WO2018014880A1 - 沃替西汀类似物及其用途和制备 - Google Patents

沃替西汀类似物及其用途和制备 Download PDF

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WO2018014880A1
WO2018014880A1 PCT/CN2017/094037 CN2017094037W WO2018014880A1 WO 2018014880 A1 WO2018014880 A1 WO 2018014880A1 CN 2017094037 W CN2017094037 W CN 2017094037W WO 2018014880 A1 WO2018014880 A1 WO 2018014880A1
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acid
compound
methyl
phenyl
trifluoromethylphenylthio
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PCT/CN2017/094037
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English (en)
French (fr)
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李勤耕
王涛
廖建
徐祥清
任亮
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李勤耕
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Priority to CA3031458A priority Critical patent/CA3031458A1/en
Priority to EA201990362A priority patent/EA201990362A1/ru
Priority to EP17830514.0A priority patent/EP3489225A4/en
Priority to CN201780045351.6A priority patent/CN109890799A/zh
Priority to JP2019503435A priority patent/JP2019523256A/ja
Priority to KR1020197003962A priority patent/KR20190032418A/ko
Priority to US16/319,750 priority patent/US20210284615A1/en
Priority to AU2017300463A priority patent/AU2017300463A1/en
Publication of WO2018014880A1 publication Critical patent/WO2018014880A1/zh
Priority to IL264403A priority patent/IL264403A/en

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    • 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
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
    • C07C321/24—Thiols, sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings
    • C07C321/26—Thiols
    • 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
    • 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
    • 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
    • C07D295/20—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 carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of chemical pharmacy.
  • the present invention relates to novel vortioxetine analogs or polymorphs or solvates thereof, compositions and kits comprising the analogs, polymorphs or solvates, and the like Use of a substance, polymorph or solvate for the manufacture of a medicament for the treatment of depression.
  • the invention also relates to a process for the preparation of said analogues and to intermediates in said process.
  • Vortioxetine developed by Lundbeck of Denmark and Takeda of Japan is suitable for the treatment of patients with Major Depressive Disorder (MDD). Approved for listing in the US in September.
  • the structure of vortioxetine hydrobromide is:
  • the invention provides a novel class of vortioxetine analogs or polymorphs or solvates thereof.
  • the vortioxetine analog of the present invention not only has better antidepressant activity, but also has an improved lipid-water distribution coefficient, a higher ability to penetrate the blood-brain barrier, and higher metabolism. Stability and other advantages. This means that the vortioxetine analog of the present invention may be used in a small amount and for a longer period of action.
  • the vortioxetine analog of the invention has the structure of formula I below:
  • R 1 is H
  • R 2 is halogen or C 1-6 alkyl substituted by one or more halogens
  • A is absent or is a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutical composition comprising a vortioxetine analogue of the invention or a polymorph or solvate thereof and one or more pharmaceutically acceptable carriers.
  • kits comprising a vortioxetine analog of the invention or a polymorph or solvate thereof or a pharmaceutical composition of the invention.
  • the invention provides a method of treating depression, in particular major depression, comprising administering to an individual in need thereof an effective amount of a vortioxetine analogue of the invention or a polymorph thereof Or a solvate.
  • a vortistatin analogue of the invention or a polymorph or solvate thereof for use in the treatment of depression, in particular major depression.
  • the invention provides the use of a vortioxetine analogue of the invention, or a polymorph or solvate thereof, for the manufacture of a medicament for the treatment of depression, in particular major depression.
  • a method of preparing a vortioxetine analogue of the invention comprising the steps of:
  • R is an amino protecting group
  • a and R 2 are as defined above;
  • step d When A is absent, the reaction of step d is not carried out.
  • an intermediate for the preparation of a vortioxetine analogue of the invention having the structure of formula IV:
  • R is an amino protecting group
  • R 2 is halogen or a C 1-6 alkyl group substituted by one or more halogens.
  • the invention provides a starting material for the preparation of a vortioxetine analogue of the invention having a structure of the following formula II or formula III:
  • R is an amino protecting group
  • R 2 is halogen or a C 1-6 alkyl group substituted by one or more halogens.
  • R 2 is as defined above.
  • R is as defined above.
  • substituted means that one or more (eg, 1, 2, 3 or 4) hydrogens on a specified atom are replaced by the selection of the indicated group, provided that the The normal valence of the specified atom in the present case and the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • protecting group means that when a multifunctional organic compound is reacted, in order to cause the reaction to occur only at the desired group, and other groups are prevented from being affected, other groups are preceded by the reaction. Protected and restored when the reaction is complete.
  • An agent that protects a certain group is referred to as a protecting group for the group. Selection of an appropriate protecting group can be readily determined by one skilled in the art. The protecting group chemistry can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.
  • amino protecting group refers to a protecting group that prevents an undesired chemical reaction of an amino group, including but not limited to t-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allylicoxycarbonyl, tri Methyl siloxane ethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, o-nitrophenylsulfonyl, p-nitrophenylsulfonyl, formyl, acetyl, trifluoroacetyl , propionyl, pivaloyl, benzoyl, trityl, benzyl, 2,4-dimethoxybenzyl, p-methoxybenzyl and the like. Selection of an appropriate amino protecting group can be readily determined by one skilled in the art.
  • C 1-6 alkyl refers to a saturated straight or branched hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and the like.
  • halo or halogen group as used herein is defined to include F, Cl, Br or I.
  • pharmaceutically acceptable acid refers to those acids which are compatible with pharmaceutical practice and animal use from the standpoint of biology, preparation and formulation, and include inorganic acids such as hydrochloric acid, hydrobromic acid, and hydrogen iodine.
  • Acid sulfuric acid, pyrosulfuric acid, nitric acid, boric acid, phosphoric acid, carbonic acid and any combination thereof; and organic acids such as formic acid, acetic acid, propionic acid, acetoacetic acid, trifluoroacetic acid, propionic acid, pyruvic acid, butyric acid, caproic acid, Heptanoic acid, undecanoic acid, lauric acid, stearic acid, palmitic acid, oxalic acid, malonic acid, Succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, benzoic acid, salicylic acid, cinnamic acid, naphthoic acid, pamoic acid, niacin, Orotic acid, methyl sulphate, lauryl sulphate, methanesulfonic acid, trifluoromethanesulfonic acid, ethane
  • the vortioxetine analogs of the invention may exist in crystalline or polymorphic form, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • the vortioxetine analog of the present invention may exist in the form of a solvate thereof, particularly a hydrate, wherein the vortioxetine analog of the present invention contains a polar solvent, such as water, as a structural element of the crystal lattice of the analog. , ethanol, isopropanol, ethyl acetate or acetone.
  • polar solvent such as water
  • the amount of polar solvent, particularly water may be present in stoichiometric or non-stoichiometric ratios.
  • the main structural difference between the vortioxetine analog and vortioxetine is that the 4-position of the left benzene ring in vortioxetine is methyl, and the corresponding position in the vortioxetine analog of the present invention is Halogen is either an alkyl group substituted by one or more halogens.
  • the vortioxetine analog of the present invention has an improved molecular lipid-water partition coefficient and enhances its ability to cross the blood-brain barrier while maintaining anti-depressant activity, thereby allowing faster crossing of the blood-brain barrier after oral administration.
  • the halogen or the alkyl group substituted by one or more halogens is less susceptible to oxidative metabolism in vivo than the methyl group, so the wortidine modification of the present invention has more than vortioxetine.
  • the invention provides a compound of formula I or a polymorph or solvate thereof:
  • R 1 is H
  • R 2 is halogen or C 1-6 alkyl substituted by one or more halogens
  • A is absent or is a pharmaceutically acceptable inorganic or organic acid.
  • R 2 is C 1-6 alkyl substituted by one or more halogens.
  • R 2 is C 1-6 alkyl substituted by one or more fluorines, such as CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CF 2 CH 3 or CF 2 CH 2 CH 3 and so on.
  • R 2 is CF 3 (trifluoromethyl).
  • A is absent.
  • A is a pharmaceutically acceptable inorganic or organic acid.
  • A is an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, nitric acid, boric acid, phosphoric acid, and carbonic acid, or selected from the group consisting of formic acid, acetic acid, propionic acid, and acetoacetic acid.
  • A is an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, and sulfuric acid or an organic acid selected from the group consisting of citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • the present invention encompasses compounds of formula I which result from the arbitrary combination of the above preferred groups.
