WO2019129176A1 - 一种菝葜皂苷元衍生物及其制备方法和应用 - Google Patents

一种菝葜皂苷元衍生物及其制备方法和应用 Download PDF

Info

Publication number
WO2019129176A1
WO2019129176A1 PCT/CN2018/124690 CN2018124690W WO2019129176A1 WO 2019129176 A1 WO2019129176 A1 WO 2019129176A1 CN 2018124690 W CN2018124690 W CN 2018124690W WO 2019129176 A1 WO2019129176 A1 WO 2019129176A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
group
alkyl
hydrogen
compound
Prior art date
Application number
PCT/CN2018/124690
Other languages
English (en)
French (fr)
Inventor
黄成钢
李扬
蒋华良
谢阳
郭飞
陆伊虹
李志雄
陈明苍
郑明月
孙兆林
高羽
田小亭
胡培
张兵
Original Assignee
中国科学院上海药物研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN201810664219.XA external-priority patent/CN109988218B/zh
Application filed by 中国科学院上海药物研究所 filed Critical 中国科学院上海药物研究所
Publication of WO2019129176A1 publication Critical patent/WO2019129176A1/zh

Links

Images

Classifications

    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring

Definitions

  • the present invention relates to the field of medicine, and in particular to a saponin derivative or a pharmaceutically acceptable salt thereof, a solvent compound, an optical isomer and a stereoisomer, and a preparation method and application thereof.
  • Depression is a common and frequently-occurring disease that endangers human health. In China, the incidence of affective psychosis is 0.76%. The incidence of depression is high, but the cause of its disease is still not very clear. Traditionally, the pathogenesis of depression is associated with abnormalities in monoamine neurotransmitters in the brain, including serotonin, acetylcholine and catecholamines, norepinephrine and epinephrine.
  • the most commonly used antidepressants in clinical practice include tricyclic and tetracyclic antidepressants, monoamine oxidase inhibitors, selective 5-HT reuptake inhibitors (SSRIs), atypical antidepressants, and lithium salts.
  • Chinese medicine believes that depression is caused by excessive anxiety, labor and spleen are sick, and treatment should be based on tranquillity, nourishing blood and nourishing yin. Therefore, in most prescriptions for the treatment of depression in Chinese medicine, Zhimu is also a commonly used Chinese herbal medicine.
  • AD Alzheimer's Disease
  • the clinical manifestations of AD are a series of symptoms such as progressive cognitive decline and aggravation of emotional disorders, including short-term memory, speech function, living habits and attention.
  • the pathogenesis of AD is unclear. Therefore, to date, the available treatments for AD drugs are very limited, and the drugs used to treat AD are mainly aimed at improving the cognitive behavioral symptoms, including: (1) improvement.
  • Cholinergic neurotransmission mainly cholinesterase inhibitors; (2) N-methyl-D-aspartate (NMDA) receptor antagonists: such as memantine.
  • NMDA N-methyl-D-aspartate
  • the main chemical components of Chinese herbal medicines are steroidal saponins, dibenzopyrones, polysaccharides and lignins, such as timosaponin A-I, A-II, A- III, A-IV, B-I, B-II and B-III, wherein the structure of the timosaponins A-II and A-IV is unknown; and the amemarsaponin A2, ie, Marcos saponin-3 -O- ⁇ -D-glucopyranosyl (1 ⁇ 2)- ⁇ -D-galactopyranoside B (marlogenin-3-O- ⁇ -D-glucopyranosy(1 ⁇ 2)- ⁇ -D-galactopyranoside B), desgalactotigonin, F-gitonin, smilageninoside, and the like.
