WO2015180342A1 - 氘取代1-[2-(2,4-二甲基-苯硫基)-苯基]哌嗪化合物或其衍生物及其药物组合物和用途 - Google Patents

氘取代1-[2-(2,4-二甲基-苯硫基)-苯基]哌嗪化合物或其衍生物及其药物组合物和用途 Download PDF

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WO2015180342A1
WO2015180342A1 PCT/CN2014/087662 CN2014087662W WO2015180342A1 WO 2015180342 A1 WO2015180342 A1 WO 2015180342A1 CN 2014087662 W CN2014087662 W CN 2014087662W WO 2015180342 A1 WO2015180342 A1 WO 2015180342A1
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phenyl
compound
piperazine
derivative
phenylthio
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PCT/CN2014/087662
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English (en)
French (fr)
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耿仲毅
陈兴海
奥玛⋅派克
彭伟
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江苏吉贝尔药业股份有限公司
镇江圣安医药有限公司
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Priority to US15/315,182 priority Critical patent/US9896423B2/en
Priority to EP14893470.6A priority patent/EP3150587B1/en
Publication of WO2015180342A1 publication Critical patent/WO2015180342A1/zh

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    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention belongs to the field of medicine, in particular to a compound of hydrazine substituted 1-[2-(2,4-dimethyl-phenylthio)-phenyl]piperazine or a derivative thereof, the derivative including pharmaceutically acceptable Salts, solvates, prodrugs, N-oxides, polymorphs, stereoisomers, geometric isomers or tautomers thereof or mixtures thereof, pharmaceutical compositions comprising these compounds and their preparation Use in medicine.
  • Depression is a mental illness that can lead to abnormal or even physical disability.
  • the prevalence of depression in China is about 3%-5%.
  • Symptoms of depression can be mood changes and other symptoms, which directly interfere with people's daily life such as work, study, sleep, and diet. Symptoms of depression include loss of interest in daily activities, restlessness, abnormal sleep, fatigue, significant changes in weight, slow thinking, guilt, lack of value, lack of concentration, and even suicidal tendencies. Of course, the symptoms of depression patients are not the same. .
  • NE central norepinephrine
  • 5-HT serotonin
  • DA dopamine
  • TCA tricyclic antidepressant
  • MAOI monoamine oxidase inhibitor
  • the third class of antidepressants are selective serotoninreuptake inhibitors (SSRIs), which increase the concentration of 5-HT in the synaptic cleft by inhibiting the reuptake of 5-HT by the presynaptic membrane. Thereby, the excitability of the 5-HT1A receptor in the postsynaptic membrane is enhanced, and finally the antidepressant effect is achieved. Its advantage is that it does not affect other neurotransmitter receptors and is therefore safer. However, because SSRI acts non-selectively on various subtypes of the 5-HT receptor, it causes some corresponding adverse reactions.
  • SSRIs serotoninreuptake inhibitors
  • Vortioxetine acts as an antidepressant by modulating 5-HT.
  • Non-clinical in vivo experiments have shown that Vortioxetine can increase the concentration of neurotransmitters serotonin, norepinephrine, dopamine, acetylcholine and histamine in specific regions of the brain.
  • Non-clinical studies have shown that Vortioxetine can modulate 5-HT3, 5-HT7, 5-HT1D, 5-HT1B, 5-HT1A, 5-HT.
  • Vortioxetine is mainly oxidized by cytochrome P450 isoenzymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6, and its metabolites bind to glucuronic acid to produce new metabolites.
  • cytochrome P450 isoenzymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6, and its metabolites bind to glucuronic acid to produce new metabolites.
  • [14C]-labeled vortioxetine After a single oral administration of [14C]-labeled vortioxetine, the recovery of radioactive metabolites in urine and feces was approximately 59% and 26%, respectively.
  • the object of the present invention is to overcome the drawbacks of the prior art and to provide a compound or a derivative thereof, which is substituted for 1-[2-(2,4-dimethyl-phenylthio)-phenyl]piperazine, a derivative thereof Included are pharmaceutically acceptable salts, solvates, prodrugs, N-oxides, polymorphs, stereoisomers, geometric isomers or tautomers thereof or mixtures thereof, pharmaceutical compositions comprising the same And the use thereof in the preparation of a medicament.
  • guanidine-substituted 1-[2-(2,4-dimethyl-phenylthio)-phenyl]piperazine compound or a pharmaceutically acceptable acid addition salt thereof and the like have good drug activity, and at the same time It can solve the problem of poor metabolism of drugs, and has little toxic side effects during the course of administration.
  • a first aspect of the present invention provides a compound or a derivative thereof which is substituted with 1-[2-(2,4-dimethyl-phenylthio)-phenyl]piperazine, the derivative of which includes pharmaceutically acceptable Salts, solvates, prodrugs, N-oxides, polymorphs, stereoisomers, geometric isomers or tautomers thereof or mixtures thereof.
  • Another aspect of the present invention is to provide a pharmaceutically acceptable acid addition salt of a hydrazine-substituted 1-[2-(2,4-dimethyl-phenylthio)-phenyl]piperazine compound.
  • Another aspect of the present invention is to provide a compound of hydrazine-substituted 1-[2-(2,4-dimethyl-phenylthio)-phenyl]piperazine in the form of a single crystal or a polymorph.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound substituted with hydrazine substituted 1-[2-(2,4-dimethyl-phenylthio)-phenyl]piperazine, or a pharmaceutically acceptable thereof Salts, solvates, prodrugs, N-oxides, polymorphs, stereoisomers, geometric isomers or tautomers thereof or mixtures thereof, and pharmaceutically acceptable carriers, excipients, One of a diluent, an adjuvant, a vehicle, or a combination thereof.
  • Another aspect of the present invention is to provide a compound in which hydrazine is substituted for 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine, or a pharmaceutically acceptable salt, solvate or prodrug thereof
  • a pharmaceutically acceptable salt, solvate or prodrug thereof Use of N-oxides, polymorphs, stereoisomers, geometric isomers or tautomers thereof or mixtures thereof in the manufacture of a medicament for the treatment of a disease selected from the group consisting of depression, craze, Affective disorder, sleep apnea, anxiety, ADHD (attention deficit hyperactivity disorder), PTSD (post-traumatic stress disorder), IBS (Irritable Bowel Syndrome), alcohol abuse, nicotine addiction, drug abuse, drug abuse.
  • a disease selected from the group consisting of depression, craze, Affective disorder, sleep apnea, anxiety, ADHD (attention deficit hyperactivity disorder), PTSD (post-traumatic stress disorder), IBS (
  • the compound of the present invention substituted with 1-[2-(2,4-dimethyl-phenylthio)-phenyl]piperazine and 1-[2-(2,4-dimethyl) in the prior art Compared with phenyl-phenylthio)-phenyl]piperazine, it has the following advantages:
  • the compound of the present invention has a better curative effect, can reduce the adverse metabolism of the drug, and can increase the concentration of the drug in the blood, thereby achieving a better therapeutic effect.
  • the compound of the present invention can increase the oral bioavailability of the drug and reduce unwanted metabolism (referred to as first pass metabolism) in the intestinal lining and in the liver. This results in a larger proportion of unmetabolized drugs reaching the target site.
  • the compounds of the present invention have less toxicity and side effects, and the active metabolites produced by drugs through adverse metabolic reactions are usually important factors for drug toxicity and other side effects, and the reduction of adverse metabolism of drugs greatly reduces the drug's Toxicity and other side effects.
  • Metal product refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. a combination Metabolites of the substance can be identified by known techniques, and the activity can be characterized by routine experimentation. Such products may be obtained by oxidative, reducing, hydrolyzing, amidating, deamidating, esterifying, defatting, and enzymatic cleavage of the administered compound. Accordingly, metabolites of the compounds of the invention include metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.
  • Figure 1 shows the reaction equation for the preparation of 1- ⁇ 2-[2,4-bis(tridemethyl)-phenylsulfanyl]-phenyl ⁇ piperazine and its hydrobromide salt.
  • Figure 2 shows the mean plasma concentration to time after oral administration of 1- ⁇ 2-[2,4-bis(tridemethyl)-phenylsulfanyl]-phenyl ⁇ piperazine hydrobromide 20 mg/kg in rats. .
  • Figure 3 is a graph showing the mean plasma concentration to time after oral administration of Vortioxetine 20 mg/kg in rats.
  • the present invention has been achieved by the following technical solutions.
  • a hydrazine-substituted 1-[2-(2,4-dimethyl-phenylthio)-phenyl]piperazine compound having the following structural formula (I), or a derivative thereof, includes a pharmaceutically acceptable salt, a solvate, a former Drugs, N-oxides, stereoisomers, geometric isomers or tautomers or mixtures thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently hydrogen or deuterium, The condition is that at least one of them is ⁇ .
  • the above-mentioned derivative of a hydrazine-substituted 1-[2-(2,4-dimethyl-phenylthio)-phenyl]piperazine compound is an addition salt thereof with a pharmaceutically acceptable acid, which is pharmaceutically acceptable Acceptable acid addition salts are preferably their addition salts with hydrobromic acid.
  • a pharmaceutical composition comprising the above compound or a derivative thereof and one or a combination of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle.
  • a disease selected from the group consisting of depression, fever, affective disorder, sleep apnea, anxiety, ADHD (attention deficit hyperactivity disorder), PTSD (post-traumatic stress) Obstacle), chronic pain, IBS (Irritable Bowel Syndrome), alcoholism, nicotine addiction, vomiting, drug abuse, drug abuse.
