WO2021115372A1 - 一种沃替西汀前药及其应用 - Google Patents

一种沃替西汀前药及其应用 Download PDF

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WO2021115372A1
WO2021115372A1 PCT/CN2020/135200 CN2020135200W WO2021115372A1 WO 2021115372 A1 WO2021115372 A1 WO 2021115372A1 CN 2020135200 W CN2020135200 W CN 2020135200W WO 2021115372 A1 WO2021115372 A1 WO 2021115372A1
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amino
general formula
group
optionally substituted
compound
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PCT/CN2020/135200
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English (en)
French (fr)
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张玲
蒋钰
陈帅
张长青
周珺
万泽红
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江苏恩华药业股份有限公司
苏州恩华生物医药科技有限公司
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Priority to CN202080080988.0A priority Critical patent/CN114728920B/zh
Publication of WO2021115372A1 publication Critical patent/WO2021115372A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—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
    • 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 medicine, and specifically relates to a new vortioxetine prodrug, a preparation method thereof, a composition containing the compound, and applications.
  • MDD Major depressive disorder
  • MMD Major depressive disorder
  • Patients with severe depression may experience pessimism, despair, hallucinations, hypofunction, and severe suicide attempts and even suicidal behavior. It poses a serious threat to human health, so it must be taken seriously.
  • Vortioxetine is a new drug for the treatment of depression. It was jointly developed by Denmark's Lundbeck and Japan's Takeda. It was approved for marketing by the FDA on September 30, 2013. The brand name is Brintellix. MDD treatment. Common adverse reactions of vortioxetine are gastrointestinal side effects, such as nausea, constipation and vomiting, which are the main side effects of SSRIs antidepressants. The incidence of adverse reactions in the 5 mg vortioxetine group was higher than that in the placebo group. The incidence of nausea (19.4 vs 9.4%) and diarrhea (11.4 vs 7.0%) were higher. With further increase in the dose, gastrointestinal side effects The incidence has also increased ([J].Pharmacology&therapeutics,2015,145:43-57).
  • WO2017215636A1 discloses a prodrug of vortioxetine, the compound structure of which is as follows:
  • CNS drugs can be modified to introduce fat-soluble side chains It is made into a fat-soluble prodrug to improve the membrane penetration ability, make it easier to enter the brain tissue through the BBB, increase the brain/blood ratio of the drug, and make it have the effect of targeted drug delivery in the central nervous system ([J].Drug discovery today,2007,12(1-2):54-61); but how to balance the penetration of the blood-brain barrier of the prodrug, reduce the breaking speed of the modified chain of the prodrug in the plasma, and the prodrug at the target location
  • the relationship between rapid metabolism and prototype drugs is the difficulty of prodrug modification.
  • the compound provided by the present invention connects vortioxetine with different fat-soluble side chains to increase the cerebral blood ratio of vortioxetine, reduce the dosage, enhance the efficacy, and reduce side effects;
  • chemically linking valproic acid, gabapentin, and pregabalin to vortioxetine for drug combination can not only increase the fat solubility of the prodrug and increase the amount of vortioxetine into the brain, but also Drugs with different mechanisms can play a synergistic effect of drugs in mammals and/or humans.
  • the present invention provides a compound represented by the general formula (A), its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof,
  • -X- is any one of single bond "——” or -(CH 2 )n 1 -;
  • R 1 and R 2 are each independently selected from any one of C 1-3 alkyl optionally substituted by halogen, amino, hydroxy or cyano, or hydrogen;
  • R 3 is selected from C 6-10 aryl groups optionally substituted by halogen, hydroxyl, cyano or amino, Any of
  • R 4 and R 5 are each independently selected from hydrogen, amino, C 6-15 alkyl optionally substituted by halogen, amino or hydroxy, or C 1-5 optionally substituted by amino, hydroxy, halogen or cyano Any one of the alkyl groups;
  • n 1 is any integer between 1 and 3;
  • a and b are each independently any integer between 0-2.
  • the present invention provides a method for preparing the compound represented by the general formula (A) of the present invention, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, comprising:
  • R 1 , R 2 and R 3 are each independently as defined above.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by general formula (A) of the present invention, its stereoisomers, its tautomers, or its pharmaceutically acceptable compounds. Accepted salt and pharmaceutically acceptable carrier.
  • the present invention provides a compound represented by general formula (A) of the present invention, its stereoisomers, its tautomers, or pharmaceutically acceptable salts or pharmaceutical compositions thereof for preparing therapeutic neuropsychiatric compounds. Use in medicines for similar diseases.
  • the neuropsychiatric disease is selected from depression, anxiety, sleep disorder, neurodegenerative disease, cognitive disorder, bipolar disorder, post-traumatic stress syndrome, addictive disease, withdrawal syndrome Or one or more of attention deficit, preferably one or more of depression, anxiety, schizophrenia, sleep disorder, cognitive disorder, neurodegenerative disease or bipolar disorder.
  • one (species) or more (species) can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 (species) Or more (species).
  • mn used herein refers to the range of m to n and the sub-range composed of each point value therein and each point value.
  • C 6 -C 15 or “C 6-15” covers the range of 6-15 carbon atoms, and should be understood to also cover any sub-range and each point value, such as C 6 -C 15 , C 7 -C 14 , C 8 -C 13 , C 9 -C 12 , C 6 -C 14 , C 6 -C 13 , C 7 -C 15 , C 10-15, etc., and C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 and so on.
  • C 1 -C 3 or “C 1-3” should also be understood in a similar way, for example, it can cover any subrange and point value contained therein, such as C 1 -C 3 , C 1 -C 2.
  • the expression “C 1 -C 5 "or “C 1-5” covers the range of 1-5 carbon atoms, and should be understood to also cover any sub-range and each point value, such as C 2 -C 5.
  • substituted and substituted mean that one or more (for example, one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that it does not exceed the specified amount.
  • the specified atom has the normal valence in the current situation and the substitution forms a stable compound.
  • Combinations of substituents and/or variables are only permissible when such combinations form stable compounds.
  • the substituent may be one or more hydrogen atoms, provided that the structure can make the compound reach a stable state.
  • each carbon atom in a group can be optionally replaced by a heteroatom, the condition is that the normal valence of all atoms in the group under the current situation is not exceeded, and a stable compound is formed.
  • R 1 is defined as "C 1-3 alkyl optionally substituted by halogen, amino, hydroxy, or cyano", meaning that R 1 is C 1-3 alkane substituted with halogen, amino, hydroxy or cyano.
  • R 1 is C 1-3 alkane substituted with halogen, amino, hydroxy or cyano.
  • an atom or group is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the atom or group may be independently selected, optional substituents Substitute.
  • the point of attachment of a substituent can be from any suitable position of the substituent.
  • a bond of a substituent is shown as a bond connecting two atoms through a ring, then such a substituent may be bonded to any ring-forming atom in the substitutable ring.
  • variable such as R
  • variables with labels such as R 1 , R 2 , R 3 , R 4 , R 5 , n 1 , a, b, etc.
  • halogen or halogen or “halo” should be understood to mean fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms, preferably fluorine, chlorine, bromine atoms.
  • alkyl refers to a linear or branched saturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond.
  • Alkyl group may have 1 to 15 carbon atoms, i.e., "C 1 -C 15 alkyl", for example C 1 - 4 alkyl group, C 1-3 alkyl, C 1-2 alkyl, C 3 alkyl , C 4 alkyl, C 1-5 alkyl, C 6-15 alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or their isomers body.
  • aryl means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic .
  • the aryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the aryl group. Examples of aryl groups may include phenyl, naphthyl, and anthracene.
  • the aryl group is optionally substituted with one or more substituents described in the present invention.
  • pharmaceutically acceptable refers to a substance that, within the scope of normal medical judgment, is suitable for contact with the patient's tissue without undue toxicity, irritation, allergic reactions, etc., and has a reasonable ratio of advantages and disadvantages. And can be effectively used for its purpose.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • preferred compounds are those isomeric compounds that exhibit superior biological activity.
  • Purified or partially purified isomers and stereoisomers, or racemic mixtures or diastereomeric mixtures of the compounds of the present invention are also included in the scope of the present invention. The purification and separation of such substances can be achieved by standard techniques known in the art.
  • pharmaceutically acceptable carrier refers to those substances that have no obvious stimulating effect on organisms and do not impair the biological activity and performance of the active compound.
  • “Pharmaceutically acceptable carriers” include but are not limited to glidants, sweeteners, diluents, preservatives, dyes/colorants, flavors, surfactants, wetting agents, dispersants, disintegrants, Stabilizer, solvent or emulsifier.
  • administration refers to a method that enables the compound or composition to be delivered to a desired site of biological action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration and the like. Especially injection or oral administration.
  • treatment includes alleviation, alleviation or amelioration of diseases or symptoms, prevention of other symptoms, amelioration or prevention of underlying metabolic factors of symptoms, inhibition of diseases or symptoms, for example, preventing the development of diseases or symptoms, alleviating diseases or symptoms, and promoting Remission of disease or symptoms, or cessation of symptoms of disease or symptoms, and extension to include prevention.
  • Treatment also includes realizing therapeutic benefits and/or preventive benefits.
  • Therapeutic benefit refers to eradicating or improving the condition being treated.
  • the therapeutic benefit is achieved by eradicating or improving one or more physical symptoms related to the underlying disease. Although the patient may still have the underlying disease, the improvement of the patient's disease can be observed.
  • Preventive benefit means that the patient uses the composition to prevent the risk of a certain disease, or when the patient has one or more physiological conditions of the disease, even though the disease has not been diagnosed.
  • cancer means that two diseases co-exist, or one disease is accompanied by another disease, or (concurrently/concomitantly) diseases. If the two groups of symptoms are considered separately, both are consistent The respective diagnostic criteria.
  • active ingredient refers to a chemical entity that can effectively treat or prevent the target disorder, disease or condition.
  • pharmaceutically acceptable salt refers to a salt made with a pharmaceutically acceptable non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids.
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts; suitable base addition salts are formed by bases that form pharmaceutically acceptable salts; methods for preparing pharmaceutically acceptable salts of the compounds of the present invention Known to those skilled in the art.
  • the terms "effective amount”, “therapeutically effective amount” or “prophylactically effective amount” refer to a sufficient amount of a drug or medicament that has acceptable side effects but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the individual, and also depends on the specific active substance. The appropriate effective amount in a case can be determined by a person skilled in the art according to routine experiments.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as those described herein.
  • non-human animals include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).
  • R 4 and R 5 are each independently directly connected to the corresponding substituted position; for example, a C 3-7 cycloalkyl group is directly connected to the corresponding substituted position.
  • R 3 can be Wait.
  • the present invention provides a compound represented by the general formula (A), its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof,
  • -X- is any one of single bond "——” or -(CH 2 )n 1 -;
  • R 1 and R 2 are each independently selected from any one of C 1-3 alkyl optionally substituted by halogen, amino, hydroxy or cyano, or hydrogen;
  • R 3 is selected from C 6-10 aryl groups optionally substituted by halogen, hydroxyl, cyano or amino, Any of
  • R 4 and R 5 are each independently selected from hydrogen, amino, C 6-15 alkyl optionally substituted by halogen, amino or hydroxy, or C 1-5 optionally substituted by amino, hydroxy, halogen or cyano Any one of the alkyl groups;
  • n 1 is any integer between 1 and 3;
  • a and b are each independently any integer between 0-2.
  • -X- is any one of single bond "——” or -(CH 2 )n 1 -;
  • R 1 and R 2 are each independently selected from any one of C 1-3 alkyl or hydrogen;
  • R 3 is selected from C 6-10 aryl groups, Any of
  • R 4 and R 5 are each independently selected from any one of hydrogen, amino, C 6-15 alkyl, or C 1-5 alkyl optionally substituted by amino;
  • n 1 is any integer between 1 and 3;
  • a and b are each independently any integer between 0-2.
  • n 1 is any integer of 1, 2 or 3; said a and b are each independently any integer of 0, 1 or 2.
  • the halogen is selected from fluorine, chlorine, bromine and iodine. In a more preferred embodiment, the halogen is selected from fluorine, chlorine and bromine. For example, fluorine or chlorine.
  • n 1 is 1 or 2, preferably 1; a and b are each independently 0, 1 or 2, preferably 1.
  • the compound represented by the general formula (A), its stereoisomer, its tautomer or its pharmaceutically acceptable salt is also selected from the general formula shown below Any one of the compound represented by (A-1), the compound represented by (A-2), or the compound represented by (A-3):
  • -X- is any one of single bond "——” or -(CH 2 )n 1 -;
  • R 1 and R 2 are each independently selected from any one of C 1-3 alkyl optionally substituted by halogen, amino, hydroxy or cyano, or hydrogen;
  • R 3 is selected from C 6-10 aryl groups optionally substituted by halogen, hydroxyl, cyano or amino;
  • R 4 and R 5 are each independently selected from hydrogen, amino, C 6-15 alkyl optionally substituted by halogen, amino or hydroxy, or C 1-5 optionally substituted by amino, hydroxy, halogen or cyano Any one of the alkyl groups;
  • n 1 is any integer between 1 and 3;
  • a and b are each independently any integer between 0-2.
  • -X- is any one of single bond "——" or -(CH 2 )n 1 -;
  • R 1 and R 2 are each independently selected from C 1-3 Any one of alkyl or hydrogen;
  • R 3 is selected from C 6-10 aryl;
  • R 4 and R 5 are each independently selected from hydrogen, amino, C 6-15 alkyl, or optionally substituted by amino Any one of C 1-5 alkyl groups;
  • n 1 is any integer between 1 and 3;
  • a and b are each independently any integer between 0 and 2.
  • n 1 is 1 or 2, preferably 1; a and b are each independently 0, 1, 2, and preferably 1.
  • the C 1-3 alkyl group optionally substituted by halogen, amino, hydroxy or cyano is selected from C 1-3 alkyl group, and the C 1-3 alkyl group The group is selected from any one of methyl, ethyl or propyl, and preferably any one of methyl or ethyl.
  • the C 1-5 alkyl group optionally substituted by amino is selected from any one of methyl, ethyl, propyl, butyl or pentyl optionally substituted by amino; preferably methyl optionally substituted by amino Any one of a group, an ethyl group, a propyl group, or a butyl group; more preferably any one of a methyl group, an ethyl group, or a propyl group optionally substituted by an amino group.
  • the propyl group is selected from n-propyl (n-Pr, -CH 2 CH 2 CH 3 ) or isopropyl ((i-Pr, -CH(CH 3 ) 2 ).
  • the butyl group is selected from n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl ( s-Bu, -CH(CH 3 )CH 2 CH 3 ) or tert-butyl (t-Bu, -C(CH 3 ) 3 ).
  • the pentyl group is selected from n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ) or 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ).
  • the C 6-15 alkyl group optionally substituted by halogen, amino or hydroxy is selected from C 6-15 alkyl group, and the C 6-15 alkyl group is selected from C 6-15 linear alkyl group, preferably C 9-15 linear alkyl group.
  • the C 6-10 aryl group optionally substituted by halogen, hydroxyl, cyano or amino is selected from C 6-10 aryl groups, and the C 6-10 aryl groups
  • the group is selected from either phenyl or naphthyl; more preferably, it is phenyl.
  • each of R 1 and R 2 is independently selected from any one of C 1-3 alkyl optionally substituted by halogen, amino, hydroxy or cyano, or hydrogen ; Preferably any one of C 1-3 alkyl or hydrogen; more preferably any one of hydrogen, methyl or ethyl; especially, preferably hydrogen or methyl.
  • said R 3 is selected from C 6-10 aryl groups optionally substituted by halogen, hydroxyl, cyano or amino, Any one of; wherein, the C 6-10 aryl group optionally substituted by halogen, hydroxyl, cyano or amino is preferably C 6-10 aryl, more preferably phenyl or naphthyl, especially , Preferably phenyl.
  • R 4 and R 5 are each independently selected from hydrogen, amino, C 6-15 alkyl optionally substituted by halogen, amino or hydroxy, or by amino, hydroxy, halogen Or any one of C 1-5 alkyl optionally substituted by cyano; more preferably hydrogen, amino, C 6-15 alkyl, or C 1-5 alkyl optionally substituted by amino
  • R 4 and R 5 are each independently preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -(CH 2 ) 8 CH 3 , -(CH 2 ) 9 CH 3 , -(CH 2 ) 12 CH 3 or -(CH 2 ) 13 CH 3
  • One kind is provided.
