkyl moiety, such as methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, sec-butylaminocarbonyl and tert-butylaminocarbonyl.
According to the invention, "aryl" is a monocyclic, bicyclic or polycyclic aromatic system, preferably having 6 to 14, in particular 6 to 10, ring carbon atoms, for example phenyl, naphthyl, anthryl, phenanthryl, preferably phenyl. Aryl is also a polycyclic system, for example tetrahydronaphthyl, indenyl, indanyl, fluorenyl, biphenyl, with the linkage side on the aromatic system.
According to the invention, a "heterocyclyl" is a carbocyclic group having at least one ring in which at least one carbon atom is replaced by a heteroatom, preferably a heteroatom selected from N, O, S, P, B, Si, Se and which is saturated or partially unsaturated. The heterocyclyl preferably contains 3 to 8 ring atoms, in particular 3 to 6 ring atoms, and one or more, preferably 1 to 4, in particular 1,2 or 3, heteroatoms in the heterocycle are preferably selected from N, O and S, but wherein two oxygen atoms should not be directly adjacent. The heterocyclic ring generally contains up to 4 nitrogen atoms, and/or up to 2 oxygen atoms and/or up to 2 sulfur atoms.
Examples of heterocyclyl groups are piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, dioxolanyl, dioxolyl, pyrazolidinyl, tetrahydrofuranyl, dihydrofuranyl, oxetanyl, oxiranyl, azetidinyl, aziridinyl, oxetanyl, oxazepanyl, azepanyl, oxazepanyl, oxopyrrolidinyl, dioxopyrrolidinyl, oxomorpholinyl, oxopiperazinyl, and oxepanyl. If the heterocyclyl or heterocyclic ring is optionally substituted, it may be fused to other carbocyclic or heterocyclic rings. In the case of optionally substituted heterocycles, the invention also includes polycyclic ring systems, for example 8-azabicyclo [3.2.1] octyl or 1-azabicyclo [2.2.1] heptyl.
According to the invention, "heteroaryl" represents a heteroaromatic compound, i.e. a completely unsaturated aromatic heterocyclic compound falling within the above definition of heterocycle. Preferably, for a 5-to 7-membered ring, there are 1 to 3, preferably 1 or 2 identical or different heteroatoms from the abovementioned group. Heteroaryl according to the invention is, for example, pyrrolyl, furyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzoxazolyl, indolyl, quinolinyl, isoquinolinyl, benzopyrazinyl, benzopyrimidinyl, benzodioxanA 1, 3-benzodioxolyl group,and the like.
The invention also relates to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient.
Suitable excipients generally include binders, antiadherents, disintegrants, fillers, diluents, flavoring agents, colorants, glidants, lubricants, preservatives, adsorbents, and sweeteners or combinations thereof.
Typical formulations are prepared by mixing a compound of the invention with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient employed will depend upon the means and purpose for which the compounds of the present invention are to be employed. The solvent is generally selected based on the knowledge of one skilled in the art of administering a safe (GRAS) solvent to a mammal. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and the like, and mixtures thereof. The formulations may also include one or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents and other known additives to provide an elegant appearance of the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or aid in the manufacture of a pharmaceutical product (drug).
The formulations may be prepared using conventional dissolution and mixing methods. For example, bulk drug substance (i.e., a stable form of a compound of the invention or a stable form of the compound (e.g., with a cyclodextrin derivative or other complexing agent)) is dissolved in a suitable solvent in the presence of one or more excipients. The compounds of the present invention are generally formulated into pharmaceutical dosage forms to provide easily controlled doses of the drug and to provide the patient with an elegant and easily handled product.
The composition is typically formulated into a dosage form selected from: tablets, aqueous or oily suspensions, ointments, patches, gels, lotions, capsules, emulsions, creams, sprays, drops, dispersible powders or granules, emulsions in hard or soft gelatin capsules, syrups and elixirs.
The pharmaceutical composition (or formulation) for use may be packaged in various forms depending on the method used for pharmaceutical administration. Generally, articles for dispensing include a container holding a pharmaceutical formulation in a suitable form. Suitable containers are well known to those skilled in the art and include, for example, bottles (plastic and glass), pouches, ampoules, plastic bags, metal drums and the like. The container may also include anti-pry means to prevent inadvertent access to the contents of the package. In addition, the container has a label thereon that describes the contents of the container. The tag may also include appropriate warnings.
The novel sertraline analogues provided by the invention can treat depression, anxiety, stress-induced incontinence, and central pain.