  • a disease selected from the group consisting of depression, fever, affective disorder, sleep apnea, anxiety, ADHD (attention deficit hyperactivity disorder), PTSD (post-traumatic stress) Obstacle), chronic pain, IBS (Irritable Bowel Syndrome), alcoholism, nicotine addiction, vomiting, drug abuse, drug abuse.
  • the hydrazine-substituted 1-[2-(2,4-dimethyl-phenylthio)-phenyl]piperazine compound of the present invention is a preferred compound selected from the group consisting of:
  • hydrazine substitution means that one or more hydrogens in the compound or group are replaced by hydrazine, and hydrazine substitution may be a Generation, disubstituted, polysubstituted or fully substituted.
  • the cerium isotope content of the cerium at the cerium substitution site is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, and even more preferably greater than 95%. More preferably greater than 99%.
  • the terms "one or more deuterated” are used interchangeably with "one or more deuterated”.
  • substituted means that one or more hydrogen atoms in a given structure may be substituted with a particular substituent. Unless otherwise indicated, an optional substituent 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.
  • hydrogen means a single hydrogen atom.
  • ⁇ means a single ruthenium atom.
  • One such atomic group is bonded to a methyl group to form a mono-deuterated methyl group (-CDH 2 ), and two deuterium atoms are bonded to a methyl group to form a di-deuterated methyl group or a di-deuterated methyl group (-CD 2 H). And three deuterium atoms are bonded to one methyl group to form a trideuteromethyl group (-CD 3 ).
  • solvate means a physical association of a compound of the invention with one or more solvent molecules. This physical association includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate can be separated.
  • Solvate includes solution phases and isolatable solvates. Non-limiting examples of solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is where the solvent molecule is H 2 O solvate. The preparation of solvates is generally known.
  • a typical, non-limiting method involves dissolving a compound of the invention in a desired amount of solvent (organic or water or a mixture thereof) above ambient temperature, cooling the solution at a rate sufficient to form crystallization, and then separating and crystallizing by standard methods.
  • Analytical techniques such as infrared spectroscopy can confirm the presence of a solvent (or water) in the crystallization of the solvate (or hydrate).
  • prodrug means a substance which is converted in vivo to form a hydrazine-substituted 1-[2-(2,4-dimethyl-phenylthio)-phenyl]piperazine or a pharmaceutically acceptable salt of the compound (for example, Prodrug). Transformation can occur by various mechanisms (eg, by metabolic or chemical treatment), such as by hydrolysis in the blood. T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACSSymposium Series, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987 A discussion of the use of prodrugs.
  • the prodrug of the compound of the present invention can be formed, for example, by substituting a hydrogen atom of an amine group with a suitable group.
  • stereoisomer includes all enantiomerically/stereomerically pure and enantiomerically/stereoisomerically enriched compounds of the invention.
  • the compound of the present invention substituted with 1-[2-(2,4-dimethyl-phenylthio)-phenyl]piperazine or a pharmaceutically acceptable acid addition salt thereof can be used as a treatment for major depression and a wide range of An active ingredient of a pharmaceutical composition for sexual anxiety, which may contain an effective amount of the compound or a pharmaceutically acceptable acid addition salt thereof, and the like, together with a pharmaceutically acceptable carrier, excipient, diluent
  • One of the adjuvants, the vehicle, or a combination thereof, is formulated into a dosage form suitable for use.
  • the administration system may be an albumin-binding injection, a liposome, a powder needle, a nanoparticle and a cyclodextrin inclusion compound; the administration dosage form may be an injection solution, or may be a solid dosage form or a semi-solid dosage form, such as It is an injection, a tablet, a capsule, a pill, a powder or a granule.
  • the pharmaceutically acceptable carriers, adjuvants and vehicles useful in the pharmaceutical compositions of the present invention include, but are not limited to, serum proteins of human serum albumin, lecithin, disodium hydrogen phosphate, sodium chloride, potassium hydrogen phosphate. , colloidal silica, magnesium trisilicate, polyvinyl, cellulose based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, polyethylene-polyoxypropylene-block polymer, Polyethylene glycol, aluminum oxide, aluminum stearate, phosphate, glycine, sorbic acid, potassium sorbate, and mixtures of partial glycerides, water, salts or electrolytes.
  • the compound of the present invention substituted with 1-[2-(2,4-dimethyl-phenylthio)-phenyl]piperazine can be formulated into a pharmaceutically acceptable salt suitable for use as a medicament, pharmaceutically acceptable
  • a salt suitable for use as a medicament means a salt suitable for use as a medicament formed by the compound of the present invention and a non-toxic acid or base, including inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids. Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrobromic acid, hydrochloric acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid.
  • the salt may also be formed from an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, cinnamic acid, citraconic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid.
  • organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, cinnamic acid, citraconic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid.
  • citric acid citric acid, picric acid, methanesulfonic acid, benzoic acid, benzenesulfonic acid benzoic acid, ascorbic acid, bismethylene salicylic acid, ethanedisulfonic acid, salicylic acid, gluconic acid, mandelic acid, aspartic Amino acid, stearic acid, palmitic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, succinic acid, theophylline acetic acid, and itaconic acid, aspartic acid, and the like.
  • composition of the present invention can be administered orally, by injection, by inhalation, topically, rectally, nasally, buccally, vaginally or through an implantable kit. Dosing. Preferred pharmaceutical compositions are administered orally, intraperitoneally or intravenously.
  • the sterile injection method of the pharmaceutical composition of the present invention may be a water or oleaginous suspension, and the suspension may be Formulated according to well-known techniques using suitable dispersing, wetting and suspending agents.
  • the pharmaceutical composition of the present invention may be in a solid form including, but not limited to, a capsule, a tablet, a pill, a granule, a powder or a suppository; the pharmaceutical composition of the present invention may also be in a liquid form including, but not limited to, a solution, a mixture. Suspension or emulsion.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be film coated or enteric coated according to methods known in the art.
  • Time delay materials may be employed including, but not limited to, glyceryl monostearate or glyceryl distearate.
  • the pharmaceutical composition of the present invention may be a tablet or capsule comprising an active ingredient; it comprises a diluent including, but not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; It comprises a lubricant, including but not limited to silica, talc, stearic acid, a salt of stearic acid, polyethylene glycol;
  • the pharmaceutical composition of the present invention may be a tablet comprising a binder including, but not limited to, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose;
  • the carrier generally includes lactose and corn starch.
  • Lubricants such as magnesium stearate are typically added; they may also contain disintegrants, adsorbents, colorants, flavors, and sweeteners, or may contain conventional inert diluents, as well as adjuvants such as preservatives, Stabilizers, wetting agents, emulsifiers and buffers.
  • suitable diluents may include lactose and dried corn starch.
  • the active ingredient consists of an emulsifier and a suspending agent.
  • the pharmaceutical composition of the present invention may also exist in discrete units, and the discrete unit form may be an aqueous liquid solution or suspension; a solution or suspension in a non-aqueous liquid; or a water-in-oil type liquid emulsion; or an oil-in-water type. a liquid emulsion; or encapsulated in a liposome; or in the form of a pill.
  • compositions of the invention may also be subjected to conventional pharmaceutical operations such as sterilization.
  • the compound of the invention or a pharmaceutically acceptable acid addition salt thereof, is crystalline, and the oral dosage form for tablets, preferably the active ingredient is crystalline.
  • the compounds of the invention may exist in crystalline form.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: 1-10 parts of HBr salt of Compound (I), 10-50 parts of microcrystalline cellulose, and 10-25 of corn starch Parts, sodium hydroxyacetate sodium 1-10 parts, talc 1-5 parts, anhydrous calcium hydrogen phosphate 30-45 parts, magnesium stearate 0.5-5 parts.
  • the therapeutically effective dose of a compound, pharmaceutical composition or combination thereof will depend on the species, weight, age and individual condition of the individual, the disorder or disease being treated, or the severity thereof degree. Physicians and clinicians can adjust the effective amount of each active ingredient required according to the progress of prevention, treatment or inhibition of the disorder or disease.
  • the compound of the above-mentioned hydrazine-substituted 1-[2-(2,4-dimethyl-phenylthio)-phenyl]piperazine or a pharmaceutically acceptable acid addition salt thereof as an active ingredient of a pharmaceutical composition It can be used to treat depression diseases including: depression, craze, affective disorder, sleep apnea, anxiety, ADHD (attention deficit hyperactivity disorder), PTSD (post-traumatic stress disorder), IBS (intestinal irritable syndrome) Disease), alcoholism, nicotine addiction, vomiting, drug abuse, drug abuse.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage for administration to a 60 kg body weight.
  • the daily dose is usually from 1 to 2000 mg, preferably from 2 to 1000 mg, preferably from 5 to 100 mg.
  • the specific dose should also consider the route of administration, the health of the patient and other factors.
  • the strontium element is an isotope of hydrogen.
  • the ⁇ -carbon” chemical bond is more stable than "hydrogen-carbon” (the CH bond cleavage rate is 6 times faster than the CD bond). It is non-toxic, non-radioactive and safe to the human body.
  • the applicant's research has found that some deuterated drugs have different effects in the human body because the " ⁇ -carbon” bond is a stronger chemical bond than the "hydrogen-carbon” bond, and this affects the rate at which the drug is decomposed.
