CN110627757B - Escitalopram derivative and preparation method and application thereof - Google Patents

Escitalopram derivative and preparation method and application thereof Download PDF

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CN110627757B
CN110627757B CN201810663509.2A CN201810663509A CN110627757B CN 110627757 B CN110627757 B CN 110627757B CN 201810663509 A CN201810663509 A CN 201810663509A CN 110627757 B CN110627757 B CN 110627757B
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闫京波
王刚
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Beijing Anbo Ruida Pharmaceutical Technology Co ltd
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Abstract

The invention relates to an escitalopram derivative shown as a formula (I) or a pharmaceutically acceptable salt thereof:

Description

Escitalopram derivative and preparation method and application thereof
Technical Field
The invention relates to a novel escitalopram derivative and a preparation method and application thereof, belonging to the field of chemical drug design and preparation.
Background
Depression is a psychological disorder resulting from dysfunction of the neurotransmitter system, such as cerebral 5-hydroxytryptamine (5-HT) and norepinephrine, which severely affects human health and has hitherto been one of the ten major diseases in the world. Selective 5-HT reuptake inhibitors (SSRIs) are novel antidepressants which are well-established worldwide for many years, and their antidepressant action is thought to be through inhibiting the reuptake of 5-hydroxytryptamine by 5-hydroxytryptamine neurons in the central nervous system, and due to the decreased reuptake, the concentration of the extracellular 5-hydroxytryptamine neurotransmitter is increased, thereby increasing the activity of the 5-hydroxytryptamine pathway. Such drugs have no inhibitory effect on cholinergic receptors, histamine and alpha-adrenergic receptors, and among the commonly used drugs include Sertraline (Sertraline), Paroxetine (Paroxetine), Fluoxetine (Fluoxetine), fluvoxamine (Fluvoxoxamine), Citalopram (Citalopram) and the like.
Escitalopram (Escitalopram), also known as Escitalopram, was marketed in the united states by north danaline pharmaceutical factory in 2002 and is S-citalopram, the dextroisomer of citalopram, the most selective antidepressant for the 5-HT transporter (SERT) developed in recent years.
Figure BDA0001707235680000011
Studies have shown significant differences in pharmacological actions and activities of escitalopram and its enantiomer R-citalopram: the R-citalopram has weak inhibition activity on SERT, dose-dependent antagonism on the effect of inhibiting rat cortical escitalopram on SERT, and antagonism on the anxiolytic and antidepressant effect of citalopram in animal models. Escitalopram mainly mediates the 5-HT reuptake inhibition of citalopram, has higher affinity for low-affinity allosteric binding sites, and the binding can obviously enhance the binding time and strength of paroxetine and venlafaxine with basic binding sites.
Escitalopram has been shown to have good therapeutic effects on depression, but its activity is to be further improved.
Disclosure of Invention
The invention provides an escitalopram derivative shown as a formula (I) or a pharmaceutically acceptable salt thereof:
Figure BDA0001707235680000021
wherein the content of the first and second substances,
R1and R2Independently of one another, are selected from the group optionally substituted by one or more RaSubstituted of the following groups: c1-6Alkyl-, C2-6Alkenyl-, C3-10cycloalkyl-C6-14Aryl-, 3-10 membered heterocycloalkyl containing 1,2, 3 or 4 heteroatoms selected from N, O and S, 5-14 membered heteroaryl containing 1,2, 3 or 4 heteroatoms selected from N, O and S-;
R3and R4Independently of one another, from F, Cl, Br, I, OH, SH, CN, NH2、C1-6An alkyl group;