  • the compound of formula I is a compound of formula I-1:
  • the vortioxetine analogue of the invention is selected from the group consisting of:
  • Another object of the present invention is to provide a method of preparing a vortioxetine analog of the present invention comprising the steps of:
  • R is an amino protecting group
  • a and R 2 are as defined above;
  • step d When A is absent, the reaction of step d is not carried out.
  • R is selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, 9-armor Oxycarbonyl, allyloxycarbonyl, trimethylsilyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, o-nitrophenylsulfonyl, p-nitrophenylsulfonyl, A Amino protecting group for acyl, acetyl, trifluoroacetyl, propionyl, pivaloyl, benzoyl, trityl, benzyl, 2,4-dimethoxybenzyl and p-methoxybenzyl .
  • R is an amino protecting group selected from the group consisting of t-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, acetyl, propionyl and benzoyl.
  • Step a and step a' are identical to Step a and step a':
  • the diazotization of step a and step a' is carried out in the presence of an acid such as hydrochloric acid, sulfuric acid or nitric acid and a nitrite such as sodium nitrite or potassium nitrite.
  • an acid such as hydrochloric acid, sulfuric acid or nitric acid
  • a nitrite such as sodium nitrite or potassium nitrite.
  • the diazotization reaction is carried out in a mixed solvent of an alcohol (such as methanol or ethanol) and water at a lower temperature (for example, -10 ° C to 10 ° C, preferably 0 to 5 ° C). .
  • an alcohol such as methanol or ethanol
  • water at a lower temperature (for example, -10 ° C to 10 ° C, preferably 0 to 5 ° C).
  • Step b and step b' are identical to Step b and step b':
  • step b and step b' is carried out in a mixed solvent of an alcohol (such as methanol or ethanol) and water at a higher temperature (for example, 30-100 ° C, preferably 50-60 ° C). ongoing.
  • an alcohol such as methanol or ethanol
  • a higher temperature for example, 30-100 ° C, preferably 50-60 ° C.
  • the reaction of step c is carried out using conventional methods for removing the amino protecting group, the particular method employed being dependent on the amino protecting group employed.
  • the tert-butoxycarbonyl group can be removed by treatment with an acid such as HCl, trifluoroacetic acid or the like;
  • the benzyloxycarbonyl group can be removed by catalytic hydrogenation by palladium (for example, Pd-C, etc.); 9-fluorenylmethoxycarbonyl can be passed through an organic base. (eg, triethylamine or piperidine, etc.) treatment removal) treatment removal;
  • the reaction of step d is carried out in a solution of an alcohol (e.g., methanol, ethanol, propanol, etc.) in an ice bath (0 ° C) to reflux temperature of the solvent.
  • an alcohol e.g., methanol, ethanol, propanol, etc.
  • Another object of the present invention is to provide an intermediate for the preparation of a vortioxetine analogue of the invention having the structure of the following formula IV:
  • R is an amino protecting group
  • R 2 is halogen or a C 1-6 alkyl group substituted by one or more halogens.
  • R is selected from the group consisting of t-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, ortho Phthaloyl, p-toluenesulfonyl, o-nitrophenylsulfonyl, p-nitrophenylsulfonyl, formyl, acetyl, trifluoroacetyl, propionyl, pivaloyl, benzoyl, trityl Amino protecting group for benzyl, 2,4-dimethoxybenzyl and p-methoxybenzyl.
  • R is an amino protecting group selected from the group consisting of t-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, acetyl, propionyl and benzoyl.
  • R 2 is C 1-6 alkyl substituted by one or more halogens.
  • R 2 is C 1-6 alkyl substituted by one or more fluorines, such as CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CF 2 CH 3 or CF 2 CH 2 CH 3 and so on.
  • R 2 is CF 3 (trifluoromethyl).
  • the present invention encompasses compounds of formula IV obtained by any combination of the above preferred groups.
  • the compound of formula IV is a compound of formula IV-1:
  • the compound of formula IV is selected from the group consisting of
  • Another object of the present invention is to provide a raw material for preparing the vortioxetine analog of the present invention, which has the structure of the following formula II,
  • R 2 is halogen or a C 1-6 alkyl group substituted by one or more halogens.
  • R 2 is C 1-6 alkyl substituted by one or more halogens.
  • R 2 is C 1-6 alkyl substituted by one or more fluorines, such as CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CF 2 CH 3 or CF 2 CH 2 CH 3 and so on.
  • R 2 is CF 3 (trifluoromethyl).
  • the compound of formula II is a compound of formula II-1:
  • the compound of formula II is prepared by the following method:
  • R 2 is as defined above.
  • the diazotization reaction of step e is carried out in the presence of an acid such as hydrochloric acid, sulfuric acid or nitric acid and a nitrite such as sodium nitrite or potassium nitrite.
  • an acid such as hydrochloric acid, sulfuric acid or nitric acid
  • a nitrite such as sodium nitrite or potassium nitrite.
  • the diazotization reaction is carried out at a lower temperature (for example, -10 ° C to 10 ° C, preferably 0 to 5 ° C) in a mixed solvent of an alcohol (such as methanol or ethanol) and water. .
  • a lower temperature for example, -10 ° C to 10 ° C, preferably 0 to 5 ° C
  • an alcohol such as methanol or ethanol
  • Step f
  • the reaction of step f is in an alkyl xanthate (the alkyl group is preferably a C 1-6 alkyl group, preferably a salt of an alkali metal such as a lithium salt, a sodium salt or Potassium salts and the like, one example of an alkylxanthate is potassium ethylxanthate) and a strong base such as sodium hydroxide or potassium hydroxide.
  • an alkyl xanthate is preferably a C 1-6 alkyl group, preferably a salt of an alkali metal such as a lithium salt, a sodium salt or Potassium salts and the like, one example of an alkylxanthate is potassium ethylxanthate
  • a strong base such as sodium hydroxide or potassium hydroxide.
  • the alkylxanthate and the strong base are added to the reaction simultaneously or sequentially.
  • Another object of the present invention is to provide a starting material for the preparation of the vortioxetine analog of the present invention having a structure of the following formula III:
  • R is an amino protecting group
  • R is selected from the group consisting of t-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, ortho Phthaloyl, p-toluenesulfonyl, o-nitrophenylsulfonyl, p-nitrophenylsulfonyl, formyl, acetyl, trifluoroacetyl, propionyl, pivaloyl, benzoyl, trityl Amino protecting group for benzyl, 2,4-dimethoxybenzyl and p-methoxybenzyl.
  • R is an amino protecting group selected from the group consisting of t-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, acetyl, propionyl and benzoyl.
  • the compound of formula III is selected from the group consisting of
  • the compound of formula III is prepared by the following method:
  • Step g
  • the diazotization reaction of step g is carried out in the presence of an acid such as hydrochloric acid, sulfuric acid or nitric acid and a nitrite such as sodium nitrite or potassium nitrite.
  • an acid such as hydrochloric acid, sulfuric acid or nitric acid
  • a nitrite such as sodium nitrite or potassium nitrite.
  • the diazotization reaction is carried out at a lower temperature (for example, -10 ° C to 10 ° C, preferably 0 to 5 ° C) in a mixed solvent of an alcohol (such as methanol or ethanol) and water. .
  • a lower temperature for example, -10 ° C to 10 ° C, preferably 0 to 5 ° C
  • an alcohol such as methanol or ethanol
  • the reaction of step h is in the alkylxanthate (the alkyl group is preferably a C 1-6 alkyl group, preferably a salt of an alkali metal such as a lithium salt, a sodium salt or An example of a potassium salt or the like, an alkylxanthate is potassium ethyl xanthate) and a strong base such as sodium hydroxide or potassium hydroxide.
  • the alkyl group is preferably a C 1-6 alkyl group, preferably a salt of an alkali metal such as a lithium salt, a sodium salt or An example of a potassium salt or the like, an alkylxanthate is potassium ethyl xanthate
  • a strong base such as sodium hydroxide or potassium hydroxide.
  • the alkylxanthate and the strong base are added to the reaction simultaneously or sequentially.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the vortioxetine analog of the present invention or a polymorph or solvate thereof and one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier in the present invention is meant a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Or the tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like.
  • the composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed.
  • compositions of the invention may be administered in a suitable route.