  • the hydrazine-substituted 1- ⁇ 2-[2,4-di(tridemethyl)-phenylthio]-phenyl ⁇ piperazine hydrobromide salt provided in the present application has a slow decomposition rate and a reduced drug in the body.
  • hydrazine replaces certain hydrogens in the structure of 1- ⁇ 2-[2,4-di(tridemethyl)-phenylthio]-phenyl ⁇ piperazine hydrobromide, such as R 12 R 13 and R 14 are hydrogens of a poor metabolic point in the Vortioxetine structure. Therefore, after the hydrazine substitution at these sites, the stability of the drug in the living body can be further improved, and the blood drug concentration of the drug can be increased, thereby achieving further Good curative effect.
  • Step 1 Preparation of 2,4-di(tridemethyl) iodide benzene 2.
  • 1,4-Dioxane (85 mL), Al 2 O 3 (40.74 g, 399.6 mmol) and periodic acid (20.33 g, 89.2 mmol) of water (20.33 g) were sequentially added to a 250 mL three-necked flask under stirring at room temperature. In solution. Then, the mixture was heated to 85 ° C for 4 hours to obtain a brown reaction solution. A solution of 1,3-bis(tridemethyl)benzene 1 (2.00 g, 17.84 mmol) in 1,4-dioxane (25 mL) was added to the above reaction. The reaction was carried out at this temperature for about 45 minutes until GC-MS showed that Compound 1 had disappeared.
  • Step 2 Preparation of 2-[2,4-di(tridemethyl)-phenylthio]-bromobenzene 4.
  • reaction system was then purged with nitrogen (3 times, about 5 minutes). The temperature was raised to 100 ° C under nitrogen protection. After 1 hour, TLC (thin layer chromatography) showed the reaction was completed. After the reaction system was cooled to room temperature, the reaction was quenched by the addition of 50 mL of water. Then, it was suction filtered through Celite, and the filter cake was washed with ethyl acetate (100 mL ⁇ 3). The filtrate was transferred to a separatory funnel and the organic phase was separated.
  • the preparation method was the same as in Example 1, and the 1,3-bis(tridemethyl)benzene in the first step of the reaction of Example 1 was replaced with 3-(tridemethyl)toluene.
  • the preparation method was the same as in Example 1, and the 1,3-bis(trihalomethyl)benzene in the first step of the reaction of Example 1 was replaced with 3-(dioxomethyl)toluene.
  • the preparation method was the same as in Example 1, and the 1,3-bis(trihalomethyl)benzene in the first step of the reaction of Example 1 was replaced with 1,3-bis(deuteromethyl)benzene.
  • the preparation method was the same as in Example 1, and the 1,3-bis(trihalomethyl)benzene in the first step of the reaction of Example 1 was replaced with 2-deuteromethyl-4-tridemethyl-benzene.
  • the preparation method is the same as in the first embodiment, the 1,3-bis(trihalomethyl)benzene in the first step of the reaction of the first embodiment is replaced with the commercial 1-methyl-3-tridemethyl-benzene;
  • the Boc-piperazine 5 in the first step 3 was replaced with the commercial Boc-piperazine-D8.
  • mice or SD rats were subjected to a mouse swimming test, a mouse tail suspension test, and a rat swimming test.
  • the test methods and results are as follows.
  • mice Male ICR mice weighing 18-20 g were used and fed on standard sterilized rat chow.
  • Votilizine (15mg) was combined with 10% hydroxypropyl- ⁇ -cyclodextrin to form 100ml, which was administered at a daily dose of 3mg/kg, 1- ⁇ 2-[2,4-di(trimethyl) )-Phenylsulfanyl]-phenyl ⁇ piperazine hydrobromide (15mg, 7.5mg) 10% hydroxypropyl- ⁇ -cyclodextrin was formed into 100 ml, and was administered in two dose groups of 3 mg/kg and 1.5 mg/kg, and venlafaxine hydrochloride (75 mg) was combined with 0.5% CMC-Na to form 100 ml. A daily dose of 30 mg/kg is administered.
  • the experimental instrument used a small animal behavior record analysis system (Noldus).
  • the experimental method is as follows:
  • mice All 80 mice were pre-screened one day prior to dosing. After the animals were fasted for 4 h, the mice were placed The glass cylinder with a water depth of 10 cm (water temperature of 25 ° C) was allowed to swim in the glass, and the animals with a fixed time of 70-160 s in 6 minutes were selected for the second day of experiment.
  • the camera system takes the entire swimming process and the Noldus software automatically collects the data and analyzes it.
  • mice Forty qualified mice were divided into 4 groups according to the complete randomization method of Excel, with 10 animals in each group.
  • Each test group was orally administered according to the corresponding drug, 0.2 ml/10 g body weight once a day for 14 days.
  • the mouse swimming test was performed 1 hour after the last oral administration, and the swimming duration was 6 min.
  • the camera system takes the entire swimming process, and the Noldus software automatically collects data and analyzes it, recording and counting the time that it stops within 4 minutes.
  • mice The experimental animals, drugs, mouse dose calculation, drug solution preparation, and experimental instruments were the same as the mouse swimming experiments.
  • test group was orally administered according to the corresponding drug, 0.2 ml/10 g body weight once a day for 14 days.
  • the tail suspension test was performed for 1 h after the last oral administration for 6 min, and the time of immobility within 6 min was recorded.
  • mice Male Sprague-Dawley rats weighing 200-220 g were used and fed on standard sterilized rat chow. The drug used was compared with the mouse tail suspension test, and the dose of the rat was 1/2 times that of the mouse.
  • the dose of the rat is 1 ml/100 g body weight, so the concentration of the drug solution is equivalent to that of the mouse.
  • each cylinder is replaced with a clean water, and after swimming, it is blown dry with a hot hair dryer.
  • test group was orally administered according to the corresponding drug, 1 ml/100 g body weight once a day for 14 days.
  • the rat swimming test was performed 1 hour after the last oral administration, and the swimming duration was 5 min. The time during which the swimming stopped for 5 minutes was recorded.
  • the positive control drug YY showed no antidepressant effect, but did not rule out the results after increasing the dose and in other animal models; the sample to be tested XX showed good results in all three animal models; the effective dose of sample XX to be tested was lower than that of control sample YY.
  • mice The following is a pharmacokinetic evaluation of preferred compounds of the invention in mice:
  • Test animals SD rats, both male and female, 150 to 250 grams.
  • the ion source is an electrospray ionization source (ESI); the detection mode is positive ion detection; the scanning mode is selective reaction monitoring (MRM) mode; the ion reaction for quantitative analysis is m/z: 305.2 ⁇ 150.0 (XX); 256.1 ⁇ 167.1 (internal standard, diphenhydramine).
  • ESI electrospray ionization source
  • MRM selective reaction monitoring
  • intragastric administration 6 SD rats, half male and half female, single oral administration of 20 mg/kg dose of XX or YY, XX or YY dissolved with 10% hydroxypropyl- ⁇ -cyclodextrin, administration After blood collection in the eyelid, the time of blood collection is 10 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours after administration;
  • Intravenous injection 4 male SD rats, calculated according to 5mL/kg body weight, at a dose of 2mg/kg, XX or YY dissolved in 3% total volume of DMSO, plus 3% total volume of castor oil vortex Mix well, then add normal saline to volume, and prepare intravenous injection of the drug in rats. After administration, blood is collected in the eyelids. The time of blood collection is 3 minutes, 8 minutes, 15 minutes, 30 minutes, 1 hour, 2 minutes after administration. Hours, 3 hours, 4 hours, 6 hours, 9 hours, 12 hours, 24 hours.
  • parameter unit 1 2 3 Mean ⁇ SD AUC 0-t Gg ⁇ h/L 594.4 637.9 624.3 618.9 ⁇ 22.2 AUC 0- ⁇ Gg ⁇ h/L 627.9 674.6 660.5 654.4 ⁇ 23.9 MRT 0- ⁇ h 6.56 6.20 6.50 6.42 ⁇ 0.19 t 1/2 h 5.72 6.15 6.22 6.03 ⁇ 0.27 CL L/h/kg 3.19 2.97 3.03 3.06 ⁇ 0.11 Vz L/kg 26.3 26.3 27.2 26.6 ⁇ 0.52 Cmax Gg/L 225.0 246.0 170.6 213.9 ⁇ 38.9
  • the 4th rat data is abnormal, and is discarded.
  • the absolute bioavailability of the 1- ⁇ 2-[2,4-di(tridemethyl)-phenylthio]-phenyl ⁇ piperazine hydrobromide salt of the present invention is higher than the corresponding non-deuterated compound Vortioxetine 60% increase in the AUC0-t ratio of 1- ⁇ 2-[2,4-di(tridemethyl)-phenylsulfanyl]-phenyl ⁇ piperazine hydrobromide compared to the corresponding non-deuterated compound Vortioxetine increased by 19%.
  • Figure 2 shows the mean plasma concentration to time after oral administration of 1- ⁇ 2-[2,4-bis(tridemethyl)-phenylsulfanyl]-phenyl ⁇ piperazine hydrobromide 20 mg/kg in rats.
  • Figure 3 shows the mean plasma concentration to time profile after oral administration of Vortioxetine 20 mg/kg in rats.
  • the compound of the formula (I) deuterated according to the present invention has better pharmacokinetics in animals than the corresponding non-deuterated compounds, and thus has better pharmacodynamic effects. Learning and healing effects.

