WO2017215636A1 - 二芳基硫醚哌嗪类化合物及其制备方法和用途 - Google Patents

二芳基硫醚哌嗪类化合物及其制备方法和用途 Download PDF

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WO2017215636A1
WO2017215636A1 PCT/CN2017/088493 CN2017088493W WO2017215636A1 WO 2017215636 A1 WO2017215636 A1 WO 2017215636A1 CN 2017088493 W CN2017088493 W CN 2017088493W WO 2017215636 A1 WO2017215636 A1 WO 2017215636A1
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group
compound
alkyl
independently
heteroaryl
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PCT/CN2017/088493
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English (en)
French (fr)
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雷鑫
李东明
罗忠华
何必飞
王茜
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广东东阳光药业有限公司
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Priority to CN201780032963.1A priority Critical patent/CN109311833B/zh
Priority to US16/308,462 priority patent/US10927089B2/en
Priority to JP2018565312A priority patent/JP2019525900A/ja
Publication of WO2017215636A1 publication Critical patent/WO2017215636A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to the field of medicine, and in particular, the present invention relates to a compound, a preparation method and application thereof, and more particularly, the present invention relates to a compound represented by the formula (I) and the formula (II), a preparation method thereof, a pharmaceutical composition and application thereof .
  • MDD Major Depressive Disorder
  • Votinoxetine Hydrobromide (Lu AA21004, Vortioxetine Hydrobromide) is a new class of chemical antidepressants developed by Danish Lingbei and Japan's Takeda Pharmaceutical Co., Ltd., and acquired in the United States on September 30, 2013.
  • the Food and Drug Administration (FDA) approves the treatment of major depression in adults. In the drug instructions for vortixetine, it is indicated that the drug needs to be taken once a day.
  • the present invention aims to solve at least one of the technical problems in the related art to some extent.
  • the invention uses 1-[2-(2,4-dimethylphenylthio)phenyl]piperazine as a raw material to prepare a batch of diaryl sulfide piperazine compounds, and carries out pharmacological experiments on animals. Unexpectedly, it has a good sustained release effect in animals. The sustained release effect of one dose can be maintained for one week to several weeks. If it can be used in clinic, it is possible to greatly reduce the frequency of taking this drug and make the patient It is more convenient to take this medicine.
  • the invention provides a compound which is a compound of formula (I),
  • HX is a C 10-20 fatty acid or pamoic acid.
  • the compound of the formula (I) can be used for the treatment of major depression, and has good pharmacokinetic properties and low solubility, so that the compound of the formula (I) can be slowly released and exerted in the body.
  • the pharmacological effect that is to say, the compound represented by the formula (I) can be pharmacologically effective for a relatively long period of time in the body, thereby reducing the number of administrations and making the administration more convenient.
  • HX is stearic acid, palmitic acid, lauric acid or pamoic acid.
  • the compound is a compound having at least one of the following structures:
  • the present invention provides a compound which is a stereoisomer, a tautomer, a solvate or a pharmaceutically acceptable compound of the compound of the formula (II) or the compound of the formula (II).
  • Acceptable salt
  • X 1 is a bond or -(CH 2 ) n -;
  • Y is a key
  • Z is a C 2-10 alkyl group, a C 5-10 heteroaryl group, a C 5-10 heterocyclic group, wherein the C 2-10 alkyl group, a C 5-10 heteroaryl group And the C 5-10 heterocyclyl is, independently, optionally substituted by one or more R groups;
  • Y When Y is When Z is a C 1-20 alkyl group, a C 6-10 aryl group, a C 5-10 heteroaryl group, a C 5-10 heterocyclic group, wherein the C 1-20 alkyl group, C 6-10 aryl group
  • the base, C 5-10 heteroaryl and C 5-10 heterocyclyl are, independently, optionally substituted by one or more R groups;
  • n 1, 2, 3, 4 or 5;
  • Each R group is independently F, Cl, Br, I, amino, hydroxy or C 1-6 alkyl
  • the compound of the formula (II) can be used for the treatment of major depression, and has good pharmacokinetic properties and low solubility, so that the compound of the formula (II) can be slowly released and exerted in the body.
  • the pharmacological effect that is to say, the compound represented by the formula (II) can be pharmacologically effective for a long period of time in the body, thereby reducing the number of administrations and making the administration more convenient.
  • Z is a C 2-10 alkyl group, a C 5-10 heteroaryl group, a C 5-10 heterocyclic group, and Z is not a tert-butyl group, wherein The C 2-10 alkyl, C 5-10 heteroaryl and C 5-10 heterocyclyl are, independently, optionally substituted by one or more R groups.
  • Z is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, 2-pentyl, 3 a pentyl group, a C 5-8 heteroaryl group, a C 5-8 heterocyclic group, wherein the ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, n-pentyl group , 2-pentyl, 3-pentyl, C 5-8 heteroaryl and C 5-8 heterocyclyl are, independently, optionally substituted by one or more R groups; n is 0, 1, 2 or 3 Each R group is independently F, Cl, Br, I, amino, hydroxy or C 1-3 alkyl.
  • Z is a C 2-5 linear alkyl group, a C 5-7 heteroaryl group, a C 5-7 heterocyclic group, wherein the C 2-5
  • the linear alkyl group, C 5-7 heteroaryl group or C 5-7 heterocyclic group is independently optionally substituted by one or more R groups; n is 1, 2 or 3; each R group is independently F, Cl, Br, I, amino, hydroxy or C 1-3 alkyl.
  • Y is Wherein Z is a C 1-20 alkyl group, a phenyl group, a C 6-8 aryl group, a C 5-8 heteroaryl group, a C 5-8 heterocyclic group, wherein the C 1-20 alkyl group, a phenyl group , C 6-8 aryl, C 5-8 heteroaryl and C 5-8 heterocyclyl are, independently, optionally substituted by one or more R groups; n is 0, 1, 2 or 3; The group is independently F, Cl, Br, I, amino, hydroxy or C 1-3 alkyl.
  • the compound is a compound having one of the following structures or one of the following a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt of a compound,
  • the present invention provides a method of preparing the compound, comprising:
  • X 1 is a bond or -(CH 2 ) n -;
  • Each R 1 is independently F, Cl, Br or I;
  • Z is a C 1-20 alkyl group, a C 6-10 aryl group, a C 5-10 heteroaryl group, a C 5-10 heterocyclic group, wherein the C 1-20 alkyl group, a C 6-10 aryl group, The C 5-10 heteroaryl and C 5-10 heterocyclyl are, independently, optionally substituted by one or more R groups;
  • n 1, 2, 3, 4 or 5;
  • Each R group is independently F, Cl, Br, I, amino, hydroxy or C 1-6 alkyl.
  • Z is C 1-20 alkyl, phenyl, C 6-8 aryl, C 5-8 heteroaryl, C 5-8 heterocyclyl, wherein said C 1-
  • the 20 alkyl, phenyl, C 6-8 aryl, C 5-8 heteroaryl and C 5-8 heterocyclic groups are each independently optionally substituted with one or more R groups; n is 1, 2 or 3; each R group is independently F, Cl, Br, I, amino, hydroxy or C 1-3 alkyl.
  • the present invention provides a pharmaceutical composition comprising the compound of the formula (I), the compound of the formula (II) or the formula (III) obtained by the method described above. ) the compound shown.
  • the pharmaceutical composition further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or vehicle.
  • the pharmaceutical composition further comprises an additional therapeutic agent for treating depression.
  • the present invention provides a compound of the formula (I), a compound of the formula (II), a compound of the formula (III) obtained by the method described above or a drug as described above.
