Novel venlafaxine derivative and preparation method and application thereof
阅读说明：本技术 一种新的文拉法辛衍生物及其制备方法和应用 (Novel venlafaxine derivative 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：本发明属于化学药物及其制备方法和应用的技术领域,具体涉及一种新的文拉法辛衍生物及其制备方法和应用。本发明的化合物具有优于文拉法辛的药学活性,并且制备方法简单。<Image he="509" wi="555" file="DDA0001706923920000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention belongs to the technical field of chemical drugs and preparation methods and applications thereof, and particularly relates to a novel venlafaxine derivative and a preparation method and application thereof. The compound of the invention has better pharmaceutical activity than venlafaxine and the preparation method is simple.)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein n is 0, 1,2, 3,4, 5 or 6;
x is selected from H, the following 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.
2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein X is selected from C1-4An alkyl group;
said C is3-10Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or is a bicyclic hydrocarbon group such as a decaline ring;
said 3-10 membered heterocycloalkyl group is selected from the group consisting of containing 1,2, 3 or 4 heteroatoms selected from N, O and S;
said C is6-14Aryl is selected from phenyl, biphenyl, indanyl, indenyl, tetrahydronaphthyl, dihydronaphthyl or 1-naphthyl, 2-naphthyl, fluorenyl, anthracenyl;
the 5-to 14-membered heteroarylthienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof.
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:
5. a process for the preparation of a compound according to any one of claims 1 to 4,
it is characterized by comprising:
scheme 1
a1) Reacting the compound A2 with A3 in the presence of a base to obtain a compound A4;
a2) reacting the compound A4 with A5 to obtain a compound A6;
a3) deprotection of compound a6 affords compound 103;
a4) reacting compound 103 with a1 in the presence of a base to give compound (I);
alternatively, scheme 2
b1) Reacting compound a2 with A8 to give compound 104;
wherein n and X have the meanings given in any of claims 1 to 4, L1、L2、L3、L4Is a leaving group;
in scheme 1, X is not cyclopropyl and n is not 0.
6. The method according to claim 5, wherein L is1、L2、L3、L4Identical or different, independently of one another, are chlorine, bromine, iodine or 1-ethoxy-1-trimethylsiloxy.
7. The method according to claim 5 or 6, wherein the base is an inorganic base.
8. 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, obsessive compulsive disorder, social phobia, or mental trauma.
9. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.
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.
Technical Field
The invention relates to a novel venlafaxine derivative and a preparation method and application thereof, belonging to the technical field of chemical drugs and preparation methods and applications thereof.
Background
Venlafaxine (Venlafaxine, structure shown as the following formula) with chemical name of (R/S) -1- [ 2-dimethylamino-1- (4-methoxyphenyl) ethyl ] cyclohexanol is three biogenic amines: reuptake inhibitors of 5-hydroxytryptamine, norepinephrine and dopamine. The compound may also be administered in its hydrochloride salt form, i.e. venlafaxine hydrochloride.
Both 5-hydroxytryptamine and norepinephrine are central neurotransmitters and play an important role in regulating emotion and sensitivity to pain. Venlafaxine inhibits neuronal reuptake of 5-hydroxytryptamine and norepinephrine, thereby increasing the concentration of these two central neurotransmitters in the brain and spinal cord, and is useful for treating mood disorders such as depression and anxiety, and relieving central pain such as diabetic peripheral neuropathic pain and female fibromyalgia. Venlafaxine also acts on 5-hydroxytryptamine and norepinephrine receptors in the urinary tract, thereby enhancing the nervous tone and contractile capacity of the urinary sphincter muscle, and is therefore also effective in the treatment of stress urinary incontinence in women.
However, the activity of venlafaxine remains to be further improved.
Disclosure of Invention
The present invention aims to overcome the above-mentioned deficiencies in the prior art and provides a compound represented by formula (1) or a pharmaceutically acceptable salt thereof:
wherein n is 0, 1,2, 3,4, 5 or 6;
x is selected from H, the following 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.
In the present invention, "substituted" means that one or more H is optionally substituted with other groups in one group. As an example, the substituents are selected from halogen (F, Cl, Br or I), -OH, -NH2-SH, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl, wherein said substituents are optionally further substituted.
The term "C1-6Alkyl "refers to an alkyl group having 1,2, 3,4, 5, or 6 carbon atoms, wherein the alkyl group can be either a straight chain or branched chain alkyl group, including but not limited toMethyl, 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- 44 alkyl group), such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly said group having 1,2 or 3 carbon atoms ("C)1-3Alkyl groups) such as methyl, ethyl, n-propyl or isopropyl.
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 consisting of 3,4, 5,6, 7, 8, 9 or 10 ring atoms, 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 through 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. "4-8 membered heterocycloalkyl" refers to a 4-8 membered group in which optionally 1-3 carbon atoms are substituted with heteroatoms, wherein the heteroatoms are independently selected from N, O or S. By way of example, the groups may include, but are not limited to
The term "C6-14Aryl "is understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular a ring having 6 carbon atoms (" C6 aryl "), for example phenyl; or biphenyl, or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or 1-naphthyl, 2-naphthyl, or a ring having 13 carbon atoms ("C13 aryl"), such as fluorenyl, or a ring having 14 carbon atoms ("C14 aryl"), 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.