The invention also provides a preparation method of the compound, which is characterized by comprising the following steps:
a compound of formula (II) and R3-L to obtain a compound of formula (I);
R1、R2、R3、R4m, n, q have the above definitions, L is a leaving group.
According to the invention, L is a leaving group, preferably 1-ethoxy-1-trimethylsiloxy.
In the above process, the compound represented by the formula (II) is prepared from a hydrochloride of the compound represented by the formula (II):
in the above step, the hydrochloride of the compound of formula (II) is reacted with potassium carbonate in the presence of water as a solvent to obtain the compound of formula (II). Preferably, the reaction is stirred at room temperature for 1-2 h. More preferably, the reaction product is extracted by EA, dried by anhydrous magnesium sulfate, filtered by suction and concentrated to obtain a pure product.
Preferably, the compound of formula (II) is prepared by:
reacting a compound shown in a formula (III) with a compound shown in a formula (IV) in the presence of alkali to obtain a compound shown in a formula (II);
wherein R is1、R2、R4M, n, q have the above-mentioned definitions, L2Is a leaving group.
In the above method, the molar ratio of the compound of formula (II) to 1-ethoxy-1-trimethylsilylcyclopropane is 1:1 to 1:2, preferably 1:1.1 to 2, more preferably 1: 1.2.
In the above process, the reaction is carried out in a solvent. The solvent is preferably an alcoholic solvent such as methanol, tetrahydrofuran, and the like or a mixture thereof. Preferably, the solvent is subjected to anhydrous treatment before use.
In the method, the catalyst for the reaction is sodium borohydride or sodium cyanoborohydride. The molar ratio of the catalyst to the compound of formula (II) is 1: 1-3: 2, preferably 2: 1.
Preferably, the catalyst is added in small portions. Preferably, the addition is carried out dropwise.
In the above method, acetic acid is also added to the reaction system. Preferably, the molar ratio of the acetic acid to the compound of formula (II) is 1:1 to 2:1, preferably 2: 1.
In the above reaction, all the raw materials are added and heated to 50-80 ℃ for reflux reaction. Preferably, the temperature is raised to 60-70 ℃.
The method also comprises the following post-treatment steps: extracting the reaction solution, drying and distilling under reduced pressure to obtain a crude product.
And purifying the crude product by column chromatography to obtain the final product.
The above extraction was performed with DCM.
The drying is carried out by using a drying agent. Preferably, the drying agent is anhydrous magnesium sulfate. The drying time is 0.5-2h, preferably 1 h.
The column chromatography is silica gel column chromatography.
The invention also provides application of the novel sertraline analogue in preparing a medicament for treating depression and obsessive-compulsive disorder.
Advantageous effects
The invention provides a novel sertraline analogue and a preparation method thereof. The analogs have superior pharmaceutical activity to sertraline. In addition, the preparation method of the compound is simple and convenient to operate, and the compound can be prepared with higher yield and/or purity, such as the yield reaches 80%, even more than 90%, and the total yield reaches more than 50%, so that the requirement of drug production is met.
Drawings
FIG. 1 is a drawing of a compound prepared according to example 1 of the present invention1H NMR (DMSO) chart;
Detailed Description
The invention is further described below with reference to the accompanying drawings and specific embodiments. However, those skilled in the art will appreciate that the following examples are only for illustrating the technical solutions of the present invention and are not intended to limit the scope of the present invention in any way.
Example 1: preparation of Compound 1
A250 ml single-neck flask was charged with the compound of formula 1-S (12g, 0.035mol, 1eq) and 150ml of water as a solvent, and excess potassium carbonate was added thereto with stirring and stirred at normal temperature for 1-2 hours.
And (3) post-treatment: extracting with 200ml 2EA, drying with anhydrous magnesium sulfate, filtering, concentrating to obtain pure product 10.9g, and directly feeding into the next step without post-treatment.
A250 ml two-neck flask was charged with the above purified product (10.9g, 0.0356mol, 1eq), 100ml of a mixed solvent of methanol and tetrahydrofuran (volume ratio 1:1) as a solvent, and 1-ethoxy-1 trimethylsilyl cyclopropane (7.5g, 0.0427mol, 1.2eq) and acetic acid (4.3g, 00712mol, 2eq) were sequentially added thereto with stirring, and finally, sodium cyanoborohydride (4.5g, 0.0712mol, 2eq) was added thereto in portions, and after completion of the addition, the mixture was heated under reflux overnight.