  • the present invention provides a compound represented by the formula (I), which is represented by the formula (II)
  • the invention provides a method of treating depression.
  • the method comprises administering to a depressed patient a compound of the formula (I), a compound of the formula (II), a compound of the formula (III) obtained by the method described above or a front The pharmaceutical composition.
  • the method further comprises administering to the depressed patient an additional therapeutic agent for treating depression.
  • substituted or “substituted” means that one or more hydrogen atoms in the structure are replaced by a particular substituent. Unless otherwise indicated, a substituted group may have one substituent substituted at each substitutable position of the group. When more than one position in the given formula can be substituted by one or more substituents selected from a particular group, the substituents may be substituted at the various positions, either identically or differently.
  • C 1 -C 6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • alkyl refers to a saturated straight or branched monovalent hydrocarbon radical containing from 1 to 20 carbon atoms. Unless otherwise specified, an alkyl group contains from 1 to 20 carbon atoms. In one embodiment, the alkyl group contains from 1 to 10 carbon atoms; in another embodiment, the alkyl group contains from 1 to 8 carbon atoms; in yet another embodiment, the alkyl group contains 1 -6 carbon atoms; in yet another embodiment, the alkyl group contains 1-4 carbon atoms; and in one embodiment, the alkyl group contains 1-3 carbon atoms.
  • the alkyl group is optionally substituted with one or more substituents described herein.
  • alkyl groups include methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ) , isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH ( CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 ) CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl- 2-butyl (-C(CH 3 ) 2 ), 2-
  • heteroatom means one or more of oxygen (O), sulfur (S), nitrogen (N), phosphorus (P) or silicon (Si), including nitrogen (N), sulfur (S) and phosphorus (P). a form of any oxidation state; a form of a primary, secondary, tertiary amine, and a quaternary ammonium salt; or a form in which a hydrogen on a nitrogen atom in a heterocyclic ring is substituted, for example, N (like 3,4-dihydro-2H-pyrrolyl) N), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).
  • heterocycle refers to a monovalent or bivalent monocyclic, bicyclic or tricyclic ring system containing from 3 to 14 ring atoms, wherein One or more atoms on the ring are independently replaced by a hetero atom having the meaning as described herein, the ring may be fully saturated or contain one or more unsaturations, but an aromatic ring not allowed.
  • a “heterocycle”, “heterocyclyl” or “heterocyclic” group is a 3-8 membered ring of a monocyclic ring (2-6 carbon atoms and selected from N, O, P, S) 1-3 heteroatoms, wherein S or P is optionally substituted with one or more oxygen atoms to give a group like SO, SO 2 , PO, PO 2 when the ring is a three-membered ring , which has only one heteroatom), or a 7-12 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally a Or a plurality of oxygen atoms are substituted to obtain a group like SO, SO 2 , PO, PO 2 ).
  • the heterocyclyl group is optionally substituted with one or more substituents described herein.
  • the heterocyclic group may be a carbon group or a hetero atom group.
  • the sulfur atom of the ring may be optionally oxidized to an S-oxide
  • the nitrogen atom of the ring may be optionally oxidized to N-oxygen compound.
  • heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrroline, 3-pyrrolyl , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl,
  • Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group, a thiomorpholino 1,1-dioxide, and the like.
  • the heterocyclyl group is optionally substituted with one or more substituents described herein.
  • aryl denotes a monovalent or polyvalent monocyclic, bicyclic or tricyclic carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 10 ring atoms, or 6 ring atoms, wherein at least one ring It is aromatic.
  • the aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group.
  • aryl can be used interchangeably with the terms "aromatic ring” or "aromatic ring”. Examples of the aryl group may include a phenyl group, a naphthyl group, an anthracene, and the like.
  • the aryl group is optionally substituted with one or more substituents described herein.
  • heteroaryl denotes a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing from 5 to 14 ring atoms, or from 5 to 10 ring atoms, or from 5 to 6 ring atoms, wherein at least one ring It is aromatic and at least one ring contains one or more heteroatoms.
  • a heteroaryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of a heteroaryl group. Operation
  • heteroaryl can be used interchangeably with the terms “heteroaryl ring” or “heteroaromatic compound”.
  • the heteroaryl group is optionally substituted with one or more substituents described herein.
  • a heteroaryl group consisting of 5-10 ring atoms comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; in another embodiment, 5-6 rings
  • the heteroaryl group consisting of atoms is a single ring system and contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-thi
  • stereoisomer refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion of a pentane-2,4-dione and a 4-hydroxypent-3-en-2-one tautomer.
  • Another example of tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridine-4(1H)-one tautomers. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or mixtures thereof.
  • hydrate means that the solvent molecule is an association formed by water.
  • the "pharmaceutically acceptable salt” as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or by other methods described in the literature, such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3 -Phenylpropionate
  • Salts obtained by appropriate bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -C 8 sulfonate and aromatic sulfonate.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -C 8 sulfonate and aromatic sulfonate.
  • Figure 1 is a graph showing the average drug time of a compound according to Example B of the present invention in a rat.
  • Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing with sodium metal.
  • Anhydrous dichloromethane and chloroform were obtained by reflux drying of calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were previously dried over anhydrous sodium sulfate.
  • the column is a silica gel column.
  • Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Plant.
  • MS mass spectrometry
  • Pure compounds were detected by UV using an Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80 mm DAC) at 210 nm / 254 nm.
  • the LC/MS/MS system for analysis includes the Agilent 1200 Series vacuum degassing furnace, binary syringe pump, orifice autosampler, column incubator, and charged spray ionization (ESI) source for the Agilent G6430 three-stage quadrupole mass spectrometer . Quantitative analysis is performed in MRM mode. The parameters of MRM conversion are shown in Table A:
  • Agilent 6330 Series LC/MS/MS spectrometer was equipped for analysis with a G1312A binary syringe pump, G1367A autosampler and MS/MS detector; LC/MS/MS with ESI source. Each analyte was subjected to the best cation model processing and MRM conversion for optimal analysis using standard solutions.
  • Agilent Poroshell HPH-C18 columns were used during the analysis and were: 100 x 4.6 mm I.D., 5 [mu]M.
  • the mobile phase was 2 mM ammonium formate + 0.1% formic acid (A) and methanol + 2 mM ammonium formate + 0.1% formic acid (B).
  • the flow rate was 0.3 mL/min; the column temperature was maintained at 40 ° C; 20 ⁇ L of the sample was injected.
  • Human liver microsome incubation system was used.
  • a typical incubation mix includes human or rat liver microsomes (0.5 mg protein/mL), target compound (1 [mu]M).
  • the amount of the compound of the present invention converted into an active arylthiophenylpiperazine compound in a human liver microsome incubation mixture is determined by a method of LC/MS/MS.
  • Table 1 lists the stability test data for some of the examples in human liver microsomes. As shown in Table 1, the invention is The compound can be converted into an active arylthiophenylpiperazine compound after being incubated in human liver microsomes.
  • Table 1 Stability data of compounds in human liver microsomes (remaining amount or production of vortioxetine)
  • WTXT represents wortite compound
  • the LC/MS/MS system for analysis included the Agilent 1200 Series Vacuum Degassing Furnace, Binary Syringe Pump, Orifice Autosampler, Column Incubator, and API 4000 Triple Quadrupole Mass Spectrometer with Electrospray Ionization (ESI) Source. Quantitative analysis is performed in MRM mode. The parameters of MRM conversion are shown in Table A:
  • the API4000 series LC/MS/MS spectrometer is equipped for analysis, equipped with G1312A binary syringe pump, G1367A automatic sampler and MS/MS detector; LC/MS/MS spectrometer uses ESI source.