Raselected from F, Cl, Br, I, OH, SH, CN, ═ O or optionally substituted by one or more ReSubstituted of the following groups: NR (nitrogen to noise ratio)cRd、C1-6Alkyl-, C2-6Alkenyl-, C3-C10cycloalkyl-C6-14Aryl-, 3-10 membered heterocycloalkyl containing 1,2, 3 or 4 heteroatoms selected from N, O and S-, 5-14 membered heteroaryl containing 1,2, 3 or 4 heteroatoms selected from N, O and S-, C1-6Alkyloxy-, C2-6Alkenyloxy-, C3-C10Cycloalkyloxy-, C6-14Aryloxy-, 3-10 membered heterocycloalkyloxy comprising 1,2, 3 or 4 heteroatoms selected from N, O and S-, 5-14 membered heteroaryloxy comprising 1,2, 3 or 4 heteroatoms selected from N, O and S-, C1-6Alkylthio-, C2-6alkenylthio-C3-C10Cycloalkylthio-, C6-14Arylthio-, 3-10 membered heterocycloalkylthio comprising 1,2, 3 or 4 heteroatoms selected from N, O and S-, 5-14 membered heteroarylthio comprising 1,2, 3 or 4 heteroatoms selected from N, O and S-, -OC (═ O) Rb、-OS(＝O)2Rb；
RbSelected from the group consisting of optionally substituted by one or more ReSubstituted of the following groups: c1-6Alkyl-, C2-6Alkenyl-, C3-10cycloalkyl-C6-14Aryl-, 3-10 membered heterocycloalkyl containing 1,2, 3 or 4 heteroatoms selected from N, O and S-, 5-1 containing 1,2, 3 or 4 heteroatoms selected from N, O and S4-membered heteroaryl-;
Rcand RdIndependently of one another, selected from H or optionally substituted by one or more ReSubstituted of the following groups: c1-6Alkyl-, C2-6Alkenyl-, C3-10cycloalkyl-C6-14Aryl-, 3-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S-, 5-14 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S-, or, RcAnd RdMay form a 3-10 membered heterocyclic group together with the nitrogen atom to which it is attached, said heterocyclic group optionally further comprising 1,2 or 3 heteroatoms selected from N, O and S;
Reselected from F, Cl, Br, I, OH, SH, CN, NH2、C1-6Alkyl radical, C2-6Alkenyl-, C3-10cycloalkyl-C1-6Alkyloxy-, C2-6Alkenyloxy-, C3-C10Cycloalkyloxy-, C1-6Alkylthio-, C2-6alkenylthio-C3-C10Cycloalkylthio-, C1-6An alkylcarbonyl group.
Preferably, R1And R2Independently of one another, from the following groups unsubstituted or optionally substituted by 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) aminoC1-6Alkyl, 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.
Term definition and interpretation
The term "C1-6Alkyl "is understood to preferably mean a linear or branched, saturated monovalent hydrocarbon radical having 1,2, 3,4, 5 or 6 carbon atoms, for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl or 1, 2-dimethylbutyl or isomers thereof. In particular, the radicals have 1,2, 3 or 4 carbon atoms ("C)1-4Alkyl groups) such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly groups having 1,2 or 3 carbon atoms ("C)1-3Alkyl groups) such as methyl, ethyl, n-propyl or isopropyl.
The term "C2-6Alkenyl "is understood to preferably mean a linear or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2,3, 4,5 or 6 carbon atoms, in particular 2 or 3 carbon atoms (" C)2-3Alkenyl "), it being understood that in the case where the alkenyl group comprises more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl group is, for example, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-enyl, hex-5-enyl, (E) -hex-4-enyl, (Z) -hex-4-enyl, m-n-2-enyl, m-n-1-enyl, m-n-E-4-enyl, m-n-2-enyl, m-n-enyl, m-E-4-enyl, m-2-enyl, m-pent-1-enyl, m-2-methyl-enyl, m-2-methylvinyl, m-2-methyl-2-methylvinyl, m-but-2-enyl, (E) -hex-3-enyl, (Z) -hex-3-enyl, (E) -Hex-2-enyl, (Z) -hex-2-enyl, (E) -hex-1-enyl, (Z) -hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E) -1-methylprop-1-enyl, (Z) -1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E) -2-methylbut-2-enyl, (Z) -2-methylbut-2-enyl, (E) -1-methylbut-2-enyl, (Z) -1-methylbut-2-enyl, (E) -3-methylbut-1-enyl, (Z) -3-methylbut-1-enyl, (E) -2-methylbut-1-enyl, (Z) -2-methylbut-1-enyl, (E) -1-methylbut-1-enyl, (Z) -1-methylbut-1-enyl, 1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.