  • R 4 and R 5 are each independently preferably hydrogen, methyl, n-propyl, isopropyl, -CH 2 CH 2 NH 2 , -(CH 2 ) 8 CH 3 , Any one of -(CH 2 ) 9 CH 3 , -(CH 2 ) 12 CH 3 or -(CH 2 ) 13 CH 3.
  • n 1 is any integer between 1 and 3; preferably any integer from 1, 2 or 3, more preferably 1.
  • the a and b are each independently any integer between 0 and 2, preferably any integer from 0, 1 or 2, and more preferably 1.
  • -X- is any one of single bond "——” or -(CH 2 )n 1 -, n 1 is 1;
  • R 1 and R 2 are each independently selected from any one of hydrogen, methyl or ethyl
  • R 3 is selected from phenyl
  • R 4 and R 5 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -(CH 2 ) 8 CH 3 , -(CH 2 ) 9 CH 3 , -(CH 2 ) 12 CH 3 or -(CH 2 ) 13 CH 3 ;
  • a is 1, and b is 1.
  • said -X- is any one of single bond "——" or -(CH 2 )n 1 -, n 1 is 1;
  • R 1 and R 2 are each independently Any one selected from hydrogen or methyl;
  • R 3 is selected from phenyl,
  • R 4 and R 5 are each independently selected from hydrogen, methyl, n-propyl, isopropyl, -CH 2 CH 2 NH 2 , -(CH 2 ) 8 CH 3 , -(CH 2 ) 9 CH 3 , -(CH 2 ) 12 CH 3 , or -(CH 2 ) 13 CH 3 ;
  • a is 1, and b is 1.
  • exemplary compounds of the compound represented by the general formula (A), its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof are as follows:
  • the compound represented by the general formula (A), its stereoisomer, its tautomer or its pharmaceutically acceptable salt is preferably the following compound:
  • the pharmaceutically acceptable salt of the compound of the present invention may be selected from hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, Acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, methanesulfonate, trifluoroacetate, gluconate, saccharate , Benzoate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate. Preference is given to hydrobromide or trifluoroacetate.
  • the pharmaceutically acceptable salt is preferably a trifluoroacetate salt.
  • the pharmaceutically acceptable salts of compounds EP-0015-014 and E-P0015-015 are preferably trifluoroacetate, more preferably monotrifluoroacetate.
  • the pharmaceutically acceptable salt is prepared from a compound, its stereoisomer or its tautomer and its corresponding acid or base.
  • the present invention further provides a method for preparing the compound represented by the general formula (A), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, including:
  • a compound of general formula (III) and a compound of general formula (IV) are prepared under the conditions of an inorganic base and an organic solvent to obtain a compound of general formula (A).
  • a suitable solvent such as DMF
  • the compound of general formula (IV) when the compound of general formula (IV) contains an amino group (for example -NH 2 ), it can be first reacted with an amino protecting reagent to remove the amino group contained in the compound of general formula (IV) After protecting, reacting with the compound of the general formula (III), and then removing the protecting group, the compound of the general formula (A) is prepared.
  • the amino protecting reagent includes, but is not limited to, di-tert-butyl dicarbonate (Boc 2 O).
  • the present invention further provides a preparation method of the compound of general formula (III), including:
  • a compound of general formula (I) is dissolved in a suitable organic solvent, and triethylamine is reacted with a compound of general formula (I) to prepare a compound of general formula (III).
  • a compound of general formula (I) is dissolved in a suitable organic solvent, and triethylamine is reacted with a compound of general formula (I) to prepare a compound of general formula (III).
  • DCM dichloromethane
  • a compound of general formula (I) triethylamine and a compound of general formula (II) are added and reacted at room temperature for 1-3 hours to obtain a compound of general formula (III).
  • -X- is any one of single bond "——” or -(CH 2 )n 1 -;
  • R 1 and R 2 are each independently selected from any one of C 1-3 alkyl optionally substituted by halogen, amino, hydroxy or cyano, or hydrogen;
  • R 3 is selected from C 6-10 aryl groups optionally substituted by halogen, hydroxyl, cyano or amino, Any of
  • R 4 and R 5 are each independently selected from hydrogen, amino, C 6-15 alkyl optionally substituted by halogen, amino or hydroxy, or C 1-5 optionally substituted by amino, hydroxy, halogen or cyano Any one of the alkyl groups;
  • n 1 is any integer between 1 and 3;
  • a and b are each independently any integer between 0-2.
  • compositions and pharmaceutical preparations are provided.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by the general formula (A), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier .
  • the pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present invention can be formulated into a dosage form for oral, buccal administration, intranasal, parenteral (for example, intravenous, intramuscular or subcutaneous) or rectal administration, or suitable for administration by inhalation or insufflation.
  • the dosage form of the medicine can also be formulated into sustained release dosage forms.
  • an effective dose of the compound of the present invention can be taken orally together with, for example, an inert diluent or a certain carrier.
  • the compound of the present invention can be encapsulated in a gelatin capsule or compressed into tablets.
  • the compound of the present invention can be used together with excipients and used in the form of tablets, lozenges, capsules, suspensions, syrups and the like.
  • the above formulation should contain at least 0.5% (w/w) of the active compound of the present invention, but it can vary according to specific dosage forms, and it is convenient to account for 4% to about 70% of the unit weight. The amount of active compound in such a pharmaceutical composition should reach an appropriate dose.
  • the active compound of the present invention can be formulated into tablets or capsules by conventional means and pharmaceutically acceptable excipients, such as binders, fillers, Lubricant, disintegrant or wetting agent.
  • the tablets can be coated by methods well known in the art.
  • Liquid preparations for oral administration such as solutions, syrups or suspensions, or volatilized into dry products, can be regenerated with water or other suitable carriers before use.
  • Such liquid preparations can be prepared by conventional means using pharmaceutical additives, such as suspending agents, emulsifiers, non-aqueous carriers and preservatives.
  • the active compound of the present invention or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof when used for parenteral administration, the compound provided by the present invention can be combined with Sterile water or organic media are combined to form an injectable solution or suspension.
  • the active compound of the present invention or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof can be formulated into rectal compositions, such as suppositories or retention enemas, for example containing Conventional suppository bases such as cocoa butter or other glycerides.
  • the present invention provides the compound of the present invention, its stereoisomer, its tautomer or its pharmaceutically acceptable salt or the pharmaceutical composition of the present invention in the preparation of a medicament for the treatment of neuropsychiatric diseases. the use of.
  • the present invention also provides a method for treating neuropsychiatric diseases, which comprises administering the compound of the present invention, its stereoisomers, and its stereoisomers to an individual in need thereof (for example, a mammalian individual, such as a human).
  • a mammalian individual such as a human
  • a tautomer or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention is administered to an individual in need thereof.
  • the neuropsychiatric disease is selected from schizophrenia, depression, anxiety, sleep disorders, neurodegenerative diseases, cognitive disorders, bipolar disorder, post-traumatic stress syndrome, addiction Any one or more of sexual disease, withdrawal syndrome or attention deficit, preferably any of depression, cognitive impairment, anxiety, schizophrenia, sleep disorder, neurodegenerative disease or bipolar disorder One or more; more preferably depression or cognitive impairment.
  • the neuropsychiatric disease is depression.
  • the present invention also provides a use of a compound represented by general formula (A), its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of depression, wherein said The medicament optionally contains another one or more active agents that modulate the mammalian nervous system or relieve depression.
  • A general formula (A)
  • the medicament optionally contains another one or more active agents that modulate the mammalian nervous system or relieve depression.
  • the present invention also provides a compound represented by general formula (A), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof for preparing treatment of depression Use in medicines for symptomatic diseases.
  • the depression includes but is not limited to mild to severe depression, in line with WHO ICD-10 ("International Classification of Diseases"), US DSM-5 ("Diagnosis and Statistics Manual of Mental Disorders") and CCMD -3 ("Chinese Mental Disease Classification and Diagnostic Criteria”) related diagnostic criteria, preferably moderate to severe depression.
  • WHO ICD-10 International Classification of Diseases
  • US DSM-5 Diagnosis and Statistics Manual of Mental Disorders
  • CCMD -3 Choinese Mental Disease Classification and Diagnostic Criteria
  • the depression is selected from mild depression, moderate depression, major depression, depression accompanied by other mental disorders, and recurrent depression; in a more preferred embodiment The depression is selected from the group consisting of moderate depression, major depression, depression accompanied by other mental disorders, and recurrent depression.
  • the depression may comorbid at least one mental disorder.
  • the mental disorder is selected from one or more of sleep disorder, cognitive disorder, anxiety disorder, obsessive-compulsive disorder, affective disorder or personality disorder, preferably cognitive disorder, anxiety disorder or Sleep disorders, more preferably cognitive disorders.
  • the depression includes co-morbidity and other mental disorders, including but not limited to depression co-morbidity cognitive disorder, depression co-morbidity sleep disorder, depression co-morbidity anxiety, depression co-morbidity Affective disorder, depression comorbid social disorder or depression comorbid personality disorder, etc., preferably depression comorbid cognitive disorder, depression comorbid anxiety disorder, or depression comorbid sleep disorder; more preferably depression comorbidity cognitive disorder obstacle.
  • the comorbid other mental disorders also refer to accompanying other mental disorders.
  • the compound represented by the general formula (A), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, or the compound represented by the general formula (A) Use of the pharmaceutical composition of the compound, its stereoisomer, its tautomer or its pharmaceutically acceptable salt in the preparation of a medicament for the treatment of depression or depression accompanied by other mental disorders, said depression accompanied by Other mental disorders are preferably depression accompanied by cognitive disorders.
  • the present invention provides a compound represented by general formula (A), its stereoisomer, its tautomer or its pharmaceutically acceptable salt,
  • -X- is any one of single bond "—" or -(CH 2 )n 1 -;
  • R 1 and R 2 are each independently selected from any one of C 1-3 alkyl or hydrogen;
  • R 4 and R 5 are each independently selected from hydrogen, amino, unsubstituted C 6-15 alkyl, C 1-5 alkyl substituted or unsubstituted by amino, C 3-7 cycloalkyl , Any one of C 6-10 aryl or not present;
  • the key "---" is any one of single key "—" or nonexistent;
  • n 1 is any integer between 1-3.
  • n 1 is 1 or 2, preferably n 1 is 1.
  • -X- is any one of single bond "—" or -(CH 2 )n 1 -;
  • R 1 and R 2 are each independently selected from any one of C 1-3 alkyl or hydrogen;
  • R 3 is selected from C 6-10 aryl groups, Any of
  • R 4 and R 5 are each independently selected from any one of hydrogen, amino, unsubstituted C 6-15 alkyl, and C 1-5 alkyl substituted or unsubstituted by amino;
  • n 1 is any integer between 1 and 3;
  • a and b are each independently any integer between 0-2.
  • n1 is 1 or 2, preferably n1 is 1; a and b are each independently 0, 1 or 2, preferably 1.
  • -X- is any one of single bond "——” or -(CH 2 )n 1 -;
  • R 1 and R 2 are each independently selected from any one of C 1-3 alkyl or hydrogen;
  • R 4 and R 5 are each independently selected from hydrogen, amino, unsubstituted C 6-15 alkyl, C 1-5 alkyl substituted or unsubstituted by amino, C 3-7 cycloalkyl , Any one of C 6-10 aryl or not present;
  • the key "---" is any one of single key “——” or nonexistent;
  • n 1 is any integer between 1-3.
  • n 1 is 1 or 2, preferably n 1 is 1.
  • the C 1-3 alkyl group is selected from methyl, ethyl or propyl, preferably methyl, ethyl, and more preferably methyl.
  • the C 1-5 alkyl substituted or unsubstituted by amino is methyl, ethyl, propyl, butyl or pentyl substituted or unsubstituted by amino .
  • the C 1-5 alkyl group substituted by an amino group is preferably a methyl group, an ethyl group or a propyl group substituted by an amino group, including but not limited to -CH 2 -NH 2 ,- (CH 2 ) 2 -NH 2 , -(CH 2 ) 3 -NH 2 .
  • the unsubstituted C 1-5 alkyl group is preferably methyl, ethyl, propyl or butyl.
  • the unsubstituted C 6-15 alkyl group is preferably a C 6-15 linear alkyl group, and more preferably a C 9-15 linear alkyl group.
  • the C3-7 cycloalkyl group is selected from an unsubstituted five-membered cycloalkyl group or a six-membered cycloalkyl group; the C6-10 aryl group is preferably unsubstituted Phenyl or naphthyl, more preferably unsubstituted phenyl.
  • -X- is a single bond Any one of "——" or -(CH 2 )n 1 -; the C 1-3 alkyl group is selected from any one of methyl or ethyl; the amino group is substituted or unsubstituted
  • the C 1-5 alkyl group is selected from any one of methyl, ethyl, propyl or butyl substituted by amino or unsubstituted; the unsubstituted C 6-15 alkyl group is selected from C 6 - 15 linear alkyl group; a C 3-7 cycloalkyl group selected from an unsubstituted five-membered cycloalkyl or any of a group of six-membered ring; a C 6-10 aryl group is selected from unsubstituted phenyl or naphthyl group either; and when
  • -X- is Single bond "——” or any one of -(CH 2 )n 1 -;
  • R 1 and R 2 are each independently selected from any one of hydrogen, methyl or ethyl;
  • R 4 and R 5 are each Independently selected from hydrogen, methyl, ethyl, propyl, butyl, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , cyclohexane, phenyl, -(CH 2 ) 9 CH 3 , -( CH 2 ) 13 CH 3 or any one of none; and when R 3 and R 4 are each independently a C3-7 cycloalkyl group or a C 6-10 aryl group, the bond "---" means not present; n 1 is 1 or 2.
  • the C 1-3 alkyl group is selected from any one of methyl or ethyl; the C 1-5 alkyl group substituted or unsubstituted by amino is selected Any one of methyl, ethyl, propyl or butyl substituted or unsubstituted by amino; the unsubstituted C 6-15 alkyl group is selected from the straight chain alkyl group of C 6-15;
  • the C 3-7 cycloalkyl group is selected from any one of an unsubstituted five-membered cycloalkyl group or a six-membered cycloalkyl group; the C 6-10 aryl group is selected from an unsubstituted phenyl group or Any one of naphthyl; and when R 4 and R 5 are each independently C 3-7 cycloalkyl or C 6-10 aryl, the bond "---" is not exist.
  • said R 1 and R 2 are each independently selected from any one of hydrogen, methyl or ethyl; said R 4 and R 5 are each independently selected from hydrogen, methyl Group, ethyl, propyl, butyl, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , cyclohexane, phenyl, -(CH 2 ) 9 CH 3 , -(CH 2 ) 13 CH 3 or There is no one of them; and when R 3 and R 4 are each independently a C 3-7 cycloalkyl group or a C 6-10 aryl group, the bond "---" is not Exist; n 1 is 1 or 2.
  • the compound represented by the general formula (A) is selected from any one of the following compounds:
  • the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphoric acid Salt, acetate, lactate, citrate, tartrate, maleate, fumarate, methanesulfonate, trifluoroacetate, gluconate, saccharate, benzyl Acid salt, ethanesulfonate, benzenesulfonate or p-toluenesulfonate, preferably trifluoroacetate.
  • the present invention provides a method for preparing a compound represented by the general formula (A), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, which comprises:
  • R 1 , R 2 , R 3 and the bond "---" are each independently as defined above.
  • the present invention provides a method for preparing a compound of general formula (III) as shown below, comprising:
  • a compound of general formula (I) is reacted with a compound of general formula (II) to prepare a compound of general formula (III);
  • R 1 and R 2 are each independently as defined above.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by general formula (A), its stereoisomers, its tautomers or its pharmaceutically acceptable salts and pharmaceutically acceptable Carrier.
  • the present invention provides a compound represented by general formula (A), its stereoisomer, its tautomer or its pharmaceutically acceptable salt or its pharmaceutical composition for preparing treatment of depression or depression accompanied by other mental disorders
  • the depression is accompanied by other mental disorders, preferably depression is accompanied by cognitive disorders.