Abstract

本发明提供了具有式(I)结构的氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪化合物或其衍生物，包含其的药物组合物以及其在制备药物中的应用。上述化合物具备降低化合物的氧化代谢，同时提高血液中药物的浓度，提高有效生物利用度，达到降低使用剂量并减少毒性和其他副作用的效果。本发明提供的氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪化合物及其衍生物可以用于情感障碍、抑郁、焦虑等相关疾病的治疗。

Description

氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪化合物或其衍生物及其药物组合物和用途 技术领域
本发明属于医药领域，具体涉及氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪的化合物或其衍生物，所述衍生物包括药学可接受的盐、溶剂化物、前药、N-氧化物、多晶型物，其立体异构体、几何异构体或互变异构体或它们的混合物，包含这些化合物的药物组合物及其在制备药物中的用途。
背景技术
抑郁症是一种精神疾病，可导致身体功能异常甚至残疾，我国抑郁症的患病率大约为3％－5％，根据世界卫生组织的预测，到2030年，抑郁症很可能是导致残疾的主要原因。
抑郁症的症状会是情绪变化和其他症状，这直接干扰人们工作、学习、睡眠、饮食等日常生活。抑郁症的症状包括日常活动丧失兴趣、不安、睡眠反常、易疲劳、体重明显变化、思维缓慢、罪恶感、无价值感、注意力不集中、甚至自杀倾向等，当然抑郁症患者的症状并非一样。
抑郁症的发生原因包括中枢去甲肾上腺素(NE)、5-羟色胺(5-HT)和多巴胺(DA)等单胺类神经递质含量过低及其受体功能低下。目前用于抑郁症治疗的药物主要有三类，一类是抑郁症的标准治疗药物-三环类抗抑郁药(tricyclic antidepressant，TCA)，此药可提高大脑中NE和5-HT的浓度，但其最大的缺点是严重不良反应，如心脏毒性，且起效很慢；第二类抗抑郁药为单胺氧化酶抑制剂(monoamine oxidaseinhibitor，MAOI)，它通过延缓大脑中NE和5-HT的降解，通过延长这些递质的作用时间而起到抗抑郁作用。第三类抗抑郁药为选择性5-HT再摄取抑制剂(selective serotoninreuptake inhibitor，SSRI)，它可通过抑制突触前膜对5-HT的再摄取，来增加突触间隙5-HT的浓度，从而提高突触后膜5-HT1A受体的兴奋性，最终达到抗抑郁的作用。它的优点是不影响其他神经递质受体，因此比较安全。但是由于SSRI非选择性地作用于5-HT受体的各种亚型，故会引起一些相应的不良反应。
2013年9月30日，美国食品药品监督管理局(FDA)批准了由Lundbeck公司和武田公司研发的一种新型抗抑郁药Vortioxetine，用于抑郁症的治疗，其化学名称为：1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪。
Vortioxetine是通过调节5-HT起到抗抑郁作用。非临床体内实验结果表明，Vortioxetine能提高大脑特定区域内神经递质血清素、去甲肾上腺素、多巴胺、乙酰胆碱和组胺的浓度。非临床研究表明Vortioxetine可以调节5-HT3、5-HT7、5-HT1D、5-HT1B、5-HT1A、5-HT。
Vortioxetine主要被细胞色素P450同工酶CYP2D6、CYP3A4/5、CYP2C19、CYP2C9、CYP2A6、CYP2C8以及CYP2B6氧化代谢，其代谢物会与葡萄糖醛酸结合产生新的代谢物。单次口服给予[14C]-标记的vortioxetine后，放射性代谢物在尿液和粪便中的回收分别约为59％和26％。
由于在使用Vortioxetine进行治疗时，通常为了达到治疗效果而加大用药剂量，从而导致产生很多药物不良代谢问题，由于药物通过不良代谢反应产生的活性代谢物通常是药物产生毒性和其他副作用的重要因素，因而在治疗过程中会对人体产生较多副作用，使用Vortioxetine治疗过程中会使患者产生的不良反应有：恶心、呕吐、腹泻、头痛和头晕等。因而目前降低抑郁症药物的副作用以及其他毒副作用是人们广泛关注的技术难点。
发明内容
发明要解决的问题
本发明的目的在于克服现有技术中的缺陷，提供氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪的化合物或其衍生物，其衍生物包括药学可接受的盐、溶剂化物、前药、N-氧化物、多晶型物，其立体异构体、几何异构体或互变异构体或它们的混合物，包含其的药物组合物及在其制备药物中的用途。本发明所述氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪的化合物或其药学可接受的酸加成盐等形式的药物活性好，同时可解决药物的不良代谢问题，在用药过程中的毒副作用小。
用于解决问题的方案
本发明第一方面在于提供一类氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪的化合物或其衍生物，其衍生物包括药学可接受的盐、溶剂化物、前药、N-氧化物、多晶型物，其立体异构体、几何异构体或互变异构体或它们的混合物。
本发明另一方面在于提供氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪化合物的药学可接受的酸加成盐。
本发明另一方面在于提供单晶或多晶型物形式的氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪的化合物。
本发明另一方面在于提供一种药物组合物，其含有氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪的化合物，或其药学可接受的盐、溶剂化物、前药、N-氧化物、多晶型物，其立体异构体、几何异构体或互变异构体或它们的混合物，以及药学可接受的载体、赋形剂、稀释剂、辅剂、媒介物中的一种或它们的组合。
本发明另一方面在于提供氘取代1-[2-(2，4-二甲基-苯硫烷基)-苯基]哌嗪的化合物，或其药学可接受的盐、溶剂化物、前药、N-氧化物、多晶型物，其立体异构体、几何异构体或互变异构体或它们的混合物在制备治疗疾病的药物中的用途，所述疾病选自抑郁、热潮、情感障碍、睡眠呼吸暂停、焦虑、ADHD(注意力缺陷多动障碍)、PTSD(创伤后应激障碍)、IBS(肠易激综合症)、酗酒、尼古丁成瘾、毒品滥用、药物滥用。
发明的效果
本发明所述氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪的化合物与现有技术中的1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪相比，具有如下优点：
(1)本发明所述化合物的疗效更好，能够减少药物的不良代谢，可以提高血液中药物的浓度,从而达到更好的疗效。
(2)本发明所述化合物能够提高药物的口服生物利用度，减少在肠道内壁和在肝脏中不需要的代谢(称为首过代谢)。这导致未代谢的药物到达作用靶位的比例较大。
(3)本发明所述化合物的毒性、副作用更少，由于药物通过不良代谢反应产生的活性代谢物通常是药物产生毒性和其他副作用的重要因素，减少药物的不良代谢，则大大降低了药物的毒性和其他副作用。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合 物的代谢产物可以通过已知的技术来进行鉴定，其活性可以通过常规试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化、还原、水解、酰氨化、脱酰氨作用、酯化、脱脂作用和酶裂解等方法得到。相应地，本发明所述化合物的代谢产物包括将本发明所述化合物与哺乳动物充分接触一段时间所产生的代谢产物。
附图说明
图1显示制备1-{2-[2，4-二(三氘代甲基)-苯硫烷基]-苯基}哌嗪及其氢溴酸盐的反应方程式。
图2显示大鼠口服1-{2-[2，4-二(三氘代甲基)-苯硫烷基]-苯基}哌嗪氢溴酸盐20mg/kg后平均血浆浓度～时间图。
图3显示大鼠口服Vortioxetine 20mg/kg后平均血浆浓度～时间图。
具体实施方式
本发明是通过以下技术方案予以实现的。
具有下列结构式(I)的氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪化合物，或其衍生物包括药学可接受的盐、溶剂化物、前药、N-氧化物，其立体异构体、几何异构体或互变异构体或它们的混合物：
Figure PCTCN2014087662-appb-000001
其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14各自独立地为氢或氘，条件是其中至少之一为氘。
上述的氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪化合物或其衍生物，其中R1、R2、R3、R4、R5、R6、R7、R8中一个或几个为氘。
上述的氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪化合物或其衍生物，其中R9、R10、R11、R12、R13、R14中一个或几个为氘。
上述的氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪化合物的衍生物是其与药学可接受的酸的加成盐，所述其与药学可接受的酸的加成盐优选为其与氢溴酸的加成盐。