The term "C3-10Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3,4, 5,6, 7, 8, 9 or 10 carbon atoms. Said C is3-10Cycloalkyl groups may be monocyclic hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic hydrocarbon groups such as decalin rings.
The term "3-10 membered heterocycloalkyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1,2, 3 or 4 heteroatoms selected from N, O and S. The heterocycloalkyl group may be attached to the rest of the molecule through any of the carbon atoms or the nitrogen atom (if present). In particular, the heterocycloalkyl group may include, but is not limited to: 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl; or a 7-membered ring, such as a diazepanyl ring. Optionally, the heterocycloalkyl group can be benzofused. The heterocyclyl group may be bicyclic, for example but not limited to a5, 5 membered ring, such as a hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring, or a5, 6 membered bicyclic ring, such as a hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl ring. The nitrogen atom containing ring may be partially unsaturated, i.e. it may contain one or more double bonds, such as but not limited to a2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 4, 5-dihydrooxazolyl or 4H- [1,4] thiazinyl ring, or it may be benzo-fused, such as but not limited to a dihydroisoquinolinyl ring.
The term "C6-14Aryl "is to be understood as preferably meaning a mono-, bi-or tricyclic hydrocarbon ring having a monovalent or partially aromatic character with 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (" C6-14Aryl group "), in particular a ring having 6 carbon atoms (" C6Aryl "), such as phenyl; or biphenyl, or is a ring having 9 carbon atoms ("C9Aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C10Aryl radicals), such as tetralinyl, dihydronaphthyl or naphthyl, or rings having 13 carbon atoms ("C13Aryl radicals), such as the fluorenyl radical, or a ring having 14 carbon atoms ("C)14Aryl), such as anthracenyl.
The term "5-to 14-membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5,6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which contain 1,2, 3 or 4 heteroatoms selected from N, O and S and which, in addition, in each case may be benzo-fused. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.
Unless otherwise indicated, the heteroaryl or heteroarylene includes all possible isomeric forms thereof, e.g., positional isomers thereof. Thus, for some illustrative, non-limiting examples, the term pyridyl or pyridinylene includes pyridin-2-yl, pyridinylene-2-yl, pyridin-3-yl, pyridinylene-3-yl, pyridin-4-yl and pyridinylene-4-yl; alternatively, the term thienyl or thienylene includes thien-2-yl, thien-3-yl, and thien-3-yl.
The term "substituted" means that one or more hydrogens on the designated atom is replaced with the listed group, provided that the designated atom's normal valency under the current circumstances is not exceeded and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term "optionally substituted with … …" means that there may be no substitution or substitution with the listed groups.
A substituent of a ring system refers to a substituent attached to an aromatic or non-aromatic ring system, e.g., the substituent replaces an available hydrogen on the ring system.
The term "one or more" as used in the definition of substituents for compounds of each general formula according to the invention is understood to include one, two, three, four or five, in particular one, two, three or four, more in particular one, two or three, for example one or two.
The term "pharmaceutically acceptable salt" refers to salts made from pharmaceutically acceptable non-toxic acids, including inorganic or organic acids. The compounds of the invention may be mono-, di-or tri-salts depending on the number of acidic functional groups present in the free base form of the compound. By way of example, the acids include acetic acid, trifluoroacetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucose, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, tartaric acid, p-toluenesulfonic acid and the like.
According to the invention, the compounds of formula (I) include the following compounds:
Figure BDA0001707235680000061
Figure BDA0001707235680000071
Figure BDA0001707235680000081
Figure BDA0001707235680000091
Figure BDA0001707235680000101
Figure BDA0001707235680000111
Figure BDA0001707235680000121
the present invention also provides a process for the preparation of a compound of formula (I) comprising the steps of:
Figure BDA0001707235680000122
1) reacting the compound A1 with A2 in the presence of a base 1 to obtain a compound A3;
2) reacting the compound A3 with A4 to obtain a compound A5;
3) deprotection of compound a5 affords compound a 6;
4) reacting compound A6 with A7 in the presence of a base 2 to obtain compound (I);
the base 1 and the base 2 are the same or different and are independently selected from inorganic bases;
wherein R is1～R4Each independently has the above definition, L1、L2、L3Identical or different, independently of one another, are leaving groups.