  • the pharmaceutical compositions of the invention are administered orally, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly or transdermally.
  • compositions of the invention may be administered in a suitable dosage form.
  • the dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups.
  • Another object of the present invention is to provide a kit comprising the vortioxetine analog of the present invention or a polymorph or solvate thereof, or a pharmaceutical composition of the present invention.
  • a method of treating depression particularly major depression, comprising administering to an individual in need thereof an effective amount of a vortioxetine analog of the invention or a polymorph or solvent thereof.
  • a further object of the present invention is to provide a vortioxetine analogue of the invention or a polymorph or solvate thereof for use in the treatment of depression, particularly major depression.
  • a further object of the present invention is to provide the use of a vortioxetine analogue of the invention, or a polymorph or solvate thereof, for the manufacture of a medicament for the treatment of depression, particularly major depression.
  • terapéuticaally effective amount refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.
  • the dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.
  • an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day.
  • a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.
  • the amount or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 150 mg, particularly preferably from 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, and the like.
  • treating means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or one or more symptoms of such a condition or condition, or Preventing such a condition or condition or one of such conditions or conditions Multiple symptoms.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein.
  • “Non-human animals” in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).
  • 1-[2-(2-methyl-4-trifluoromethylphenylthio)phenyl]piperazine decanoate can be obtained by the procedure of Example 15 using compound 1 and decanoic acid as starting materials. (Compound 9).
  • the compound of the present invention has a lipid-water partition coefficient greater than that of vortioxetine, indicating that the compounds of the present invention are more lipophilic and more easily cross the blood-brain barrier (BBB).
  • BBB blood-brain barrier
  • the SLC6A4 gene was amplified from the plasmid Pcmv6-XL4-SLC6A4 (Origene, Cat# SC119478) by PCR (polymerase chain reaction), and the HIS tag was added at the C-terminus, and then cleaved with 5'EcoR1 and 3 ⁇ Hind111. The site was inserted into the pcDNA3.1(-) vector and constructed as pcDNA3.1-SLC6A4-His.
  • CHO cells in the logarithmic growth phase Choinese hamster ovary cells, Institute of Cell Biology, Chinese Academy of Sciences, Cat# CCL-61) were collected and counted. The cells were resuspended in F-12 medium (Gibco, Cat #11330-032), seeded into 96-well plates, and 100 ⁇ L (20,000 cells/well) per well. Incubate for 24 h at 37 ° C in a 5% CO 2 incubator (relative humidity 100%).
  • the above modified plasmid (0.48 ⁇ g) was diluted with Opti-MEM medium (25 ⁇ L, Gibco, Cat#11058021), and gently mixed. FuGENE HD Transfection Reagent (1.44 ⁇ L, Promega, Cat# E2311) was diluted with Opti-MEM medium (25 ⁇ L, Gibco, Cat#11058021). After gently blowing and mixing, it was allowed to stand at room temperature for 5 min. The solutions prepared in the first two steps were mixed, gently mixed, and allowed to stand at room temperature for 12 min. The resulting transfection complex was added to a 96-well cell plate at 50 ⁇ L/well, and the cell plate was gently shaken before and after, and then incubated at 37 ° C in a 5% CO 2 incubator for 48 hours.
  • Compound 1 and vortioxetine were diluted to 1 mM in Opti-MEM medium, diluted 10 times every 4 times, and added to the wells of the transfected cells at 20 ⁇ L/well (corresponding concentration was 100 uM-0.0004 uM, A total of 10 concentration points, the concentration ratio between each concentration point is 4, each concentration of 3 parallel holes). After the addition was completed, incubation was carried out for 30 min, followed by the addition of [ 3 H]serotonin (25 nM, Perkinelmer, Cat# NET 1167250UC).
  • the cells were lysed with 0.5 M NaOH, 50 ⁇ L of lysed cell fluid was taken, 200 ⁇ L of scintillation fluid was added, and the reading was performed with MicroBeta2.
  • % inhibition rate [100% active pore - sample well] / 100% active pore * 100
  • mice male, 18-22 g, Experimental Animal Center of Chongqing Medical University
  • 5-HTP 5-hydroxytryptophan
  • the experimental results show that the compound of the present invention has the effect of vortioxetine-like inhibition of reuptake of 5-HT neurotransmitters and is stronger than vortioxetine.
  • mice Male, 18-22 g, Experimental Animal Center of Chongqing Medical University
  • Animals of each test group were intravenously injected with equimolar vortioxetine (20 mg/kg) and compound 1 (23.6 mg/kg) according to the following table.
  • Blood and mouse brain tissue samples were taken 1 hour and 2 hours after injection, and the concentrations of vortioxetine and compound 1 in plasma and brain tissues were measured, and their ratios (brain concentration/plasma concentration) were calculated.
  • equimolar vortioxetine 20 mg/kg
  • compound 1 23.6 mg/kg
  • the experimental results show that the compound of the present invention is easier to cross the blood-brain barrier than the vortioxetine, and its brain exposure is higher than that of vortioxetine, thereby making it easier to function.
  • mice male, 38-42 g, Experimental Animal Center of Chongqing Medical University
  • mice were taken and randomly divided into groups of 6 each. After the mice were fasted for 4 hours, they were placed in a glass circular cylinder having a diameter of 18 cm, a height of 40 cm, and a water depth of 15 cm (water temperature of 25 ° C) for 6 minutes, and then dried by a hot hair dryer after swimming.
  • the corresponding drug solutions (oral gavage, 20 mg/kg) were administered to the animals of each test group according to the following table. One hour after the administration, the mice were placed in a glass circular cylinder having a diameter of 18 cm, a height of 40 cm, and a water depth of 15 cm (water temperature of 25 ° C) for swimming for 6 minutes.
  • the camera system was used to record the swimming condition of the mice within 6 minutes.
  • the data was automatically collected and analyzed by Noldus software.
  • the immobility time of stopping swimming within 4 minutes after recording and statistics was recorded.