  • the present invention provides a new prodrug of vortioxetine.
  • central nervous system drugs are really effective for free drugs that enter the brain, and the known vortioxetine binds more to peripheral tissues.
  • the prototype drug vortioxetine was directly administered, and the drug concentration of free vortioxetine in the brain was basically not detected, while the vortioxetine prodrug was administered.
  • the drug concentration of free vortioxetine in the brain of cynomolgus monkeys is significantly increased, which has the advantage of potentially improving the drug effect.
  • the vortioxetine prodrug compound of the present invention has a significantly increased cerebral blood ratio, reduces peripheral exposure, has the potential to improve the gastrointestinal side effects of vortioxetine, and has significant brain-targeted drug delivery. Effect;
  • the prodrug compound has good pharmacokinetic properties, including the release profile of the drug in the body is more gentle than that of vortioxetine, the brain exposure (AUC 0-last ) is higher, and the vorti is lower.
  • FIG. 1 AUC ratio (cerebral blood ratio, B/P) of vortioxetine and vortioxetine prodrug compounds in rats.
  • Figure 4 The drug-time curve of vortioxetine and vortioxetine prodrugs in the plasma of rats.
  • Figure 6 The total AUC exposure of vortioxetine and vortioxetine prodrugs in cynomolgus monkeys.
  • the oily substance is 100 mg, the yield is 52.7%, and the purity is 99%.
  • Example 8 1-((3-(Aminomethyl)-5-methylhexanoyl)oxo)ethyl 4-(2-((2,4-dimethylphenyl)thio)phenyl )Piperazine-1-carboxylic acid trifluoroacetate (compound EP-0015-015 trifluoroacetate)
  • EP-X is prepared by referring to the method described in Example 6 of patent PCT/CN2017/088493, and its structure is as follows:
  • test compounds of the present invention were prepared according to the methods described in Examples 1-8.
  • Test Example 1 Microsomal metabolic stability and plasma stability test of the tested prodrug molecule
  • the cofactor used in the test is the NADPH regeneration system, which consists of 6.5mM NADP, 16.5mM G-6-P, 3U/mL G-6-P D;
  • the quencher is composed of acetonitrile containing toluene sulfamide and propanol (used as an internal standard);
  • the buffer used in the test is 100 mM phosphate buffer, containing 3.3 mM MgCl 2 ;
  • the mixture contains 0.2 mg/mL liver microsomal protein and 1 ⁇ M test compound/positive control, and is incubated in 100 mM potassium phosphate buffer.
  • Test example 1-2 plasma stability test
  • the quencher is composed of acetonitrile (used as an internal standard) containing toluene sulfamide and propranolol.
  • Test example 1-3 the metabolic characteristics of the tested drug in rats
  • Chromatographic conditions chromatographic column is WELCH Xtimate-C18 column (50 ⁇ 2.1mm, 3.5mm); mobile phase: A: aqueous solution (0.1% formic acid); B: acetonitrile (0.1% formic acid); gradient elution (0.10-0.80min) , 10%B-95%B; 0.80-1.80min, 95%B-95%B; 1.80-1.81min, 95%B-10%B; 1.81-3.00min, 10%B-10%B;); Flow rate: 350 ⁇ L ⁇ min-1; column temperature: 30°C.
  • Mass spectrometry conditions Electrospray ion source (ESI), positive ion scanning multiple reaction monitoring mode (MRM). Ion source temperature: 500°C; ion injection voltage: 5000V; atomizer (GS1): 50psi; auxiliary gas (GS2): 35psi; collision gas (CAD): High; curtain gas (CUR): 25psi.
  • ESI Electrospray ion source
  • MRM positive ion scanning multiple reaction monitoring mode
  • Ion source temperature 500°C
  • ion injection voltage 5000V
  • atomizer (GS1) 50psi
  • auxiliary gas (GS2) 35psi
  • collision gas (CAD) High
  • curtain gas (CUR) 25psi.
  • the ion pairs used for quantitative analysis were m/z 299.3 ⁇ 109.2 (vortioxetine), 455.3 ⁇ 165.1 (internal standard verapamil).
  • Plasma sample processing take 20 ⁇ L of plasma sample, place it in a 2.0mL centrifuge tube, add 200 ⁇ L of precipitant solution (acetonitrile solution, containing 60.0ng ⁇ mL -1 dexamethasone, 5.0ng ⁇ mL -1 verapamil , 30.0ng ⁇ mL -1 buspirone solution), vortex for 3min, centrifuge (12,000rpm) for 3min, take 75 ⁇ L of supernatant and transfer to a 96-well plate, then add 75 ⁇ L of aqueous solution, mix well and take 10 ⁇ L for LC -MS/MS analysis.
  • precipitant solution acetonitrile solution, containing 60.0ng ⁇ mL -1 dexamethasone, 5.0ng ⁇ mL -1 verapamil , 30.0ng ⁇ mL -1 buspirone solution
  • Processing of brain tissue samples Take 50 ⁇ L of brain tissue sample, place it in a 2.0mL centrifuge tube, add 500 ⁇ L of precipitant solution (acetonitrile solution, containing 60.0ng ⁇ mL -1 dexamethasone, 5.0ng ⁇ mL -1 vera Pamir, 30.0ng ⁇ mL -1 buspirone solution), vortex for 3min, centrifuge (12,000rpm) for 3min, take 75 ⁇ L of supernatant and transfer to a 96-well plate, then add 75 ⁇ L of aqueous solution, mix well and take 10 ⁇ L Perform LC-MS/MS analysis.
  • precipitant solution acetonitrile solution, containing 60.0ng ⁇ mL -1 dexamethasone, 5.0ng ⁇ mL -1 vera Pamir, 30.0ng ⁇ mL -1 buspirone solution
  • the positive control and test compound groups were calculated as the same dose of vortioxetine according to the molecular weight of the prodrug and the purity of the compound.
  • the sample was treated with a spray drying process, and then pure water was used as a solvent. Add an appropriate volume of the solvent to fully dissolve and dissolve it. Mix well to prepare the vortioxetine prodrug solution for each group.
  • each group of vortioxetine prodrugs is calculated as the dose of the same dose of vortioxetine according to the molecular weight and compound purity. Label the prepared liquid medicine for later use. If the test product does not dissolve well, or the suspension is uneven, appropriate vortex or ultrasound can be performed.
  • the cerebral blood ratio (B/P) of the metabolite vortioxetine of the compound EP-0015-010 of the present invention is 50.47, and the metabolite vortioxetine of EP-X
  • the B/P of EP-0015-010 is 33.54.
  • the cerebral blood ratio (B/P) of the metabolite of EP-0015-010, vortioxetine, is significantly higher than that of EP-X, suggesting that the compound of the present invention has strong brain tissue targeting.
  • the drug effect significantly increases the exposure of the active metabolite vortioxetine in the brain.
  • the vortioxetine prodrug EP-0015-010 of the present invention maintains a rapid release of the active product, vortioxetine, and can maintain a certain level of exposure after entering the blood and brain.
  • the blood concentration of the drug indicates that EP-0015-010 has a reasonable prodrug clearance rate and the release rate of the active metabolite vortioxetine; and EP-X not only has a significantly lower exposure of the metabolite vortioxetine in the brain tissue
  • EP-0015-010 AUC 0-last , 10800 vs 6640
  • Test Example 2 In vivo pharmacokinetic test of prodrug molecules in rats
  • Chromatographic conditions chromatographic column is WELCH Xtimate-C18 column (50 ⁇ 2.1mm, 3.5 ⁇ m); mobile phase: A: aqueous solution (0.1% formic acid); B: acetonitrile (0.1% formic acid); gradient elution (0.10-0.80min) , 10%B-95%B; 0.80-1.80min, 95%B-95%B; 1.80-1.81min, 95%B-10%B; 1.81-3.00min, 10%B-10%B;); Flow rate: 350 ⁇ L ⁇ min -1 ; column temperature: 30°C.
  • Mass spectrometry conditions Electrospray ion source (ESI), positive ion scanning multiple reaction monitoring mode (MRM). Ion source temperature: 500°C; ion injection voltage: 5000V; atomizer (GS1): 50psi; auxiliary gas (GS2): 35psi; collision gas (CAD): High; curtain gas (CUR): 25psi.
  • ESI Electrospray ion source
  • MRM positive ion scanning multiple reaction monitoring mode
  • Ion source temperature 500°C
  • ion injection voltage 5000V
  • atomizer (GS1) 50psi
  • auxiliary gas (GS2) 35psi
  • collision gas (CAD) High
  • curtain gas (CUR) 25psi.
  • the ion pairs used for quantitative analysis were m/z 299.3 ⁇ 109.2 (vortioxetine), 455.3 ⁇ 165.1 (internal standard verapamil).
  • Plasma sample processing take 20 ⁇ L of plasma sample, place it in a 2.0mL centrifuge tube, add 200 ⁇ L of precipitant solution (acetonitrile solution, containing 60.0ng ⁇ mL -1 dexamethasone, 5.0ng ⁇ mL -1 verapamil , 30.0ng ⁇ mL -1 buspirone solution), vortex for 3min, centrifuge (12,000rpm) for 3min, take 75 ⁇ L of supernatant and transfer to a 96-well plate, then add 75 ⁇ L of aqueous solution, mix well and take 10 ⁇ L for LC -MS/MS analysis.
  • precipitant solution acetonitrile solution, containing 60.0ng ⁇ mL -1 dexamethasone, 5.0ng ⁇ mL -1 verapamil , 30.0ng ⁇ mL -1 buspirone solution
  • Processing of brain tissue samples Take 50 ⁇ L of brain tissue sample, place it in a 2.0mL centrifuge tube, add 500 ⁇ L of precipitant solution (acetonitrile solution, containing 60.0ng ⁇ mL -1 dexamethasone, 5.0ng ⁇ mL -1 vera Pamir, 30.0ng ⁇ mL -1 buspirone solution), vortex for 3min, centrifuge (12,000rpm) for 3min, take 75 ⁇ L of supernatant and transfer to a 96-well plate, then add 75 ⁇ L of aqueous solution, mix well and take 10 ⁇ L Perform LC-MS/MS analysis.
  • precipitant solution acetonitrile solution, containing 60.0ng ⁇ mL -1 dexamethasone, 5.0ng ⁇ mL -1 vera Pamir, 30.0ng ⁇ mL -1 buspirone solution
  • Vortioxetine group Weigh 28 mg of Vortioxetine compound (homemade), use 5% DMSO solution + 95% (0.5% CMC-Na solution) as a solvent, add an appropriate volume of solvent, fully dissolve and mix, and get The 0.5mg/mL complete suspension is a solution for vortioxetine administration.
  • Vortioxetine prodrug groups EP-0015-003 group, EP-0015-004 group, EP-0015-006 group, EP-0015-010 group, EP-0015-011 group, EP-0015-013 group , EP-0015-014 group, EP-0015-015 group calculated according to the molecular weight of each prodrug and the purity of the compound as the dose of the same dose of vortioxetine, using 5% DMSO solution + 95% (0.5% CMC-Na Solution) as a solvent, add an appropriate volume of the solvent, fully dissolve and mix well to prepare the vortioxetine prodrug each group dosing solution.
  • each group of vortioxetine prodrugs is calculated as the dose of the same dose of vortioxetine according to the molecular weight and compound purity. Label the prepared liquid medicine for later use. If the test product does not dissolve well, or the suspension is uneven, appropriate vortex or ultrasound can be performed.
  • the results of the pharmacokinetic parameters of vortioxetine and vortioxetine prodrug compounds detected in rat brain tissue are shown in Table 5.
  • the drug of vortioxetine detected in rat plasma The results of the kinetic parameters are shown in Table 6, and the AUC ratios (cerebral blood ratio, B/P) of vortioxetine and vortioxetine prodrug compounds in rat brain tissue and plasma are shown in Figure 1.
  • the total AUC exposure comparison of vortioxetine and vortioxetine prodrug compounds is shown in Figure 2, and the relative bioavailability comparison of vortioxetine and vortioxetine prodrug compounds is shown in Figure 3.
  • the AUC cerebral blood ratio (B/P) of the vortioxetine prodrug compound of the present invention is significantly increased, such as EP-0015-003, EP-0015-004, EP-0015-
  • the blood-to-brain ratio of 006, EP-0015-010, EP-0015-011, EP-0015-014, EP-0015-015 has a significant change compared with the blood-to-brain ratio of vortioxetine, suggesting that it has a strong
  • the targeted drug delivery effect of brain tissue see Figure 1
  • the brain exposure (AUC 0-last ) is also higher (see Figure 2), when the same dose of vortioxetine acts on the central nervous system
  • the prodrug of the present invention can reduce the administered dose, thus at the same time reducing the effect of vortioxetine on the peripheral nervous system.
  • the vortioxetine prodrug provided by the present invention has a smoother drug-time curve in plasma and brain, suggesting that it can maintain a relatively stable profile in the human body.
  • the therapeutic concentration of the drug has good pharmacokinetic properties.
  • Chromatographic conditions ACQUITY UPLC Protein BEH C4 column 1.7 ⁇ m 2.1 ⁇ 50mm; mobile phase: A: 2mM HCOONH 4 in water/ACN(v:v,95:5); B: 2mM HCOONH4 in ACN/water(v:v,95:5); gradient elution ( 0.10-0.30min, 15%-40%B; 0.30-1.40min, 40%-60%B; 1.40-1.60min, 60%-90%B; 1.60-2.00min, 90%B, 2.00-2.20min, 90%B-15%B;); flow rate: 700 ⁇ L ⁇ min-1; column temperature: 55°C.
  • Electrospray ion source (ESI) is used, reaction detection scan mode (SRM) is selected.
  • Ion source temperature 500°C; ion injection voltage: 5000V; atomizer (GS1): 50psi; auxiliary gas (GS2): 35psi; collision gas (CAD): High; curtain gas (CUR): 25psi.
  • GS1 atomizer
  • GS2 auxiliary gas
  • CAD collision gas
  • CUR curtain gas
  • Plasma sample processing add aliquots of 20 ⁇ L unknown samples, calibration standards, quality control, dilution quality control, single blank and double blank samples to 96-well plates; each sample (except double blank samples) is used separately 200 ⁇ L IS1 quenched (double blank sample was quenched with 200 ⁇ L MeOH), then the mixture was vortexed at 800rpm for 10 minutes, and then centrifuged at 3220g for 15 minutes (4000rpm), 4°C. Inject 2 ⁇ L of supernatant for LC-MS/MS analysis;
  • cerebrospinal fluid samples are added with plasma and ethanol (v; v; v 1; 1; 1); aliquots of 20 ⁇ L unknown samples, calibration standards, quality control, dilution quality control, single blank and Add double blank samples to a 96-well plate; each sample (except double blank samples) was quenched with 200 ⁇ L IS1 (double blank samples were quenched with 200 ⁇ L MeOH), then the mixture was vortexed at 800 rpm for 10 minutes, and then at 3220 g Centrifuge for 15 minutes (4000 rpm) at 4°C. Inject 2 ⁇ L of supernatant for LC-MS/MS analysis.
  • Vortioxetine group accurately weigh the vortioxetine compound, use 90% PEG400/10% water as the solvent, add an appropriate volume of the solvent, fully dissolve and mix, to obtain a complete suspension of 2 mg/mL, which is the vortioxetine Xetine administration solution.
  • EP-0015-010 group Weigh the EP-0015-010 compound accurately, use 90% PEG400/10% water as the solvent, add an appropriate volume of the solvent, fully dissolve and mix, to obtain a complete suspension of 3.82 mg/mL. It is EP-0015-010 dosing solution (equivalent to 2mg/mL vortioxetine).
  • the test product When preparing the test product, calculate the theoretical weighing amount according to the design concentration and the required volume. According to the molecular weight and compound purity of each group of vortioxetine prodrugs, the dose of vortioxetine at the same dose of 3mg/kg is calculated. Label the prepared liquid medicine for later use. If the test product does not dissolve well, or the suspension is uneven, appropriate vortex or ultrasound can be performed.