  • timosaponin A-I, A-II, A- III, A-IV, B-I, B-III and B-III
  • anemalan A/B/C/D contains anemalan A/B/C/D, cis-hinokiresinol, monomethyl-cis-hinokiresinol, oxidized-cis- Oxy-cis-himokiresinol, 2,6,4'-trihydroxy-4-methoxybenzophenone (2,6,4'-trihydroxy-4-methoxy benzophenone), p-hydroxybenzene P-hydroxyphenyl crotonic acid, pentacosyl vinyl ester, ⁇ -sitosterol, mangiferin, nicotinic acid, nicotinamide (nicotinamide) and pantothenic acid.
  • cis-hinokiresinol monomethyl-cis-hinokiresinol
  • oxidized-cis- Oxy-cis-himokiresinol 2,6,4'-trihydroxy-4-methoxybenzophenone (2,6,4'-trihydroxy-4-methoxy benzo
  • timosaponin has a certain role in anti-senile dementia symptoms, anti-aging, anti-depression and the like.
  • Zhimu total soap has antidepressant effects in various depression models, which may be related to the enhancement of noradrenergic and serotonergic nervous system (New Chinese Medicine and Clinical Pharmacology, 2007, 18, 29). It was confirmed by animal experiments that the saponins contained in Zhimu had a certain effect on experimental depression in mice, which could affect the activity of dopamine and monoamine oxidase in the brain of mice, and made the saponins have antidepressant activity (Biol. Pharm.Bull., 2006, 29, 2304-2306).
  • I Jia et al. found that timosaponin B-II has antidepressant activity, and its mechanism may be related to enhancing the effects of 5-HT and DA nervous system in the brain (CN101214253A; Journal of Pharmaceutical Practice, 2010, 28, 283-287). ).
  • a compound of formula I or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer or mixture thereof,
  • the compound represented by the formula I is formed by linking the following fragment A and fragment B.
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, alkenyl Substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocycle,
  • any two of R 1 , R 2 , R 3 and the associated N form a 3-7 membered saturated or unsaturated impurity having 1-3 N, 0-2 O and/or 0-2 S atoms.
  • a ring which is unsubstituted or monosubstituted or polysubstituted by hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl , alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, alkanoyl, substituted alkanoyl, alkoxycarbonyl, Arylalkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylalkylsulfonyl, carbamoyl, substituted carbamoy
  • R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b are each independently selected from the group consisting of none, hydrogen, Halogen, alkyl, substituted alkyl, hydroxy, decyl, alkyl fluorenyl, alkoxy, substituted alkoxy, amino, substituted amino, alkylamino, substituted alkylamino, disubstituted amino, alkane
  • X 1 is O, S or NR 5 , and R 5 is selected from the group consisting of hydrogen, alkyl, cyano, hydroxy, alkoxy,
  • R 4a and R 4b are each independently selected from hydrogen, hydroxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkyne.
  • R 4a , R 4b and the attached C form a 3-7 membered saturated or unsaturated heterocyclic ring containing 0-3 N, 0-2 O and/or 0-2 S atoms, said "hetero a ring “unsubstituted or monosubstituted or polysubstituted by: hydrogen, hydroxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl;
  • X 2 is OR h , N(R i )(R j ), and R 4a and R 4b together with the attached carbon form -X a R k
  • R h , R i , R j , R k are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkanoyl, substituted alkanoyl, alkoxycarbonyl, alkoxycarbonyl, alkane Aminocarbonyl, arylalkoxycarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, carbamoyl, substituted carbamoyl, carboxy, amide, substituted amide;
  • Each * independently represents a racemic, S or R configuration.
  • R 3 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl a heterocyclic group, a substituted heterocyclic group; or R 2 , R 3 and a bonded N form the following structure:
  • R 11 is selected from the group consisting of alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, alkanoyl, substituted Alkanoyl, alkoxycarbonyl, arylalkoxycarbonyl, carbamoyl, substituted carbamoyl, carboxy, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylalkylsulfonyl, An amide, a substituted amide, a sulfonamide group, a substituted sulfonamide group;
  • n 0, 1 or 2.