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Abstract

提供了一种式I所示的沃替西汀类似物或者其多晶型物或溶剂合物，包含所述类似物、多晶型物或溶剂合物的组合物和药盒，所述类似物、多晶型物或溶剂合物在制备用于治疗抑郁症的药物中的用途，所述类似物的制备方法和所述方法中的中间体。

Description

沃替西汀类似物及其用途和制备
相关申请的交叉引用
本申请要求2016年7月22日提交的中国专利申请201610584432.0的优先权，所述申请的公开内容均以其整体援引加入本文。
发明领域
本发明属于化学制药领域。具体而言，本发明涉及新型沃替西汀类似物或者其多晶型物或溶剂合物，包含所述类似物、多晶型物或溶剂合物的组合物和药盒，及所述类似物、多晶型物或溶剂合物在制备用于治疗抑郁症的药物中的用途。本发明还涉及所述类似物的制备方法和所述方法中的中间体。
发明背景
由丹麦灵北制药公司(Lundbeck)和日本武田制药株式会社(Takeda)开发的沃替西汀(vortioxetine)适用于患有重度抑郁症(Major Depressive Disorder,MDD)的患者的治疗，其于2013年9月在美国获准上市。沃替西汀氢溴酸盐的结构为：
Figure PCTCN2017094037-appb-000001
沃替西汀口服吸收良好，生物利用度约为75％。实验表明，雄性Listar Hooded大鼠口服14C-沃替西汀(20mg/kg)2h后，脑中分布仅为2.77μg/g，这低于其在肝脏(22.3μg/g)、肺(15.5μg/g)和肾脏(10.3μg/g)中的分布浓度(参见FDA PHARMACOLOGY REVIEW(S)，第24页)。上述数据说明沃替西汀能够穿过血脑屏障，但其穿透能力较弱是其缺点之一。
另外，实验还发现，人口服14C-沃替西汀游离碱(50mg)4小时后，血浆 中主要是其代谢产物，药物本身约占8％(FDA PHARMACOLOGY REVIEW(S)，第26页)。在这些代谢产物中，值得关注的是沃替西汀芳环4-位甲基氧化的产物LUAA34443和LUAA34443的葡萄糖醛酸化产物(LUAA34443 glucuronide)，两者所占比例达44％。沃替西汀游离碱在体内的代谢过程如下所示：
Figure PCTCN2017094037-appb-000002
显然，LUAA34443及其与葡萄糖醛酸的结合物不能透过血脑屏障，故不能发挥抗抑郁作用。因此，有必要对沃替西汀的结构进行改进以提高其血脑屏障穿透能力并提高其代谢稳定性。
发明概述
根据本发明的第一方面，本发明提供一类新型沃替西汀类似物或者其多晶型物或溶剂合物。与沃替西汀相比，本发明的沃替西汀类似物不但具有更好的抗抑郁活性，还具有改善的脂水分布系数、更高的穿透血脑屏障的能力以及更高的代谢稳定性等优点。这意味本发明的沃替西汀类似物可能用药量少，作用时间更长。
本发明的沃替西汀类似物具有如下式I的结构：
Figure PCTCN2017094037-appb-000003
其中：
R1为H；
R2为卤素或者被一个或多个卤素取代的C1-6烷基；并且
A不存在或者为药学上可接受的无机酸或有机酸。
根据本发明的第二方面，本发明提供药物组合物，其包含本发明的沃替西汀类似物或者其多晶型物或溶剂合物以及一种或多种药学上可接受的载体。
根据本发明的第三方面，本发明提供药盒，其包含本发明的沃替西汀类似物或者其多晶型物或溶剂合物或者本发明的药物组合物。
根据本发明的第四方面，本发明提供治疗抑郁症(特别是重度抑郁症)的方法，其包括向需要其的个体给药有效量的本发明的沃替西汀类似物或者其多晶型物或溶剂合物。
根据本发明的第五方面，本发明提供本发明的沃替西汀类似物或者其多晶型物或溶剂合物，其用于治疗抑郁症，特别是重度抑郁症。
根据本发明的第六方面，本发明提供本发明的沃替西汀类似物或者其多晶型物或溶剂合物在制备用于治疗抑郁症(特别是重度抑郁症)的药物中的用途。
根据本发明的第七方面，本发明提供制备本发明的沃替西汀类似物的方法，其包括以下步骤：
Figure PCTCN2017094037-appb-000004
或者，
Figure PCTCN2017094037-appb-000005
其中，
R为氨基保护基；
A和R2如上述所定义；并且
当A不存在时，不进行步骤d的反应。
根据本发明的第八方面，本发明提供用于制备本发明的沃替西汀类似物的中间体，所述中间体具有如下式IV的结构：
Figure PCTCN2017094037-appb-000006
其中：
R为氨基保护基；并且
R2为卤素或者被一个或多个卤素取代的C1-6烷基。
根据本发明的第九方面，本发明提供用于制备本发明的沃替西汀类似物的原料，所述原料具有如下式II或式III的结构：
Figure PCTCN2017094037-appb-000007
其中，
R为氨基保护基；并且
R2为卤素或者被一个或多个卤素取代的C1-6烷基。
根据本发明的第十方面，本发明提供制备式II的化合物的方法，其包括以下步骤：
Figure PCTCN2017094037-appb-000008
其中R2如上述所定义。
根据本发明的第十一方面，本发明提供制备式III的化合物的方法，其包括以下步骤：
Figure PCTCN2017094037-appb-000009
其中R如上述所定义。
发明详述
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很 好理解，但仍然阐述以下定义以更好地解释本发明。
本文所用的术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
本文所用的术语“取代的”指所指定的原子上的一个或多个(例如1个、2个、3个或4个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
本文中所用的术语“保护基”是指当多功能基有机化合物进行反应时，为使反应只发生在所希望的基团处，而避免其他基团遭受影响，此反应前将其他基团先加以保护，当反应完成后再恢复。能保护某种基团的试剂称为该基团的保护基。选择适当的保护基可由本领域技术人员容易地确定。保护基化学可见于例如T.W.Greene及P.G.M.Wuts,Protective Groups in Organic Synthesis,第3版,Wiley&Sons,Inc.,New York(1999)中，将其以其整体援引加入本文中。
本文中所用的术语“氨基保护基”是指防止氨基发生不期望的化学反应的保护基，包括但不限于叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、烯丙氧羰基、三甲基硅乙氧羰基、甲氧羰基、乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、邻硝基苯磺酰基、对硝基苯磺酰基、甲酰基、乙酰基、三氟乙酰基、丙酰基、特戊酰基、苯甲酰基、三苯甲基、苄基、2,4-二甲氧基苄基、对甲氧基苄基等。选择适当的氨基保护基可由本领域技术人员容易地确定。
本文所用的术语“C1-6烷基”是指具有1-6个碳原子的饱和的直链或支链烃基，例如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基等。
本文所用的术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。
本文所用的术语“药学上可接受的酸”是指那些与从生物、制备和配制的角度出发与药学实践和动物用途相容的酸，其包括无机酸，例如盐酸、氢溴酸、氢碘酸、硫酸、焦硫酸、硝酸、硼酸、磷酸、碳酸及其任意组合；和有机酸，例如甲酸、乙酸、丙酸、乙酰乙酸、三氟乙酸、丙酸、丙酮酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、硬脂酸、棕榈酸、草酸、丙二酸、 丁二酸、戊二酸、己二酸、马来酸、富马酸、乳酸、苹果酸、枸橼酸、酒石酸、苯甲酸、水杨酸、肉桂酸、萘甲酸、扑酸、烟酸、乳清酸、甲基硫酸、十二烷基硫酸、甲磺酸、三氟甲磺酸、乙磺酸、乙二磺酸、羟乙基磺酸、苯磺酸、对甲苯磺酸、1,5-萘二磺酸、2-萘磺酸、樟脑磺酸、氨基磺酸、谷氨酸、天冬氨酸、葡糖酸、葡糖醛酸及其任意组合。
本发明的沃替西汀类似物可以结晶形式或多晶型物形式存在，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
本发明的沃替西汀类似物可以其溶剂合物特别是水合物的形式存在，其中本发明的沃替西汀类似物包含作为所述类似物晶格的结构要素的极性溶剂，例如水、乙醇、异丙醇、乙酸乙酯或丙酮。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
化合物和制备方法