  • Cerebral blood ratio (B/P) AUC 0-last (cerebrospinal fluid)/AUC 0-last (plasma)
  • Vortioxetine and vortioxetine prodrug compounds detected in cynomolgus monkey plasma and cerebrospinal fluid are shown in the following 7; vortioxetine and vortioxetine prodrug compounds
  • Figure 6 shows the total AUC exposure results of vortioxetine in the cerebrospinal fluid and plasma of cynomolgus monkeys.
  • the total AUC of the vortioxetine prodrug provided by the present invention is significantly higher than that of vortioxetine, and the vortioxetine prodrug metabolite is significantly higher than that of vortioxetine.
  • the total AUC of Tioxetine and vortioxetine is basically the same (see Figure 6 for details); in addition, the B/P ratio of the vortioxetine drug concentration produced by the vortioxetine prodrug provided by the present invention after being metabolized is significantly higher For vortioxetine, it is suggested that the prodrug provided by the present invention can be targeted to the brain for administration.
  • the concentration of free vortioxetine produced by the prodrug compound of the present invention in the cerebrospinal fluid metabolism is much higher than the free drug concentration of vortioxetine in the cerebrospinal fluid, suggesting that the prodrug of the present invention can significantly improve the therapeutic effect of vortioxetine. Therefore, the prodrug provided by the present invention can improve the antidepressant effect, and at the same time, can reduce the dosage under the premise of maintaining the same drug effect, thereby reducing adverse reactions.

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Abstract

一种沃替西汀前药及其应用，其具有如式(A)所示的化合物结构，该类化合物可用于制备治疗神经精神类疾病的药物。

Description

一种沃替西汀前药及其应用
本申请要求申请日为2019/12/10的中国专利申请201911254627.9的中国专利申请的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于医药领域，具体涉及一种新的沃替西汀前药、其制备方法和包含该化合物的组合物，以及应用。
背景技术
重度抑郁症(Major depressive disorder，MDD)是一种情绪性功能障碍，以持久自发性的情绪低落为主的一系列抑郁症状，对患者的工作能力、睡眠、学习、饮食及享受当下的快乐产生困扰。重度抑郁症患者会出现悲观厌世、绝望、幻觉妄想、功能减退、并伴有严重的自杀企图，甚至自杀行为。对人类健康构成严重威胁，因此必须引起高度重视。
沃替西汀(vortioxetine)是治疗抑郁症的新药，由丹麦灵北制药(Lundbeck)和日本武田制药(Takeda)联合研发，于2013年9月30日由FDA批准上市，商品名Brintellix，用于MDD的治疗。沃替西汀常见的不良反应为胃肠道副反应，如恶心，便秘和呕吐，是SSRIs类抗抑郁药的主要副作用。5mg沃替西汀组不良反应发生率与安慰剂组相比，恶心(19.4 vs 9.4％)和腹泻(11.4 vs 7.0％)发生率高，随着给药剂量的进一步增加，胃肠道副反应发生率也随之提高([J].Pharmacology&therapeutics,2015,145:43-57)。
WO2017215636A1公开了一种沃替西汀的前药，其化合物结构如下所示：
Figure PCTCN2020135200-appb-000001
由于血脑屏障(BBB)的存在，脂溶性越高的溶质，通过血脑屏障进入脑组织的速度也越快，例如根据这一规律，可将某些CNS药物加以改造，引入脂溶性侧链做成脂溶性前药，提高膜穿透能力，使之更容易通过BBB进入脑组织，增大药物的脑/血比例，使其具有中枢神经系统靶向给药效果([J].Drug discovery today,2007,12(1-2):54-61)；但如何平衡提高前药血脑屏障的穿透能力、降低前药的修饰链在血浆中的断裂速度、以及前药在 靶向位置快速代谢为原型药这三者的关系是前药修饰的难点。正如专利WO2017215636A1说明书第21页表1所记载的内容，随着修饰侧链的脂溶性的改变，药物代谢酶将沃替西汀前药代谢为原型药物的速度也在随之改变，因而需要付出大量工作寻找到在血浆中断裂速度较慢，而在靶向释药位置(如脑组织中)快速断裂的修饰链，这样修饰得到的沃替西汀前药可使原型药物沃替西汀能够快速释放入脑，又能够降低在血浆中的药物浓度，达到快速起效、降低胃肠道不良反应的作用。
综上所述，对于沃替西汀前药的改构仍然是抑郁治疗领域关注的重点，能够显著减少给药剂量，提高入脑率的沃替西汀前药为目前研究的热点。
发明内容
本发明所提供的化合物，一方面，将沃替西汀与不同的脂溶性侧链连接，用以提高沃替西汀的脑血比，减少给药剂量，增强药效，并降低副作用；另一方面，通过化学方式将丙戊酸、加巴喷丁、普瑞巴林分别与沃替西汀连接，进行药物联用，不仅可增加前药的脂溶性，提高沃替西汀入脑量，而且两种不同机制的药物在哺乳动物和/或人体内可起到药物协同的作用。
在一方面，本发明提供一种通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐，
Figure PCTCN2020135200-appb-000002
其中：
-X-为单键“——”或-(CH 2)n 1-中的任意一种；
R 1和R 2各自独立地选自被卤素、氨基、羟基或氰基任选取代的C 1-3的烷基，或氢中的任意一种；
R 3选自被卤素、羟基、氰基或氨基任选取代的C 6-10的芳基，
Figure PCTCN2020135200-appb-000003
中 的任意一种；
R 4和R 5各自独立地选自氢，氨基，被卤素、氨基或羟基任选取代的C 6-15的烷基，或被氨基、羟基、卤素或氰基任选取代的C 1-5的烷基中的任意一种；
n 1为1～3之间的任意一个整数；
a和b各自独立地为0～2之间的任意一个整数。
在另一方面，本发明提供一种制备本发明的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐的方法，包括：
Figure PCTCN2020135200-appb-000004
通式(III)的化合物与通式(IV)的化合物通过取代反应得到通式(A)的化合物；
其中：
-X-，R 1，R 2和R 3各自独立地如上述所定义。
在又一方面，本发明提供一种药物组合物，其包含治疗有效量的本发明的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐和药学上可接受的载体。
在还一方面，本发明提供本发明的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐或药物组合物在制备治疗神经精神类疾病的药物中的用途。
特定地，所述神经精神类疾病选自抑郁症、焦虑症、睡眠障碍、神经退行性疾病、认知障碍、双相情感障碍、创伤后应激综合征、成瘾性疾病、戒断综合征或注意力缺陷中的一种或多种，优选抑郁症、焦虑症、精神分裂症、睡眠障碍、认知障碍、神经退行性疾病或双相情感障碍中的一种或多种。
发明详述
一般术语和定义
除非另有定义，本文所用所有技术和科学术语与本发明所属领域的普通技术人员通常理解的含义相同。若存在矛盾，则以本申请提供的定义为准。当本文中出现商品名时，意在指代其对应的商品或其活性成分。本文引用的所有专利、已经公开的专利申请和出版物均通过引用并入到本文中。
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或开放式的，且不排除其它未列举的元素或方法步骤。本领域技术人员应当理解，上述术语如“包括”涵盖“由…组成”的含义。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“分别独立地为”或“各自独立地为”应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
术语“一个(种)或多个(种)”或者类似的表述“至少一个(种)”可以表示例如1、2、3、4、5、6、7、8、9、10个(种)或更多个(种)。
当公开了数值范围的下限和上限时，落入该范围中的任何数值和任何包括的范围都被具体公开。特别地，本文公开的值的每个取值范围应理解为表示涵盖于较宽范围中的每个数值和范围。
本文所用的表述m-n指m至n的范围以及由其中的各个点值组成的亚范围以及各个点值。例如，表述“C 6-C 15”或“C 6-15”涵盖6-15个碳原子的范围，并应理解为还涵盖其中的任意亚范围以及每个点值，例如C 6-C 15、C 7-C 14、C 8-C 13、C 9-C 12、C 6-C 14、C 6-C 13、C 7-C 15、C 10-15等，以及C 6、C 7、C 8、C 9、C 10、C 11、C 12等。例如，表述“C 1-C 3”或“C 1-3”也应当以类似的方式理解，例如可以涵盖包含于其中的任意亚范围和点值，例如C 1-C 3、C 1-C 2、C 2-C 3等以及C 1、C 2、C 3等。又例如，表述“C 1-C 5”或“C 1-5”涵盖1-5个碳原子的范围，并应理解为还涵盖其中的任意亚范围以及每个点值，例如C 2-C 5、C 3-C 4、C 1-C 2、C 1-C 3、C 1-C 4、C 1-C 5等，以及C 1、C 2、C 3、C 4、C 5等。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。
术语“取代”和“取代的”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)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。当描述某取代基不存在时，应当理解该取代基可以为一个或多个氢原子，前提是所述结构能使化合物达到稳定的状态。当描述基团中的每个碳原子可以任选地被杂原子代替时，条件是未超过基团中的所有原子在当前情况下的正常原子价，并且形成稳定的化合物。
如果取代基被描述为“被…任选地取代”或“被…任选取代的”，则取代基可以是未被取代的(非取代的)，或者可以是被取代的。例如，R 1定义为“被卤素、氨基、羟基或氰 基任选取代的C 1-3的烷基”，表示R 1为被卤素、氨基、羟基或氰基取代的C 1-3的烷基或非取代的C 1-3的烷基，当R 1仅表述为C 1-3的烷基时，C 1-3的烷基是未被取代的(非取代的)，R 2、R 3、R 4和R 5等的定义同R 1。如果某个原子或基团被描述为任选地被取代基列表中的一个或多个取代，则该原子或基团上的一个或多个氢可被独立地选择的、任选的取代基替代。当取代基为氧代(即＝O)时，意味着两个氢原子被替代。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
当任何变量(例如R)，以及带有标记的变量(例如R 1、R 2、R 3、R 4、R 5、n 1、a、b等)在化合物的组成或结构中出现一次以上时，其在每次出现时在每一种情况下的定义都是独立的。例如，如果一个基团被0、1、2、3或4个R取代基所取代，则所述基团可以任选地至多被四个R取代基所取代，并且每种情况下的每个R取代基的选项都是相互独立的。
术语“卤”或“卤素”或“卤代”应理解为表示氟(F)、氯(Cl)、溴(Br)或碘(I)原子，优选氟、氯、溴原子。
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和的脂肪烃基团，其通过单键与分子的其余部分连接。“烷基”可以具有1-15个碳原子，即“C 1-C 15烷基”，例如C 1- 4烷基、C 1-3烷基、C 1-2烷基、C 3烷基、C 4烷基、C 1-5烷基、C 6-15烷基。烷基的非限制性实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基，或者它们的异构体。
术语“芳基”表示含有6-14个环原子、或6-12个环原子、或6-10个环原子的单环、双环和三环的碳环体系，其中至少一个环是芳香族的。芳基基团通常，但不必须地通过芳基基团的芳香性环与母体分子连接。芳基基团的实例可以包括苯基、萘基和蒽。所述芳基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“药学上可接受”的物质指这样的物质，其在正常的医学判断范围内适用于与患者的组织接触而不会有不适当毒性、刺激性、过敏反应等，具有合理的利弊比，且能有效用于其目的用途。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化 合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。在某些实施方案中，优选化合物为那些显示更优生物活性的异构体化合物。本发明化合物已纯化的或部分纯化的异构体和立体异构体、或者外消旋混合物或非对映异构体混合物也均包括于本发明范围内。此类物质的纯化和分离可通过本领域已知的标准技术实现。
术语“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些物质。“药学上可接受的载体”包括但不限于助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、崩解剂、稳定剂、溶剂或乳化剂。
术语“给药”或“给予”等指可以使化合物或组合物能够递送至期望的生物作用位点的方法。这些方法包括但不限于口服或肠胃外(包括脑室内、静脉内、皮下、腹膜内、肌内、血管内注射或输注)、局部、直肠给药等。特别是注射或口服。
如本文所用，术语“治疗”包括缓解、减轻或改善疾病或症状，预防其他症状，改善或预防症状的潜在代谢因素，抑制疾病或症状，例如，阻止疾病或症状发展，减轻疾病或症状，促进疾病或症状缓解，或使疾病或症状的病征停止，和延伸至包括预防。“治疗”还包括实现治疗性获益和/或预防性获益。治疗性获益是指根除或改善所治疗的病症。此外，治疗性获益通过根除或改善一个或多个与潜在疾病相关的生理病征达到，尽管患者可能仍患有潜在疾病，但可观察到患者疾病的改善。预防性获益是指，患者为预防某种疾病风险而使用组合物，或患者出现一个或多个疾病生理病症时服用，尽管尚未诊断此疾病。
术语“共病(comorbidity)”，其含义是指两种疾病共同存在，或者一种疾病伴随另外一种疾病存在，或者(同時产生/伴随)的疾病，如将两组症状分别考虑，均符合各自相应的诊断标准。
术语“活性成分”、“治疗剂”、“活性物质”或“活性剂”是指一种化学实体，其可以有效地治疗或预防目标紊乱、疾病或病症。
术语“可药用的盐”或“药学上可接受的盐”是指与药学上可接受的无毒的碱或酸，包括无机或有机碱和无机或有机酸制成的盐。本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。适合的酸加成盐由形成药学可接受盐的酸来形成；适合的碱加成盐由形成药学可接受盐的碱来形成；用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。
针对药物、药物单元或活性成分而言，术语“有效量”、“治疗有效量”或“预防有效量” 是指副作用可接受的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于个体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