  • Each analyte was subjected to the best cation model processing and MRM conversion for optimal analysis using standard solutions.
  • the mobile phase was 2 mM ammonium formate + 0.1% formic acid (A) and methanol + 2 mM ammonium formate + 0.1% formic acid (B).
  • the flow rate was 0.5 mL/min; the column temperature was maintained at 40 ° C; 15 ⁇ L of the sample was injected.
  • the present invention evaluates the pharmacokinetic study of a series of compounds of the invention in rats.
  • the compound of the present invention is added to a mixture formed by dissolving and dispersing Tween-20 and/or Span-20 in water after being subjected to a pretreatment operation such as grinding, sieving, etc., and is uniformly dispersed and fixed to a constant volume; the suspension is subjected to a ball mill.
  • the drug is administered after grinding.
  • the animals were given a suspension of vortioxetine solution (17.5 mg/kg) and a vortioxetine compound (75 mg/kg).
  • T max is between 6-26h, at 196h
  • AUC last exposure
  • WTXT represents wortite compound
  • first and second are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implicitly indicating the number of technical features indicated.
  • features defining “first” or “second” may include at least one of the features, either explicitly or implicitly.
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Abstract

提供二芳基硫醚哌嗪类化合物及其制备方法和用途，具体地，所述化合物为式(I)所示化合物，其中，HX为C 10-20脂肪酸或双羟萘酸。

Description

二芳基硫醚哌嗪类化合物及其制备方法和用途
优先权信息
本申请请求2016年06月16日向中国国家知识产权局提交的、专利申请号为201610446737.5的专利申请的优先权和权益，并且通过参照将其全文并入此处。
技术领域
本发明涉及药物领域，具体的，本发明涉及化合物及其制备方法和应用，更具体的，本发明涉及式(I)和式(II)所示化合物及其制备方法、药物组合物及其应用。
背景技术
重度抑郁症(Major Depressive Disorder，MDD)是一种常见的精神疾病，主要表现为情绪低落，兴趣减低，悲观，思维迟缓，缺乏主动性，自责自罪，饮食、睡眠差，担心自己患有各种疾病，感到全身多处不适，严重者可出现自杀念头和行为。
沃替西汀氢溴酸盐(Lu AA21004,Vortioxetine Hydrobromide)是一类新的化学类抗抑郁药物，该药物由丹麦灵北和日本武田制药公司共同研究开发，于2013年9月30日获美国食品药品管理局(FDA)批准用于治疗成年人重度抑郁症。沃替西汀的药品说明书中，指出该药品需要每天一次服用。
然而，目前用于治疗重度抑郁症的药物沃替西汀仍然有待改进。
发明内容
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。
本发明以1-[2-(2,4-二甲基苯基硫基)苯基]哌嗪为原料，制备了一批二芳基硫醚哌嗪类化合物，通过对动物进行药理实验，出乎意料的发现其在动物体内具有很好的缓释效果，一次给药持续释放药效可以保持一周至数周，如果能应用于临床，有可能大大的减少服用此药的频率，使患者服用此药物更加方便。
根据本发明的一个方面，本发明提出了一种化合物，其为式(I)所示化合物，
Figure PCTCN2017088493-appb-000001
其中，HX为C10-20脂肪酸或双羟萘酸。所述式(I)所示化合物可以用于治疗重度抑 郁症，并且具有良好的药代动力学性质和较低的溶解度，从而可以使得式(I)所示化合物可以在体内缓慢地释放，发挥其药效，也就是说，式(I)所示化合物可以在体内相当长的一段时间内均有药效作用，由此可以减少用药次数、用药更加方便。
根据本发明的一些实施例，HX为硬脂酸、棕榈酸、月桂酸或双羟萘酸。
根据本发明的一些实施例，所述化合物为具有以下至少之一结构的化合物：
Figure PCTCN2017088493-appb-000002
根据本发明的再一个方面，本发明提出了一种化合物，其为式(II)所示化合物或式(II)所示化合物的立体异构体、互变异构体、溶剂化物或药学上可接受的盐
Figure PCTCN2017088493-appb-000003
其中，
X1为一个键或-(CH2)n-；
Y为一个键或者
Figure PCTCN2017088493-appb-000004
当Y为一个键时，Z为C2-10烷基、C5-10杂芳基、C5-10杂环基，其中，所述C2-10烷基、C5-10杂芳基和C5-10杂环基独立任选地被一个或者多个R基团所取代；
当Y为
Figure PCTCN2017088493-appb-000005
时，Z为C1-20烷基、C6-10芳基、C5-10杂芳基、C5-10杂环基，其中，所述C1-20烷基、C6-10芳基、C5-10杂芳基和C5-10杂环基独立任选地被一个或者多个R基团所取代；
n为1、2、3、4或5；
各R基团独立地为F、Cl、Br、I、氨基、羟基或C1-6烷基；
当条件是X1为一个键和Y为一个键时，Z不为叔丁基。所述式(II)所示化合物可以用于治疗重度抑郁症，并且具有良好的药代动力学性质和较低的溶解度，从而可以使得式(II)所示化合物可以在体内缓慢地释放，发挥其药效，也就是说，式(II)所示化合物可以在体内相当长的一段时间内均有药效作用，由此可以减少用药次数、用药更加方便。
根据本发明的一些实施例，当Y为一个键时，Z为C2-10烷基、C5-10杂芳基、C5-10杂环基，且Z不为叔丁基，其中，所述C2-10烷基、C5-10杂芳基和C5-10杂环基独立任选地被一个或者多个R基团所取代。
根据本发明的一些实施例，当Y为一个键时，Z为乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、正戊基、2-戊基、3-戊基、C5-8杂芳基、C5-8杂环基，其中，所述乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、正戊基、2-戊基、3-戊基、C5-8杂芳基和C5-8杂环基独立任选地被一个或者多个R基团所取代；n为0、1、2或3；各R基团独立地为F、Cl、Br、I、氨基、羟基或C1-3烷基。
根据本发明的一些实施例，当Y为一个键时，Z为C2-5直链烷基、C5-7杂芳基、C5-7杂环基，其中，所述C2-5直链烷基、C5-7杂芳基或C5-7杂环基独立任选地被一个或者多个R基团所取代；n为1、2或3；各R基团独立地为F、Cl、Br、I、氨基、羟基或C1-3烷基。
根据本发明的一些实施例，当Y为
Figure PCTCN2017088493-appb-000006
时，Z为C1-20烷基、苯基、C6-8芳基、C5-8杂芳基、C5-8杂环基，其中，所述C1-20烷基、苯基、C6-8芳基、C5-8杂芳基和C5-8杂环基独立任选地被一个或者多个R基团所取代；n为0、1、2或3；各R基团独立地为F、Cl、Br、I、氨基、羟基或C1-3烷基。
根据本发明的一些实施例，所述化合物为具有下列之一结构的化合物或者下列之一结 构的化合物的立体异构体、互变异构体、溶剂化物或药学上可接受的盐，