By way of example, the groups may include, but are not limited to
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.
Exemplary compounds of formula (1) of the present invention include the following:
another objective of the present invention is to provide a method for preparing the novel venlafaxine analog, comprising:
scheme 1
a1) Reacting the compound A2 with A3 in the presence of a base to obtain a compound A4;
a2) reacting the compound A4 with A5 to obtain a compound A6;
a3) deprotection of compound a6 affords compound 103;
a4) reacting compound 103 with a1 in the presence of a base to give compound (I);
alternatively, scheme 2
b1) Reacting compound a2 with A8 to give compound 104;
wherein n and X have the above-mentioned meanings, L1、L2、L3、L4Is a leaving group;
in scheme 1, X is not cyclopropyl and n is not 0.
Preferably, L1、L2、L3、L4Identical or different, independently of one another, are chlorine, bromine, iodine or 1-ethoxy-1-trimethylsiloxy.
Preferably, the base is an inorganic base, such as sodium carbonate, potassium carbonate or a mixture thereof.
Preferably, compound a2 can be prepared by conventional organic synthesis methods.
In the case of the scheme 1, the reaction,
the molar ratio of the compound A2 in the step a1) to the base is 1: 1-1: 2, preferably 1: 1.1.
The solvent used for the reaction of step a1) was DMF.
The molar ratio of the compound A2 to the compound A3 in the step a1) is 1: 1-1: 1.5, preferably 1: 1.2. Preferably the reaction is carried out at 0 ℃.
Step a2) compound A4 and A5 molar ratio is 1: 1-1: 2, preferably 1: 1.5.
The step a2) reaction is carried out in a solvent, 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.
The catalyst for the reaction in the step a2) is sodium borohydride or sodium cyanoborohydride, and the molar ratio of the catalyst to the compound 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 a 2). Preferably, the molar ratio of the acetic acid to the compound A4 is 1: 1-1: 2, preferably 1:1.
Step a2) adding all the raw materials, and heating to 50-80 ℃ for reflux reaction. Preferably, the temperature is raised to 60-70 ℃.
The step a2) reaction is specifically as follows:
a4(3.0g, 0.0088mol, 1eq) and 50ml of a mixed solvent of methanol and tetrahydrofuran (volume ratio 1:1) were charged in a 250ml two-neck flask, and compound A5(2.3g, 0.0132mol, 1.5eq) and acetic acid (0.53g, 0.0088mol, 1eq) were added thereto in this order with stirring, and finally sodium cyanoborohydride (1.1g, 0.0176mol, 2eq) was added thereto in portions, and after completion of the addition, the mixture was heated under reflux overnight.
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 extraction is carried out by adopting ethyl acetate.
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.
Step A3) compound A6 catalyzed hydrogenation reduction deprotection to give compound A7.
The catalytic catalyst was Pd/C.
The molar ratio of the compound 103 to the base in the step a4) is 1: 1-1: 2, preferably 1: 2.
The solvent used for the reaction of step a4) was DMF.
The molar ratio of the compound 103 to the A1 in the step a4) is 1: 1-1: 4, preferably 1: 2. Preferably the reaction is carried out at 0 ℃.
In the case of the embodiment 2, the following,
the molar ratio of the compound A2 to the compound A8 in the step b1) is 1: 1-1: 2, preferably 1: 2.
Wherein 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.
Wherein, the catalyst for the reaction is sodium borohydride or cyano sodium borohydride. The molar ratio of the catalyst to the compound A2 is 1: 1-1: 2, preferably 1: 2.
Preferably, the catalyst is added in small portions. Preferably, the addition is carried out dropwise.
Wherein acetic acid is also added into the reaction system. Preferably, the molar ratio of the acetic acid to the compound A2 is 1: 1-1: 2, preferably 1:1.
Wherein, all the raw materials are added and heated to 50-80 ℃ for reflux reaction. Preferably, the temperature is raised to 60-70 ℃.
The reaction is specifically as follows:
a250 ml two-neck flask was charged with 2(10g, 0.0401mol, 1eq) of compound A, a mixed solvent of methanol and tetrahydrofuran (volume ratio 1:1) as a solvent, and while stirring, 8(14.0g, 0.0802mol, 2eq) of compound A and acetic acid (2.4g, 0.0401mol, 1eq) were added thereto in this order, and finally, sodium cyanoborohydride (5.0g, 0.0802mol, 2eq) was added thereto in portions with a slight exotherm during the addition, and after the addition was completed, the mixture was heated under reflux overnight.
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 extraction is carried out by EA.
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 the following technical scheme:
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 medicament is preferably used in medicaments for treating depression, anxiety, obsessive compulsive disorder, social phobia and mental trauma.
Advantageous effects
The invention provides a novel venlafaxine analogue and a preparation method thereof. The analogs have superior pharmaceutical activity to venlafaxine. In addition, the preparation method has the advantage of simple operation, and the compound can be prepared respectively with higher yield and/or purity, such as the yield reaches 80 percent, even more than 90 percent, and the total yield reaches more than 50 percent, thereby meeting the requirement of drug production.
Drawings
FIG. 1 is a drawing of compound 103 of the present invention1H NMR (DMSO) chart.
FIG. 2 is a drawing of inventive Compound 1041H 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.