According to the invention, L1、L2、L3Identical or different, independently of one another, are chlorine, bromine, iodine or 1-ethoxy-1-trimethylsiloxy.
According to the invention, the inorganic base is selected from potassium carbonate or sodium carbonate.
The molar ratio of the compound A1 to the base 1 in the step 1) is 1: 1-1: 3, preferably 1: 2.
The solvent used in the reaction of step 1) is DMF.
The molar ratio of the compound A1 to the compound A2 in the step 1) is 1: 1-1: 1.5, preferably 1: 1.2. Preferably the reaction is carried out at 0 ℃.
The molar ratio of the compounds A3 and A4 in the step 2) is 1: 1-1: 2, preferably 1: 1.5.
The step 2) reaction is carried out in a solvent, preferably an alcoholic solvent such as methanol, tetrahydrofuran, etc. or a mixture thereof. Preferably, the solvent is subjected to anhydrous treatment before use.
The catalyst for the reaction in the step 2) is sodium borohydride or sodium cyanoborohydride, and the molar ratio of the catalyst to the compound A3 is 1: 1-1: 2, preferably 1: 2.
Preferably, the catalyst is added in small portions. Preferably, the addition is carried out dropwise.
Acetic acid is also added into the reaction system in the step 2). Preferably, the molar ratio of the acetic acid to the compound A3 is 1: 1-1: 2, preferably 1:1.
And 2) adding all the raw materials, and heating to 50-80 ℃ for reflux reaction. Preferably, the temperature is raised to 60-70 ℃.
Step 3) compound A5 is catalyzed by hydrogenation, reduction and deprotection to obtain compound A6.
The catalytic catalyst was Pd/C.
The molar ratio of the compound A6 to the alkali 2 in the step 4) is 1: 1-1: 2, preferably 1: 2.
The solvent used in the reaction of step 4) is DMF.
The molar ratio of the compound A6 to the compound A7 in the step 4) is 1: 1-1: 4, preferably 1: 2. Preferably the reaction is carried out at 0 ℃.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
These compositions can be used to achieve a desired pharmacological effect by administration to a patient in need thereof. For the purposes of the present invention, a patient is a mammal, including a human, in need of treatment for a particular condition or disease. Accordingly, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A pharmaceutically acceptable carrier is preferably one that is relatively non-toxic and non-injurious to a patient at concentrations consistent with effective activity of the active ingredient, such that any side effects caused by the carrier do not destroy the beneficial effects of the active ingredient. A pharmaceutically effective amount of a compound or a pharmaceutically acceptable salt thereof is preferably an amount that results in, or affects, the particular condition being treated. The compounds of the present invention may be administered together with pharmaceutically acceptable carriers well known in the art in any effective conventional dosage unit form including immediate release, sustained release and timed release formulations in the following manner: oral, parenteral, topical, nasal, ocular, sublingual, rectal, vaginal, and the like.
For oral administration, the compound or a pharmaceutically acceptable salt thereof may be formulated into solid or liquid preparations such as capsules, pills, tablets, troches (troche), dragees (lozenes), melt gels (melt), powders, solutions, suspensions or emulsions, and may be prepared according to methods known in the art for preparing pharmaceutical compositions. The solid unit dosage form may be a capsule, which may be of the ordinary hard or soft capsule type, containing, for example, surfactants, lubricants, and inert fillers (e.g., lactose, sucrose, calcium phosphate, and corn starch).
