Novel fluoxetine analogue and preparation method and application thereof
阅读说明：本技术 一种新的氟西汀类似物及其制备方法和应用 (Novel fluoxetine analogue and preparation method and application thereof ) 是由 闫京波 李松 钟武 肖军海 王刚 于 2018-06-25 设计创作，主要内容包括：本发明涉及一种新的氟西汀类似物及其制备方法和应用,属于化合物及其制备方法和应用的技术领域。本发明所述氟西汀类似物具有下述式(I)所示的结构：<Image he="535" wi="700" file="DDA0001707411310000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to a novel fluoxetine analogue, and a preparation method and application thereof, belonging to the technical field of compounds, and preparation methods and applications thereof. The fluoxetine analogue has a structure shown in the following formula (I):)
1. A fluoxetine analog or pharmaceutically acceptable salt thereof having the structure depicted 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;
x is selected from O, S or NH;
n is an integer of 0 to 5;
m is an integer of 0 to 5.
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;
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, C1-6An alkylthio group is a group of one or more,amino group, 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.
3. An analogue according to claim 1 or 2,
x is selected from O;
n is 1,2 or 3;
m is 0, 1 or 2.
4. An analogue according to any one of claims 1 to 3 wherein the fluoxetine 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:
a compound of formula (II) and R3-L to obtain a compound of formula (I);
wherein R is1、R2、R3、R4M, n, X have the meanings given 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 formula (II) is prepared by:
reacting a compound shown in a formula (III) with a compound shown in a formula (III-1) in the presence of alkali to obtain a compound shown in a formula (I);
wherein R is1、R2、R3、R4M, n, X have the meanings given in any of claims 1 to 4, L3Is a leaving group; said L3Is chlorine, bromine or iodine.
8. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
9. The composition of claim 8, further comprising other compounds capable of treating depression, anxiety, stress-induced incontinence, central pain.
10. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-4, in the manufacture of a medicament; the medicament is used for treating depression, anxiety, stress-induced incontinence, central pain.
Technical Field
The invention relates to a novel fluoxetine analogue, and a preparation method and application thereof, belonging to the technical field of compounds, and preparation methods and applications thereof.
Background
Fluoxetine (Fluoxetine) chemical name (±) -N-methyl- γ - [ 4-trifluoromethyl-phenoxy ] -amphetamine (structural formula shown in formula (I-M)) or Fluoxetine hydrochloride (Fluoxetine hydrochloride/cymboha, also referred to simply as Fluoxetine) chemical name (±) -N-methyl- γ - [ 4-trifluoromethyl-phenoxy ] -amphetamine hydrochloride (structural formula shown in formula (II-M)):
is a selective 5-hydroxytryptamine reuptake inhibitor. Fluoxetine increases the level of serotonin that can bind to postsynaptic receptors extracellularly by inhibiting the reuptake of the neurotransmitter serotonin by neurosynaptic cells. Fluoxetine has little binding to other receptors such as alpha-adrenergic, beta-adrenergic, 5-hydroxytryptamine, dopaminergic, and the like. The antidepressant drug produced by fluoxetine, buildou, was first approved for the market for treatment of depression in belgium in 1986, was approved by the U.S. FDA to enter the us market in the end of 1987, and entered the chinese market in 1995 at 30 months 3. Fluoxetine is used clinically for the treatment of obsessive compulsive disorder and bulimia nervosa, as well as panic disorders with or without agoraphobia, in addition to adult depression.
However, the pharmaceutical activity of fluoxetine is still to be further improved.
Disclosure of Invention
The present invention aims to overcome the above-mentioned deficiencies in the prior art and to provide a novel fluoxetine analogue having a significantly superior pharmaceutical activity to fluoxetine.
Another object of the present invention is to provide a process for the preparation of the above novel fluoxetine analogs.
It is a further object of the present invention to provide the use of the novel fluoxetine analogs described above for the preparation of a medicament for the treatment of depression, anxiety, stress-induced incontinence, central pain.
Based on the above, the present invention provides a novel fluoxetine analog or pharmaceutically acceptable salt thereof, which has the structure shown in 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;
x is selected from O, S or NH;
n is an integer of 0 to 5;
m is an integer of 0 to 5.
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 X is selected from O.
According to the invention, preferably n is 1,2 or 3; more preferably n is 1.
According to the invention, preferably m is 0, 1 or 2; more preferably m is 0.
According to a preferred embodiment of the invention, the fluoxetine analog is selected from the group consisting of:
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, furanyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzoxazolyl, indolyl, quinolinyl, isoquinolinyl, benzopyrazinyl, benzopyrimidinyl, benzodioxanyl, 1, 3-benzodioxolyl,and the like.
The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) as described above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
Preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a therapeutically effective amount.
Preferably, the composition further comprises other compounds capable of treating depression, anxiety, stress-induced incontinence, central pain.
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 fluoxetine analogue provided by the invention can be used for treating 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);
wherein R is1、R2、R3、R4M, n, X have the above definitions, L is a leaving group.
Preferably, L is 1-ethoxy-1-trimethylsiloxy.
In the above process, the compound of formula (II) is obtained by liberating the hydrochloride salt of formula (II) with NaOH. Preferably, the concentration of NaOH is 1 mol/L.
Preferably, formula (II) is prepared by the following method:
reacting a compound shown in a formula (III) with a compound shown in a formula (III-1) in the presence of alkali to obtain a compound shown in a formula (I);
wherein R is1、R2、R3、R4M, n, X have the above-mentioned definitions, L3Is a leaving group. Said L3Is chlorine, bromine or iodine.
In the above process, the compound of formula (II) is reacted with R3The molar ratio of-L is 1:1 to 1:2, preferably 1: 2.
In the above method, the initial temperature of the reaction is 10-50 deg.C and the humidity is 20-80%. Preferably, the initial temperature is 15-40 ℃ and the humidity is 30-70%. More preferably, the initial temperature is 20-30 ℃ and the humidity is 40-60%.
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: 1-2: 1, 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: and adjusting the reaction solution to be alkalescent, extracting, 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 extraction is carried out by EA.
The drying is carried out by using a drying agent. Preferably, the drying agent is anhydrous sodium sulfate. The drying time is 0.5-2h, preferably 1 h.
The column chromatography is silica gel column chromatography.
The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described above in the manufacture of a medicament for the treatment of depression, anxiety, stress-induced incontinence, central pain.
Advantageous effects
The invention provides a novel fluoxetine analogue and a preparation method thereof. The analogue has obviously better pharmaceutical activity than fluoxetine. Meanwhile, the preparation method has the advantages of simple and convenient operation and the like. The method can prepare the compound with higher yield and/or purity respectively, for example, the yield reaches 80 percent, even more than 90 percent, and the total yield reaches more than 50 percent, thereby meeting the requirement of pharmaceutical production.
Drawings
FIG. 1 is a schematic representation of compound 103 of example 1 of the present invention1H NMR (DMSO) chart;
Detailed Description
The invention is further described with reference to specific examples. 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.
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