Figure PCTCN2017088493-appb-000007
Figure PCTCN2017088493-appb-000008
根据本发明的又一个方面，本发明提出了一种制备所述化合物的方法，包括：
(1)使式(a)所示化合物与式(b)所示化合物进行接触，以便获得式(c)所示化合物；
(2)使式(c)所示化合物与式(d)所示化合物进行接触，以便获得式(III)所示化合物，
其中，
X1为一个键或-(CH2)n-；
各R1分别独立地为F、Cl、Br或I；
Z为C1-20烷基、C6-10芳基、C5-10杂芳基、C5-10杂环基，其中，所述C1-20烷基、C6-10芳基、C5-10杂芳基和C5-10杂环基独立任选地被一个或者多个R基团所取代；
n为1、2、3、4或5；
各R基团独立地为F、Cl、Br、I、氨基、羟基或C1-6烷基，
Figure PCTCN2017088493-appb-000009
根据本发明的一些实施例，Z为C1-20烷基、苯基、C6-8芳基、C5-8杂芳基、C5-8杂环基，其中，所述C1-20烷基、苯基、C6-8芳基、C5-8杂芳基和C5-8杂环基独立任选地被一个或者多个R基团所取代；n为1、2或3；各R基团独立地为F、Cl、Br、I、氨基、羟基或C1-3烷基。
根据本发明的又一个方面，本发明提出了一种药物组合物，包含所述式(I)所示化合物、所述式(II)所示化合物或者利用前面所述方法制备获得的式(III)所示化合物。
根据本发明的一些实施例，所述药物组合物进一步包含药学上可接受的载体，赋形剂，稀释剂，辅剂或媒介物中的至少一种。
根据本发明的一些实施例，所述药物组合物进一步包含附加治疗剂，所述附加治疗剂用于治疗抑郁症。
根据本发明的又一个方面，本发明提出了式(I)所示化合物、所述式(II)所示化合物、利用前面所述方法制备获得的式(III)所示化合物或者前面所述药物组合物在制备药物中的用途，其中，所述药物用于治疗抑郁症。
根据本发明的又一个方面，本发明提出了式(I)所示化合物、所述式(II)所示化合 物、利用前面所述方法制备获得的式(III)所示化合物或者前面所述药物组合物在治疗抑郁症中的用途。
根据本发明的又一方面，本发明提出了一种治疗抑郁症的方法。根据本发明的实施例，所述方法包括为抑郁症患者给药式(I)所示化合物、式(II)所示化合物、利用前面所述方法制备获得的式(III)所示化合物或者前面所述药物组合物。
根据本发明的一些实施例，所述方法进一步包括为抑郁症患者给药附加治疗剂，所述附加治疗剂用于治疗抑郁症。
定义和一般术语
术语“任选”或“任选地”是指随后描述的事件或情形可以但不一定出现，并且该描述包括其中所述事件或情形出现的情况以及其中它不出现的情况。
术语“取代”或“取代的”表示所述结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个取代的基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
在本说明书的各部分，本发明化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C1-C6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。
术语“烷基”或“烷基基团”是指含有1-20个碳原子的饱和直链或支链的一价烃基。除非另外详细说明，否则烷基基团含有1-20个碳原子。在一实施方案中，烷基基团含有1-10个碳原子；在另一实施方案中，烷基基团含有1-8个碳原子；在又一实施方案中，烷基基团含有1-6个碳原子；在又一实施方案中，烷基基团含有1-4个碳原子；还在一实施方案中，烷基基团含有1-3个碳原子。所述烷基基团任选地被一个或多个本发明所描述的取代基所取代。
烷基基团的一些非限制性实例包括，甲基(Me、-CH3)，乙基(Et、-CH2CH3)，正丙基(n-Pr、-CH2CH2CH3)，异丙基(i-Pr、-CH(CH3)2)，正丁基(n-Bu、-CH2CH2CH2CH3)，异丁基(i-Bu、-CH2CH(CH3)2)，仲丁基(s-Bu、-CH(CH3)CH2CH3)，叔丁基(t-Bu、-C(CH3)3)，正戊基(-CH2CH2CH2CH2CH3)，2-戊基(-CH(CH3)CH2CH2CH3)，3-戊基(-CH(CH2CH3)2)，2-甲基-2-丁基(-C(CH3)2CH2CH3)，3-甲基-2-丁基(-CH(CH3)CH(CH3)2)，3-甲基-1-丁基(-CH2CH2CH(CH3)2)，2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)，正己基(-CH2CH2CH2CH2CH2CH3)，2-己基(-CH(CH3)CH2CH2CH2CH3)，3-己基(-CH(CH2CH3)(CH2CH2CH3))，2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)，3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)，4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)，3-甲基-3-戊基 (-C(CH3)(CH2CH3)2)，2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)，2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)，3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)，正庚基，正辛基，等等。
术语“杂原子”表示一个或多个氧(O)，硫(S)，氮(N)，磷(P)或硅(Si)，包括氮(N)，硫(S)和磷(P)任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。
术语“杂环”、“杂环基”或“杂环的”在此处可交换使用，是指包含3-14个环原子的，单价或多价的单环、双环或者三环体系，其中环上一个或多个原子独立地被杂原子所替换，所述杂原子具有如本发明所述的含义，环可以是完全饱和的或包含一个或多个不饱和度，但一个芳香性环都不能有。在一实施方案中，“杂环”，“杂环基”或“杂环的”基团是3-8元环的单环(2-6个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO，SO2，PO，PO2的基团，当所述的环为三元环时，其中只有一个杂原子)，或7-12元的双环(4-9个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO，SO2，PO，PO2的基团)。所述杂环基基团任选地被一个或多个本发明所描述的取代基所取代。
杂环基可以是碳基或杂原子基。其中环的-CH2-基团可以任选地被-C(＝O)-替代，环的硫原子可以任选地被氧化成S-氧化物，环的氮原子可以任选地被氧化成N-氧化合物。杂环基的实例包括，但不限于，环氧乙烷基、氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂
Figure PCTCN2017088493-appb-000010
基，二氮杂
Figure PCTCN2017088493-appb-000011
基，硫氮杂
Figure PCTCN2017088493-appb-000012
基，2-氧杂-5-氮杂双环[2.2.1]庚-5-基，等等。杂环基中-CH2-基团被-C(＝O)-替代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基、嘧啶二酮基，等等。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、硫代吗啉基1,1-二氧化物，等等。所述杂环基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“芳基”表示含有6-14个环原子，或6-10个环原子，或6个环原子的，单价或多价的单环、双环或三环的碳环体系，其中至少一个环是芳香族的。芳基基团通常，但不必须地通过芳基基团的芳香性环与母体分子连接。术语“芳基”可以和术语“芳香环”或“芳环”交换使用。芳基基团的实例可以包括苯基、萘基、蒽，等等。所述芳基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“杂芳基”表示含有5-14个环原子，或5-10个环原子，或5-6个环原子的，单价或多价的单环、双环或三环体系，其中至少一个环是芳香族的，且至少一个环包含一个或多个杂原子。杂芳基基团通常，但不必须地通过杂芳基基团的芳香性环与母体分子连接。术 语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，5-10个环原子组成的杂芳基包含1、2、3或4个独立选自O、S和N的杂原子；在另一实施方案中，5-6个环原子组成的杂芳基为单环体系且包含1、2、3或4个独立选自O、S和N的杂原子。