The reaction mixture was cooled to room temperature, and water was added to stop the reaction. 200ml of 2DCM extraction, saturated salt water washing of organic phase twice, anhydrous magnesium sulfate drying, suction filtration, concentration, 120g of silica gel column packing, wet loading, column chromatography to obtain pure white solid 7.9g, yield: 65.3 percent. The nuclear magnetic characterization data are shown in FIG. 1. MS (m/z): 346.3(M + H).
Compounds 2 to 103 were prepared in the same manner as in reference example 1, and the yields and characterization data for compounds 1 to 103 are shown in the following table:
example 2: test for pharmaceutical Activity
2.1 determination of antidepressant Activity by mouse Tail suspension test
Male ICR mice (SPF grade) weighing 18-22g were suspended by attaching a clip to the central cord of the top plate of a tail box of 25X 25cm, holding the tip of the mouse 1cm away from the tip of the tail and hanging the mouse upside down with the head 4-5cm away from the bottom surface of the box. A dose (24mg/kg) of an exemplary compound of the examples of the invention, sertraline, 0.5% sodium carboxymethylcellulose solution was milled to prepare a suspension for use. Samples to be tested with different doses are orally taken 60min before the experiment, the tail is suspended for 6 minutes after the administration, and the mouse immobility time is accumulated for 4 minutes. The results are shown in Table 2.
2.2 determination of antidepressant Activity by forced swimming test of mice
Male ICR mice (SPF grade) weighing 18-22g were placed in a glass jar (10 cm diameter, 20cm height) at 25 deg.C in water and 10cm depth. A dose (24mg/kg) of an exemplary compound of the examples of the invention, sertraline, was milled with 0.5% sodium carboxymethylcellulose solution to make a suspension ready for use. The samples to be tested were given different doses orally 60min before the experiment, observed 6 min after administration, and the cumulative immobility time of the animals (i.e. the time during which the hind limbs of the animals were motionless or in which the hind limbs were micromoted but the body was kept floating) was recorded within 4 min after administration, and the results are shown in table 2.
Sample name Tail suspension experiment (motionless time/s) Forced swimming experiment (motionless time/s)
Solvent control group 95.4±38.8 123.6±52.3
Sertraline 48.3±18.2* 58.7±42.7*
2 41.1±13.4* 49.4±13.5*
3 40.7±11.7* 47.4±15.2*
4 37.1±12.3* 43.6±20.6*
5 39.2±13.0* 46.0±32.2*
9 37.4±15.2* 51.1±34.5*
13 37.2±15.8* 51.4±34.5*
19 39.2±7.8* 50.5±20.4*
20 37.6±12.3* 44.1±30.8*
30 40.1±13.4* 48.1±33.0*
31 36.5±12.5* 43.4±30.2*
39 40.6±13.3* 49.1±33.4*
53 35.0±12.1* 41.1±28.2*
54 39.5±13.2* 46.4±22.2*
55 38.0±7.0* 49.1±26.2*
57 36.0±12.1* 42.5±30.0*
59 41.6±14.2* 48.1±24.4*
67 38.0±12.5* 44.5±21.1*
76 39.2±9.1* 49.4±17.2*
77 38.4±13.1* 45.4±21.6*
78 39.3±8.0* 50.7±22.1*
81 35.4±12.1* 42.0±29.2*
93 40.0±10.8* 50.1±11.1*
97 40.4±10.4* 50.1±10.2*
101 39.7±13.3* 47.4±22.4*
*: compared with the solvent control group, p is less than 0.05.
Example 3 acute toxicity study of exemplary example Compounds
Experimental materials:
ICR mice, each half of male and female, weigh 18-22g, and are fed with pellet feed for free food intake and drinking.
The compounds tested in Table 2 were each formulated with 0.5% CMC-Na to a 500mg/mL suspension.
Experimental methods
ICR mice were gavaged with 10ml/kg of the compound tested in Table 2 in a single gavage of body weight, and animals were observed for toxicity and mortality within 14 days after dosing. As a result, after the single gastric lavage administration, the mice have slow activity, lie still and move little, and the mice can recover to normal after 40-60 minutes. Within 14 days after administration, the mice did not die, and on day 15, all mice were sacrificed, dissected, and examined by naked eyes for each organ, and no obvious lesion was observed.
The acute toxicity test result shows that the maximum tolerance MTD of the gavage administration is not lower than 7g/kg, which indicates that the compound of the embodiment of the invention has lower acute toxicity.