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, -MX 3 PX 5 Q, where
  • M is an alkylene group, a substituted alkylene group, a cycloalkylene group, a substituted cycloalkylene group,
  • Q is hydrogen, hydroxy, alkoxy, aryloxy, NR f R g , alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted Heterocyclyl, R f , R g are, independently of each other, hydrogen, hydroxy, alkyl, alkoxy, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy a carbonyl group, or a combination of R f and R g to form a 3-7 membered saturated or unsaturated heterocyclic ring containing 0-3 N, 0-2 O and/or 0-2 S atoms.
  • the ring is unsubstituted or monosubstituted or polysubstituted by hydrogen, hydroxy, amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl.
  • the fragment B is selected from the group consisting of fragment B1-fragment B20, wherein X 4 is CH 2 OR 12 , CH 2 N(R 13 )(R 14 ), aldehyde group, COOR 12 , CON(R 13 )(R 14 ), R 12 , R 13 , and R 14 are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted Alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, alkanoyl, substituted alkanoyl, alkoxycarbonyl , arylalkoxycarbonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylalkylsulfonyl, carbam
  • R 4a and R 4b are each independently selected from hydrogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, and said substitution means having one, two or three substituents selected from the group consisting of halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy; or R 4a , R 4b and attached C form a 3-7 membered saturated or unsaturated heterocyclic ring containing 1-2 O and/or 1-2 S atoms
  • the "heterocycle” is unsubstituted or monosubstituted or polysubstituted by hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, hydroxy;
  • X 1 is O, S, NR 5 , and R 5 is selected from the group consisting of hydrogen, an alkyl group, and a hydroxyl group.
  • R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b are none, hydrogen, alkyl, substituted Alkyl, hydroxy or decyl, or between R 6a and R 6b and/or between R 7a and R 7b and/or between R 8a and R 8b and/or R 9a , R 9b a combination of two and two and / or R 10a , R 10b two to form a carbonyl group,
  • X 1 is O.
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, C3-C12 cycloalkyl, C6-C10 aryl, C3-C8 saturated heterocyclic, C1-C4 alkyl, wherein cycloalkane
  • R 2 , R 3 and the attached N form a 3-7 membered saturated or unsaturated heterocyclic ring containing 1-3 N, 0-2 O and/or 0-2 S atoms;
  • heterocycle is unsubstituted or monosubstituted or polysubstituted by hydrogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, 3-8 membered heteroaryl.
  • R 2 is hydrogen or a substituted or unsubstituted C1-C4 alkyl group, and the substituent is selected from the group consisting of a hydroxyl group, an amino group, -NHCO(C1-C4 alkylene)N R f1 R g1 , wherein Each R f1 and each R g1 are independently selected from the group consisting of hydrogen and a C1-C4 alkyl group.
  • X 1 is O
  • R 1 is hydrogen
  • R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b are all hydrogen;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C6-C10 aryl, C3-C8 saturated heterocyclic group, C1-C4 alkyl group, wherein cycloalkyl, aryl, saturated hetero
  • the "heterocycle” is unsubstituted or monosubstituted or polysubstituted by hydrogen, C1-C4 al
  • segment B is any of segment B1-slice B8.
  • R 1 is H
  • R 2 is H
  • R 3 is a cyclohexyl group.
  • the segment B is a segment B1, a segment B3, a segment B5 or a segment B7.
  • X 1 is O
  • R 1 is hydrogen
  • R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b are all hydrogen;
  • R 2 is cyclohexyl, cyclopentyl, adamantyl
  • Fragment B is
  • R 3 is -MX 3 PX 5 Q, where
  • M is selected from the group consisting of C1-C4 alkylene groups
  • X 3 is selected from O, NRa or none, and Ra is selected from the group consisting of hydrogen and alkyl.
  • Q is hydrogen, hydroxy, alkoxy, amino, alkyl, substituted alkyl, NR f R g , R f , R g are independent of each other, are hydrogen, alkyl, substituted alkyl, or R f , R g
  • a 3-7 membered saturated or unsaturated heterocyclic ring containing 0-3 N, 0-2 O and/or 0-2 S atoms is formed between the two, and the "heterocyclic ring" is unsubstituted or is substituted by the following groups.