上述的氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪化合物或其衍生物，所述化合物为单晶或多晶型物形式。
药物组合物，其含有上述化合物或其衍生物以及药学可接受的载体、赋形剂、稀释剂、辅剂、媒介物中的一种或它们的组合。
上述化合物或其衍生物在制备治疗疾病的药物中的用途，所述疾病选自抑郁、热潮、情感障碍、睡眠呼吸暂停、焦虑、ADHD(注意力缺陷多动障碍)、PTSD(创伤后应激障碍)、慢性疼痛、IBS(肠易激综合症)、酗酒、尼古丁成瘾、呕吐、毒品滥用、药物滥用。
本发明所述氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪化合物是选自下组的优选化合物：
优选例1：1-[2-(2-甲基-4-三氘代甲基-苯硫基)-苯基]哌嗪：
Figure PCTCN2014087662-appb-000002
优选例2：1-{2-[2，4-二(三氘代甲基)-苯硫基]-苯基}哌嗪：
Figure PCTCN2014087662-appb-000003
优选例3：1-[2-(2-甲基-4-二氘代甲基-苯硫基)-苯基]哌嗪：
Figure PCTCN2014087662-appb-000004
优选例4：1-[2-(2,4-二(单氘代甲基)-苯硫基)-苯基]哌嗪：
Figure PCTCN2014087662-appb-000005
优选例5：1-[2-(2-单氘代甲基-4-三氘代甲基-苯硫基)-苯基]哌嗪：
Figure PCTCN2014087662-appb-000006
优选例6：1-[2-(2-甲基-4-三氘代甲基-苯硫基)-苯基]八氘代哌嗪：
Figure PCTCN2014087662-appb-000007
优选例7：1-{2-[2，4-二(三氘代甲基)-苯硫基]-苯基}八氘代哌嗪：
Figure PCTCN2014087662-appb-000008
在本发明中，氘取代指化合物或基团中的一个或多个氢被氘取代，氘取代可以是一取 代、二取代、多取代或全取代。所述氘在氘取代位置的氘同位素含量至少是大于天然氘同位素含量(0.015％)，较佳地大于30％，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于99％。术语“一个或多个氘代的”与“一次或多次氘代”可互换使用。
一般而言，术语“取代”表示所给结构中的一个或多个氢原子可以被具体取代基所取代。除非其他方面表明，一个任选的取代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“氢”表示单个氢原子。术语“氘”表示单个氘原子。一个这样的原子团与一个甲基相连，形成单氘代甲基(-CDH2)，两个氘原子与一个甲基相连，形成双氘代甲基或二氘代甲基(-CD2H)，以及三个氘原子与一个甲基相连，形成三氘代甲基(-CD3)。
术语“溶剂化物”表示本发明化合物与一种或多种溶剂分子的物理缔合。该物理缔合包括各种程度的离子和共价结合，包括氢键合。在某些情况中，例如当一种或多种溶剂分子掺入结晶固体的晶格中时，能够分离溶剂化物。“溶剂化物”包括溶液相和可分离的溶剂化物。溶剂化物的非限制性实例包括乙醇化物、甲醇化物等。“水合物”是其中溶剂分子是H2O的溶剂化物。溶剂化物的制备通常是已知的。典型的非限制性方法包括在高于环境温度下将本发明化合物溶解于需要量的需要的溶剂中(有机物或水或者其混合物)，以足以形成结晶的速度冷却溶液，然后通过标准方法分离结晶。分析技术例如红外光谱可以证实作为溶剂化物(或水合物)的结晶中溶剂(或水)的存在。
术语“前药”表示在体内转化生成氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪或该化合物的药学可接受的盐的物质(例如，药物前体)。转化可以通过各种机制(例如，通过代谢或化学处理)，例如通过在血液中水解发生。T.Higuchi和W.Stella，“Pro-drugs as Novel Delivery Systems,”A.C.S.Symposium Series的第14卷，和Bioreversible Carriers in Drug Design，编辑.Edward B.Roche，American Pharmaceutical Association and Pergamon Press，1987中提供了前药使用的讨论。本发明化合物的前药可以通过例如用适当的基团取代胺基的氢原子等方式形成。
本发明使用的术语“立体异构体”包括所有对映异构/立体异构纯的和对映异构/立体异构富集的本发明的化合物。
本发明所述氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪的化合物或其药学可接受的酸加成盐可作为治疗重度抑郁症和广泛性焦虑症的药物组合物的活性成分，所述药物组合物中可含有有效量的所述化合物或其药学可接受的酸加成盐等形式以及药学可接受的载体、赋形剂、稀释剂、辅剂、媒介物中的一种或它们的组合，制成适合使用的剂型。给药系统可以是白蛋白结合型注射液、脂质体、粉针、纳米粒和环糊精包合物等；给药剂型可以是注射液，也可以是固体剂型、半固体剂型，如可以是注射剂、片剂、囊剂、丸剂、散剂或颗粒剂等。
本发明所述可用于医药组成物的医药学上可接受的载体、辅剂及媒介物包括但不限于人类血清白蛋白的血清蛋白质，卵磷脂，磷酸氢二钠，氯化钠，磷酸氢钾，胶态二氧化硅，三硅酸镁，聚乙烯基,基于纤维素的物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，聚乙烯-聚氧丙烯-嵌段聚合物，聚乙二醇,氧化铝，硬脂酸铝，磷酸盐、甘胺酸、山梨酸、山梨酸钾，以及偏甘油酯的混合物，水，盐或电解质。
本发明所述氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪的化合物可制成药学可接受的适合用作药物的盐，药学可接受的适合用作药物的盐是指本发明所述化合物与无毒的酸或碱所形成的适合用作药物的盐，包括无机盐和有机盐。一类优选的盐是本发明所述化合物与酸形成的盐。适合形成盐的酸包括但并不限于：无机酸，如氢溴酸、盐酸、氢氟酸、硫酸、硝酸或磷酸。所述盐也可由有机酸形成，有机酸，如甲酸、乙酸、丙酸、草酸、丙二酸、肉桂酸、柠康酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸、苯磺酸苯甲酸、抗坏血酸、双亚甲基水杨酸、乙二磺酸、水杨酸、葡糖酸、扁桃酸、天冬氨酸、硬脂酸、棕榈酸、乙醇酸、对氨基苯甲酸、谷氨酸、苯磺酸、琥珀酸、茶碱乙酸，以及衣康酸、天冬氨酸、等酸性氨基酸。
除非其他方面表明，本发明所述化合物所有的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学可接受的盐和前药都属于本发明的范围。
本发明所述药物组合物可以经口服给药，注射给药，喷雾吸入法，局部给药，经直肠给药，经鼻给药，含服给药，阴道给药或通过植入性药盒给药。优选的药物组合物给药方式为口服给药、向腹膜内给药或静脉注射。
本发明所述药物组合物无菌的注射方式可以是水或油脂性的悬浮液，这些悬浮液可以 根据公知技术采用合适的分散剂、湿润剂和悬浮剂按配方制造。
本发明所述药物组合物可以是固体形式包括但不限于胶囊剂、片剂、丸剂、颗粒剂、散剂或栓剂；本发明所述药物组合物也可以是液体形式包括但不限于溶液剂、混悬剂或乳剂。
根据本领域已知的方法,固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂,可以是膜包衣的或肠包衣的。可以应用延时材料，包括但不限于单硬脂酸甘油酯或二硬脂酸甘油酯。
本发明所述药物组合物可以是片剂或胶囊剂，其包含活性成分；其包含稀释剂，包括但不限于乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素和/或甘氨酸；其包含润滑剂，包括但不限于二氧化硅、滑石粉、硬脂酸、硬脂酸的盐、聚乙二醇；
本发明所述药物组合物可以是片剂，其包含粘合剂包括但不限于硅酸镁铝、淀粉糊、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠；关于片剂口服使用，载体一般包括乳糖和玉米淀粉。润滑剂如硬脂酸镁都典型地被添加；还可以包含崩解剂，吸附剂、着色剂、矫味剂和甜味剂，或可以包含常规的惰性稀释剂、以及佐剂例如防腐剂、稳定剂、润湿剂、乳化剂和缓冲剂。
对于胶囊剂口服给药，合适的稀释剂可以是包括乳糖和干的玉米淀粉。当口服给药为水制悬浮液时，其有效成分由乳化剂和悬浮剂组成。
本发明所述药物组合物还可以离散单位形式存在,其离散单位形式可以是水性液体溶液或悬浮液；非水性液体中的溶液或悬浮液；或油包水型液体乳液；或水包油型液体乳液；或封装于脂质体中；或丸剂形式等。
本发明所述药物组合物还可以进行常规制药操作，例如灭菌。
在一个实施方案中本发明所述化合物或其药学可接受的酸加成盐为晶体，口服剂型对于片剂而言，优选的是活性组分为晶体。
在一个实施方案中，本发明所述化合物可以以晶体形式存在。
在一个实施方案中，本发明提供了一种药物组合物，所述药物组合物中含有：化合物(I)的HBr盐1-10份，微晶纤维素10-50份，玉米淀粉10-25份，羟基乙酸淀粉钠1-10份，滑石1-5份，无水磷酸氢钙30-45份，硬脂酸镁0.5-5份。化合物、其药物组合物或组合的治疗有效剂量取决于个体的种类、体重、年龄和个体条件、治疗的障碍或疾病或其严重 程度。医师、临床医师可以根据预防、治疗或抑制障碍或疾病的进程调整所需的每种活性成分的有效量.