杂芳基基团的实例包括，但并不限于，2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、哒嗪基(如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(如5-四唑基)、三唑基(如2-三唑基和5-三唑基)、2-噻吩基、3-噻吩基、吡唑基(如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基，等等；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基，等等。
术语“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸、乙醇胺或其混合物。术语“水合物”是指溶剂分子是水所形成的缔合物。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸 盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N+(C1-4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C1-C8磺酸化物和芳香磺酸化物。
附图说明
图1是根据本发明的实施例B的化合物在大鼠体内的平均药时曲线图。
具体实施方式
下面详细描述本发明的实施例，所述实施例的示例在附图中示出，其中自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。下面通过参考附图描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，天津市福晨化学试剂厂，武汉鑫华远科技发展有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。
无水四氢呋喃，二氧六环，甲苯，乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正己烷，N，N-二甲基乙酰胺和N，N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。
1H NMR谱使用Bruker 400MHz或600MHz核磁共振谱仪记录。1H NMR谱以CDC13、 DMSO-d6、CD3OD或丙酮-d6为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、dd(doublet of doublets，双二重峰)、dt(doublet of triplets，双三重峰)。偶合常数，用赫兹(Hz)表示。
低分辨率质谱(MS)数据的测定条件是：Agilent 6120四级杆HPLC-M(柱子型号：Zorbax SB-C18,2.1x 30mm,3.5微米,6min,流速为0.6mL/min。流动相：5％-95％(含0.1％甲酸的CH3CN)在(含0.1％甲酸的H2O)中的比例)，采用电喷雾电离(ESI)，在210nm/254nm下，用UV检测。
纯的化合物的使用Agilent 1260pre-HPLC或Calesep pump 250pre-HPLC(柱子型号：NOVASEP 50/80mm DAC)，在210nm/254nm用UV检测。
下面简写词的使用贯穿本发明：
WTXT  沃替西汀
mL  毫升
min  分钟
g  克
mg  毫克
ng  纳克
h  小时
DMF  N，N-二甲基甲酰胺
Et3N  三乙胺
EA  乙酸乙酯
CDCl3  氘代氯仿
DMSO  二甲基亚砜
Cs2CO3  碳酸铯
DMDO-OH  4-(羟甲基)-5-甲基-[1,3]二氧杂环戊烯-2-酮
DCM  二氯甲烷
1N  1mol/L
mL,ml  毫升
mmol,mM  毫摩尔
Tween-20  吐温-20
Span-20  司盘-20
实施例
实施例1 1-[2-(2,4-二甲基苯硫基)苯基]哌嗪硬脂酸盐
Figure PCTCN2017088493-appb-000013
合成操作：
在100ml的单口瓶中分别加入4.0g WTXT00，80mL丙酮，4.4g硬脂酸,升温50℃搅拌30min，溶清，降温0℃，析出固体，分别过滤，45℃减压干燥得6.4g化合物(1)，纯度为99.95％。
1H NMR(600MHz,CDCl3):δ11.0(br s,1H),6.96-7.02(m,2H),6.82(m,1H),6.67(m,2H),6.40(m,2H),3.47(t,4H),2.78(t,4H),2.35(s,6H)2.23(m,2H),2.0(br s,1H),1.56(m,2H),1.30-1.33(m,28H),0.96(t,3H).
实施例2 1-[2-(2,4-二甲基苯硫基)苯基]哌嗪棕榈酸盐
Figure PCTCN2017088493-appb-000014
合成操作：
在100ml的单口瓶中分别加入4.0g WTXT00，80mL丙酮，3.8g棕榈酸,升温50℃搅拌30min，溶清，降温0℃，析出固体，分别过滤，45℃减压干燥得5.4g化合物(2)，纯度为99.98％。
1HNMR(600MHz,CDCl3):δ11.0(br s,1H),6.96-7.02(m,2H),6.82(m,1H),6.67(m,2H),6.40(m,2H),3.47(t,4H),2.78(t,4H),2.35(s,6H)2.23(m,2H),2.0(br s,1H),1.56(m,2H),1.30-1.33(m,24H),0.96(t,3H).
实施例3 1-[2-(2,4-二甲基苯硫基)苯基]哌嗪基羧酸乙酸甲酯基酯
Figure PCTCN2017088493-appb-000015
合成操作：
在50ml反应瓶中分别加入2.0g CXZJ001707，1.26g乙酸钠、20ml DMF，90℃恒温搅拌反应15小时后TLC监测反应结束，甲苯萃取，水洗，浓缩，30ml正庚烷0℃析晶，过滤，50℃真空干燥10h得1.2g目标化合物(5)，HPLC纯度97.92％。
LC-MS:M+H：415；
1H NMR(600MHz,CDCl3):δ7.02(m,2H),6.87(s,2H),6.82(m,1H),6.67(m,2H),6.40(m,2H),3.61(m,4H),3.19(m,4H),2.35(s,6H),2.01(s,3H).
实施例4 1-[2-(2,4-二甲基苯硫基)苯基]哌嗪月桂酸盐
Figure PCTCN2017088493-appb-000016
合成操作：
在500ml的单口瓶中,加入20g WTXT,200mL DCM，20mL 25％氢氧化钠溶液，搅拌30min，溶清，静置分层，有机相加入200mL水洗，分去水相，有机相浓缩干得油状物，加入甲基叔丁基醚50mL室温搅拌2h，过滤，固体40℃减压干燥得12g游离碱WTXT00.
在100ml的单口瓶中分别加入4.0g WTXT00，80mL丙酮，3g月桂酸升温50℃搅拌30min，溶清，降温0℃，析出固体，分别过滤，45℃减压干燥得3.2g化合物(3),纯度99.93％。
1H NMR(600MHz,CDCl3):δ11.0(br s,1H),6.96-7.02(m,2H),6.82(m,1H),6.67(m,2H),6.40(m,2H),3.47(t,4H),2.78(t,4H),2.35(s,6H)2.23(m,2H),2.0(br s,1H),1.56(m,2H),1.30-1.33(m,16H),0.96(t,3H).
实施例5 1-[2-(2,4-二甲基苯硫基)苯基]哌嗪基羧酸乙酯
Figure PCTCN2017088493-appb-000017
合成操作：
在250ml反应瓶中,分别加入5g WTXT00、100ml EA、2.02g Et3N，0℃下搅拌，加入2.16g氯甲酸乙酯的EA溶液(50ml)，滴完后反应,TLC检测结束后,水洗两遍，加入无水硫酸钠静置2h，过滤，有机相浓缩干，加入30ml的正庚烷，室温搅拌过夜,过滤，固体45℃真空干燥8h得3.02g化合物(6)，纯度为99.41％。
LC-MS:M+H：371；
1H NMR(600MHz,DMSO):δ7.35(d,1H),7.24(s,1H),7.12(m,3H),6.92(m,1H),6.40(m,1H),4.12(q,J＝8.0Hz,2H),3.61(m,4H),3.19(m,2H),2.35(s,6H),1.21(t,J＝8.0Hz,3H).