  • Monosubstituted or polysubstituted hydrogen, hydroxy, amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl.
  • the compound is any one of the compounds prepared in the examples.
  • the compound is:
  • the compound is any one of the compounds prepared in the examples.
  • segment A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 3a is selected from the group consisting of cyclohexane, cyclopentyl, cyclobutane, phenyl;
  • R 3b is selected from the group consisting of hydrogen, (C1-C6) alkoxycarbonyl, and a carboxyl group;
  • Fragment B is selected from the following group:
  • the compound is:
  • segment A is among them
  • R 3c is selected from cyclohexane, cyclopentyl, cyclobutane, hydrogen, methyl, phenyl or substituted phenyl, and the substituent is selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, hydroxyl, A Oxyl, trifluoromethyl, trifluoromethoxy;
  • D is selected from Or D is linked to R 3c to form a 3-7 membered saturated heterocyclic ring containing 1 N.
  • R 3d is selected from
  • Fragment B is selected from the following group:
  • the compound is:
  • segment A is among them
  • R 3e is selected from cyclohexane, cyclopentyl, cyclobutane, hydrogen, methyl, phenyl or substituted phenyl, and the substituent is selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, hydroxy, A Oxyl, trifluoromethyl, trifluoromethoxy,
  • R dd is O or NH
  • D is selected from Or connected to R 3e to form a 3-7-membered saturated heterocyclic ring containing 1 N.
  • R 3f is selected from the group consisting of hydrogen, amino, C1-C6 alkylamino, substituted C1-C6 alkylamino, C3-C6 cycloalkylamino, substituted C3-C6 cycloalkylamino, C1-C6 alkyl , substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl,
  • Fragment B is selected from the following group:
  • the compound is selected from the group consisting of:
  • a process for the preparation of a compound according to the first aspect, or a pharmaceutically acceptable salt, solvate, optically pure isomer or stereoisomer thereof comprising the steps of:
  • the above 3-aminosteroid ligand may be an optically pure chiral compound or an optically pure chiral compound in various ratios.
  • the preparation method further comprises the step of fractionating the compound of the first aspect obtained in the step a) to obtain an optically pure chiral compound.
  • a third aspect of the invention there is provided a method of preparing a compound according to the first aspect, or a pharmaceutically acceptable salt, solvate, optically pure isomer or stereoisomer thereof, the method comprising the steps of:
  • the preparation method further comprises the following steps:
  • the obtained product can be subjected to further chemical reaction to obtain a new compound, the -NHBoc substituent is removed by Boc reaction to obtain -NH 2 , and the -COOCH 3 substituent is hydrolyzed to obtain -COOH.
  • the above 3-aminosteroid ligand may be an optically pure chiral compound or an optically pure chiral compound in various ratios.
  • the preparation method further comprises the step of fractionating the compound of the first aspect obtained in the step ii) to obtain an optically pure chiral compound.
  • the compounds of the invention are synthesized using the following route:
  • a pharmaceutical mixture comprising two or more compounds selected from the group consisting of the compound of the first aspect, or a pharmaceutically acceptable salt thereof, a solvent Compound, optically pure isomer, stereoisomer.
  • the drug mixture is a mixture of any two or more of the compound C-1 to the compound C-32.
  • the components in the drug mixture in the present invention may be mixed in any mass ratio.
  • the mass ratio is 0.01: 0.99 - 0.99: 0.01, preferably 1: 9 - 9: 1, 2: 8 - 8:2, 3:7-7:3 or 4:6-6:4.
  • a pharmaceutical composition comprising the compound of the first aspect, or a pharmaceutically acceptable salt, solvate, optically pure isomer or stereoisomer thereof Or the pharmaceutical mixture of the fourth aspect; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may further comprise an additional therapeutic agent selected from the group consisting of: an antidepressant, an anti-manic drug, a Parkinson's disease therapeutic, an Alzheimer's disease therapeutic, or a combination.