In another embodiment, a compound of the invention or a pharmaceutically acceptable salt thereof may be compressed into a tablet with a conventional tablet base (e.g., lactose, sucrose and corn starch) and in combination with: binders (e.g., acacia, corn starch or gelatin), disintegrating agents to aid in the disintegration and dissolution of the tablet after administration (e.g., potato starch, alginic acid, corn starch and guar gum, gum tragacanth, acacia), lubricants to improve the flowability of the tablet granulation and to prevent adhesion of the tablet materials to the surfaces of the tablet die and punch (e.g., talc, stearic acid or magnesium stearate, calcium stearate or zinc stearate), dyes, colorants, and flavoring agents (e.g., peppermint, oil of wintergreen or cherry flavoring) to improve the organoleptic properties of the tablets and make them more acceptable to the patient. Suitable excipients for oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols (e.g., ethanol, benzyl alcohol and polyvinyl alcohol), with or without the addition of pharmaceutically acceptable surfactants, suspending agents or emulsifying agents. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar or both.
Dispersible powders and granules are suitable for use in the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, such as those described above, may also be present.
The pharmaceutical composition of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) natural gums, for example gum acacia and gum tragacanth, (2) natural phosphatides, for example soya bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, (4) condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. The suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate; one or more colorants; one or more flavoring agents; and one or more sweetening agents, such as sucrose or saccharin.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent and a preservative (e.g., methyl and propyl parabens) as well as flavoring and coloring agents.
The compounds of the invention may also be administered parenterally, i.e., subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly or intraperitoneally, in injectable doses of the compounds, preferably in a physiologically acceptable diluent with a pharmaceutical carrier, which may be a sterile liquid or a mixture of liquids, such as water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol, isopropanol or cetyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2, 2-dimethyl-1, 1-dioxolane-4-methanol, ethers such as polyethylene glycol 400(PEG400), oils, fatty acids, fatty acid esters or glycerides or acetylated glycerides, with or without the addition of pharmaceutically acceptable surfactants such as soaps or detergents, suspending agents such as pectin, carbomer, methylcellulose, hypromellose or carboxymethylcellulose, or emulsifying agents and other pharmaceutically acceptable adjuvants.
Exemplary oils useful in the parenteral formulations of the invention are those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium and triethanolamine salts, and suitable detergents include cationic detergents such as dimethyl dialkyl ammonium halides, alkyl pyridinium halides and alkylamine acetates; anionic detergents such as alkyl sulfonates, aryl sulfonates and olefin sulfonates, alkyl sulfates and alkyl sulfosuccinates, olefin sulfates and olefin sulfosuccinates, ether sulfates and ether sulfosuccinates, and monoglyceride sulfates and monoglycerides sulfosuccinates; nonionic detergents such as fatty amine oxides, fatty acid alkanolamides, and poly (oxyethylene-oxypropylene), ethylene oxide copolymers or propylene oxide copolymers; and amphoteric detergents such as alkyl-beta-aminopropionates and 2-alkylimidazoline quats, and mixtures thereof.
The parenteral compositions of the invention will typically comprise from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be advantageously employed. To minimize or eliminate irritation at the injection site, such compositions may comprise a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) of preferably from about 12 to about 17. The amount of surfactant in such formulations is preferably from about 5% to about 15% by weight. The surfactant may be a single component having the above HLB, or a mixture of two or more components having the desired HLB.
Exemplary surfactants for parenteral formulations are polyethylene sorbitan fatty acid esters, such as sorbitan monooleate, and the high molecular weight adducts of ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide and propylene glycol.
The pharmaceutical composition may be in the form of a sterile aqueous suspension for injection. Such suspensions may be formulated according to known methods using: suitable dispersing or wetting agents and suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide (for example lecithin), a condensation product of an alkylene oxide with a fatty acid (for example polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (for example heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (for example polyoxyethylene sorbitol monooleate), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (for example polyoxyethylene sorbitan monooleate).
The sterile injectable preparation may also be a sterile solution or suspension for injection in a non-toxic parenterally-acceptable diluent or solvent. Diluents and solvents which can be used are, for example, water, ringer's solution, isotonic sodium chloride solution and isotonic glucose solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. In this regard, any less irritating fixed oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids (e.g., oleic acid) may be used in the preparation of injectables.
The compositions of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycols.
Controlled release formulations for parenteral administration include liposomal microspheres, polymeric microspheres, and polymeric gel formulations known in the art.