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)。
在本文中，“X”和“-X-”均表示为同一特定的基团，其可以互换使用。
在本发明中，当所描述的键“------”为不存在时，其所连接的取代基和其被取代位置直接相连，例如当R 3为
Figure PCTCN2020135200-appb-000005
时，当其中任意一个“------”不存在时，R 4和R 5各自独立地与对应的被取代位置直接相连；例如，C 3-7的环烷基与对应的被取代位置直接相连时，R 3可为
Figure PCTCN2020135200-appb-000006
等。
下述发明详述旨在举例说明非限制性实施方案，使本领域其它技术人员更充分地理解本发明的技术方案、其原理及其实际应用，以便本领域其它技术人员可以以许多形式修改和实施本发明，使其可最佳地适应特定用途的要求。
式(A)化合物
在一方面，本发明提供通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐，
Figure PCTCN2020135200-appb-000007
其中：
-X-为单键“——”或-(CH 2)n 1-中的任意一种；
R 1和R 2各自独立地选自被卤素、氨基、羟基或氰基任选取代的C 1-3的烷基，或氢中的任意一种；
R 3选自被卤素、羟基、氰基或氨基任选取代的C 6-10的芳基，
Figure PCTCN2020135200-appb-000008
中的任意一种；
R 4和R 5各自独立地选自氢，氨基，被卤素、氨基或羟基任选取代的C 6-15的烷基，或被氨基、羟基、卤素或氰基任选取代的C 1-5的烷基中的任意一种；
n 1为1～3之间的任意一个整数；
a和b各自独立地为0～2之间的任意一个整数。
在本发明一个优选的实施方案中，其中：
-X-为单键“——”或-(CH 2)n 1-中的任意一种；
R 1和R 2各自独立地选自C 1-3的烷基或氢中的任意一种；
R 3选自C 6-10的芳基，
Figure PCTCN2020135200-appb-000009
中的任意一种；
R 4和R 5各自独立地选自氢，氨基，C 6-15的烷基，或被氨基任选取代的C 1-5的烷基中的任意一种；
n 1为1～3之间的任意一个整数；
a和b各自独立地为0～2之间的任意一个整数。
在本发明的一个实施方案中，所述n 1为1，2或3中的任意一个整数；所述a和b各自独立地为0，1或2中的任意一个整数。
在本发明的一个实施方案中，所述卤素选自氟、氯、溴和碘。在一个更优选的实施方案，所述卤素选自氟、氯和溴。例如氟或氯。
本发明的一个优选的实施方案中，所述n 1为1或2，优选为1；a、b各自独立地为0、1或2，优选为1。
在本发明的另外一个实施方案中，所述通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐还选自如下所示通式(A-1)所示的化合物、(A-2)所示的化合物或(A-3)所示的化合物中的任意一种：
Figure PCTCN2020135200-appb-000010
其中：
-X-为单键“——”或-(CH 2)n 1-中的任意一种；
R 1和R 2各自独立地选自被卤素、氨基、羟基或氰基任选取代的C 1-3的烷基，或氢中的任意一种；
R 3选自被卤素、羟基、氰基或氨基任选取代的C 6-10的芳基；
R 4和R 5各自独立地选自氢，氨基，被卤素、氨基或羟基任选取代的C 6-15的烷基，或被氨基、羟基、卤素或氰基任选取代的C 1-5的烷基中的任意一种；
n 1为1～3之间的任意一个整数；
a和b各自独立地为0～2之间的任意一个整数。
在本发明一个优选的实施方案中，-X-为单键“——”或-(CH 2)n 1-中的任意一种；R 1和R 2各自独立地选自C 1-3的烷基或氢中的任意一种；R 3选自C 6-10的芳基；R 4和R 5各自独立地选自氢，氨基，C 6-15的烷基，或被氨基任选取代的C 1-5的烷基中的任意一种；n 1为1～3之间的任意一个整数；a和b各自独立地为0～2之间的任意一个整数。
在本发明的一个优选的实施方案中，所述n 1为1或2，优选为1；a、b各自独立地为0、1、2，优选为1。
在本发明一个优选的实施方案中，所述被卤素、氨基、羟基或氰基任选取代的C 1-3的烷基选自C 1-3的烷基，所述C 1-3的烷基选自甲基、乙基或丙基中的任意一种，优选甲基或乙基中的任意一种。
在本发明一个优选的实施方案中，所述被氨基、羟基、卤素或氰基任选取代的C 1-5的烷基选自被氨基任选取代的C 1-5的烷基，所述被氨基任选取代的C 1-5的烷基选自被氨基任选取代的甲基、乙基、丙基、丁基或戊基中的任意一种；优选为被氨基任选取代的甲基、乙基、丙基或丁基中的任意一种；更优选为被氨基任选取代的甲基、乙基或丙基中的任意一种。
在本发明一个更优选的实施方案中，所述丙基选自正丙基(n-Pr、-CH 2CH 2CH 3)或异丙基((i-Pr、-CH(CH 3) 2)。所述丁基选自正丁基(n-Bu、-CH 2CH 2CH 2CH 3)，异丁基(i-Bu、-CH 2CH(CH 3) 2)，仲丁基(s-Bu、-CH(CH 3)CH 2CH 3)或叔丁基(t-Bu、-C(CH 3) 3)。所述戊基选自正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)或2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)。
在本发明一个优选的实施方案中，所述被卤素、氨基或羟基任选取代的C 6-15的烷基选自C 6-15的烷基，所述C 6-15的烷基选自C 6-15的直链烷基，优选C 9-15的直链烷基。
在本发明一个优选的实施方案中，所述被卤素、羟基、氰基或氨基任选取代的C 6-10的芳基选自C 6-10的芳基，所述C 6-10的芳基选自苯基或萘基中的任意一种；更优选为苯基。
在本发明一个优选的实施方案中，所述R 1和R 2各自独立地选自被卤素、氨基、羟基或氰基任选取代的C 1-3的烷基，或氢中的任意一种；优选C 1-3的烷基或氢中的任意一种；更优选氢，甲基或乙基中的任意一种；特别的，优选为氢或甲基。
在本发明一个优选的实施方案中，所述R 3选自被卤素、羟基、氰基或氨基任选取代的C 6-10的芳基，
Figure PCTCN2020135200-appb-000011
中的任意一种；其中，所述被卤素、羟基、氰基或氨基任选取代的C 6-10的芳基优选为C 6-10的芳基，更优选为苯基或萘基，特别的，优选为苯基。
在本发明的一个优选的实施方案中，R 4和R 5各自独立地选自氢，氨基，被卤素、氨基或羟基任选取代的C 6-15的烷基，或被氨基、羟基、卤素或氰基任选取代的C 1-5的烷基中的任意一种；更优选为氢，氨基，C 6-15的烷基，或被氨基任选取代的C 1-5的烷基中的任意一种；特别的，R 4和R 5各自独立地优选为氢，甲基，乙基，正丙基，异丙基，正丁基，-CH 2NH 2，-CH 2CH 2NH 2，-CH 2CH 2CH 2NH 2，-(CH 2) 8CH 3，-(CH 2) 9CH 3，-(CH 2) 12CH 3或-(CH 2) 13CH 3中的任意一种。
在本发明一个更优选的实施方案中，R 4和R 5各自独立地优选为氢，甲基，正丙基，异丙基，-CH 2CH 2NH 2，-(CH 2) 8CH 3，-(CH 2) 9CH 3，-(CH 2) 12CH 3或-(CH 2) 13CH 3中的任意一种。
在本发明的一个优选的实施方案中，所述n 1为1～3之间的任意一个整数；优选为1，2或3中的任意一个整数，更优选为1。
在本发明的一个优选的实施方案中，所述a和b各自独立地为0～2之间的任意一个整数，优选为0，1或2中的任意一个整数，更优选为1。
在本发明中，仅表述为“C 1-3的烷基”、“C 6-15的烷基”、“C 6-15的直链烷基”和“C 6-10的芳基”等是非取代的或未被取代的。
本发明优选的另外一个实施方案中，提供一种式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐，
Figure PCTCN2020135200-appb-000012
其中：
-X-为单键“——”或-(CH 2)n 1-中的任意一种，n 1为1；
R 1和R 2各自独立地选自氢，甲基或乙基中的任意一种；
R 3选自苯基，
Figure PCTCN2020135200-appb-000013
中的任意一种；
R 4和R 5各自独立地选自氢，甲基，乙基，正丙基，异丙基，正丁基，-CH 2NH 2，-CH 2CH 2NH 2，-CH 2CH 2CH 2NH 2，-(CH 2) 8CH 3，-(CH 2) 9CH 3，-(CH 2) 12CH 3或-(CH 2) 13CH 3中的任意一种；
a为1，和b为1。
在本发明一个优选的实施方案中，所述-X-为单键“——”或-(CH 2)n 1-中的任意一种，n 1为1；R 1和R 2各自独立地选自氢或甲基中的任意一种；R 3选自苯基，
Figure PCTCN2020135200-appb-000014
中的任意一种；R 4和R 5各自独立地选自氢，甲基，正丙基，异丙基，-CH 2CH 2NH 2，-(CH 2) 8CH 3，-(CH 2) 9CH 3，-(CH 2) 12CH 3，或-(CH 2) 13CH 3中的任意一种；a为1，和b为1。
本发明优选的其他实施方案中，所述通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐的示例化合物如下所示：
表1通式(A)所示的化合物的示例化合物
Figure PCTCN2020135200-appb-000015
Figure PCTCN2020135200-appb-000016
Figure PCTCN2020135200-appb-000017
本发明优选的其他实施方案中，所述通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐优选如下所示化合物：
Figure PCTCN2020135200-appb-000018
本发明化合物的药学上可接受的盐中，所述药学上可接受的盐可选自盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、乙酸盐、乳酸盐、柠檬酸盐、酒石酸盐、马来酸盐、富马酸盐、甲磺酸盐、三氟乙酸盐、葡糖酸盐、糖二酸盐、苯甲酸盐、乙磺酸盐、苯磺酸盐或对甲苯磺酸盐。优选氢溴酸盐或三氟乙酸盐。
在本发明一个优选的实施方案中，所述药学上可接受的盐优选三氟乙酸盐。
在本发明一个优选的实施方案中，化合物EP-0015-014和E-P0015-015的药学上可接受的盐优选三氟乙酸盐，更优选单三氟乙酸盐。
在本发明的实施方案中，所述药学上可接受的盐为化合物、其立体异构体或其互变异构体与其对应的酸或碱制备得到。
制备通式(A)化合物的方法
通式(A)所示的化合物的制备
本发明进一步提供通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐的制备方法，包括：
Figure PCTCN2020135200-appb-000019
通式(III)的化合物与商业可得的通式(IV)的化合物取代反应得到通式(A)的化合物。
在本发明一个优选的实施方案中，将通式(III)的化合物与通式(IV)的化合物在无机碱及有机溶剂条件下制备得到通式(A)的化合物。如在氮气保护下，在合适溶剂中，如DMF中加入通式(III)的化合物、无机碱如碳酸铯或者碳酸钾，在40℃条件下反应0.5-3小时得到通式(A)的化合物。
在本发明优选的其他实施方案中，通式(IV)的化合物在包含氨基(例如-NH 2)的情况下，可先与氨基保护试剂反应，将通式(IV)的化合物所包含的氨基进行保护，然后与通式(III)的化合物反应，再脱去保护基，制备得到通式(A)的化合物。所述氨基保护试剂包括但不限于二碳酸二叔丁酯(Boc 2O)。
通式(III)所示化合物的制备
本发明进一步提供通式(III)的化合物的制备方法，包括：
Figure PCTCN2020135200-appb-000020
通式(I)的化合物与商业可得的通式(II)的化合物反应制备得到通式(III)的化合物。
本发明优选的实施方案中，将通式(I)的化合物溶解于合适的有机溶剂中，三乙胺和通式(I)的化合物反应，制备得到通式(III)的化合物。例如在二氯甲烷(DCM)中，加入通式(I)的化合物、三乙胺和通式(II)的化合物，室温反应1-3小时得到通式(III)的化合物。
在本发明上述制备方法实施方案中，
其中：
-X-为单键“——”或-(CH 2)n 1-中的任意一种；
R 1和R 2各自独立地选自被卤素、氨基、羟基或氰基任选取代的C 1-3的烷基，或氢中的 任意一种；
R 3选自被卤素、羟基、氰基或氨基任选取代的C 6-10的芳基，
Figure PCTCN2020135200-appb-000021
中的任意一种；
R 4和R 5各自独立地选自氢，氨基，被卤素、氨基或羟基任选取代的C 6-15的烷基，或被氨基、羟基、卤素或氰基任选取代的C 1-5的烷基中的任意一种；
n 1为1～3之间的任意一个整数；
a和b各自独立地为0～2之间的任意一个整数。
药物组合物和药物制剂
本发明进一步提供包含治疗有效量的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐和药学上可接受的载体的药物组合物。
本发明优选的实施方案中，药物组合物可以利用一种或多种可药用的载体按照常规的方式加以配制。因此，本发明的活性化合物可以被配制成口服、口腔含化给药、鼻内、肠胃外(例如静脉内、肌内或皮下)或直肠给药的剂型，或者适用于通过吸入或吹入给药的剂型。本发明的化合物也可以被配制成持续释放的剂型。
本发明优选的实施方案中，有效剂量的本发明化合物可与如惰性稀释剂或某种载体一起口服。根据本发明的一些实施例，可将本发明的化合物包裹于明胶胶囊中或压制成片。为口服治疗的目的，本发明化合物可与赋形剂一起使用并以片剂、锭剂、胶囊、混悬剂、糖浆剂等形式使用。根据本发明的实施例，上述制剂应含有至少0.5％(w/w)的本发明的活性化合物，但可根据特定的剂型变化，其中占单位重量的4％至约70％是便利的。在这样的药物组合物中活性化合物的量应达到适当的剂量。
本发明优选的实施方案中，关于口服给药，本发明的活性化合物例如可通过常规手段与可药用的赋形剂加以配制成片剂或胶囊，赋形剂例如粘合剂，填充剂，润滑剂，崩解剂或润湿剂。片剂可以通过本领域熟知的方法加以包衣。用于口服给药的液体制剂，如可以采用溶液、糖浆或悬液，或挥发为干燥产物，使用前用水或其他合适的载体再生。这类液体制剂可利用药用的添加剂通过常规手段加以制备，添加剂例如悬浮剂，乳化剂，非水性载体和防腐剂。
本发明优选的实施方案中，当本发明的活性化合物或其立体异构体、互变异构体或其药学上可接受的盐用于胃肠外施用时，可将本发明提供的化合物与无菌水或有机介质组合形成可注射的溶液或悬液。
本发明优选的实施方案中，本发明的活性化合物或其立体异构体、互变异构体或其药学上可接受的盐可以被配制成直肠组合物，例如栓剂或保留灌肠剂，例如含有常规的栓剂基质，例如可可脂或其他甘油酯。
治疗用途和方法
在还一方面，本发明提供本发明的化合物、其立体异构体、其互变异构体或其药学上可接受的盐或本发明的药物组合物在制备治疗神经精神类疾病的药物中的用途。
在另一方面，本发明还提供一种治疗神经精神类疾病的方法，其包括向有此需要的个体(例如哺乳动物个体，如人)给药本发明的化合物、其立体异构体、其互变异构体或其药学上可接受的盐或本发明的药物组合物。
在一个实施方案中，所述神经精神类疾病选自精神分裂症、抑郁症、焦虑症、睡眠障碍、神经退行性疾病、认知障碍、双相情感障碍、创伤后应激综合征、成瘾性疾病、戒断综合征或注意力缺陷中的任意一种或多种，优选抑郁症、认知障碍、焦虑症、精神分裂症、睡眠障碍、神经退行性疾病或双相情感障碍中的任意一种或多种；更优选抑郁症或认知障碍。在一个优选的实施方案中，所述神经精神类疾病为抑郁症。
本发明还提供一种通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐在制备治疗抑郁症的药物中的用途，其中所述药物任选包含另外一种或多种调节哺乳动物神经系统或缓解抑郁症的活性剂。
在本发明一个优选的实施方案中，本发明还提供一种通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐在制备治疗抑郁症的药物中的用途。
本发明优选的实施方案中，所述的抑郁包括但不限于轻至重度抑郁，符合WHO ICD-10(《国际疾病分类》)、美国DSM-5(《精神障碍诊断与统计手册》)和CCMD-3(《中国精神疾病分类和诊断标准》)的相关诊断标准，优选中至重度抑郁。
本发明优选的实施方案中，所述的抑郁症选自轻度抑郁症、中度抑郁症、重度抑郁症、伴有其他精神障碍的抑郁症以及复发性抑郁症；在更优选的实施方案中，所述抑郁症选自中度抑郁症、重度抑郁症、伴随其他精神障碍的抑郁症以及复发性抑郁症。
在本发明的一个实施方案中，所述抑郁症可共病至少一种精神障碍。
在本发明的一个优选的实施方案中，所述精神障碍选自睡眠障碍、认知障碍、焦虑症、强迫症、情感障碍或人格障碍的一种或多种，优选认知障碍、焦虑症或睡眠障碍，更优选认知障碍。
在本发明一个优选的实施方案中，所述抑郁症包括共病其他精神障碍，包括但不限于抑郁症共病认知障碍、抑郁症共病睡眠障碍、抑郁症共病焦虑症、抑郁症共病情感障 碍、抑郁症共病社交障碍或抑郁症共病人格障碍等，优选抑郁症共病认知障碍、抑郁症共病焦虑症或抑郁症共病睡眠障碍；更优选抑郁症共病认知障碍。