本发明的一个目的在于提供一系列新型沃替西汀类似物。所述沃替西汀类似物与沃替西汀的主要结构差异在于沃替西汀中左侧苯环的4-位为甲基，而本发明的沃替西汀类似物中对应位置处为卤素或者为被一个或多个卤素取代的烷基。本发明的沃替西汀类似物具有改善的分子脂水分配系数，并且在保持抗抑郁活性下，增强其穿过血脑屏障的能力，从而在口服后更快地穿过血脑屏障以更快地发挥作用；同时，与甲基相比，卤素或者被一个或多个卤素取代的烷基在体内较不易发生氧化代谢，因此本发明的沃替西汀类似物具有比沃替西汀更高的代谢稳定性，具有更长的作用时间，从而可以减少给药剂量及频率。因此，本发明的沃替西汀类似物克服了沃替西汀穿透血脑屏障能力差，代谢稳定性差的缺点。
具体而言，本发明提供式I的化合物或者其多晶型物或溶剂合物：
Figure PCTCN2017094037-appb-000010
其中：
R1为H；
R2为卤素或者被一个或多个卤素取代的C1-6烷基；并且
A不存在或者为药学上可接受的无机酸或有机酸。
根据本发明的一个实施方案，R2为被一个或多个卤素取代的C1-6烷基。在一优选的实施方案中，R2为被一个或多个氟取代的C1-6烷基，例如CF3、C2F5、CHF2、CH2F、CF2CH3或CF2CH2CH3等。在一特别优选的实施方案中，R2为CF3(三氟甲基)。
根据本发明的一个实施方案，A不存在。
根据本发明的另一实施方案，A为药学上可接受的无机酸或有机酸。在一优选的实施方案中，A为选自盐酸、氢溴酸、氢碘酸、硫酸、焦硫酸、硝酸、硼酸、磷酸和碳酸的无机酸或选自甲酸、乙酸、丙酸、乙酰乙酸、三氟乙酸、丙酸、丙酮酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、硬脂酸、棕榈酸、草酸、丙二酸、丁二酸、戊二酸、己二酸、马来酸、富马酸、乳酸、苹果酸、枸橼酸、酒石酸、苯甲酸、水杨酸、肉桂酸、萘甲酸、扑酸、烟酸、乳清酸、甲基硫酸、十二烷基硫酸、甲磺酸、三氟甲磺酸、乙磺酸、乙二磺酸、羟乙基磺酸、苯磺酸、对甲苯磺酸、1,5-萘二磺酸、2-萘磺酸、樟脑磺酸、氨基磺酸、谷氨酸、天冬氨酸、葡糖酸和葡糖醛酸的有机酸。在一特别优选的实施方案中，A为选自盐酸、氢溴酸和硫酸的无机酸或者选自枸橼酸、甲磺酸、乙磺酸、苯磺酸和对甲苯磺酸的有机酸。
本发明涵盖对上述优选基团进行任意组合所得的式I的化合物。
根据本发明的一个实施方案，所述式I的化合物为如下式I-1的化合物：
Figure PCTCN2017094037-appb-000011
其中A如上述所定义。
根据本发明的一个实施方案，本发明的沃替西汀类似物选自：
Figure PCTCN2017094037-appb-000012
Figure PCTCN2017094037-appb-000013
本发明的另一目的在于提供制备本发明的沃替西汀类似物的方法，其包括以下步骤：
Figure PCTCN2017094037-appb-000014
或者，
Figure PCTCN2017094037-appb-000015
其中，
R为氨基保护基；
A和R2如上述所定义；并且
当A不存在时，不进行步骤d的反应。
根据本发明的一个实施方案，R为选自叔丁氧羰基、苄氧羰基、9-芴甲 氧羰基、烯丙氧羰基、三甲基硅乙氧羰基、甲氧羰基、乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、邻硝基苯磺酰基、对硝基苯磺酰基、甲酰基、乙酰基、三氟乙酰基、丙酰基、特戊酰基、苯甲酰基、三苯甲基、苄基、2,4-二甲氧基苄基和对甲氧基苄基的氨基保护基。在一优选的实施方案中，R为选自叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、乙酰基、丙酰基和苯甲酰基的氨基保护基。
步骤a和步骤a’：
根据本发明的一个实施方案，步骤a和步骤a’的重氮化反应是在酸(如盐酸、硫酸或硝酸)和亚硝酸盐(如亚硝酸钠、亚硝酸钾)的存在下进行的。
在一优选的实施方案中，所述重氮化反应在较低温度(例如-10℃至10℃，优选0-5℃)下，于醇(如甲醇或乙醇)和水的混合溶剂中进行。
步骤b和步骤b’：
根据本发明的一个实施方案，步骤b和步骤b’的反应是在醇(如甲醇或乙醇)和水的混合溶剂中，于较高温度(例如30-100℃，优选50-60℃)下进行的。
步骤c：
根据本发明的一个实施方案，步骤c的反应采用常规的脱除氨基保护基的方法进行，所采用的具体方法取决于所使用的氨基保护基。例如，叔丁氧羰基可通过酸(例如HCl、三氟乙酸等)处理脱除；苄氧羰基可通过钯(例如Pd-C等)催化氢化脱除；9-芴甲氧羰基可通过有机碱(例如三乙胺或哌啶等)处理脱除)处理脱除；等等。
步骤d：
根据本发明的一个实施方案，步骤d的反应在醇(例如甲醇、乙醇、丙醇等)溶液中，于冰浴(0℃)至溶剂回流的温度下进行。
本发明的另一目的在于提供用于制备本发明的沃替西汀类似物的中间体，所述中间体具有如下式IV的结构：
Figure PCTCN2017094037-appb-000016
其中：
R为氨基保护基；并且
R2为卤素或者被一个或多个卤素取代的C1-6烷基。
根据本发明的一个实施方案，R为选自叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、烯丙氧羰基、三甲基硅乙氧羰基、甲氧羰基、乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、邻硝基苯磺酰基、对硝基苯磺酰基、甲酰基、乙酰基、三氟乙酰基、丙酰基、特戊酰基、苯甲酰基、三苯甲基、苄基、2,4-二甲氧基苄基和对甲氧基苄基的氨基保护基。在一优选的实施方案中，R为选自叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、乙酰基、丙酰基和苯甲酰基的氨基保护基。
根据本发明的一个实施方案，R2为被一个或多个卤素取代的C1-6烷基。在一优选的实施方案中，R2为被一个或多个氟取代的C1-6烷基，例如CF3、C2F5、CHF2、CH2F、CF2CH3或CF2CH2CH3等。在一特别优选的实施方案中，R2为CF3(三氟甲基)。
本发明涵盖对上述优选基团进行任意组合所得的式IV的化合物。
根据本发明的一个实施方案，所述式IV的化合物为如下式IV-1的化合物：
Figure PCTCN2017094037-appb-000017
根据本发明的一个实施方案，所述式IV的化合物选自：
Figure PCTCN2017094037-appb-000018
本发明的另一目的在于提供用于制备本发明的沃替西汀类似物的原料，所述原料具有如下式II的结构，
Figure PCTCN2017094037-appb-000019
其中R2为卤素或者被一个或多个卤素取代的C1-6烷基。
根据本发明的一个实施方案，R2为被一个或多个卤素取代的C1-6烷基。在一优选的实施方案中，R2为被一个或多个氟取代的C1-6烷基，例如CF3、C2F5、CHF2、CH2F、CF2CH3或CF2CH2CH3等。在一特别优选的实施方案中，R2为CF3(三氟甲基)。
根据本发明的一个实施方案，所述式II的化合物为如下式II-1的化合物：
Figure PCTCN2017094037-appb-000020
根据本发明的一个实施方案，所述式II的化合物是通过以下方法制备的：
Figure PCTCN2017094037-appb-000021
其中R2如上述所定义。
步骤e：
根据本发明的一个实施方案，步骤e的重氮化反应是在酸(如盐酸、硫酸或硝酸)和亚硝酸盐(如亚硝酸钠、亚硝酸钾)的存在下进行的。
在一优选的实施方案中，所述重氮化反应在较低温度下(例如-10℃至10℃，优选0-5℃)，于醇(如甲醇或乙醇)和水的混合溶剂中进行。
步骤f：
根据本发明的一个实施方案，步骤f的反应是在烷基黄原酸盐(所述烷基优选为C1-6烷基，所述盐优选为碱金属盐(如锂盐、钠盐或钾盐等)，烷基黄原酸盐的一个实例为乙基黄原酸钾)和强碱(例如氢氧化钠或氢氧化钾)的存在下进行的。
在一优选的实施方案中，所述烷基黄原酸盐和所述强碱同时或顺序加入反应中。
本发明的另一目的在于提供用于制备本发明的沃替西汀类似物的原料，所述原料具有下式III的结构：
Figure PCTCN2017094037-appb-000022
其中R为氨基保护基。
根据本发明的一个实施方案，R为选自叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、烯丙氧羰基、三甲基硅乙氧羰基、甲氧羰基、乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、邻硝基苯磺酰基、对硝基苯磺酰基、甲酰基、乙酰基、三氟乙酰基、丙酰基、特戊酰基、苯甲酰基、三苯甲基、苄基、2,4-二甲氧基苄基和对甲氧基苄基的氨基保护基。在一优选的实施方案中，R为选自叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、乙酰基、丙酰基和苯甲酰基的氨基保护基。