It may be desirable or necessary to deliver the pharmaceutical composition to a patient by a mechanical delivery device. The construction and use of mechanical delivery devices for delivering pharmaceutical agents is well known in the art. Direct techniques such as administering drugs directly to the brain typically involve placing a drug delivery catheter into the ventricular system of the patient to bypass the blood brain barrier.
The compounds of the present invention may be administered as a single agent or in combination with one or more other agents, wherein the combination does not cause unacceptable adverse effects. The invention also relates to such combinations. For example, the compounds of the present invention or pharmaceutically acceptable salts thereof may be combined with known antidepressants and with mixtures and combinations thereof.
In general, the following effects will occur when the compounds of the present invention or pharmaceutically acceptable salts thereof are used in combination with known antidepressants and with mixtures and combinations thereof:
(1) produces better efficacy in antidepressant than either agent alone,
(2) allowing for the administration of smaller amounts of the administered chemotherapeutic agent,
(3) providing a chemotherapeutic treatment that is well tolerated by patients and has fewer harmful pharmacological complications than observed with single agent chemotherapy and certain other combination therapies,
(4) allowing for the treatment of a wider range of mammals (particularly humans),
(5) providing a higher response in the treated patient,
(6) efficacy and tolerability at least as good as those of the agents used alone are obtained compared to what is known for other antidepressant combinations to produce antagonistic effects.
The invention also provides the use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament. The use of said medicament is preferably in medicaments for the treatment of depression, anxiety, stress-induced incontinence, central pain.
Advantageous effects
The invention provides a novel escitalopram derivative and a preparation method thereof. The derivatives have superior pharmaceutical activity to escitalopram. In addition, the preparation method has the advantage of simple and convenient operation, can respectively obtain target products with higher yield and/or purity, and can meet the requirements of medicine production.
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.
EXAMPLE 1 preparation of Compound 1
Figure BDA0001707235680000181
1.1 preparation of Compounds 1-3
In a 500ml single-neck flask, compound 1-1(5.9g, 0.02mol, 1eq) and 200ml of DMF as a solvent were charged, potassium carbonate (3.04g, 0.022mol, 1.1eq) was added thereto with stirring, and benzyl chloride (3.02g, 0.024mol, 1.2eq) was slowly added dropwise at 0 ℃ and reacted at room temperature overnight.
And (3) judging the termination of the reaction: sampling, adding water EA to extract, and dotting the plate.
And (3) post-treatment: adding water to stop the reaction, extracting with 200ml 2EA, washing the organic phase with saturated salt water, drying with anhydrous magnesium sulfate, filtering, concentrating to obtain crude product, and purifying with column to obtain pure product 6.1 g. Yield: 79.9 percent.
1.2 preparation of Compounds 1-5
A250 ml two-neck flask was charged with 1 to 3(3.860g, 0.01mol, 1eq) of compound, 10ml of a mixed solvent of methanol and tetrahydrofuran (volume ratio 1:1) as a solvent, and 1-ethoxy-1-trimethylsilylcyclopropane (2.6g, 0.015mol, 1.5eq) and acetic acid (0.9g, 0.01mol, 1eq) were sequentially added thereto with stirring, and finally, sodium cyanoborohydride (1.88g, 0.02mol, 2eq) was added thereto in portions, and after completion of the addition, the mixture was heated under reflux overnight.
And (3) judging the termination of the reaction: sampling, adding water, and performing EA extraction to obtain a back spot plate.
And (3) post-treatment: adding water to stop the reaction, extracting with 250ml ethyl acetate, drying with anhydrous magnesium sulfate, filtering, concentrating, passing through a column to obtain a pure product 3.08g, and obtaining the yield: 72.3 percent.
1.3 preparation of Compounds 1-6
A100 ml single-neck flask was charged with 1-5(2.13g, 0.005mol, 1eq) compounds and 60ml of anhydrous methanol as solvent, stirred, added with 1g Pd/C, hydrogenated, and monitored by TLC until the reaction was complete.
And (3) post-treatment: the Pd/C is removed by suction filtration, the filtrate is concentrated and passes through a column, and the pure product is 1.42g of white solid, the yield is 84.3 percent.