Claims (10)

1. A sertraline analog or a pharmaceutically acceptable salt thereof, having the structure shown in formula (I):
wherein:
R1and R2Each independently selected from H, halogen, C1-6Alkyl radical, C3-8Cycloalkyl, hydroxy, C1-6Alkoxy radical, C1-6A haloalkyl group;
R3is selected from C3-8A cycloalkyl group;
R4selected from the following groups unsubstituted or optionally substituted with Rs: c1-6Alkyl, hydroxy C1-6Alkyl radical, C3-10Cycloalkyl radical, C1-6Alkyl radical C3-10Cycloalkyl, hydroxy, mercapto, C1-6Alkoxy, hydroxy C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkoxy radical, C1-6Alkylthio, mercapto C1-6Alkylthio radical, C1-6Alkylthio group C1-6Alkylthio, amino, C1-6Alkylamino, di (C)1-6Alkyl) amino, C3-8Cycloalkylamino, di (C)3-8Cycloalkyl) amino, hydroxy C1-6Alkylamino, 3-to 10-membered heterocycloalkyl, C1-6Alkyl 3-10 membered heterocycloalkyl, C1-6Alkoxy radical C1-6Alkyl, hydroxy C1-6Alkoxy radical C1-6Alkyl, mercapto C1-6Alkyl radical, C1-6Alkylthio group C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, di (C)1-6Alkyl) amino C1-6Alkyl, hydroxy C1-6Alkylamino radical C1-6Alkyl radical, C6-14Aryl, 5-14 membered heteroaryl;
rs is selected from halogen, C1-6Alkyl or C3-10A cycloalkyl group;
n is an integer of 0 to 4;
m is an integer of 0 to 5;
q is an integer of 0 to 3.
2. An analogue as claimed in claim 1 wherein R is1And R2Each independently selected from H, halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6A haloalkyl group;
R3selected from the group consisting of cyclopropane.
3. An analogue as claimed in claim 1 or 2 wherein R is4Selected from H, C1-6Alkyl, hydroxy C1-6Alkyl radical, C3-8Cycloalkyl, hydroxy, mercapto, C1-6Alkoxy, hydroxy C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkoxy radical, C1-6Alkylthio, amino, C1-6Alkylamino, di (C)1-6Alkyl) amino, C3-8Cycloalkylamino, hydroxy C1-6Alkylamino radical, C1-6Alkoxy radical C1-6Alkyl, hydroxy C1-6Alkoxy radical C1-6Alkyl, mercapto C1-6Alkyl radical, C1-6Alkylthio group C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, di (C)1-6Alkyl) amino C1-6Alkyl, hydroxy C1-6Alkylamino radical C1-6Alkyl, and unsubstituted or substituted by halogen, C1-6Alkyl, substituted C3-8Heterocyclic group, C6-14Aryl radical, C6-14A heteroaryl group;
n is 0, 1 or 2;
m is 1,2 or 3;
q is 0, 1 or 2.
4. An analogue according to any one of claims 1 to 3, wherein the sertraline analogue is selected from the group consisting of:
5. a process for the preparation of an analogue according to any one of claims 1 to 4, comprising the steps of:
a compound of formula (II) and R3-L to obtain a compound of formula (I);
R1、R2、R3、R4m, n, q have the definitions as defined in any of claims 1 to 4, L is a leaving group.
6. The method according to claim 5, wherein L is 1-ethoxy-1-trimethylsiloxy.
7. The process according to claim 5 or 6, wherein the compound of formula (II) is prepared by:
reacting a compound shown in a formula (III) with a compound shown in a formula (IV) in the presence of alkali to obtain a compound shown in a formula (II);
wherein R is1、R2、R4M, n, q have the meanings given in any of claims 1 to 4, L2Is a leaving group.
8. Use of an analogue according to any one of claims 1 to 4 or a pharmaceutically salt thereof for the manufacture of a medicament for the treatment of depression, anxiety, stress-induced incontinence, central pain.
9. A pharmaceutical composition comprising an analogue of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.
10. The pharmaceutical composition of claim 9, further comprising a therapeutically effective amount of an analog of formula (I) according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
CN201810661677.8A 2018-06-25 2018-06-25 Novel sertraline analogue and preparation method and application thereof Active CN110627657B (en)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
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Publication number Priority date Publication date Assignee Title
US4045488A (en) * 1974-11-06 1977-08-30 Pfizer Inc. Aminophenyltetralin compounds
US20100092479A1 (en) * 2008-08-18 2010-04-15 Combinatorx (Singapore) Pte. Ltd. Compositions and methods for treatment of viral diseases

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Title
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