根据本发明的一个实施方案，所述式III的化合物选自：
Figure PCTCN2017094037-appb-000023
Figure PCTCN2017094037-appb-000024
根据本发明的一个实施方案，所述式III的化合物是通过以下方法制备的：
Figure PCTCN2017094037-appb-000025
其中R如上述所定义；
步骤g：
根据本发明的一个实施方案，步骤g的重氮化反应是在酸(如盐酸、硫酸或硝酸)和亚硝酸盐(如亚硝酸钠、亚硝酸钾)的存在下进行的。
在一优选的实施方案中，所述重氮化反应在较低温度下(例如-10℃至10℃，优选0-5℃)，于醇(如甲醇或乙醇)和水的混合溶剂中进行。
步骤h：
根据本发明的一个实施方案，步骤h的反应是在烷基黄原酸盐(所述烷基优选为C1-6烷基，所述盐优选为碱金属盐(如锂盐、钠盐或钾盐等)，烷基 黄原酸盐的一个实例为乙基黄原酸钾))和强碱(例如氢氧化钠或氢氧化钾)的存在下进行的。
在一优选的实施方案中，所述烷基黄原酸盐和所述强碱同时或顺序加入反应中。
药物组合物和药盒
本发明的另一目的在于提供药物组合物，其包含本发明的沃替西汀类似物或者其多晶型物或溶剂合物以及一种或多种药学上可接受的载体。
本发明中的“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。
本发明的药物组合物可以适合的途径给药。优选地，本发明的药物组合物通过口服、静脉内、动脉内、皮下、腹膜内、肌内或经皮途径给药。
对于这些给药途径，可以适合的剂型给药本发明的组合物。
所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂。
本发明的另一目的在于提供药盒，其包含本发明的沃替西汀类似物或者其多晶型物或溶剂合物，或者本发明的药物组合物。
治疗方法和用途
本发明的又一目的在于提供治疗抑郁症(特别是重度抑郁症)的方法，其包括向需要其的个体给药有效量的本发明的沃替西汀类似物或者其多晶型物或溶剂合物。
本发明的又一目的在于提供本发明的沃替西汀类似物或者其多晶型物或溶剂合物，其用于治疗抑郁症，特别是重度抑郁症。
本发明的又一目的在于提供本发明的沃替西汀类似物或者其多晶型物或溶剂合物在制备用于治疗抑郁症(特别是重度抑郁症)的药物中的用途。
如本文中所使用的术语“治疗有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约50mg，例如约0.01至约10mg/kg/日(单次或分次给药)。对70kg的人而言，这会合计为约0.007mg/日至约3500mg/日，例如约0.7mg/日至约700mg/日。在一些情况下，不高于前述范围的下限的剂量水平可以是足够的，而在其它情况下，仍可在不引起任何有害副作用的情况下采用较大剂量，条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。
本发明的化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg，适合地是0.1-500mg，优选0.5-300mg，更优选1-150mg，特别优选1-50mg，例如1.5mg、2mg、4mg、10mg、25mg等。
除非另外说明，否则如本文中所使用，术语“治疗(treating)”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或 多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
实施例
为了使本发明的目的和技术方案更加清楚，以下结合具体实施例进一步阐述本发明。要说明的是：以下实施例只用于对本发明进行进一步的说明，而不能理解为对本发明保护范围的限制。本领域的技术人员根据本发明的上述内容做出的一些非本质的改进和调整均属于本发明的保护范围。并且，下列实施例中未提及的具体实验方法，均按照常规实验方法进行。
本文中的缩写具有以下含义：
缩写 含义
NaNO2 亚硝酸钠
HPLC 高效液相色谱法
THF 四氢呋喃
化合物制备例
A.式II的化合物的制备
实施例1
4-三氟甲基-2-甲基苯硫酚的制备
1)在0-5℃下，将4-三氟甲基-2-甲基苯胺(10mmol)溶于乙醇-水(20ml，1:1)中。滴加浓盐酸(20mmol)，分批缓慢加入NaNO2(10.05mmol)的水溶液(5ml)。加完后，将反应物在0-5℃下保温30min，制得4-三氟甲基-2-甲基苯胺的重氮盐，备用。
2)在40-45℃下，将步骤1)中制备得到的重氮盐溶液缓慢滴加到乙基黄原酸钾(10.1mmol)在去离子水中的溶液(10ml)。通过HPLC检测反应，反应完成后，将水层用二氯甲烷(10ml*3)萃取，合并有机层，并将其用饱和食盐水(10ml*1)洗涤，无水硫酸钠干燥、过滤、减压蒸除溶剂。将残余 物通过制备色谱法分离，得到O-乙基S-[4-(三氟甲基)-2-甲基苯基]二硫代碳酸酯。
3)在室温下，将步骤2)中制得的O-乙基S-[4-(三氟甲基)-2-甲基苯基]二硫代碳酸酯(5mmol)溶于乙醇(20ml)中。向所得的溶液中缓慢滴加氢氧化钾(1.2g)在95％乙醇(10ml)中的溶液，将其在室温下搅拌30分钟。将反应物减压蒸馏，将残余物用水(20ml)稀释，将水层用乙醚(20ml*4)萃取后，将水层的pH调节至2，将所得的水层再用乙醚(20ml*3)萃取，用饱和氯化钠溶液洗涤两次，将有机相干燥，减压蒸馏得标题化合物。
ESI-MS[M-H]-191.17；
1H-NMR(DMSO)δ:2.36(3H),3.48(1H),7.25-7.42(3H).
B.式III的化合物的制备
实施例2
1-叔丁氧羰基-4-[2-(巯基)苯基]哌嗪(化合物10)的制备
1)在0-5℃下，将4-(2-氨基苯基)-1-叔丁氧羰基哌嗪(5mmol)溶于乙醇-水(20ml，1:1)中。滴加浓盐酸(10mmol)，分批缓慢加入NaNO2(5.05mmol)的水溶液(3ml)，加完后，将反应物在0-5℃下保温30min，制得4-(2-氨基苯基)-1-叔丁氧羰基哌嗪的重氮盐，备用。
2)在40-45℃下，将步骤1)中制备得到的重氮盐溶液缓慢滴加到乙基黄原酸钾(10.1mmol)在去离子水中的溶液(10ml)。通过HPLC检测反应，反应完成后，将水层用二氯甲烷(10ml*3)萃取，合并有机层，并将其用饱和食盐水(10ml*1)洗涤，无水硫酸钠干燥、过滤、减压蒸除溶剂，将残余物通过制备色谱法分离，得到O-乙基S-[1-叔丁氧羰基-4-苯基哌嗪]二硫代碳酸酯，备用。
3)在室温下，将步骤2)中制得的二硫代碳酸酯(5mmol)溶于乙醇(20ml)中。向所得的溶液中缓慢滴加氢氧化钾(1.2g)在95％乙醇(10ml)中的溶液，将其在室温下搅拌30分钟。将反应物减压蒸馏，将残余物用水(20ml)稀释，将水层用乙醚(20ml*4)萃取后，将水层的pH调节至2，将所得的水层再用乙醚(20ml*3)萃取，用饱和氯化钠溶液洗涤两次，将有机相干燥，减压蒸馏得标题化合物。
ESI-MS[M-H]-276.34。
实施例3
1-苄氧羰基-4-[2-(巯基)苯基]哌嗪(化合物11)的制备
以1-苄氧羰基-4-(2-氨基苯基)哌嗪为原料，按照实施例2的操作，可以制得化合物11。
ESI-MS[M-H]-310.35。
实施例4
1-(9-芴甲氧羰基)-4-[2-(巯基)苯基]哌嗪(化合物12)的制备
以1-(9-芴甲氧羰基)-4-(2-氨基苯基)哌嗪为原料，按照实施例2的操作，可以制得化合物12。
ESI-MS[M-H]-398.46。
C.式IV的化合物的制备
实施例5
1-叔丁氧羰基-4-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪(化合物16)的制备
1)在0-5℃下，将4-(2-氨基苯基)-1-叔丁氧羰基哌嗪(10mmol)溶于乙醇-水(20ml，1:1)中。滴加浓盐酸(20mmol)，分批缓慢加入NaNO2(10.05mmol)的水溶液(5ml)。加完后，将反应物在0-5℃下保温30min，制得4-(2-氨基苯基)-1-叔丁氧羰基哌嗪的重氮盐，备用。
2)在50-60℃下，将步骤1)中制备得到的重氮盐溶液缓慢滴加到4-三氟甲基-2-甲基苯硫酚(实施例1，10mmol)在乙醇:水(1:1)中的溶液(10ml)。通过HPLC检测反应，反应完成后，将反应物用二氯甲烷(10ml*3)萃取，合并有机层，并将其用饱和食盐水(10ml*1)洗涤，无水硫酸钠干燥、过滤、减压蒸除溶剂。将残余物通过制备色谱法分离，得到标题化合物。
ESI-MS[M+H]+453.52；
1H-NMR(DMSO)δ:1.37(9H),2.36(3H),2.88(4H),3.10(4H),6.93(1H),7.04(1H),7.18(2H),7.38(1H),7.46(1H),7.65(1H).