在本发明的实施方案中，所述共病其他精神障碍也指伴随其他精神障碍。
本发明优选的其他实施方案中，所述通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐或包含通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐的药物组合物在制备治疗抑郁症或抑郁症伴随其他精神障碍的药物中的用途，所述抑郁症伴随其他精神障碍优选抑郁症伴随认知障碍。
实施方案
本发明提供一种通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐，
Figure PCTCN2020135200-appb-000022
其特征在于，
-X-为单键“—”或-(CH 2)n 1-中的任意一种；
R 1和R 2各自独立地选自C 1-3的烷基或氢中的任意一种；
R 3为
Figure PCTCN2020135200-appb-000023
R 4和R 5各自独立地选自氢，氨基，未被取代的C 6-15的烷基，被氨基取代或未被取代的C 1-5的烷基，C 3-7的环烷基，C 6-10的芳基或不存在中的任意一种；
键“---”为单键“—”或不存在中的任意一种；
n 1为1～3之间的任意一个整数。
在本发明进一步优选的实施方案中，所述n 1为1或2，优选n 1为1。
在本发明一个优选的实施方案中，所述的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐，其中：
-X-为单键“—”或-(CH 2)n 1-中的任意一种；
R 1和R 2各自独立地选自C 1-3的烷基或氢中的任意一种；
R 3选自C 6-10的芳基，
Figure PCTCN2020135200-appb-000024
中的任意一种；
R 4和R 5各自独立地选自氢，氨基，未被取代的C 6-15的烷基，被氨基取代或未被取代的C 1-5的烷基中的任意一种；
n 1为1～3之间的任意一个整数；
a和b各自独立地为0～2之间的任意一个整数。
在本发明进一步优选的实施方案中，所述n1为1或2，优选n1为1；a和b各自独立地为0、1或2，优选1。
本发明优选的另外一个实施例方案中，提供一种式(A-1)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐，
Figure PCTCN2020135200-appb-000025
其中：
-X-为单键“——”或-(CH 2)n 1-中的任意一种；
R 1和R 2各自独立地选自C 1-3的烷基或氢中的任意一种；
R 4和R 5各自独立地选自氢，氨基，未被取代的C 6-15的烷基，被氨基取代或未被取代的C 1-5的烷基，C 3-7的环烷基，C 6-10的芳基或不存在中的任意一种；
键“---”为单键“——”或不存在中的任意一种；
n 1为1～3之间的任意一个整数。
本发明进一步优选的实施例方案中，所述n 1为1或2，优选n 1为1。
本发明进一步优选的实施例方案中，所述C 1-3的烷基选自甲基、乙基或丙基，优选甲基、乙基，更优选甲基。
本发明进一步优选的实施例方案中，所述被氨基取代或未被取代的C 1-5的烷基为被氨基取代或未被取代的甲基、乙基、丙基、丁基或戊基。
本发明进一步优选的实施例方案中，所述被氨基取代的C 1-5的烷基优选被氨基取代的甲基、乙基或丙基，包括但不限于如-CH 2-NH 2，-(CH 2) 2-NH 2，-(CH 2) 3-NH 2。
本发明进一步优选的实施例方案中，所述未被取代的C 1-5的烷基优选甲基、乙基、丙基或丁基。
本发明进一步优选的实施例方案中，所述未被取代的C 6-15的烷基优选C 6-15的直链烷基，进一步优选C 9-15的直链烷基。
本发明进一步优选的实施例方案中，所述C3-7的环烷基选自未被取代的五元环烷基或六元环烷基；所述C 6-10的芳基优选未被取代的苯基或萘基，更优选未被取代的苯基。
本发明优选的实施例方案中，在所述的通式(A)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐中，-X-为单键“——”或-(CH 2)n 1-中的任意一种；所述C 1-3的烷基选自甲基或乙基中的任意一种；所述被氨基取代或未被取代的C 1-5的烷基选自被氨基取代或未被取代的甲基、乙基、丙基或丁基中的任意一种；未被取代的C 6-15的烷基选自C 6- 15的直链烷基；所述C 3-7的环烷基选自未被取代的五元环烷基或六元环烷基中的任意一种；所述C 6-10的芳基选自未被取代的苯基或萘基中的任意一种；且当R 4和R 5各自独立地为C 3- 7的环烷基或C 6-10的芳基中的任意一种时，键“---”为不存在。
本发明另外一个优选的实施例方案中，在所述的通式(A)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐中，-X-为单键“——”或-(CH 2)n 1-中的任意一种；R 1和R 2各自独立地选自氢，甲基或乙基中的任意一种；R 4和R 5各自独立地选自氢，甲基，乙基，丙基，丁基，-CH 2NH 2，-CH 2CH 2NH 2，环己烷，苯基，-(CH 2) 9CH 3，-(CH 2) 13CH 3或不存在中的任意一种；且当R 3和R 4各自独立地为C3-7的环烷基或C 6-10的芳基中的任意一种时，键“---”为不存在；n 1为1或2。
在本发明一个优选的实施方案中，所述C 1-3的烷基选自甲基或乙基中的任意一种；所述被氨基取代或未被取代的C 1-5的烷基选自被氨基取代或未被取代的甲基、乙基、丙基或丁基中的任意一种；未被取代的C 6-15的烷基选自C 6-15的直链烷基；所述C 3-7的环烷基选自未被取代的五元环烷基或六元环烷基中的任意一种；所述C 6-10的芳基选自未被取代的苯基或萘基中的任意一种；且当R 4和R 5各自独立地为C 3-7的环烷基或C 6-10的芳基中的任意一种时，键“---”为不存在。
在本发明一个优选的实施方案中，所述R 1和R 2各自独立地选自氢，甲基或乙基中的任意一种；所述R 4和R 5各自独立地选自氢，甲基，乙基，丙基，丁基，-CH 2NH 2，-CH 2CH 2NH 2，环己烷，苯基，-(CH 2) 9CH 3，-(CH 2) 13CH 3或不存在中的任意一种；且当R 3和R 4各自独立地为C 3-7的环烷基或C 6-10的芳基中的任意一种时，键“---”为不存在；n 1为1或2。
在本发明一个优选的实施方案中，所述通式(A)所示的化合物选自如下所示化合物的任意一个：
Figure PCTCN2020135200-appb-000026
Figure PCTCN2020135200-appb-000027
优选
Figure PCTCN2020135200-appb-000028
在本发明一个优选的实施方案中，所述药学上可接受的盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、乙酸盐、乳酸盐、柠檬酸盐、酒石酸盐、马来酸盐、富马酸盐、甲磺酸盐、三氟乙酸盐、葡糖酸盐、糖二酸盐、苯甲酸盐、乙磺酸盐、苯磺酸盐或对甲苯磺酸盐，优选三氟乙酸盐。
本发明提供一种制备通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐的方法，包括：
Figure PCTCN2020135200-appb-000029
通式(III)的化合物与通式(IV)的化合物通过取代反应得到通式(A)的化合物；
其中：
-X-，R 1，R 2，R 3和键“---”各自独立地如上述所定义。
本发明提供一种如下所示通式(III)的化合物的制备方法，包括：
Figure PCTCN2020135200-appb-000030
通式(I)的化合物与通式(II)的化合物反应制备得到通式(III)的化合物；
其中：
R 1和R 2各自独立地如上述所定义。
本发明提供一种药物组合物，包含治疗有效量的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐和药学上可接受的载体。
本发明提供一种通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐或其药物组合物在制备治疗抑郁或抑郁伴随其他精神障碍的药物中的用途，所述抑郁伴随其他精神障碍优选抑郁伴随认知障碍。
本发明有益的技术效果
本发明提供一种新的沃替西汀的前药，一般而言，中枢神经系统药物真正起效的为入脑的游离药物，而已知的沃替西汀与外周组织结合较多。在本发明的测试例中，在食蟹猴中，直接以原型药沃替西汀给药，基本未检测到脑中游离沃替西汀的药物浓度，而给予沃替西汀前药，可明显提高食蟹猴脑中的游离的沃替西汀的药物浓度，具有潜在的提高药效的优点。此外，本发明所述的沃替西汀前药化合物的脑血比例明显提高，降低外周的暴露量，具有潜在的改善沃替西汀胃肠道副作用的效果，具有显著的脑靶向给药效果；同时，前药化合物具有良好的药代动力学性质，包括药物在体内的释放曲线与沃替西汀相比更为平缓，脑中暴露量(AUC 0-last)更高，降低沃替西汀在血浆中的暴露量，相对生物利用度提高，改善沃替西汀的摄取等优势，具有潜在的提高药效的效果。
附图说明
图1沃替西汀及沃替西汀前药化合物在大鼠中AUC比值(脑血比，B/P)。
图2沃替西汀及沃替西汀前药化合物在大鼠中总AUC暴露量比较。
图3沃替西汀及沃替西汀前药化合物在大鼠中的相对生物利用度比较。
图4沃替西汀及沃替西汀前药在大鼠中的血浆中的药-时曲线。
图5沃替西汀及沃替西汀前药在大鼠中的脑组织中的药-时曲线。
图6沃替西汀及沃替西汀前药在食蟹猴中总AUC暴露量。
具体实施方式
下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。除非另外指明，本文所指的比例、百分比等均以重量计。
合成实施例
实施例1、1-(异丁酰氧基)乙基4-(2-((2,4-二甲基苯基)硫代)苯基)哌嗪-1-羧酸(化合物EP-0015-003)
Figure PCTCN2020135200-appb-000031
(1)在50mL单口瓶中，加入0.5g沃替西汀(1.68mmol)和5mL二氯甲烷，再依次加入510mg三乙胺(5.04mmol)和360mg 1-氯乙基氯甲酸酯(2.52mmol)，室温下搅拌反应2小时。反应结束后，加入10mL水和15mL二氯甲烷萃取得有机相，有机相减压浓缩得粗产品，经过柱层析分离(石油醚：乙酸乙酯＝10:1，v/v)得黄色油状物EP0015-003-A 550mg，收率81.1％,
1H NMR(400MHz,CDCl 3)δ7.36(d,J＝7.6Hz,1H),7.15(s,1H),7.10–7.00(m,3H),6.91-6.87(m,1H),6.65–6.60(m,1H),6.53(d,J＝8.0Hz,1H),3.75–3.66(m,4H),3.08–3.03(m,4H),2.36(s,3H),2.31(s,3H),1.84(d,J＝8.0Hz,3H)；LCMS
[M+H] +405.0。
(2)在50mL单口瓶中，加入150mg EP0015-003-A(0.37mmol)、39mg异丁酸(0.44mmol)、362mg碳酸铯(1.11mmol)和3mL N,N-二甲基甲酰胺，40℃下加热搅拌反应2小时。反应结束后，加入10mL水和15mL乙酸乙酯萃取得有机相，有机相减压浓缩得粗产品，经过预制备板分离(石油醚：乙酸乙酯＝5:1，v/v)得黄色油状物90mg，收率53.2％，纯度99％。
1H NMR(400MHz,CDCl 3)δ7.36(d,J＝7.8Hz,1H),7.19–7.13(m,1H),7.11–6.99(m,3H),6.91–6.79(m,2H),6.52(m,1H),3.67(m,4H),3.03(m,4H),2.63–2.49(m,1H),2.36(s,3H),2.31(s,3H),1.51(d,J＝5.4Hz,3H),1.18(m,6H)；LCMS
[M+H] +457.1.0
实施例2、1-(异丁酰氧基氧代)-2-甲基丙基4-(2-((2,4-二甲基苯基)硫代)苯基)哌嗪-1-羧酸(化合物EP-0015-004)
Figure PCTCN2020135200-appb-000032
(1)在50ml单口瓶中，加入200mg沃替西汀(0.671mmol)，三乙胺(0.805mmol)和乙腈(2mL)，降温至0℃，1-氯-2-甲基丙基氯甲酸酯(137mg，0.805mmol)溶于乙腈(2mL)滴加至上述溶液。搅拌反应2h，TLC监测，原料反应完毕。将反应液倒入25mL水中，并用20ml EA(乙酸乙酯)萃取两遍。有机层用Na 2SO 4干燥后浓缩得粗品。用洗脱剂(石油醚：乙酸乙酯＝5:1，v/v)柱层析分离得白色固体225mg EP0015-004–A，78％收率。LCMS[M+H]+433.1
(2)取第一步产物EP0015-004–A 200mg(0.461mmol)，碳酸铯750mg(2.3mmol)和异丁酸81mg(0.922mmol)溶于DMF(5mL)，升温至40℃搅拌反应3h，TLC监测原料基本反应完毕。降温至室温后，加入30mL水后用25ml乙酸乙酯萃取两遍，有机层用Na 2SO 4干燥后浓缩得粗品。用洗脱剂(石油醚：乙酸乙酯＝2:1，v/v)柱层析分离得白色固体80mg，37％收率。HPLC纯度：99％。
1H NMR(400MHz,CDCl 3):δ7.36(d,J＝8.0Hz,1H),7.15(s,1H),7.10-7.00(m,3H),6.90-6.86(m,1H),6.65(d,J＝8.0Hz,1H),6.53-6.51(m,1H),3.67(s,4H),3.03(s,4H),2.62-2.55(m,1H),2.36(s,3H),2.31(s,3H),2.11-2.03(m,1H),1.21-1.16(m,6H),1.01-0.99(m,6H)；LCMS[M+H] +485.1
实施例3、1-(苯甲酰氧基)乙基4-(2-((2,4-二甲基苯基)硫代)苯基)哌嗪-1-羧酸(化合物EP-0015-006)
Figure PCTCN2020135200-appb-000033
取中间体EP0015-003-A 150mg(0.371mmol)，碳酸铯600mg(1.85mmol)和苯甲酸68mg(0.562mmol)溶于DMF(3mL)，升温至45℃搅拌反应3h，TLC监测原料基本反应完毕。反应液加入30mL水后用25mL乙酸乙酯萃取两遍，有机层用Na 2SO 4干燥后浓缩得粗品。用洗脱剂(石油醚：乙酸乙酯＝2:1，v/v)柱层析分离得白色固体40mg，22％收率。HPLC纯度：99％。
1H NMR(400MHz,CDCl 3):8.09-8.06(m,2H),7.60-7.56(m,1H),7.47-7.43(m,2H),7.36(d,J＝8.0Hz,2H),7.16-7.00(m,5H),6.90-6.86(m,1H),6.53-6.51(m,1H),3.69(s,4H),3.04(s,4H),2.36(s,3H),2.3(s,3H),1.65(d,J＝4.0Hz,3H)；LCMS[M+H] +491.1.
实施例4、1-(十二烷酰氧基)乙基4-(2-((2,4-二甲基苯基)硫代)苯基)哌嗪-1-羧酸(化合物EP-0015-010)
Figure PCTCN2020135200-appb-000034
取中间体EP0015-003-A 150mg(0.371mmol)，碳酸铯600mg(1.85mmol)和月桂酸111mg(0.557mmol)溶于DMF(5ml)，室温搅拌反应3h，TLC监测原料基本反应完毕。反应液加入30mL水后用25mL乙酸乙酯萃取两遍，有机层用Na 2SO 4干燥后浓缩得粗品。用洗脱剂(石油醚：乙酸乙酯＝2:1,v/v)柱层析分离得白色固体45mg，22％收率，HPLC纯度:97％。
1HNMR(400MHz,CDCl 3)δ7.36(d,J＝8.0Hz,1H),7.15(s,1H),7.10-7.00(m,3H),6.90-6.86(m,1H),6.53-6.51(m,1H),3.67(s,4H),3.03(s,4H),2.62-2.55(m,1H),2.36(s,3H),2.31(s,3H),2.36-2.28(m,8H),1.67-1.61(m,2H),1.51(d,J＝8.0Hz,3H),1.34-1.20(m,16H),0.09-0.85(m,3H),[M+H] +569.2.
实施例5、1-(十六烷酰氧基)乙基4-(2-((2,4-二甲基苯基)硫代)苯基)哌嗪-1-羧酸(化合物EP-0015-011)
Figure PCTCN2020135200-appb-000035
在50mL单口瓶中，加入200mg中间体EP0015-003-A(0.49mmol)、151mg棕榈酸(0.59mmol)、479mg碳酸铯(1.47mmol)和4mL N,N-二甲基甲酰胺，40℃下搅拌反应2小时。反应结束后，加入10mL水和15mL乙酸乙酯萃取得有机相，有机相减压浓缩得粗产品，经过预制备板分离(石油醚：乙酸乙酯＝20:1,v/v)得黄色油状物160mg，收率51.8％，纯度97％。
1H NMR(400MHz,CDCl 3)δ7.36(d,J＝7.8Hz,1H),7.15(s,1H),7.11–6.99(m,3H),6.92–6.84(m,2H),6.52(m,1H),3.67(m,4H),3.03(m,4H),2.49–2.20(m,8H),1.62(q,J＝7.2Hz,2H),1.51(d,J＝5.6Hz,3H),1.24(m,24H),0.90–0.84(m,3H)；LCMS[M+H] +569.2.