实施例6 1-[2-(2,4-二甲基苯硫基)苯基]哌嗪基羧酸十二烷基甲酯基酯
Figure PCTCN2017088493-appb-000018
合成操作：
在1000ml的单口瓶中，加入20gWTXT00、1.8g三乙胺、400mL EA、降温0℃，10.36g氯甲酸氯甲酯溶于200mLEA滴加至上述溶液，搅拌反应2h，TLC检测，原料消失，加入200mL水洗，有机相浓缩干，加入100mL正庚烷，搅拌2h，过滤，固体45℃减压干燥10h得中间体产物CXZJ001707 24.4g，HPLC纯度95.30％。
在50ml反应瓶中分别加入3.0g CXZJ001707，2.0g碳酸氢钠，0.57g碘化钠，20mlDMF，3.0g月桂酸，升温100℃反应3h，中控反应基本完全后，降温至室温，加入30mL水，析出固体发粘，加入甲苯30mL萃取，浓缩干得3.0g化合物(7)，HPLC纯度：97.89％。
LC-MS:M+H：555；
1H NMR(600MHz,CDCl3):δ7.38(m,1H),7.17(m,1H),6.98-7.11(m,3H),6.91(m,1H),6.56(m,1H),5.84(s,2H),3.81(m,4H),3.06(m,4H),2.27-2.42(m,8H),1.67(m,2H),1.28(m,16H),0.93(m,3H)
实施例7 1-[2-(2,4-二甲基苯硫基)苯基]哌嗪基羧酸十六烷基甲酯基酯
Figure PCTCN2017088493-appb-000019
合成操作：
在50ml反应瓶中分别加入2.0gCXZJ001707，2.62g棕榈酸、1.67g碳酸铯、26ml DMF，60℃恒温搅拌反应17小时后送样监测反应结束，甲苯萃取，水洗，浓缩，20ml正庚烷打 浆纯化，过滤，烘干得2.1g化合物(8)。
LC-MS:M+H：611；
1H NMR(600MHz,CDCl3):δ7.38(m,1H),7.17(m,1H),6.98-7.11(m,3H),6.91(m,1H),6.56(m,1H),5.84(s,2H),3.81(m,4H),3.06(m,4H),2.27-2.42(m,8H),1.67(m,2H),1.28(m,24H),0.93(m,3H)
实施例8 1-[2-(2,4-二甲基苯硫基)苯基]哌嗪基羧酸十八烷基甲酯基酯
Figure PCTCN2017088493-appb-000020
合成操作：
在100ml反应瓶中分别加入3.0gCXZJ001707，4.37g硬脂酸、2.50g碳酸铯、40ml DMF，60℃恒温搅拌反应15小时后TLC监测反应结束，甲苯萃取，水洗，浓缩，30ml正庚烷打浆纯化，过滤，烘干得3.5g目标化合物(9)。
LC-MS:M+H：639；
1H NMR(600MHz,CDCl3):δ7.38(m,1H),7.17(m,1H),6.98-7.11(m,3H),6.91(m,1H),6.56(m,1H),5.84(s,2H),3.81(m,4H),3.06(m,4H),2.27-2.42(m,8H),1.67(m,2H),1.28(m,28H),0.93(m,3H)
实施例9 1-[2-(2,4-二甲基苯硫基)苯基]哌嗪基羧酸苯甲酸甲酯基酯
Figure PCTCN2017088493-appb-000021
合成操作：
在100ml反应瓶中分别加入3.9g的CXZJ001707，3.36g苯甲酸、2.0g Cs2CO3、40ml DMF，90℃恒温搅拌反应4小时后TLC监测反应结束，40ml水洗,40ml甲苯萃取，合并有机相浓缩，30ml正庚烷室温打浆析晶，过滤，50℃真空干燥10h得4.4g目标化合物(10)，HPLC纯度97.6％。
LC-MS:M+H：477；
1H NMR(600MHz,CDCl3):δ8.14(d,J＝12Hz,2H),7.62(t,J＝6Hz,1H),7.49(t,J＝6Hz,2H),7.35(d,J＝12Hz,1H),7.17(s,1H),7.06(m,3H),6.92(m,1H),6.56(d,J＝6Hz,1H),6.10(s,2H),3.06(m,4H),3.73(s,4H),3.06(d,J＝36Hz,4H),2.38(s,3H),2.34(s,3H).
实施例10 1-[2-(2,4-二甲基苯硫基)苯基]哌嗪基羧酸(4,5-二甲基-1,3-二氧杂环戊烯)-2-酮基酯
Figure PCTCN2017088493-appb-000022
合成操作：
100mL反应瓶中加入3.0g DMDO-OH，1.9g吡啶，25mL DCM，降温0℃，4.9g氯甲酸硝基苯酯的DCM溶液(25ml)，滴加至上述溶液，滴完后室温反应过夜，取样检测反应结束后,分别用1％氢氧化钠溶液洗涤，1N盐酸洗涤，有机相浓缩干，加入50mL甲苯室温打浆纯化，过滤,45℃真空干燥得3g中间体CXZJ001713,HPLC纯度97.6％。
在250mL反应瓶中,加入2.8gWTXT00，3.0gCXZJ001713，60mlDMF,20℃搅拌反应3～4h，取样检测反应基本结束后，滴加50mL水，析出固体，过滤，固体加入60mL异丙醚20℃搅拌过夜，过滤，固体45℃真空干燥12h得3.4g白色固体产物化合物(11),HPLC纯度97.7％。
LC-MS:M+H：455；
1H NMR(600MHz,CDCl3):δ7.38(m,1H),7.18(s,1H),7.03-7.12(m,3H),6.91(m,1H),6.56(m,1H),4.91(s,2H),3.69(m,4H),3.06(m,4H),2.38(s,3H),2.34(s,3H),2.23(s,3H).
实施例11 1-[2-(2,4-二甲基苯硫基)苯基]哌嗪基羧酸丁酸甲酯基酯
Figure PCTCN2017088493-appb-000023
合成操作：
在100ml反应瓶中分别加入3.0gCXZJ001707，1.35g正丁酸、2.5g Cs2CO3、40ml DMF，60℃恒温搅拌反应12小时后TLC监测反应结束，40ml水洗,40ml甲苯萃取，合并有机相浓缩至干得3.0g目标化合物(12)，HPLC纯度95.9％。
LC-MS:M+H：443；
1H NMR(600MHz,CDCl3):δ7.02(m,2H),6.87(s,2H),6.82(m,1H),6.67(m,2H),6.40(m,2H),3.61(m,4H),3.19(m,4H),2.35(s,6H),2.25(m,2H),1.72(m,2H),0.96(m,3H).
实施例12 1-[2-(2,4-二甲基苯硫基)苯基]哌嗪基羧酸己酸甲酯基酯
Figure PCTCN2017088493-appb-000024
合成操作：
在100ml反应瓶中分别加入2.0gCXZJ001707，1.2g正己酸、1.66g Cs2CO3、27ml DMF，60℃恒温搅拌反应12小时后TLC监测反应结束，40ml水洗,40ml甲苯萃取，合并有机相浓缩至干得2.1g目标化合物(13)，HPLC纯度95.1％。
LC-MS:M+H：471；
1H NMR(600MHz,CDCl3)δ7.28(s,1H),7.20(s,1H),6.89(s,2H),6.62(s,1H),6.55(d,J＝20.0Hz,2H),6.36(s,2H),3.30(d,J＝15.0Hz,8H),2.40–2.24(m,8H),1.66(s,2H),1.29(d,J＝40.0Hz,4H),0.89(s,3H).
实施例13 1-[2-(2,4-二甲基苯硫基)苯基]哌嗪基羧酸辛酸甲酯基酯
Figure PCTCN2017088493-appb-000025
合成操作：
在100ml反应瓶中分别加入2.0g的CXZJ001707，1.5g辛酸、1.66g Cs2CO3、27ml DMF，60℃恒温搅拌反应12小时后TLC监测反应结束，40ml水洗,40ml甲苯萃取，合并有机相浓缩至干得2.0g目标化合物(14)，HPLC纯度94.5％。
LC-MS:M+H：499；
1H NMR(600MHz,CDCl3)δ7.26(s,1H),7.18(s,1H),6.87(s,2H),6.64–6.47(m,3H),6.33(s,2H),3.30(d,J＝15.0Hz,8H),2.40–2.22(m,8H),1.66(s,2H),1.29(d,J＝34.9Hz,8H),0.89(s,3H).