1.4 preparation of Compound 1
Dissolving the compounds 1 to 6(0.336g,0.001mol,1eq) prepared in step 1.3 and iodoethane (0.31g,0.002mol,2eq) in DMF (20mL), adding potassium carbonate (0.152g,0.0011mol,1.1eq), reacting at 0 ℃, monitoring the reaction, washing with water, EA extraction, and passing through a column after completion of concentration to obtain 10.226g of compound, yield: 62.3 percent. MS (m/z): 365.2(M + H).
Compounds 2 to 102 were prepared in the same manner as in reference example 1, and the yields and characterization data for compounds 1 to 102 are shown in the following table:
Figure BDA0001707235680000191
Figure BDA0001707235680000201
Figure BDA0001707235680000211
example 2: test for pharmaceutical Activity
Effect of Compounds of illustrative examples of the invention on forced swimming test in mice
Kunming white mice with the weight of 20-22g are grouped and bred in cages before the test, and each box is provided with 5 mice. Animals were kept in a clean, ventilated, 12-hour light-dark cycle, quiet environment, with free access to drinking water. Animal grouping: the vehicle control group, escitalopram, the tested group and each group of animals are orally administrated, and the dosage is 0.33 mg/kg. After dosing, each animal was gently placed in a swimming device (plexiglas jar, diameter 18cm, height 30cm, water depth 10cm, water temperature 23 ± 2 ℃, water inside the swimming device changed after each animal was swimming), the mice were swim for 6 minutes, and the cumulative immobility time (seconds, s) within 4 minutes after swimming was recorded. Data were processed using SPSS12.0 statistical software. And (4) carrying out one-way analysis of variance. The test results are shown in Table 2.
Table 2 effect of compounds of the exemplary embodiments of the present invention on forced swimming of mice (n ═ 10, X ± S)
Sample name Swimming experiment (motionless time/s)
Vehicle control group 189.17±17
Escitalopram group 167±15
2 153.4±9.0
9 154.2±9.1
15 160.1±13.6
18 156.5±10.1
25 146.5±8.0
29 155.1±9.4
31 161.7±5.5
37 160.1±6.1
43 159.3±6.0
48 158.0±9.4
51 151.4±8.9
57 158.2±11.1
63 148.7±8.1
67 150.4±8.4
70 160.7±12.1
77 157.4±10.4
82 160.4±10.4
87 160.1±12.0
92 160±8.0
96 159.2±10.5
In the forced swimming test, the immobility time (despair state) of the mice is shortened, and the antidepressant effect of the medicine is reflected. In this experiment, the exemplified example compounds significantly shortened immobility time in mice compared to vehicle control and escitalopram groups, suggesting: the exemplified example compounds have an antidepressant effect superior to that of escitalopram.
Example 3 acute toxicity study of exemplary example compounds of the invention:
experimental materials:
the Kunming white rat is half male and female, the weight of the Kunming white rat is 18-22 g, and animals are fed with pellet feed and can freely eat and drink water.
The compounds tested in Table 2 were each formulated with 0.5% CMC-Na to a 500mg/mL suspension.
Experimental methods
Mice of Kunming species were gavaged with 20ml/kg of the compound tested in Table 2 at a single weight, and observed for toxicity and mortality within 15 days of the animals following administration. 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 14g/kg, which indicates that the compound of the embodiment of the invention has lower acute toxicity.