本发明所述的氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪的化合物或其药学可接受的酸加成盐作为药物组合物的活性成分可用于治疗抑郁症疾病，所述疾病包括：抑郁、热潮、情感障碍、睡眠呼吸暂停、焦虑、ADHD(注意力缺陷多动障碍)、PTSD(创伤后应激障碍)、IBS(肠易激综合症)、酗酒、尼古丁成瘾、呕吐、毒品滥用、药物滥用。
本发明所述化合物可以单独给药，或者与其他药学可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明所述化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1－2000mg，优选2－1000mg，优选5－100mg。当然具体剂量还应考虑给药途径、病人健康状况等因素。
氘元素是氢的同位素，作为氢的一种稳定形态同位素，它的原子核由一颗质子和一颗中子组成，较氢原子核多一个中子(氘原子量＝2，氢原子量＝1)使“氘—碳”化学键较“氢—碳”稳定(C-H键断裂速率比C-D键快6倍)。氘无毒、无放射性，对人体是安全的。本申请人研究发现，一些氘化药物在人体内有不同的功效，因为“氘-碳”键是比“氢-碳”键结合更强的化学键，而这会影响药物被分解的速度，也就是说将特定位置的氢替换为氘后，可能封闭代谢位点，延长药物半衰期，同时不影响药理活性。将Vortioxetine结构中特定的位置，也就是不良代谢点的“氢—碳”键替换为了“氘—碳”键，由于“氘—碳”键比“氢—碳”键更稳定，不易被代谢分解，因此本申请提供的氘取代1-{2-[2，4-二(三氘代甲基)-苯硫基]-苯基}哌嗪氢溴酸盐在体内分解速度慢、减少了药物的不良代谢；延长了药物的半衰期，增加了药物的血药浓度，从而达到更好的疗效；另外可以在保持疗效的同时，减小了药物的使用剂量，进一步降低了药物的毒副作用。
本申请人研究发现，氘取代1-{2-[2，4-二(三氘代甲基)-苯硫基]-苯基}哌嗪氢溴酸盐结构中的某些氢如R12、R13、R14是Vortioxetine结构中的不良代谢点的氢，所以，针对这些位点进行氘取代之后，能够进一步提高药物在生物体内的稳定性，增加了药物的血药浓度，从而达到更好的疗效。实验结果证实，1-{2-[2，4-二(三氘代甲基)-苯硫基]-苯基}哌嗪氢溴酸盐，即R9、R10、R11、R12、R13、R14为氘时，与Vortioxetine相比，显 著提高血液中药物的浓度，提高了药物的稳定性，同时大大增加了药物绝对生物利用度，在动物体内具有更好的药物动力学，因而具有更好的药效学和治疗效果。
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。
实施例1
制备1-{2-[2，4-二(三氘代甲基)-苯硫基]-苯基}哌嗪及其氢溴酸盐
反应方程式见图1。
制备步骤如下：
步骤一：制备2，4-二(三氘代甲基)碘化苯2.
Figure PCTCN2014087662-appb-000009
室温搅拌下，向250mL三口瓶中依次加入1,4-二噁烷(85mL)，Al2O3(40.74g,399.6mmol)以及高碘酸(20.33g,89.2mmol)的水(20.33g)溶液中。然后升温至85℃反应4小时，得棕褐色反应液。将1，3-二(三氘代甲基)苯1(2.00g,17.84mmol)的1,4-二噁烷(25mL)溶液加入至上述反应中。并在此温度下反应约45min，至GC-MS显示化合物1已经消失。将反应体系冷至室温后，抽滤，滤饼用甲基叔丁基醚淋洗(100mL×3)。滤液转至分液漏斗中，用饱和NaHSO3溶液洗涤(200mL×3)。分出有机相，水相再用甲基叔丁基醚萃取(200mL×1)。合并有机相，经水洗涤(200mL×3)后，无水Na2SO4干燥，过滤，30℃下减压浓缩得黄色油状物(4.11g,收率96.82％)。2，4-二(三氘代甲基)碘化苯2的粗产品未经提纯，直接用于下一步。
GC-MS：m/z 238(M+)；1H-NMR(300MHz,CDCl3)δ8.01(d,J＝8.1Hz,1H),7.12-7.06(m,1H),6.73-6.70(m,1H)。
步骤二：制备2-[2，4-二(三氘代甲基)-苯硫基]-溴化苯4.
Figure PCTCN2014087662-appb-000010
室温搅拌下，向100mL三口瓶中依次加入甲苯(70mL)、化合物2(4.11g,17.27mmol)、化合物3(3.26g,17.27mmol)、rac-BINAP((+/－)-2，2’-双(二苯基膦)-1,1’-联萘，0.398g,0.639mmol)、Pd(dba)2(三(二亚苄基丙酮)二钯，0.285g,0.31mmol)和t-BuONa(5.81g,60.45mmol)。然后将反应体系用氮气吹扫(3次，约5分钟)。氮气保护下升温至100℃反应。1小时后，TLC(薄层色谱法)显示反应完全。待反应体系降至室温后，加入50mL水淬灭反应。然后经硅藻土抽滤，滤饼用乙酸乙酯洗涤(100mL×3)。将滤液转至分液漏斗中，分出有机相。水相再用乙酸乙酯萃取(50mL×2)，合并有机相，无水Na2SO4干燥，过滤，减压浓缩得棕色油状物(7.2g)。该粗产品经硅胶柱层析(洗脱液：正己烷)提纯得无色油状产品(4.64g,收率89.92％)。
HPLC：～100％；1H-NMR(300MHz,CDCl3)δ7.54(d,J＝7.8Hz,1H),7.4(d,J＝7.8Hz,1H),7.19(d,J＝1.5Hz,1H),7.11-7.06(m,1H),7.00-6.95(m,1H),6.97-6.58(m,1H),6.55(d,J＝1.2Hz,1H)。
步骤三：制备1-Boc-{2-[2，4-二(三氘代甲基)-苯硫基]-苯基}哌嗪6
Figure PCTCN2014087662-appb-000011
室温搅拌下，向100mL三口瓶中依次加入甲苯(30mL)、化合物4(4.64g,15.52 mmol)、Boc-哌嗪5(8.67g,46.56mmol)、rac-BINAP(1.353g,2.17mmol)和t-BuONa(5.22g,54.32mmol)。氮气保护下，向上述反应中加入Pd(dba)2(1.02g,1.12mmol)，然后升温至50℃反应1小时(TLC显示此时原料剩余～50％)。再升温至80℃反应5小时(TLC显示此时原料剩余～10％)。将反应体系降至室温，加水(50mL)淬灭，经硅藻土抽滤，并用乙酸乙酯(100mL×2)洗涤滤饼。将滤液转至分液漏斗中，分出有机相。水相再用乙酸乙酯(50mL×2)萃取。合并有机相，经无水Na2SO4干燥，过滤，减压浓缩得棕色油状物(15g)。该粗产品经硅胶柱层析提纯(洗脱液：正己烷/乙酸乙酯＝1/40)，得黄色固体产品(3.93g，收率65.8％)。
HPLC：93.6％；1H-NMR(300MHz,CDCl3)δ7.39(d,J＝7.8Hz,1H),7.17(s,1H),7.09-7.03(m,3H),6.92-6.87(m,1H),6.54(d,J＝8.1Hz,1H),3.65-3.62(t,J＝4.8Hz,4H),3.04-3.01(t,J＝4.5Hz,4H),1.51(s,9H)。
步骤四：制备1-{2-[2，4-二(三氘代甲基)-苯硫基]-苯基}哌嗪及其氢溴酸盐7
Figure PCTCN2014087662-appb-000012
氮气保护下，向250mL单口瓶中依次加入乙醚(97.2mL)和化合物6(3.24g8.02mmol)，室温水浴下搅拌。向上述反应中滴加40％HBr溶液(4.87g,24.06mmol)。15min滴完。然后在室温下反应6h(此时TLC显示剩余少量原料)。停止搅拌，静置数分钟，分出上层清液。所得粘稠固体中加入乙醚(10mL×2)，超声。静置后分出上层清液。向所得固体中加入异丙醇(4.5mL)，室温搅拌5min。再加20mL乙醚，室温搅拌10min。抽滤，滤饼用乙醚(10mL×3)洗涤。室温干燥后得类白色粉末(2.4g，收率77％)。
HPLC：99.8％；LC-MS(ESI+)：m/z 305.28(M+H)；1H-NMR(300MHz,CD3OD)δ7.34(d,J＝7.8Hz,1H),7.24(s,1H),7.24-7.17(m,2H),7.12-7.09(m,1H),6.56(d,J＝7.5Hz,1H),3.42-3.39(m,4H),3.33-3.30(m,4H)。 13C-NMR(75MHz,CD3OD)：149.1,143.0,140.8,136.8,135.6,132.8,129.0,128.8,127.8,127.2,126.6,121.5,49.7,45.4。
实施例2
制备1-{2-[2，4-二(三氘代甲基)-苯硫基]-苯基}哌嗪及其氢溴酸盐
Figure PCTCN2014087662-appb-000013
制备方法同实施例1，将实施例1反应步骤一中的1，3-二(三氘代甲基)苯替换为3-(三氘代甲基)甲苯。
3-(三氘代甲基)甲苯的制备方法参见Kwa,T.L.；Boelhouwer,C.Tetrahedron(1969),25(24),5771-6。
实施例3
制备1-[2-(2-甲基-4-二氘代甲基-苯硫基)-苯基]哌嗪及其氢溴酸盐
Figure PCTCN2014087662-appb-000014
制备方法同实施例1，将实施例1反应步骤一中的1，3-二(三氘代甲基)苯替换为3-(二氘代甲基)甲苯。
3-(二氘代甲基)甲苯的制备方法参见Harper,Robert J.；Kemball,Charles,Journal of the Chemical Society,Faraday Transactions(1994),90(4),659-65.
实施例4
制备1-{2-[2，4-二(氘代甲基)-苯硫基]-苯基}哌嗪及其氢溴酸盐。
Figure PCTCN2014087662-appb-000015
制备方法同实施例1，将实施例1反应步骤一中的1，3-二(三氘代甲基)苯替换为1，3-二(氘代甲基)苯。
1，3-二(氘代甲基)苯的制备方法参见Trimitsis,George B.；Tuncay,A.；Beyer,R.D.；Ketterman,K.J.Journal of Organic Chemistry(1973),38(8),1491-6.