实施例14 1-[2-(2,4-二甲基苯硫基)苯基]哌嗪基羧酸葵酸甲酯基酯
Figure PCTCN2017088493-appb-000026
合成操作：
在100ml反应瓶中分别加入2.0g的CXZJ001707，1.76g葵酸、1.66g Cs2CO3、27ml DMF，60℃恒温搅拌反应12小时后TLC监测反应结束，40ml水洗,40ml甲苯萃取，合并有机相浓缩至干得2.2g目标化合物(15)，HPLC纯度94.9％。
LC-MS:M+H：527；
1H NMR(600MHz,CDCl3)δ7.27(s,1H),7.19(s,1H),6.88(s,2H),6.64–6.48(m,3H),6.34(s,2H),3.30(d,J＝15.0Hz,8H),2.41–2.22(m,8H),1.66(s,2H),1.29(d,J＝35.0Hz,12H),0.89(s,3H).
实施例15 1-[2-(2,4-二甲基苯硫基)苯基]哌嗪基羧酸十四酸甲酯基酯
Figure PCTCN2017088493-appb-000027
合成操作：
在100ml反应瓶中分别加入2.0g的CXZJ001707，2.3g十四烷酸、1.66g Cs2CO3、27ml DMF，60℃恒温搅拌反应12小时后TLC监测反应结束，40ml水洗,40ml甲苯萃取，合并有机相浓缩至干得2.5g目标化合物(16)，HPLC纯度94.2％。
LC-MS:M+H：584；
1H NMR(600MHz,CDCl3)δ7.28(s,1H),7.20(s,1H),6.89(s,2H),6.65–6.48(m,3H),6.34(s,2H),3.30(d,J＝15.0Hz,8H),2.42–2.18(m,8H),1.66(s,2H),1.35–1.22(m,20H),0.89(s,3H).
实施例16 1-[2-(2,4-二甲基苯硫基)苯基]哌嗪双羟萘酸盐
Figure PCTCN2017088493-appb-000028
合成操作：
在100ml的单口瓶中分别加入2.0g WTXT00，80mL丙酮，5.7g双羟萘酸,升温60℃搅拌30min，溶清，降温0℃，析出固体，分别过滤，45℃减压干燥得6.2g化合物(4)，纯度为99.4％。
1H NMR(600MHz,CDCl3):δ8.43(s,2H),8.13(s,2H),7.80(s,2H),7.41–7.13(m,8H),6.89(s,4H),6.67–6.46(m,6H),4.82(s,2H),3.46(s,8H),2.81(s,8H),2.32(d,J＝15.0Hz,12H),1.88(s,2H).
生物试验数据
分析用的LC/MS/MS系统包括Agilent 1200系列真空脱气炉，二元注射泵，孔板自动采样器，柱恒温箱，带电喷雾电离(ESI)源的Agilent G6430三级四级杆质谱仪。定量分析在MRM模式下进行，MRM转换的参数如表A所示：
表A
多反应检测扫描 299.1→150
碎裂电压 25V
毛细管电压 3500V
干燥器温度 350℃
雾化器 40psi
干燥器流速 9L/min
分析使用Agilent Poroshell HPH-C18，2.1×50mm，2.7μM柱，注入20μL样品。分析条件：流动相为2mM甲酸铵+0.1％甲酸(A)和甲醇+2mM甲酸铵+0.1％甲酸(B)。流速为0.3mL/min。流动相梯度如表B所示：
表B
时间 流动相B的梯度(WTXT\实施例1\实施例2)
1.1min 5％
1.2min 75％
1.8min 85％
2.6min 85％
2.7min 5％
4.0min stop
或
时间 流动相B的梯度(WTXT\实施例1\实施例3)
0.5min 10％
0.8min 85％
2.7min 90％
2.8min 10％
4.0min stop
或
时间 流动相B的梯度(实施例9\实施例11)
0.5min 10％
1.5min 85％
2.7min 85％
2.71min 10％
4.0min stop
或
时间 流动相B的梯度(实施例9\实施例11)
0.5min 20％
1.0min 100％
2.7min 100％
2.8min 20％
4.0min stop
此外，用于分析的还有Agilent 6330系列LC/MS/MS光谱仪，配备有G1312A二元注射泵，G1367A自动采样器和MS/MS检测器；LC/MS/MS采用ESI源。使用标准液对每一个分析物进行合适的阳离子模型处理和MRM转换进行最佳的分析。在分析期间使用Agilent Poroshell HPH-C18柱，规格为：100×4.6mm I.D.，5μM。流动相为2mM甲酸铵+0.1％甲酸(A)和甲醇+2mM甲酸铵+0.1％甲酸(B)。流速为0.3mL/min；柱温保持在40℃；注入20μL样品。
实施例A 人肝微粒体中的稳定性
采用人肝微粒体孵育体系。典型的孵育混合液包括人或大鼠肝微粒体(0.5mg蛋白质/mL)，目标化合物(1μM)。将化合物溶解在DMSO中，并使用乙腈水将其稀释，后与肝微粒体磷酸钾缓冲溶液(pH＝7.4)混合液混合。以上操作均在湿冰上完成。并在37℃的恒温孵育箱中进行孵育。在不同的时间点(0和60min)，加入冰冷乙腈终止反应。主要考察酯酶对其转化的影响。样品于-80℃下保存直到进行LC/MS/MS分析。
本发明化合物在人肝微粒体孵育混合物中转化为具备活性的芳硫基苯基哌嗪类化合物的量是通过LC/MS/MS的方法来测定的。
表1列出了部分实施例在人肝微粒体中的稳定性试验数据。如表1所示，将本发明化 合物孵育在人肝微粒体中后均可转化为具备活性的芳硫基苯基哌嗪类化合物。
表1：化合物在人肝微粒体中的稳定性数据(沃替西汀剩余量或生成量)
Figure PCTCN2017088493-appb-000029
备注：WTXT表示沃替西汀化合物
实施例B 大鼠肌肉注射定量本发明化合物后的药代动力学评价
分析用的LC/MS/MS系统包括Agilent 1200系列真空脱气炉，二元注射泵，孔板自动采样器，柱恒温箱，带电喷雾电离(ESI)源的API4000三级四级杆质谱仪。定量分析在MRM模式下进行，MRM转换的参数如表A所示：
表A
多反应检测扫描 299.1→150
碎裂电压 30V
毛细管电压 5500V
干燥器温度 550℃
Gas1 50psi
Gas2 50psi
CUR 20psi
分析使用Waters XBridgeTMC18，2.1×30mm，3.5μM柱，注入20μL样品。分析条件：流动相为2mM甲酸铵+0.1％甲酸(A)和甲醇+2mM甲酸铵+0.1％甲酸(B)。流速为0.5mL/min。流动相梯度如表B所示：
表B
时间 流动相B的梯度
0.5min 20％
1.2min 100％
2.7min 100％
2.71min 20％
4.0min stop
或
时间 流动相B的梯度
0.5min 10％
1.5min 85％
2.7min 85％
2.71min 10％
4.0min stop
此外，用于分析的还有API4000系列LC/MS/MS光谱仪，配备有G1312A二元注射泵，G1367A自动采样器和MS/MS检测器；LC/MS/MS光谱仪采用ESI源。使用标准液对每一个分析物进行合适的阳离子模型处理和MRM转换进行最佳的分析。在分析期间使用Waters XBridgeTMC18，规格为：2.1×30mm，3.5μM。动相为2mM甲酸铵+0.1％甲酸(A)和甲醇+2mM甲酸铵+0.1％甲酸(B)。流速为0.5mL/min；柱温保持在40℃；注入15μL样品。