Claims (10)

1. An escitalopram derivative of formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0003279557140000011
wherein the content of the first and second substances,
R1selected from cyclopropyl;
R2selected from the group consisting of optionally substituted by one or more RaSubstituted C1-6Alkyl-;
R3and R4Independently of one another from F,Cl、Br、I、OH、SH、CN、NH2、C1-6An alkyl group;
Raselected from F, Cl, Br, I, OH, SH, CN, ═ O or optionally substituted by one or more ReSubstituted of the following groups: NR (nitrogen to noise ratio)cRd、C1-6Alkyl-, C2-6Alkenyl-, C3-C10cycloalkyl-C6-14Aryl-, 3-10 membered heterocycloalkyl containing 1,2, 3 or 4 heteroatoms selected from N, O and S-, 5-14 membered heteroaryl containing 1,2, 3 or 4 heteroatoms selected from N, O and S-, C1-6Alkyloxy-, C2-6Alkenyloxy-, C3-C10Cycloalkyloxy-, C6-14Aryloxy-, 3-10 membered heterocycloalkyloxy comprising 1,2, 3 or 4 heteroatoms selected from N, O and S-, 5-14 membered heteroaryloxy comprising 1,2, 3 or 4 heteroatoms selected from N, O and S-, C1-6Alkylthio-, C2-6alkenylthio-C3-C10Cycloalkylthio-, C6-14Arylthio-, 3-10 membered heterocycloalkylthio comprising 1,2, 3 or 4 heteroatoms selected from N, O and S-, 5-14 membered heteroarylthio comprising 1,2, 3 or 4 heteroatoms selected from N, O and S-, -OC (═ O) Rb、-OS(＝O)2Rb；
RbSelected from the group consisting of optionally substituted by one or more ReSubstituted of the following groups: c1-6Alkyl-, C2-6Alkenyl-, C3-10cycloalkyl-C6-14Aryl-, 3-10 membered heterocycloalkyl containing 1,2, 3 or 4 heteroatoms selected from N, O and S-, 5-14 membered heteroaryl containing 1,2, 3 or 4 heteroatoms selected from N, O and S-;
Rcand RdIndependently of one another, selected from H or optionally substituted by one or more ReSubstituted of the following groups: c1-6Alkyl-, C2-6Alkenyl-, C3-10cycloalkyl-C6-14Aryl-, 3-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S-, 5-14 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S-, or, RcAnd RdMay be taken together with the nitrogen atom to which it is attached to form a 3-10 membered heterocyclic group, said heterocyclic group optionally further comprising 1,2 or 3 substituents selected from N, N,O and S heteroatoms;
Reselected from F, Cl, Br, I, OH, SH, CN, NH2、C1-6Alkyl radical, C2-6Alkenyl-, C3-10cycloalkyl-C1-6Alkyloxy-, C2-6Alkenyloxy-, C3-C10Cycloalkyloxy-, C1-6Alkylthio-, C2-6alkenylthio-C3-C10Cycloalkylthio-, C1-6An alkylcarbonyl group;
wherein the following specific compounds are excluded:
R1is cyclopropyl; r2Is methyl; r3Is fluorine; r4Is cyano.
2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that
R2Selected from the following groups unsubstituted or optionally substituted with Rs: c1-6Alkyl, hydroxy C1-6Alkyl 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 C1-6An alkyl group;
rs is selected from C1-6Alkyl or C3-10A cycloalkyl group.
3. Compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of mono-, di-and tri-salts.
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that said compound is selected from the following compounds:
Figure FDA0003279557140000021
Figure FDA0003279557140000031
Figure FDA0003279557140000041
Figure FDA0003279557140000051
Figure FDA0003279557140000061
Figure FDA0003279557140000071
5. a process for the preparation of a compound according to any one of claims 1 to 4, or a pharmaceutically salt thereof, characterized in that it comprises the following steps:
Figure FDA0003279557140000081
1) reacting the compound A1 with A2 in the presence of a base 1 to obtain a compound A3;
2) reacting the compound A3 with A4 to obtain a compound A5;
3) deprotection of compound a5 affords compound a 6;
4) reacting compound A6 with A7 in the presence of a base 2 to obtain compound (I);
the base 1 and the base 2 are the same or different and are independently selected from inorganic bases;
wherein R is1～R4Each independently having the definitions of any one of claims 1 to 4, L1、L2、L3Identical or different, independently of one another, are leaving groups.
6. The production method according to claim 5,
L1、L2、L3identical or different, independently of one another, are chlorine, bromine, iodine or 1-ethoxy-1-trimethylsiloxy;
the inorganic base is selected from potassium carbonate or sodium carbonate.
7. Use of a compound 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.
8. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.
9. The pharmaceutical composition of claim 8, further comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
10. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4, together with known antidepressants and with mixtures thereof.
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