实施例5
制备1-[2-(2-氘代甲基-4-三氘代甲基-苯硫基)-苯基]哌嗪及其氢溴酸盐
Figure PCTCN2014087662-appb-000016
制备方法同实施例1，将实施例1反应步骤一中的1，3-二(三氘代甲基)苯替换为2-氘代甲基-4-三氘代甲基-苯。
2-氘代甲基-4-三氘代甲基-苯的制备方法参见Harper,Robert J.；Kemball,Charles,Journal of the Chemical Society,Faraday Transactions(1994),90(4),659-65
实施例6
制备1-[2-(2-甲基-4-三氘代甲基-苯硫基)-苯基]八氘代哌嗪及其氢溴酸盐
Figure PCTCN2014087662-appb-000017
制备方法同实施例1，将实施例1反应步骤一中的1，3-二(三氘代甲基)苯替换为商品1-甲基-3-三氘代甲基-苯；将实施例1步骤三中的Boc-哌嗪5替换为商品Boc-哌嗪-D8。
实施例7
制备1-{2-[2，4-二(三氘代甲基)-苯硫烷]-苯基}八氘代哌嗪及其氢溴酸盐。
Figure PCTCN2014087662-appb-000018
制备方法同实施例1，将实施例1步骤三中的Boc-哌嗪5替换为商品Boc-哌嗪-D8。
<抗抑郁作用效果>
对于本申请化合物抗抑郁作用的实验研究采用如下方法。采用ICR小鼠或SD大鼠，连续经口灌胃给药2周后，对其进行了小鼠游泳实验、小鼠尾悬挂实验、大鼠游泳实验的测试，测试方法和结果如下。
小鼠游泳试验
使用体重为18～20g的雄性ICR小白鼠，以标准灭菌鼠饲料喂养。
药品采用1-{2-[2，4-二(三氘甲基)-苯硫烷基]-苯基}哌嗪氢溴酸盐(简称XX)，对照样品为沃替西汀(Vortioxetine，简称YY)、怡诺思胶囊(盐酸文拉法辛，来自美国惠氏制药公司，作为阳性对照药)。
沃替西汀(15mg)配合10％羟丙基-β-环糊精形成100ml，以3mg/kg的日用药量剂量给药，1-{2-[2，4-二(三氘甲基)-苯硫烷基]-苯基}哌嗪氢溴酸盐(15mg、7.5mg)配 合10％羟丙基-β-环糊精形成100ml，以3mg/kg、1.5mg/kg的2个剂量组给药，盐酸文拉法辛(75mg)配合0.5％CMC-Na形成100ml，以30mg/kg的日用药量剂量给药。
实验仪器使用小动物行为记录分析系统(Noldus)。
实验方法如下：
第一：游泳实验预筛
所有80只小鼠于给药前一天进行预筛。动物禁食4h后，将小鼠放入
Figure PCTCN2014087662-appb-000019
水深10cm(水温25℃)的玻璃圆缸内使其游泳，选择6min内不动时间在70–160s的动物备第二天实验用。摄像系统摄制整个游泳过程，Noldus软件自动采集数据并进行分析。
第二：动物分组及给药量
40只合格小鼠按Excel完全随机分组法分为4组，每组10只动物。
Figure PCTCN2014087662-appb-000020
第三：试验方法
各试验组按相应药物经口灌胃给药，0.2ml/10g体重，每日一次，连续给药14天。最后一次口服给药1h后进行小鼠游泳试验，游泳持续时间为6min。摄像系统摄制整个游泳过程，Noldus软件自动采集数据并进行分析，记录并统计后4min内停止不动的时间。
数据以平均值±标准差(
Figure PCTCN2014087662-appb-000021
)表示，数据差异统计采用单因素方差分析(ANOVA)，组间差异以P<0.05判断。
实验结果：
连续经口灌胃给予30mg/kg的阳性药文拉法辛两周明显缩短了小鼠停止游泳不动的时间(P<0.05v.s空白对照组)，说明此试验方法的可靠性；而3mg/kg的对照样品YY没有缩短小鼠停止游泳不动的时间，说明在此剂量下、在小鼠游泳实验中YY没有显示其抗抑郁作用；1.5mg/kg和3mg/kg的待测样品XX均明显缩短了小鼠停止游泳不动的时间(P<0.05v.s空白对照组)(表1)。
表1待测样品XX经口灌胃给药14天对小鼠游泳实验的影响(n＝10,
Figure PCTCN2014087662-appb-000022
)
Figure PCTCN2014087662-appb-000023
Figure PCTCN2014087662-appb-000024
小鼠尾悬挂实验
实验动物、药品、小鼠给药量计算、药液配制、实验仪器与小鼠游泳实验相同。
实验方法：
各试验组按相应药物经口灌胃给药，0.2ml/10g体重，每日一次，连续给药14天。最后一次口服给药1h后进行小鼠尾悬挂试验，持续时间为6min，记录6min内静止不动的时间。
数据以平均值±标准差(
Figure PCTCN2014087662-appb-000025
)表示，数据差异统计采用单因素方差分析(ANOVA)，组间差异以P<0.05判断。
实验结果：
同小鼠游泳实验，连续经口灌胃给予30mg/kg的阳性药文拉法辛两周明显缩短了尾悬挂小鼠停止不动的时间(P<0.01v.s空白对照组)，也说明了此试验方法的可靠性；而3mg/kg的对照样品YY同样没有缩短尾悬挂小鼠停止不动的时间，说明在此剂量下、在小鼠尾悬挂实验中YY没有显示其抗抑郁作用；3mg/kg的待测样品XX明显缩短了尾悬挂小鼠停止不动的时间(P<0.01v.s空白对照组)，1.5mg/kg的待测样品XX也有缩短小鼠停止不动时间的趋势(表2)。
表2待测样品XX经口灌胃给药14天对小鼠尾悬挂实验的影响(n＝10,
Figure PCTCN2014087662-appb-000026
)
Figure PCTCN2014087662-appb-000027
Figure PCTCN2014087662-appb-000028
大鼠游泳实验
实验动物：
采用体重为200-220g的雄性SD大鼠，以标准灭菌鼠饲料喂养。所采用的药品同小鼠尾悬挂实验，大鼠给药量为小鼠的1/2倍。
药液配制：大鼠给药量为1ml/100g体重，因此其药液浓度与小鼠等同。
实验仪器：同小鼠游泳实验。
实验方法：
第一：大鼠预游泳
动物禁食4h后，将大鼠放入一
Figure PCTCN2014087662-appb-000029
水深15cm(水温25℃)的玻璃圆缸内使其游泳15min。每缸一只鼠，每鼠换一缸干净水，游泳后用热吹风机吹干。
第二：动物分组及给药量
40只大鼠按Excel完全随机分组法分为4组，每组10只动物。
Figure PCTCN2014087662-appb-000030
第三：试验方法
各试验组按相应药物经口灌胃给药，1ml/100g体重，每日一次，连续给药14天。最后一次口服给药1h后进行大鼠游泳试验，游泳持续时间为5min，记录5min内游泳停止不动的时间。
数据以平均值±标准差(
Figure PCTCN2014087662-appb-000031
)表示，数据差异统计采用单因素方差分析(ANOVA)， 组间差异以P<0.05判断。
实验结果：
连续经口灌胃给予1.5mg/kg的对照样品YY仍然没有缩短大鼠停止游泳不动的时间，说明在此剂量下、在大鼠游泳实验中YY仍然没有显示其抗抑郁作用；1.5mg/kg的待测样品XX明显缩短了大鼠停止游泳不动的时间(P<0.05v.s空白对照组)，0.75mg/kg则有一定的缩短大鼠停止游泳不动时间的趋势(表3)。
表3待测样品XX经口灌胃给药14天对大鼠游泳实验的影响(n＝10,
Figure PCTCN2014087662-appb-000032
)
Figure PCTCN2014087662-appb-000033
根据上述实验可以得出初步研究结论：
在所选择的3个急性应激性抑郁症模型的动物实验中，阳性对照药YY均未显示出抗抑郁作用，但不排除增加剂量后以及在其它的动物模型中有效的结果；待测样品XX在3个动物模型中均显示出了良好的效果；待测样品XX的有效剂量低于对照样品YY。
<药代动力学研究>
以下为本发明优选化合物在鼠中的药代动力学评价：
药品：1-{2-[2，4-二(三氘代甲基)-苯硫烷基]-苯基}哌嗪氢溴酸盐(简称XX)
沃替西汀(Vortioxetine)(简称YY)
仪器：戴安公司Ultimate3000液相色谱系统和AB公司4000Q-Trap型串联质谱仪，配有电喷雾电离源(ESI源)。
受试动物：SD大鼠，雌雄兼用，150～250克。
测定条件：
(1)HPLC色谱条件：
色谱柱：
Figure PCTCN2014087662-appb-000034
C18(150×2.1mm)
柱温：25℃；进样盘温度：4℃
进样体积：2μL
流动相：10mM甲酸铵水溶液：甲醇＝15:85
流速：0.3mL/min
(2)质谱条件：
离子源为电喷雾离子化源(ESI)；检测方式为正离子检测；扫描方式为选择反应监测(MRM)方式；用于定量分析的离子反应为m/z：305.2\150.0(XX)；256.1\167.1(内标，苯海拉明)。
药动学研究方法：
(1)灌胃给药：SD大鼠6只，雌雄各半，单次口服给予20mg/kg剂量的XX或YY，XX或YY用10％羟丙基-β-环糊精溶解，给药后在眼眶采血，采血的时间点为给药后10分钟、30分钟、1小时、1.5小时、2小时、3小时、4小时、6小时、8小时、10小时、12小时、24小时；
(2)静脉注射：雄性SD大鼠4只，按5mL/kg体重计算，按2mg/kg的剂量，XX或YY用3％总体积的DMSO溶解后，再加3％总体积蓖麻油涡旋混匀，后加生理盐水至体积，制得大鼠静脉注射药液，给药后在眼眶采血，采血的时间点为给药后3分钟、8分钟、15分钟、30分钟、1小时、2小时、3小时、4小时、6小时、9小时、12小时、24小时。