实施例6、1-((2-丙基戊酰基)氧基)乙基4-(2-((2,4-二甲基苯基)硫代)苯基)哌嗪-1-羧酸(化合物EP-0015-013)
Figure PCTCN2020135200-appb-000036
在50mL单口瓶中，加入150mg中间体EP0015-003-A(0.37mmol)、81mg丙戊酸(0.56mmol)、362mg碳酸铯(1.11mmol)和3mL N,N-二甲基甲酰胺，40℃下搅拌反应2小时。反应结束后，加入10mL水和15mL乙酸乙酯萃取得有机相，有机相减压浓缩得粗产品，经过预制备板分离(石油醚：乙酸乙酯＝10:1，v/v)得无色油状物100mg，收率52.7％，纯度99％。
1H NMR(400MHz,CDCl 3)δ7.36(d,J＝7.8Hz,1H),7.15(s,1H),7.05(m,3H),6.94–6.85(m,2H),6.53(m,1H),3.65(m,4H),3.02(m,4H),2.42–2.28(m,7H),1.66–1.58(m,2H),1.51(d,J＝5.6Hz,3H),1.47–1.39(m,2H),1.32(m,4H),0.90(t,J＝7.2Hz,6H)；LCMS[M+H] +513.2.
实施例7、1-(2-(1-(氨基甲基)环己基)乙酰氧基)乙基4-(2-((2,4-二甲基苯基)硫代)苯基)哌嗪-1-羧酸三氟乙酸盐(化合物EP-0015-014三氟乙酸盐)
Figure PCTCN2020135200-appb-000037
(1)在50mL单口瓶中，加入180mg中间体EP0015-003-A(0.44mmol)、179mg 2-(1-(((叔丁氧基羰基)氨基)甲基)环己基)乙酸(0.66mmol)、430mg碳酸铯(1.32mmol)和3mLN,N-二甲基甲酰胺，40℃下搅拌反应0.5小时。反应结束后加入10mL水和15mL二氯甲烷萃取得有机相，有机相减压浓缩得粗产品，粗产品经过预制备板分离(石油醚：乙酸乙酯＝10:1，v/v)得150mg无色油状物，收率52.7％,LCMS[M+H-56] +584.2.
(2)在50mL单口瓶中，加入150mg第三步产物、1.5mL三氟乙酸和1.5mL二氯甲烷，室温下搅拌反应0.5小时。反应结束后，反应液减压浓缩得170mg无色油状物，纯度98％。
1H NMR(400MHz,Chloroform-d)δ7.51(m,3H),7.31(d,J＝7.8Hz,1H),7.19–7.09(m,3H),7.03(d,J＝7.7Hz,1H),6.97(m,1H),6.83(m,1H),6.66–6.59(m,1H),3.73(m,4H),3.19(m,4H),2.58(s,2H),2.36(s,3H),2.31(s,3H),1.61–1.38(m,15H)；LCMS[M+H] +540.2.
实施例8、1-((3-(氨基甲基)-5-甲基己酰基)氧代)乙基4-(2-((2,4-二甲基苯基)硫代)苯基)哌嗪-1-羧酸三氟乙酸盐(化合物EP-0015-015三氟乙酸盐)
Figure PCTCN2020135200-appb-000038
(1)在50mL单口瓶中，加入150mg中间体EP0015-003-A(0.37mmol)、145mg3-(((叔丁氧基羰基)氨基)甲基)-5-甲基己酸(0.56mmol)、362mg碳酸铯(1.11mmol)和3mL N,N-二甲基甲酰胺，40℃下搅拌反应0.5小时。反应结束后加入10mL水和15mL二氯甲烷萃取得有机相，有机相减压浓缩得粗产品，粗产品经过预制备板分离(石油醚：乙酸乙酯＝3:1，v/v)得180mg无色油状物，收率77.4％,LCMS[M+H-56] +572.2.
(2)在50mL单口瓶中，加入110mg EP0015-015-A、1mL三氟乙酸和1mL二氯甲烷，室温下搅拌反应0.5小时。反应结束后，反应液减压浓缩得110mg无色油状物，纯度97％。
1H NMR(400MHz,DMSO-d 6)δ7.76(m,3H),7.33(d,J＝8.0Hz,1H),7.24(m,1H),7.15–7.06(m,3H),6.94(m,1H),6.73(m,1H),6.44–6.37(m,1H),3.53(m,4H),2.97(m,4H),2.78(m,2H),2.61–2.51(m,1H),2.33(s,3H),2.24(s,3H),2.12(m,1H),1.61(m,1H), 1.46(d,J＝5.6Hz,3H),1.24–1.04(m,3H),0.88–0.82(m,6H),LCMS[M+H] +528.2.
测试实施例
测试药物
EP-X参照专利PCT/CN2017/088493实施例6所述方法制备，其结构如下所示：
Figure PCTCN2020135200-appb-000039
其他各本发明所述测试化合物按照上述实施例1-8所述方法进行制备。
测试例1、受试前药分子的微粒体代谢稳定性和血浆稳定性测试
测试例1-1、微粒体代谢稳定性测试
实验系统
(1)、使用DMSO作为稀释剂，以10mM的浓度制备待测试化合物和阳性对照的原液，然后将所有储备溶液用70％乙腈稀释至0.25mM的工作浓度；
(2)、测试中使用的辅因子是NADPH再生系统，它由6.5mM NADP，16.5mM G-6-P，3U/mL G-6-P D组成；
(3)、淬灭剂由含有甲苯磺丁酰胺和丙醇(用作内标)的乙腈组成；
(4)、测试中使用的缓冲液为100mM磷酸盐缓冲液，含3.3mM MgCl 2；
(5)、混合物含有0.2mg/mL肝微粒体蛋白和1μM测试化合物/阳性对照，在100mM磷酸钾缓冲液中进行孵育。
实验方法
(1)、通过将各孵育混合物的80μL等分试样加入300μL淬灭试剂中以沉淀蛋白质来制备0分钟样品。将样品涡旋，然后加入20μL NADPH再生系统的等分试样。
(2)、通过将130μL的NADPH再生系统添加到520μL的各孵育混合物中开始启动反应。在650μL中达到的最终温育条件为：0.2mg/mL微粒体蛋白，1μM受检物/阳性对照，1.3mM NADP，3.3mM 6-磷酸葡萄糖，0.6U/mL 6-磷酸葡萄糖脱氢酶。
(3)、将混合物在37℃水浴中轻轻摇动孵育。在5、10、30、60分钟将各混合物的100μL等分试样移至干净的96孔板中，该板中装有300μL淬灭剂以沉淀蛋白质，然后离心(5000×g，10分钟)。
(4)将100μL上清液放入预先加入300μL超纯水的96孔测定板中，然后通过LC-MS/MS进行分析。
结果
表1测试化合物在微粒体中的代谢稳定性数据
Figure PCTCN2020135200-appb-000040
结论
通过上述表1所示结果可知，本发明所述化合物在微粒体代谢过程中具有较长的半衰期，清除率相对较低，提示本发明化合物具有良好的微粒体代谢稳定性，可在体内维持较长时间的有效血药浓度，明显优于EP-X。
测试例1-2、血浆稳定性测试
实验系统
(1)、使用DMSO作为稀释剂，以10mM的浓度制备测试化合物和阳性对照的原液。然后将阳性对照的储备溶液用50％乙腈稀释至0.2mM的工作浓度，然后将测试化合物的储备溶液用50％乙腈稀释至1mM的工作浓度。
(2)、淬灭剂由含有甲苯磺丁酰胺和普萘洛尔的乙腈(用作内标)组成。
实验方法
(1)、将阳性对照和测试物品工作溶液(一式两份)加到血浆中，分别浓缩至1μM和5μM。
(2)、通过将80μL各孵育混合物的等分试样添加到320μL淬灭试剂中以沉淀蛋白质来制备0分钟样品。
(3)、将混合物置于37℃水浴中温和摇动孵育。在30、60、120、240分钟将各混合物的80μL等分试样移至干净的96孔板中，该板中装有320μL淬灭剂以沉淀蛋白质，然后离心(4000×g，15分钟)。
(4)、将80μL上清液放入预先加入的160μL超纯水的96孔测定板中，然后通过LC-MS/MS进行分析。
结果
表2测试化合物在血浆中的代谢稳定性数据
Figure PCTCN2020135200-appb-000041
结论
通过上述表2所示结果可知，本发明所述化合物具有较长的血浆半衰期，提示本发明化合物可在体内维持较长时间的有效血药浓度，明显优于EP-X。
测试例1-3、受试药物的大鼠体内代谢特性
目的：采用LC-MS-MS方法，考察本发明的沃替西汀前药化合物与EP-X在大鼠体内的药动学特征比较。
色谱条件：色谱柱为WELCH Xtimate-C18柱(50×2.1mm，3.5mm)；流动相：A：水溶液(0.1％甲酸)；B：乙腈(0.1％甲酸)；梯度洗脱(0.10-0.80min，10％B-95％B；0.80-1.80min，95％B-95％B；1.80-1.81min，95％B-10％B；1.81-3.00min，10％B-10％B；)；流速：350μL·min-1；柱温：30℃。
质谱条件：采用电喷雾离子源(ESI)，正离子扫描多反应监测模式(MRM)。离子源温度：500℃；离子喷射电压：5000V；雾化器(GS1)：50psi；辅助气(GS2)：35psi；碰撞气(CAD)：High；气帘气(CUR)：25psi。用于定量分析的离子对分别为m/z299.3→109.2(沃替西汀)，455.3→165.1(内标维拉帕米)。
血浆样品的处理：取血浆样品20μL，置于2.0mL离心管中，加入200μL沉淀剂溶液(乙腈溶液，含有60.0ng·mL -1的地塞米松、5.0ng·mL -1的维拉帕米、30.0ng·mL -1的丁螺环酮溶液)，涡旋3min，离心(12,000rpm)3min，取75μL上清液转移到96孔板，再加入75μL水溶液，充分混匀后取10μL进行LC-MS/MS分析。
脑组织样品的处理：取脑组织样品50μL，置于2.0mL离心管中，加入500μL沉淀剂溶液(乙腈溶液，含有60.0ng·mL -1的地塞米松、5.0ng·mL -1的维拉帕米、30.0ng·mL -1的丁螺环酮溶液)，涡旋3min，离心(12,000rpm)3min，取75μL上清液转移到96孔板，再加入75μL水溶液，充分混匀后取10μL进行LC-MS/MS分析。
试供品配制：
将阳性对照和测试化合物组根据前药的分子量和化合物纯度计算为等剂量沃替西汀的给药量，使用喷雾干燥工艺处理样品，然后用纯水作为溶媒，加入适量体积溶媒，充分溶解并混匀制备得到沃替西汀前药各组给药溶液。
配制供试品时，按设计浓度和所需体积计算理论称样量，沃替西汀前药各组根据分子量和化合物纯度计算为等剂量沃替西汀的给药量。将配制好的药液贴好标签备用。如供试品溶解不好，或混悬不均匀，可进行适当的涡旋或超声。
试验设计：
每个化合物取健康雄性大鼠18只，每个时间点3只动物，共6个时间点(0.5、1、2、4、6、10h)，按照10mg/kg同等剂量沃替西汀的给药剂量，各组同时进行单次的灌胃给药。在给药后的指定时间点收集血浆、全脑组织样品。然后运用API-4000QTRAP LC-MS-MS测定样品中化合物浓度(沃替西汀前药和沃替西汀)。用WinNonLin软件计算相关的PK参数，药代动力学参数报告如下：AUC (0-t)、AUC (0-∞)、MRT (0-t)、C max、T max、T 1/2。
脑血比(B/P)＝AUC 0-last(脑组织)/AUC 0-last(血浆)
阳性对照和测试化合物组在大鼠脑组织和血浆中检测到的沃替西汀的药代动力学参数结果见表3，在大鼠脑组织和血浆中检测到的前药的药代动力学参数结果见表4。
结果
表3测试化合物在大鼠体内的沃替西汀的药代动力学参数
Figure PCTCN2020135200-appb-000042
表4测试化合物在大鼠体内的前药的药代动力学参数
Figure PCTCN2020135200-appb-000043
Figure PCTCN2020135200-appb-000044
结论
通过上述表3～4所示结果可知，本发明所述化合物EP-0015-010的代谢产物沃替西汀的脑血比(B/P)为50.47，EP-X的代谢产物沃替西汀的B/P为33.54，EP-0015-010的代谢产物沃替西汀的脑血比例(B/P)相对于EP-X显著提高，提示本发明化合物具有较强的脑组织的靶向给药效果，显著提高活性代谢产物沃替西汀在脑中暴露量。
另外通过表3～4还可发现，本发明所述沃替西汀前药EP-0015-010在保持快速释放活性产物沃替西汀的同时，在入血和入脑后可维持一定的前药血药浓度，提示EP-0015-010具有合理的前药清除速度和活性代谢产物沃替西汀的释放速度；而EP-X不仅代谢产物沃替西汀在脑组织中的暴露量显著低于EP-0015-010(AUC 0-last，10800 vs 6640)，其本身也难以在血浆和脑组织中检测到，提示清除速度过快，难以维持较长时间的有效的沃替西汀血药浓度。
测试例2、前药分子大鼠体内药代动力学测试
目的：采用LC-MS-MS方法，考察沃替西汀前药化合物在大鼠体内的药动学特征。
色谱条件：色谱柱为WELCH Xtimate-C18柱(50×2.1mm，3.5μm)；流动相：A：水溶液(0.1％甲酸)；B：乙腈(0.1％甲酸)；梯度洗脱(0.10-0.80min，10％B-95％B；0.80-1.80min，95％B-95％B；1.80-1.81min，95％B-10％B；1.81-3.00min，10％B-10％B；)；流速：350μL·min -1；柱温：30℃。
质谱条件：采用电喷雾离子源(ESI)，正离子扫描多反应监测模式(MRM)。离子源温度：500℃；离子喷射电压：5000V；雾化器(GS1)：50psi；辅助气(GS2)：35psi；碰撞气(CAD)：High；气帘气(CUR)：25psi。用于定量分析的离子对分别为m/z 299.3→109.2(沃替西汀)，455.3→165.1(内标维拉帕米)。
血浆样品的处理：取血浆样品20μL，置于2.0mL离心管中，加入200μL沉淀剂溶液(乙腈溶液，含有60.0ng·mL -1的地塞米松、5.0ng·mL -1的维拉帕米、30.0ng·mL -1的丁螺环酮溶液)，涡旋3min，离心(12,000rpm)3min，取75μL上清液转移到96孔板，再加入75μL水溶液，充分混匀后取10μL进行LC-MS/MS分析。
脑组织样品的处理：取脑组织样品50μL，置于2.0mL离心管中，加入500μL沉淀剂溶 液(乙腈溶液，含有60.0ng·mL -1的地塞米松、5.0ng·mL -1的维拉帕米、30.0ng·mL -1的丁螺环酮溶液)，涡旋3min，离心(12,000rpm)3min，取75μL上清液转移到96孔板，再加入75μL水溶液，充分混匀后取10μL进行LC-MS/MS分析。
试供品配制：
沃替西汀组：精密称取沃替西汀化合物(自制)28mg，用5％DMSO溶液+95％(0.5％CMC-Na溶液)作为溶媒，加入适量体积溶媒，充分溶解并混匀，得0.5mg/mL的完全混悬液，为沃替西汀给药溶液。
沃替西汀前药各组：EP-0015-003组、EP-0015-004组、EP-0015-006组、EP-0015-010组、EP-0015-011组、EP-0015-013组、EP-0015-014组、EP-0015-015组根据各前药的分子量和化合物纯度计算为等剂量沃替西汀的给药量，用5％DMSO溶液+95％(0.5％CMC-Na溶液)作为溶媒，加入适量体积溶媒，充分溶解并混匀制备得到沃替西汀前药各组给药溶液。
配制供试品时，按设计浓度和所需体积计算理论称样量，沃替西汀前药各组根据分子量和化合物纯度计算为等剂量沃替西汀的给药量。将配制好的药液贴好标签备用。如供试品溶解不好，或混悬不均匀，可进行适当的涡旋或超声。
试验设计：
每个化合物取健康雄性大鼠18只，每个时间点3只动物，共6个时间点(0.5、1、2、4、6、10h)，按照1mg/kg同等剂量沃替西汀的给药剂量，各组同时进行单次的灌胃给药。在给药后的指定时间点收集血浆、全脑组织样品。然后运用API-4000QTRAP LC-MS-MS测定样品中化合物浓度(沃替西汀前药和沃替西汀)。用WinNonLin软件计算相关的PK参数，药代动力学参数报告如下：AUC (0-t)、AUC (0-∞)、MRT (0-t)、C max、T max、T 1/2、F％。
相对生物利用度计算(Relative Bioavailability(％))＝AUC 0-last(沃替西汀)(前药)/AUC 0-last(沃 替西汀)(沃替西汀)
脑血比(B/P)＝AUC 0-last(脑组织)/AUC 0-last(血浆)
沃替西汀及沃替西汀前药化合物在大鼠脑组织中检测到的沃替西汀的药代动力学参数结果见表5，在大鼠血浆中检测到的沃替西汀的药代动力学参数结果见表6，沃替西汀及沃替西汀前药化合物在大鼠脑组织与血浆中的沃替西汀AUC比值(脑血比，B/P)结果见图1，沃替西汀及沃替西汀前药化合物总AUC暴露量比较见图2，沃替西汀及沃替西汀前药化合物的相对生物利用度比较见图3。