  • an additional therapeutic agent selected from the group consisting of: an antidepressant, an anti-manic drug, a Parkinson's disease therapeutic, an Alzheimer's disease therapeutic, or a combination.
  • the pharmaceutical composition may further comprise an additional therapeutic agent, such as moclobemide, toloxacin, fluoxetine, paroxetine, citalopram, sertraline, Venlafaxine, trimipramine, trazodone, imipramine, desipramine, clomipramine, amitriptyline, nortriptyline, doxepin, maprotiline, loxapine , amoxapine, mirtazapine, buspirone, clomiprazole, tandospirone, lithium carbonate, tacrine, huperzine A, galantamine, donepezil, Lifansi Mingmei King Kong, pramexole, helix, ropironi, or a combination thereof.
  • an additional therapeutic agent such as moclobemide, toloxacin, fluoxetine, paroxetine, citalopram, sertraline, Venlafaxine, trimipramine, trazodone, imipramine, desipramine
  • the compounds of the invention may be used alone or in combination with other therapeutic agents.
  • Combination therapy can provide a synergistic effect, i.e., an effect achieved when the active ingredients are used together, greater than the sum of the effects produced by the use of the compounds, respectively.
  • the combination therapy can be administered in a simultaneous or continuous regimen. When administered continuously, the combination can be administered in two or more ways.
  • the compounds can be administered together in a single pharmaceutical combination, or separately, and when administered separately, can be carried out simultaneously or sequentially in any order.
  • the compounds of the invention may be administered by any route appropriate to the condition being treated. Suitable routes include, but are not limited to, oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal), vaginal, intraperitoneal, intrapulmonary, and intranasal. It will be appreciated that the preferred route may vary, for example, from the condition of the patient.
  • parenteral including subcutaneous, intramuscular, intravenous, intraarterial, intradermal
  • vaginal intraperitoneal, intrapulmonary, and intranasal.
  • intrapulmonary intrapulmonary
  • intranasal intranasal. It will be appreciated that the preferred route may vary, for example, from the condition of the patient.
  • the compound When the compound is administered orally, it can be formulated into a pill, capsule, tablet or the like with a pharmaceutically acceptable carrier or excipient.
  • the compound When the compound is formulated parenterally, it can be formulated with a pharmaceutically acceptable parenteral carrier.
  • the present invention can be administered in any convenient form of the formulation, and the term "formulation" as used herein refers to a dosage form containing a compound of the formula I of the present invention, such as, but not limited to, an aqueous solution injection, Powder injection, pill, powder, tablet, patch, suppository, emulsion, cream, gel, granule, capsule, aerosol, spray, powder, sustained release and controlled release.
  • formulation refers to a dosage form containing a compound of the formula I of the present invention, such as, but not limited to, an aqueous solution injection, Powder injection, pill, powder, tablet, patch, suppository, emulsion, cream, gel, granule, capsule, aerosol, spray, powder, sustained release and controlled release.
  • These pharmaceutical excipients may be conventionally used in various preparations such as, but not limited to, isotonic agents, buffers, flavoring agents, excipients, fillers, binders, disintegrators, lubricants, and the like
  • excipients can effectively improve the stability of the compounds contained in the composition And solubility or changing the release rate and absorption rate of the compound, etc., thereby improving the metabolism of the compound of the present invention in vivo, thereby enhancing the administration effect.
  • excipients such as, but not limited to, gelatin, albumin, and chitosan may be used for achieving specific administration purposes or modes such as sustained release administration, controlled release administration, and pulse administration.
  • Polyether and polyester polymer materials such as, but not limited to, polyethylene glycol, polyurethane, polycarbonate and copolymers thereof.