本发明对本发明系列化合物在大鼠体内的药代动力学研究进行了评估。本发明化合物经研磨、过筛等预处理操作后加入到由Tween-20和/或Span-20溶解分散于水中形成的混合物中，搅拌使之均匀分散，定容；将混悬液采用球磨机进行研磨后进行给药。采用肌肉注射给药，动物给予沃替西汀溶液剂(17.5mg/kg)及沃替西汀类化合物的混悬制剂(75mg/kg)后。在0.25、1、2、5、7、24、48、72、96、120、148和196h采集全血，分离血浆后冻存待测。并在12,000下离心2分钟。收集血浆，并于-20℃或-70℃下保存直到进行上述的LC/MS/MS分析。表2列出了本发明系列化合物在大鼠体内的PK数据。本发明化合物具有良好的药代动力学性质，与溶液剂相比体现出不同的缓释趋势。包括理想的达峰时间(Tmax)、半衰期(T1/2)和暴露量(AUClast)，吸收及释放曲线与溶液剂相比较为平缓，Tmax在6-26h之间，在196h沃替西汀血药浓度基本可以维持在7ng/mL以上。本发明部分化合物在大鼠肌肉注射后体内平均药时曲线见图1。
表2：化合物在大鼠体内的药代动力学数据
Figure PCTCN2017088493-appb-000030
Figure PCTCN2017088493-appb-000031
备注：WTXT表示沃替西汀化合物
此外，术语“第一”、“第二”仅用于描述目的，而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括至少一个该特征。在本发明的描述中，“多个”的含义是至少两个，例如两个，三个等，除非另有明确具体的限定。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (17)

  1. 一种化合物，其特征在于，其为式(I)所示化合物，
    Figure PCTCN2017088493-appb-100001
    其中，HX为C10-20脂肪酸或双羟萘酸。
  2. 根据权利要求1所述的化合物，其特征在于，HX为硬脂酸、棕榈酸、月桂酸或双羟萘酸。
  3. 根据权利要求1所述的化合物，其特征在于，其为具有以下至少之一结构的化合物：
    Figure PCTCN2017088493-appb-100002
  4. 一种化合物，其特征在于，其为式(II)所示化合物或式(II)所示化合物的立体异构体、互变异构体、溶剂化物、或药学上可接受的盐，
    Figure PCTCN2017088493-appb-100003
    其中，
    X1为一个键或-(CH2)n-；
    Y为一个键或者
    Figure PCTCN2017088493-appb-100004
    当Y为一个键时，Z为C2-10烷基、C5-10杂芳基、C5-10杂环基，其中，所述C2-10烷基、C5-10杂芳基和C5-10杂环基独立任选地被一个或者多个R基团所取代；
    当Y为
    Figure PCTCN2017088493-appb-100005
    时，Z为C1-20烷基、C6-10芳基、C5-10杂芳基、C5-10杂环基，其中，所述C1-20烷基、C6-10芳基、C5-10杂芳基和C5-10杂环基独立任选地被一个或者多个R基团所取代；
    n为1、2、3、4或5；
    各R基团独立地为F、Cl、Br、I、氨基、羟基或C1-6烷基；
    当条件是X1为一个键和Y为一个键时，Z不为叔丁基。
  5. 根据权利要求4所述化合物，其特征在于，
    当Y为一个键时，Z为乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、正戊基、2-戊基、3-戊基、C5-8杂芳基、C5-8杂环基，其中，所述乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、正戊基、2-戊基、3-戊基、C5-8杂芳基和C5-8杂环基独立任选地被一个或者多个R基团所取代；
    n为1、2或3；
    各R基团独立地为F、Cl、Br、I、氨基、羟基或C1-3烷基。
  6. 根据权利要求4所述化合物，其特征在于，
    当Y为一个键时，Z为C2-5直链烷基、C5-7杂芳基、C5-7杂环基，其中，所述C2-5直链烷基、C5-7杂芳基或C5-7杂环基独立任选地被一个或者多个R基团所取代；
    n为1、2或3；
    各R基团独立地为F、Cl、Br、I、氨基、羟基或C1-3烷基。
  7. 根据权利要求4所述化合物，其特征在于，
    当Y为
    Figure PCTCN2017088493-appb-100006
    时，Z为C1-20烷基、苯基、C6-8芳基、C5-8杂芳基、C5-8杂环基，其中，所述C1-20烷基、苯基、C6-8芳基、C5-8杂芳基和C5-8杂环基独立任选地被一个或者多个R基团所取代；
    n为1、2或3；
    各R基团独立地为F、Cl、Br、I、氨基、羟基或C1-3烷基。
  8. 根据权利要求4所述的化合物，其特征在于，其为具有下列之一结构的化合物或者下列之一结构的化合物的立体异构体、互变异构体、溶剂化物或药学上可接受的盐，
    Figure PCTCN2017088493-appb-100007
    Figure PCTCN2017088493-appb-100008
  9. 一种制备权利要求4-8任一项所述化合物的方法，其特征在于，包括：
    (1)使式(a)所示化合物与式(b)所示化合物进行接触，以便获得式(c)所示化合物；
    (2)使式(c)所示化合物与式(d)所示化合物进行接触，以便获得式(III)所示化合物，
    其中，
    X1为一个键或-(CH2)n-；
    各R1分别独立地为F、Cl、Br或I；
    Z为C1-20烷基、C6-10芳基、C5-10杂芳基、C5-10杂环基，其中，所述C1-20烷基、C6-10芳基、C5-10杂芳基和C5-10杂环基独立任选地被一个或者多个R基团所取代；
    n为1、2、3、4或5；
    各R基团独立地为F、Cl、Br、I、氨基、羟基或C1-6烷基，
    Figure PCTCN2017088493-appb-100009
  10. 根据权利要求9所述方法，其特征在于，Z为C1-20烷基、苯基、C6-8芳基、C5-8杂芳基、C5-8杂环基，其中，所述C1-20烷基、苯基、C6-8芳基、C5-8杂芳基和C5-8杂环基独立任选地被一个或者多个R基团所取代；
    n为1、2或3；
    各R基团独立地为F、Cl、Br、I、氨基、羟基或C1-3烷基。
  11. 一种药物组合物，其特征在于，包含权利要求1-3任一项所述的化合物、权利要求4-8任一项所述的化合物或者利用权利要求9或10所述方法制备获得的化合物。
  12. 根据权利要求11所述的药物组合物，其特征在于，进一步包含药学上可接受的载体，赋形剂，稀释剂，辅剂或媒介物中的至少一种。
  13. 根据权利要求11或12所述的药物组合物，其特征在于，进一步包含附加治疗剂，所述附加治疗剂用于治疗抑郁症。
  14. 权利要求1-3任一项所述化合物、权利要求4-8任一项所述化合物、利用权利要求 9或10所述方法制备获得的化合物或者权利要求11-13任一项所述药物组合物在制备药物中的用途，其中，所述药物用于治疗抑郁症。
  15. 权利要求1-3任一项所述化合物、权利要求4-8任一项所述化合物、利用权利要求9或10所述方法制备获得的化合物或者权利要求11-13任一项所述药物组合物在治疗抑郁症中的用途。
  16. 一种治疗抑郁症的方法，其特征在于，包括：
    为抑郁症患者给药权利要求1-3任一项所述化合物、权利要求4-8任一项所述化合物、利用权利要求9或10所述方法制备获得的化合物或者权利要求11-13任一项所述药物组合物。
  17. 根据权利要求16所述的方法，其特征在于，进一步包括为抑郁症患者给药附加治疗剂，所述附加治疗剂用于治疗抑郁症。
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