结果
表5沃替西汀及沃替西汀前药化合物在大鼠脑中的沃替西汀的药代动力学参数
Figure PCTCN2020135200-appb-000045
表6沃替西汀及沃替西汀前药化合物在大鼠血浆中的沃替西汀的药代动力学参数
Figure PCTCN2020135200-appb-000046
结论
雄性SD大鼠单次灌胃给药沃替西汀和沃替西汀前药化合物后，在大鼠脑组织中，相比于沃替西汀，EP-0015-003、EP-0015-010、EP-0015-014、EP-0015-015的代谢产物沃替西汀的相对生物利用度(相对于沃替西汀)均有所提高，尤其是EP-0015-015的相对生物 利用度有了明显提高(具体见图3)，提示本发明化合物具有明显减少沃替西汀的给药剂量的治疗潜力，将更有利于减少药物的相关不良反应，如降低胃肠道副反应发生率。
相比于沃替西汀，本发明所述的沃替西汀前药化合物的AUC脑血比例(B/P)明显提高，如EP-0015-003、EP-0015-004、EP-0015-006、EP-0015-010、EP-0015-011、EP-0015-014、EP-0015-015的血脑比例与沃替西汀的血脑比例相比具有显著性变化，提示具有较强的脑组织的靶向给药效果(见图1)，因而脑中暴露量(AUC 0-last)也更高(见图2)，在相同的剂量的沃替西汀作用于中枢神经系统的情况下，本发明前药可减少给药剂量，因而同时也减少了沃替西汀对外周神经系统的作用。另外通过图2可知，本发明所提供的绝大多数沃替西汀前药，如EP-0015-003、EP-0015-004、EP-0015-010、EP-0015-014、EP-0015-015的总AUC基本与沃替西汀持平或大于沃替西汀。
此外，通过图4和图5可知，本发明提供的沃替西汀前药与沃替西汀相比，血浆中和脑中的药-时曲线更加平缓，提示可在人体中保持较为平稳的药物治疗浓度，具有良好的药代动力学特性。
测试例3、前药分子食蟹猴体内药代动力学测试
目的：采用LC-MS-MS方法，考察沃替西汀前药化合物在食蟹猴体内的药动学特征。
色谱条件：色谱柱为ACQUITY UPLC Protein BEH C4
Figure PCTCN2020135200-appb-000047
1.7μm 2.1×50mm；流动相：A：2mM HCOONH 4 in water/ACN(v:v,95:5)；B：2mM HCOONH4 in ACN/water(v:v,95:5)；梯度洗脱(0.10-0.30min，15％-40％B；0.30-1.40min,40％-60％B；1.40-1.60min，60％-90％B；1.60-2.00min，90％B,2.00-2.20min，90％B-15％B；)；流速：700μL·min-1；柱温：55℃。
质谱条件：采用电喷雾离子源(ESI)，选择反应检测扫描模式(SRM)。离子源温度：500℃；离子喷射电压：5000V；雾化器(GS1)：50psi；辅助气(GS2)：35psi；碰撞气(CAD)：High；气帘气(CUR)：25psi。用于定量分析的离子对分别为m/z 300.4→150.2(沃替西汀)，455.2→164.9(内标维拉帕米)。
血浆样品的处理：将等分试样的20μL未知样品，校准标准品，质量控制，稀释质量控制，单个空白和双重空白样品添加到96孔板中；每个样品(双空白样品除外)分别用200μL IS1淬灭(双空白样品用200μL MeOH淬灭)，然后将混合物在800rpm涡旋混合10分钟，然后在3220g离心15分钟(4000rpm)，4℃。注入2μL上清液用于LC-MS/MS分析；
脑脊液样品的处理：所有脑脊液样品均添加血浆和乙醇(v；v；v 1；1；1)；将等分试样的20μL未知样品，校准标准品，质量控制，稀释质量控制，单个空白和双重空白样品添 加到96孔板中；每个样品(双空白样品除外)分别用200μL IS1淬灭(双空白样品用200μL MeOH淬灭)，然后将混合物在800rpm涡旋混合10分钟，然后在3220g离心15分钟(4000rpm)，4℃。注入2μL上清液用于LC-MS/MS分析。
试供品配制：
沃替西汀组：精密称取沃替西汀化合物，用90％PEG400/10％water作为溶媒，加入适量体积溶媒，充分溶解并混匀，得2mg/mL的完全混悬液，为沃替西汀给药溶液。
EP-0015-010组：精密称取EP-0015-010化合物，用90％PEG400/10％water作为溶媒，加入适量体积溶媒，充分溶解并混匀，得3.82mg/mL的完全混悬液，为EP-0015-010给药溶液(相当于2mg/mL的沃替西汀)。
配制供试品时，按设计浓度和所需体积计算理论称样量，沃替西汀前药各组根据分子量和化合物纯度计算为3mg/kg等剂量沃替西汀的给药量。将配制好的药液贴好标签备用。如供试品溶解不好，或混悬不均匀，可进行适当的涡旋或超声。
试验设计：
取健康雄性食蟹猴和雌性食蟹猴各2只，年龄≥2周岁，体重≥2.5kg。试验分实验一、实验二，两部分实验均在4只食蟹猴上进行，前后间隔一周，以便药物代谢，实验一、实验二均按照3mg/kg同等剂量沃替西汀的给药剂量，单次鼻饲给药(经胃管给药)，分别在6个时间点(0.25、0.5、1、2、4、6、8、24h)收集血浆、脑脊液样品。然后运用ACQUITYUPLCMS-MS测定样品中化合物浓度(沃替西汀和沃替西汀前药)。用WinNonLin软件计算相关的PK参数，药代动力学参数报告如下：AUC (0-t)、AUC (0-∞)、MRT (0-t)、C max、T max、T 1/2、F％。
相对生物利用度计算(Relative Bioavailability(％))＝AUC0-last (沃替西汀)(前药)/AUC0-last (沃替西汀)(沃替西汀)
脑血比(B/P)＝AUC 0-last(脑脊液)/AUC 0-last(血浆)
沃替西汀及沃替西汀前药化合物在食蟹猴血浆和脑脊液中检测到的沃替西汀的药代动力学参数结果见下7；沃替西汀及沃替西汀前药化合物在食蟹猴脑脊液与血浆中的沃替西汀总AUC暴露量结果见图6。
结果
表7沃替西汀及沃替西汀前药化合物在食蟹猴血浆和脑脊液中的药代动力学参数
Figure PCTCN2020135200-appb-000048
Figure PCTCN2020135200-appb-000049
备注：“NA”表示未检测出。
结论
通过上述结果可知，本发明所提供的沃替西汀前药与沃替西汀相比，沃替西汀前药总AUC明显高于沃替西汀，且沃替西汀前药代谢产物沃替西汀与沃替西汀各自的总AUC基本持平(具体见图6)；此外本发明提供的沃替西汀前药经代谢后产生的沃替西汀药物浓度的B/P比值明显高于沃替西汀，提示本发明提供的前药能够靶向脑部给药。此外本发明前药化合物在脑脊液中代谢产生的游离沃替西汀的浓度远远高于沃替西汀在脑脊液中的游离药物浓度，提示本发明前药可明显提高沃替西汀的治疗有效浓度，因而本发明提供的前药可提高抗抑郁效果，同时可在维持相同药效的前提下，减少给药剂量，进而减少不良反应发生。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (16)

  1. 一种通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐，
    Figure PCTCN2020135200-appb-100001
    其中：
    -X-为单键“-”或-(CH 2)n 1-中的任意一种；
    R 1和R 2各自独立地选自被卤素、氨基、羟基或氰基任选取代的C 1-3的烷基，或氢中的任意一种；
    R 3选自被卤素、羟基、氰基或氨基任选取代的C 6-10的芳基，
    Figure PCTCN2020135200-appb-100002
    中的任意一种；
    R 4和R 5各自独立地选自氢，氨基，被卤素、氨基或羟基任选取代的C 6-15的烷基，或被氨基、羟基、卤素或氰基任选取代的C 1-5的烷基中的任意一种；
    n 1为1～3之间的任意一个整数；
    a和b各自独立地为0～2之间的任意一个整数。
  2. 如权利要求1所述的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐，其特征在于，
    R 1和/或R 2中，所述被卤素、氨基、羟基或氰基任选取代的C 1-3的烷基选自C 1-3的烷基；
    和/或，R 3中，所述被卤素、羟基、氰基或氨基任选取代的C 6-10的芳基选自C 6-10的芳基；
    和/或，R 4和R 5中，所述被卤素、氨基或羟基任选取代的C 6-15的烷基选自C 6-15的烷基；
    和/或，R 4和R 5中，所述被氨基、羟基、卤素或氰基任选取代的C 1-5的烷基选自被氨基任选取代的C 1-5的烷基；
    和/或，所述n 1为1，2或3中的任意一个整数；
    和/或，所述a和b各自独立地为0，1或2中的任意一个整数。
  3. 如权利要求2所述的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐，其特征在于，
    R 1和/或R 2中，所述C 1-3的烷基选自甲基、乙基或丙基中的任意一种；
    和/或，R 3中，所述C 6-10的芳基选自苯基或萘基中的任意一种；
    和/或，R 4和R 5中，所述C 6-15的烷基选自C 6-15的直链烷基；
    和/或，R 4和R 5中，所述被氨基任选取代的C 1-5的烷基选自被氨基任选取代的甲基、乙基、丙基、丁基或戊基中的任意一种；
    和/或，所述n 1为1；
    和/或，所述a和b各自独立地为1。
  4. 如权利要求3所述的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐，其特征在于，
    R 1和/或R 2中，所述C 1-3的烷基为甲基或乙基中的任意一种；
    和/或，R 3中，所述C 6-10的芳基为苯基；
    和/或，R 4和R 5中，所述C 6-15的直链烷基选自C 9-15的直链烷基；
    和/或，R 4和R 5中，所述被氨基任选取代的C 1-5的烷基为被氨基任选取代的甲基、乙基、丙基或丁基中的任意一种；优选为被氨基任选取代的甲基、乙基或丙基中的任意一种。
  5. 如权利要求1-4任一项所述的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐，其特征在于，
    所述R 1和R 2各自独立地选自C 1-3的烷基或氢中的任意一种；优选氢，甲基或乙基中的任意一种；特别的，优选为氢或甲基；
    和/或，R 3为苯基或萘基，优选苯基；
    和/或，R 4和R 5各自独立地为氢，氨基，C 6-15的烷基，或被氨基任选取代的C 1-5的烷基中的任意一种；特别的，R 4和R 5各自独立地优选为氢，甲基，乙基，正丙基，异丙基，正丁基，-CH 2NH 2，-CH 2CH 2NH 2，-CH 2CH 2CH 2NH 2，-(CH 2) 8CH 3，-(CH 2) 9CH 3，-(CH 2) 12CH 3或-(CH 2) 13CH 3中的任意一种；更特别的，R 4和R 5各自独立地优选为氢，甲基，正丙基，异丙基，-CH 2CH 2NH 2，-(CH 2) 8CH 3，-(CH 2) 9CH 3，-(CH 2) 12CH 3或-(CH 2) 13CH 3中的任意一种。
  6. 如权利要求1-5任一项所述的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐，其特征在于，
    -X-为单键“-”或-(CH 2)n 1-中的任意一种；
    R 1和R 2各自独立地选自C 1-3的烷基或氢中的任意一种；
    R 3选自C 6-10的芳基，
    Figure PCTCN2020135200-appb-100003
    中的任意一种；
    R 4和R 5各自独立地选自氢，氨基，C 6-15的烷基，或被氨基任选取代的C 1-5的烷基中的任意一种；
    n 1为1～3之间的任意一个整数；
    a和b各自独立地为0～2之间的任意一个整数。
  7. 如权利要求6所述的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐，其特征在于，
    所述C 1-3的烷基选自甲基、乙基或丙基中的任意一种，优选甲基或乙基中的任意一种；
    所述被氨基任选取代的C 1-5的烷基选自被氨基任选取代的甲基、乙基、丙基或丁基中的任意一种；所述C 6-15的烷基选自C 6-15的直链烷基；所述C 6-10的芳基选自苯基或萘基中的任意一种。
  8. 如权利要求1-7任一项所述的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐，其特征在于，
    -X-为单键“-”或-(CH 2)n 1-中的任意一种，n 1为1；
    R 1和R 2各自独立地选自氢，甲基或乙基中的任意一种；
    R 3选自苯基，
    Figure PCTCN2020135200-appb-100004
    中的任意一种；
    R 4和R 5各自独立地选自氢，甲基，乙基，正丙基，异丙基，正丁基，-CH 2NH 2，-CH 2CH 2NH 2，-CH 2CH 2CH 2NH 2，-(CH 2) 8CH 3，-(CH 2) 9CH 3，-(CH 2) 12CH 3或-(CH 2) 13CH 3中的任意一种；
    a为1和b为1。
  9. 如权利要求1所述的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐，其特征在于，所述通式(A)所示的化合物选自如下所示化合物的任意一个：
    Figure PCTCN2020135200-appb-100005
  10. 如权利要求1-9任一项所述的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐，其特征在于，所述药学上可接受的盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、乙酸盐、乳酸盐、柠檬酸盐、酒石酸盐、马来酸盐、富马酸盐、甲磺酸盐、三氟乙酸盐、葡糖酸盐、糖二酸盐、苯甲酸盐、乙磺酸盐、苯磺酸盐或对甲苯磺酸盐，优选氢溴酸盐或三氟乙酸盐。
  11. 一种制备如权利要求1-10中任一项所述的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐的方法，其特征在于，该方法包括：
    Figure PCTCN2020135200-appb-100006
    通式(III)的化合物与通式(IV)的化合物通过取代反应得到通式(A)的化合物；
    其中：
    -X-，R 1，R 2和R 3各自独立地如权利要求1-8中任一项所定义。
  12. 如权利要求11所述的制备方法，其特征在于，所述通式(III)的化合物的制备方法包括：
    Figure PCTCN2020135200-appb-100007
    通式(I)的化合物与通式(II)的化合物反应制备得到通式(III)的化合物；
    其中：
    R 1和R 2各自独立地如权利要求1-8中任一项所定义。
  13. 一种药物组合物，其特征在于，包含治疗有效量的如权利要求1-10中任一项所述的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐和药学上可接受的载体。
  14. 如权利要求1-10中任一项所述的通式(A)所示的化合物、其立体异构体、其互变异构体或其药学上可接受的盐或如权利要求13中所述的药物组合物在制备治疗神经精神类疾病的药物中的用途。
  15. 如权利要求14所述的用途，其特征在于，所述神经精神类疾病选自精神分裂症、抑郁症、焦虑症、睡眠障碍、认知障碍、神经退行性疾病、双相情感障碍、创伤后应激综合征、成瘾性疾病、戒断综合征或注意力缺陷中的任意一种或多种，优选抑郁症、认知障碍、焦虑症、精神分裂症、睡眠障碍、神经退行性疾病或双相情感障碍中的任意一种或多种，更优选为抑郁症。
  16. 如权利要求15所述的用途，其特征在于，所述抑郁症选自轻度抑郁症、中度抑郁 症、重度抑郁症、伴随其他精神障碍的抑郁症以及复发性抑郁症；所述精神障碍选自睡眠障碍、认知障碍、焦虑症、强迫症、情感障碍或人格障碍的一种或多种，优选认知障碍、焦虑症或睡眠障碍。
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