实施例6
1-苄氧羰基-4-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪(化合物17)的制 备
以实施例1的化合物和4-(2-氨基苯基)-1-苄氧羰基哌嗪为原料，按照实施例5的操作，可以制得标题化合物。
ESI-MS[M+H]+487.53。
实施例7
1-(9-芴甲氧羰基)-4-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪(化合物18)的制备
以实施例1的化合物和4-(2-氨基苯基)-1-(9-芴甲氧羰基)哌嗪为原料，按照实施例5的操作，可以制得标题化合物。
ESI-MS[M+H]+561.61。
实施例8
由化合物10制备化合物16
1)在0-5℃下，将4-三氟甲基-2-甲基苯胺(10mmol)溶于乙醇-水(20ml，1:1)中。滴加浓盐酸(20mmol)，分批缓慢加入NaNO2(10.05mmol)的水溶液(5ml)。加完后，将反应物在0-5℃下保温30min，制得4-三氟甲基-2-甲基苯胺的重氮盐，备用。
2)在50-60℃下，将步骤1)中制备得到的重氮盐溶液缓慢滴加到1-叔丁氧羰基-4-[2-(巯基)苯基]哌嗪(化合物10，10mmol)在乙醇-水(1:1)中的溶液(10ml)。通过HPLC检测反应，反应完成后，将反应物用二氯甲烷(10ml*3)萃取，合并有机层，并将其用饱和食盐水(10ml*1)洗涤，无水硫酸钠干燥、过滤、减压蒸除溶剂。将残余物通过制备色谱法分离，得到标题化合物。
实施例9
由化合物11制备化合物17
以4-三氟甲基-2-甲基苯胺和1-苄氧羰基-4-[2-(巯基)苯基]哌嗪(化合物11)为原料，按照实施例8的操作，可以制得化合物17。
实施例10
由化合物12制备化合物18
以4-三氟甲基-2-甲基苯胺和1-(9-芴甲氧羰基)-4-[2-(巯基)苯基]哌嗪(化合物12)为原料，按照实施例8的操作，可以制得化合物18。
D.本发明的沃替西汀类似物的制备
实施例11
由化合物16制备化合物1
1)在室温下，将实施例5制备得到的化合物16(5mmol)溶于干燥的乙醚(20ml)中，向其中缓慢地通入HCl气体。通过HPLC检测反应，反应完成后，减压蒸除乙醚，得到1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪盐酸盐(化合物2)。
2)将步骤1)中制备得到的化合物2(5mmol)溶于水(20ml)。在冰浴下，用1N NaOH调节pH为10-11后，用二氯甲烷(10ml*3)萃取水层，合并有机层，将其用饱和食盐水(10ml*1)洗涤，无水硫酸钠干燥、过滤、减压蒸除溶剂，得到1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪(化合物1)。
ESI-MS[M+H]+353.39。
1H-NMR(DMSO)δ:2.37(3H),3.30(4H),3.17(4H),6.95(1H),7.08(1H),7.20(2H),7.32(1H),7.48(1H),7.68(1H)；m.p＝206-208℃。
实施例12
由化合物17制备化合物1
在室温下，将1-苄氧羰基-4-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪(化合物17，10mmol)溶解于THF(50ml)中。加入5％Pd-C(500mg)，并将空气用氢气置换，在室温下反应。通过HPLC监测，反应完成后，将反应物过滤、减压蒸除溶剂，得到化合物1。
实施例13
由化合物18制备化合物1
在冰浴下，将1-(9-芴甲氧羰基)-4-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪(化合物18，10mmol)溶解于甲醇(50ml)中。加入哌啶(10mmol)，并撤去冰浴，在室温下反应。通过HPLC监测，反应完成后，减压蒸除溶剂。将残余物通过制备色谱法分离，得到化合物1。
实施例14
化合物3的制备
在氮气保护下，将实施例11中制得的化合物1(10mmol)溶于无水乙醇(15ml)后，将溶液加热至回流。缓慢滴加含有40％氢溴酸(10mmol)的无水 乙醇溶液(1ml)，回流15min。使反应物自然冷却，有白色固体析出，过滤，并将滤饼减压干燥，得到1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪氢溴酸盐(化合物3)。
m.p.:170-172℃。
实施例15
化合物4的制备
在冰浴下，将化合物1(5mmol)溶于无水乙醇(20ml)中。缓慢滴加含有硫酸(10mmol)的乙醇溶液(10ml)，有固体析出，过滤得到1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪硫酸盐(化合物4)。
m.p.:164-166℃。
实施例16
化合物5的制备
以化合物1和甲磺酸为原料，按照实施例15的操作，可以制得1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪甲磺酸盐(化合物5)。
m.p.:152-155℃。
实施例17
化合物6的制备
以化合物1和乙磺酸为原料，按照实施例15的操作，可以制得1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪乙磺酸盐(化合物6)。
m.p.:149-151℃。
实施例18
化合物7的制备
以化合物1和苯磺酸为原料，按照实施例15的操作，可以制得1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪苯磺酸盐(化合物7)。
m.p.:145-147℃。
实施例19
化合物8的制备
以化合物1和对甲苯磺酸为原料，按照实施例15的操作，可以制得1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪对甲苯磺酸盐(化合物8)。
m.p.:141-143℃。
实施例20
化合物9的制备
以化合物1和枸橼酸为原料，按照实施例15的操作，可以制得1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪枸橼酸盐(化合物9)。
m.p.:151-154℃。
生物学实施例
实施例21
脂水分配系数测定
分别将沃替西汀氢溴酸盐和化合物3各6mg溶于pH 7.4的磷酸盐缓冲液(3ml)与正辛醇(3ml)所组成的混合液中，将混合液在37℃下静置3小时。分别检测各物质在水相和油相中的浓度，并通过logP＝-log(C油/C水)计算，结果为：
logP沃＝2.1；logP化合物3＝2.7。
本发明的化合物的脂水分配系数大于沃替西汀，说明本发明的化合物具有更好的亲脂性，更易穿过血脑屏障(BBB)。
实施例22
[3H]5-羟色胺(5-HT)再摄取半数抑制率(IC50)测定
用PCR(聚合酶链式反应)将SLC6A4基因从质粒Pcmv6-XL4-SLC6A4(Origene，Cat#SC119478)中扩增出来，同时在C端加入HIS标签，再用5`EcoR1和3`Hind111酶切位点插入到pcDNA3.1(-)载体中，构建为pcDNA3.1-SLC6A4-His。
收集对数生长期的CHO细胞(中国仓鼠卵巢细胞，中科院细胞生物研究所，Cat#CCL-61)，计数。用F-12培养基(Gibco，Cat#11330-032)重新悬浮细胞，接种至96孔板上，每孔接种100μL(20000个细胞/孔)。在37℃下，在5％CO2培养箱(相对湿度100％)中孵育24h。
用Opti-MEM培养基(25μL，Gibco，Cat#11058021)稀释上述修饰过的质粒(0.48μg)，轻吹混匀。用Opti-MEM培养基(25μL，Gibco，Cat#11058021)稀释FuGENE HD转染试剂(1.44μL，Promega，Cat#E2311)。轻吹混匀后，在室温下静置5min。将前两步配制的溶液混合，轻吹混匀， 在室温下静置12min。将所得的转染复合物以50μL/孔加入到96孔细胞板中，前后轻摇细胞板混合均匀后，于37℃、5％CO2培养箱中孵育48h。
分别用Opti-MEM培养基将化合物1和沃替西汀稀释至1mM后，每4倍梯度稀释10次，按20μL/孔加入到被转染的细胞孔中(对应浓度为100uM-0.0004uM，共10个浓度点，每个浓度点之间浓度比值为4，每个浓度3个平行孔)。加完后，孵育30min，然后加入[3H]5-羟色胺(25nM，Perkinelmer，Cat#NET1167250UC)。在37℃下孵育30min后，用0.5M NaOH裂解细胞，取50μL裂解细胞液，加入200μL闪烁液，用MicroBeta2读数。
计算公式为：％抑制率＝[100％活性孔-样本孔]/100％活性孔*100
实验结果如下表所示：
半数抑制率 沃替西汀 化合物1
IC50 266.6nM 230.6nM
实验结果表明，本发明的化合物与沃替西汀对[3H]5-HT再摄取的IC50相当，说明本发明的化合物具有与沃替西汀相当的5-HT再摄取抑制活性。
实施例23
小鼠甩头实验
取KM种小鼠(雄性，18-22g，重庆医科大学实验动物中心)，随机分组，每组6只。按照下表对各试验组动物分别给予对应的药液后，再给予200mg/kg 5-HTP(5-羟色氨酸)，观察0-10min内沃替西汀和化合物3对小鼠甩头频率的影响(具体实验方法参见文献[J]Brit.J.Pharmacol.(1963),20,106-120)。给药途径、剂量、观察时间和甩头频率见下表：
Figure PCTCN2017094037-appb-000026
1.与阴性对照组(生理盐水组)相比，小鼠经腹腔给药化合物3后，其甩头次数明显增加，初步说明化合物3作用于5-HT中枢神经系从而抑制了5-HT神经递质的再摄取；