血样采集后，立即温和地颠倒试管至少5次，保证混合充分后放置于冰上。血液用肝素抗凝，8000rpm离心5分钟，将血清与红细胞分离。用移液器吸出血清转移至2mL聚丙烯管，标明化合物的名称和时间点，在进行LC-MS分析前保存在-40℃冰箱，待测。高浓度样品用大鼠空白血浆稀释。
测定时，50μL血浆，加入2.5μL Meth-H2O、5μL内标溶液(20ng/mL IS)，用150μL甲醇沉淀蛋白，13000rpm×5min离心。取上层有机相，0.22μM微孔滤膜过滤，2μL样品进样LC-MS分析。
实验结果显示于表4-10中。
表4大鼠口服20mg/kg XX后血浆中XX浓度(ng/mL)
Figure PCTCN2014087662-appb-000035
表5大鼠口服20mg/kg YY后血浆中YY浓度(ng/mL)
Figure PCTCN2014087662-appb-000036
Figure PCTCN2014087662-appb-000037
表6大鼠静脉注射2mg/kgXX后血浆中XX浓度(ng/mL)
Figure PCTCN2014087662-appb-000038
表7大鼠静脉注射2mg/kgYY后血浆中YY浓度(ng/mL)
Figure PCTCN2014087662-appb-000039
Figure PCTCN2014087662-appb-000040
表8大鼠口服20mg/kg XX后血浆XX药代动力学参数(Mean±SD，n＝6)
参数 单位 1 2 3 4 5 6 Mean±SD
AUC0-t μg·h/L 523.6 552.3 487.5 659.3 703.9 569.8 582.7±82.7
AUC0-∞ μg·h/L 532.2 552.5 488.9 666.0 705.3 571.4 586.0±82.8
MRT0-∞ h 5.62 4.92 5.44 5.08 4.24 4.28 4.93±0.58
t1/2 h 4.0 1.7 2.8 3.5 2.6 2.9 2.92±0.80
Cmax μg/L 78.6 91.6 77.8 120.8 144 115.8 104.8±26.5
F％   11.0 11.5 10.1 13.8 14.6 11.9 12.2±1.72
表9大鼠静脉注射2mg/kg XX后血浆XX药代动力学参数(Mean±SD，n＝4)
参数 单位 1 2 3 4 Mean±SD
AUC0-t μg·h/L 462.2 492.9 466.0 421.5 460.6±29.5
AUC0-∞ μg·h/L 467.1 512.0 489.7 459.8 482.1±23.6
MRT0-∞ h 6.59 6.14 6.67 8.08 6.87±0.84
t1/2 h 3.72 5.15 5.66 7.33 5.47±1.49
CL L/h/kg 4.28 3.91 4.09 4.35 4.16±0.20
Vz L/kg 23.0 29.0 33.4 46.0 32.9±9.76
Cmax μg/L 134.2 123.2 127.2 121.4 126.5±5.68
表10大鼠口服20mg/kg YY后血浆YY药代动力学参数(Mean±SD，n＝6)
参数 单位 1 2 3 4 5 6 Mean±SD
AUC0-t μg·h/L 836.1 415.8 480.4 467.8 427.0 309.2 489.4±180.3
AUC0-∞ μg·h/L 839.3 416.2 484 469.3 428.7 310.6 491.3±181.0
MRT0-∞ h 4.49 4.65 4.73 4.67 4.60 5.35 4.75±0.31
t1/2 h 3.05 2.20 3.50 2.83 3.06 3.10 2.96±0.43
Cmax μg/L 182.0 85.2 91.8 89.2 93.2 56.4 99.6±42.6
F％   12.83 6.36 7.40 7.17 6.55 4.75 7.51±2.77
表11大鼠静脉注射2mg/kg YY后血浆YY药代动力学参数(Mean±SD，n＝3)
参数 单位 1 2 3 Mean±SD
AUC0-t μg·h/L 594.4 637.9 624.3 618.9±22.2
AUC0-∞ μg·h/L 627.9 674.6 660.5 654.4±23.9
MRT0-∞ h 6.56 6.20 6.50 6.42±0.19
t1/2 h 5.72 6.15 6.22 6.03±0.27
CL L/h/kg 3.19 2.97 3.03 3.06±0.11
Vz L/kg 26.3 26.3 27.2 26.6±0.52
Cmax μg/L 225.0 246.0 170.6 213.9±38.9
注：第4只大鼠数据异常，舍去
根据上述测试数据，大鼠灌胃给予20mg/kg XX后，血浆中1-{2-[2，4-二(三氘代甲基)-苯硫烷基]-苯基}哌嗪氢溴酸盐的AUC0-t为582.7±82.7μg·h/L；而大鼠灌胃给予20mg/kg YY后，血浆中Vortioxetine的AUC0-t为489.4。大鼠灌胃给药的绝对生物利用度(absolute bioavailablity)以血浆1-{2-[2，4-二(三氘代甲基)-苯硫基]-苯基}哌嗪氢溴酸盐的AUC与大鼠静脉注射给予1-{2-[2，4-二(三氘代甲基)-苯硫烷基]-苯基} 哌嗪氢溴酸盐的AUC经剂量折算后比较，为12.2±1.72％；Vortioxetine的AUC经剂量折算后比较，为7.51±2.77％。本发明1-{2-[2，4-二(三氘代甲基)-苯硫基]-苯基}哌嗪氢溴酸盐的绝对生物利用度，比相应的非氘代的化合物Vortioxetine增加60％，1-{2-[2，4-二(三氘代甲基)-苯硫烷基]-苯基}哌嗪氢溴酸盐的AUC0-t比相应的非氘代的化合物Vortioxetine增加19％。
图2显示大鼠口服1-{2-[2，4-二(三氘代甲基)-苯硫烷基]-苯基}哌嗪氢溴酸盐20mg/kg后平均血浆浓度～时间图；图3显示大鼠口服Vortioxetine 20mg/kg后平均血浆浓度～时间图。根据图2和3的对比结果可知，本发明氘代的式(I)化合物，与相应的非氘代的化合物相比，在动物体内具有更好的药物动力学，因而具有更好的药效学和治疗效果。
这里本发明的描述和应用是说明性的，并非想将本发明的范围限制在上述实施例中，因此，本发明不受本实施例的限制，任何采用等效替换取得的技术方案均在本发明保护的范围内。

Claims (8)

  1. 如结构式(I)所示的氘取代1-[2-(2，4-二甲基-苯硫基)-苯基]哌嗪的化合物或其衍生物，所述衍生物为其药学可接受的盐、溶剂化物、前药、N-氧化物，其立体异构体、几何异构体或互变异构体或它们的混合物：
    Figure PCTCN2014087662-appb-100001
    其特征在于，式(I)中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14各自独立地为氢或氘，条件是其中至少之一为氘。
  2. 如权利要求1所述的化合物或其衍生物，其特征在于R1、R2、R3、R4、R5、R6、R7、R8中的一个或多个为氘。
  3. 如权利要求1所述的化合物或其衍生物，其特征在于，R9、R10、R11、R12、R13、R14中的一个或多个为氘。
  4. 如权利要求1所述的化合物或其衍生物，选自下列的化合物：
    1-[2-(2-甲基-4-三氘代甲基-苯硫基)-苯基]哌嗪，
    1-{2-[2，4-二(三氘代甲基)-苯硫基]-苯基}哌嗪，
    1-[2-(2-甲基-4–二氘代甲基-苯硫基)-苯基]哌嗪，
    1-[2-(2,4-二(氘代甲基)-苯硫基)-苯基]哌嗪，
    1-[2-(2-氘代甲基-4-三氘代甲基-苯硫基)-苯基]哌嗪，
    1-[2-(2-甲基-4-三氘代甲基-苯硫基)-苯基]八氘代哌嗪，
    1-{2-[2，4-二(三氘代甲基)-苯硫基]-苯基}八氘代哌嗪。
  5. 如权利要求1所述的化合物或其衍生物，其特征在于，所述药学可接受的盐为式(I)化合物与氢溴酸的加成盐。
  6. 如权利要求1－5任一项所述的化合物或其衍生物，其特征在于，所述化合物为单晶或多晶型物形式。
  7. 药物组合物，其特征在于，含有如权利要求1－6中任一项所述的化合物或其衍生物和药学可接受的载体、赋形剂、稀释剂、辅剂、媒介物中的一种或它们的组合。
  8. 如权利要求1－6中任一项所述的化合物或其衍生物在制备治疗疾病的药物中的用途，所述疾病选自抑郁、热潮、情感障碍、睡眠呼吸暂停、焦虑、ADHD(注意力缺陷多动障碍)、PTSD(创伤后应激障碍)、IBS(肠易激综合症)、酗酒、尼古丁成瘾、毒品滥用、药物滥用。
PCT/CN2014/087662 2014-05-30 2014-09-28 氘取代1-[2-(2,4-二甲基-苯硫基)-苯基]哌嗪化合物或其衍生物及其药物组合物和用途 WO2015180342A1 (zh)

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CN107513048B (zh) * 2016-06-17 2020-07-14 江苏吉贝尔药业股份有限公司 一种氘代沃替西汀氢溴酸盐的合成方法
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