2.与沃替西汀相比，在相同给药途径及相同给药剂量下，在化合物3 作用于5-HTP诱导的小鼠甩头行为模型后，小鼠震颤强度及震颤持续时间都比沃替西汀强。
实验结果表明，本发明的化合物具有沃替西汀样的抑制了5-HT神经递质的再摄取的作用，且作用强度强于沃替西汀。
实施例24
脑浓度与血浆浓度实验
取KM种小鼠(雄性，18-22g，重庆医科大学实验动物中心)，随机分组，每组6只。按照下表对各试验组动物分别静脉注射等摩尔的沃替西汀(20mg/kg)和化合物1(23.6mg/kg)。于注射后1小时和2小时取血和小鼠脑组织样本，分别检测血浆与脑组织中的沃替西汀与化合物1的浓度，并计算它们的比值(脑浓度/血浆浓度)，实验结果如下表所示：
Figure PCTCN2017094037-appb-000027
实验结果表明，本发明的化合物较沃替西汀更易穿过血脑屏障，其脑暴露量高于沃替西汀，从而更易发挥作用。
实施例25
大鼠血药浓度实验
取SD大鼠(雄性，180-220g，重庆医科大学实验动物中心)，随机分组，每组4只。给药前禁食不禁水8h。灌胃给药，给药剂量如下表所示：
Figure PCTCN2017094037-appb-000028
给药后，在第0、1、2、4、6、8小时，从眼眶静脉丛取全血，每个时间点取至少0.3ml，肝素抗凝。将所得的全血(200μl)血液加入到乙腈(800μl)中，漩涡震荡1min混匀，在12000rpm下离心10min。取上清液，在-20℃下保存，将上清液用LC/MS/MS检测血药浓度，每组各只动物的数据如下表所示：
Figure PCTCN2017094037-appb-000029
由以上结果可以看出，化合物3的血药浓度在口服给药后各个时间点均高于等摩尔剂量给药的沃替西汀的血药浓度，表明本发明提供的化合物较沃替西汀更易吸收，代谢更慢。
实施例26
小鼠强迫游泳实验
取KM种小鼠(雄性，38-42g，重庆医科大学实验动物中心)，并随机分组，每组6只。使小鼠禁食4h后，将其放入直径18cm、高40cm、水深15cm(水温25℃)的玻璃圆缸内使其游泳6min，游泳后用热吹风机吹干。按照下表对各试验组动物分别给予对应的药液(口服灌胃，20mg/kg)。给药1小时后，将小鼠放入直径18cm、高40cm、水深15cm(水温25℃)的玻璃圆缸内使其游泳，持续时间为6min。用摄像系统摄制整个6min内小鼠的游泳情况，经Noldus软件自动采集数据并进行分析，记录并统计后4min内停止游泳的不动时间(实验方法参见文献THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS(2012)，Vol.340,No.3：666-675)。实验结果如下表所示：
Figure PCTCN2017094037-appb-000030
实验结果表明，当将本发明的化合物与沃替西汀氢溴酸盐以相同量给药时，本发明提供的化合物3缩短了小鼠的不动时间，因而本发明提供的化合物具有抗抑郁作用。
除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (10)

  1. 式I的化合物或者其多晶型物或溶剂合物：
    Figure PCTCN2017094037-appb-100001
    其中：
    R1为H；
    R2为卤素或者被一个或多个卤素取代的C1-6烷基，优选为被一个或多个氟取代的C1-6烷基，更优选为三氟甲基；并且
    A不存在或者为药学上可接受的无机酸或有机酸，
    所述无机酸优选地选自盐酸、氢溴酸、氢碘酸、硫酸、焦硫酸、硝酸、硼酸、磷酸和碳酸，更优选为盐酸、氢溴酸或硫酸；
    所述有机酸优选地选自甲酸、乙酸、丙酸、乙酰乙酸、三氟乙酸、丙酸、丙酮酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、硬脂酸、棕榈酸、草酸、丙二酸、丁二酸、戊二酸、己二酸、马来酸、富马酸、乳酸、苹果酸、枸橼酸、酒石酸、苯甲酸、水杨酸、肉桂酸、萘甲酸、扑酸、烟酸、乳清酸、甲基硫酸、十二烷基硫酸、甲磺酸、三氟甲磺酸、乙磺酸、乙二磺酸、羟乙基磺酸、苯磺酸、对甲苯磺酸、1,5-萘二磺酸、2-萘磺酸、樟脑磺酸、氨基磺酸、谷氨酸、天冬氨酸、葡糖酸和葡糖醛酸，更优选为枸橼酸、甲磺酸、乙磺酸、苯磺酸或对甲苯磺酸。
  2. 如权利要求1所述的化合物或者其多晶型物或溶剂合物，其中所述化合物选自：
    编号 名称 1 1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪 2 1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪盐酸盐 3 1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪氢溴酸盐 4 1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪硫酸盐
    5 1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪甲磺酸盐 6 1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪乙磺酸盐 7 1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪苯磺酸盐 8 1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪对甲苯磺酸盐 9 1-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪枸橼酸盐
  3. 药物组合物，其包含如权利要求1或2所述的化合物或者其多晶型物或溶剂合物以及一种或多种药学上可接受的载体
  4. 药盒，其包含如权利要求1或2所述的化合物或者其多晶型物或溶剂合物，或者如权利要求3所述的药物组合物。
  5. 如权利要求1或2所述的化合物或者其多晶型物或溶剂合物在制备用于治疗抑郁症、特别是重度抑郁症的药物中的用途，其中所述药物优选为通过口服、静脉内、动脉内、皮下、腹膜内、肌内或经皮途径给药的剂型。
  6. 制备权利要求1或2的化合物的方法，其包括以下步骤：
    Figure PCTCN2017094037-appb-100002
    或者，
    Figure PCTCN2017094037-appb-100003
    其中，
    R为氨基保护基，优选为叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、烯丙氧羰基、三甲基硅乙氧羰基、甲氧羰基、乙氧羰基、邻苯二甲酰基、对甲苯磺酰基、邻硝基苯磺酰基、对硝基苯磺酰基、甲酰基、乙酰基、三氟乙酰基、丙酰基、特戊酰基、苯甲酰基、三苯甲基、苄基、2,4-二甲氧基苄基或对甲氧基苄基，更优选为叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、乙酰基、丙酰基或苯甲酰基；
    A和R2如权利要求1所定义；
    当A不存在时，不进行步骤d的反应。
  7. 式IV的化合物：
    Figure PCTCN2017094037-appb-100004
    其中：
    R为氨基保护基，优选为叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、烯丙氧羰基、三甲基硅乙氧羰基、甲氧羰基、乙氧羰基、邻苯二甲酰基、对甲 苯磺酰基、邻硝基苯磺酰基、对硝基苯磺酰基、甲酰基、乙酰基、三氟乙酰基、丙酰基、特戊酰基、苯甲酰基、三苯甲基、苄基、2,4-二甲氧基苄基或对甲氧基苄基，更优选为叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、乙酰基、丙酰基或苯甲酰基；并且
    R2为卤素或者被一个或多个卤素取代的C1-6烷基，优选为被一个或多个氟取代的C1-6烷基，更优选为三氟甲基。
  8. 如权利要求7所述的化合物，其选自：
    16 1-叔丁氧羰基-4-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪 17 1-苄氧羰基-4-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪 18 1-(9-芴甲氧羰基)-4-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪 19 1-乙酰基-4-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪 20 1-丙酰基-4-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪 21 1-苯甲酰基-4-[2-(2-甲基-4-三氟甲基苯硫基)苯基]哌嗪。
  9. 式II的化合物：
    Figure PCTCN2017094037-appb-100005
    其中R2为卤素或者被一个或多个卤素取代的C1-6烷基，优选为被一个或多个氟取代的C1-6烷基，更优选为三氟甲基。
  10. 制备权利要求9的化合物的方法，其包括以下步骤：
    Figure PCTCN2017094037-appb-100006
    其中R2如权利要求9所定义。
PCT/CN2017/094037 2016-07-22 2017-07-24 沃替西汀类似物及其用途和制备 WO2018014880A1 (zh)

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