  • the main manifestations of "favorable administration” are: but not limited to improving the therapeutic effect, improving bioavailability, reducing toxic side effects, and improving patient compliance.
  • a sixth aspect of the invention provides the compound according to the first aspect, or a pharmaceutically acceptable salt, solvate, optically pure isomer or stereoisomer thereof, the pharmaceutical mixture of the fourth aspect or the Use of a pharmaceutical composition according to the fifth aspect, for the use of a medicament for protecting, treating, treating or ameliorating a disease, disorder or condition of a patient selected from the group consisting of depression, anxiety, Parkinson's disease Disease, Alzheimer's disease, Huntington's disease, schizophrenia, mania, cancer, metastasis, hyperglycemia, hyperlipidemia, viral disease, bacterial infection, angiogenic, autoimmune, inflammatory The condition associated with organ transplantation.
  • the disease, condition or condition is selected from the group consisting of depression, anxiety, Parkinson's disease, Alzheimer's disease, Huntington's disease, schizophrenia, mania.
  • the disease, condition or condition is selected from the group consisting of depression, anxiety, Parkinson's disease, Alzheimer's disease, mania.
  • the disease, condition or condition is selected from the group consisting of depression.
  • a seventh aspect of the invention provides a method for preventing and/or treating depression comprising the compound of the first aspect, or a pharmaceutically acceptable salt, solvate, optically pure isomer or stereoisomeric thereof
  • the composition, the pharmaceutical mixture of the fourth aspect or the pharmaceutical composition of the fifth aspect is administered to a patient in need thereof.
  • Figure 1 is a graph showing the effect of gavage administration of Example 29 on the duration of forced swimming in ICR mice ("*" indicates P ⁇ 0.05; “**” indicates P ⁇ 0.01).
  • Figure 2 is a graph showing the effect of gavage administration of Example 29 on the time of suspension of ICR mice ("*" indicates P ⁇ 0.05; "**” indicates P ⁇ 0.01).
  • Figure 3 is a graph showing the effect of intragastric administration of Example 30 on the time of forced swimming in rats ("*” means P ⁇ 0.05; “**” means P ⁇ 0.01).
  • Figure 4 is a graph showing the effect of gavage administration of Example 30 on the time of suspension of the rat tail ("*" means P ⁇ 0.05; “**” means P ⁇ 0.01).
  • Figure 5 is a graph showing the effect of the compound C-11 administered by the gavage on the social failure depression animal model in Example 31 ("*" indicates P ⁇ 0.05; “**” indicates P ⁇ 0.01).
  • Figure 6 is a graph showing the oral and tail vein injections of C-49 in rats.
  • Figure 7 is a graph of weight gain.
  • the inventors of the present application have extensively and intensively studied to develop a novel structural compound for the first time, which is formed by linking a urea group and a steroid ligand, and has a structure as shown in Formula I.
  • the compounds of the present invention can be used to protect, treat, treat or alleviate various diseases and conditions such as depression. On the basis of this, the present invention has been completed.
  • substituted refers to any of the substituents mentioned in the specification of the invention, including but not limited to, halogen, nitro, cyano, carboxy, oxo, alkyl, substituted alkyl, cycloalkyl, Substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocycle, Hydroxy, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkanoylamino, aroylamino, arylalkylacylamino, heteroarylalkylamido, aminoalkylamido , alkylaminoalkyl acylamino, dialkylaminoalkyl acylamino, alkylamino, arylamino, arylalkylamino, di
  • halogen refers to fluoro, chloro, bromo, iodo.
  • alkyl refers to a straight or branched unsubstituted hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, and the like.
  • substituted alkyl refers to an alkyl group substituted with from 1 to 4 substituents such as halo, nitro, cyano, carboxy, oxo, alkyl, substituted alkyl, Cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted Heterocyclic, hydroxy, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkanoylamino, aroylamino, arylalkylacylamino, heteroarylalkylamido, amino Alkyl acylamino, alkylaminoalkyl acylamino, dialkylaminoalkyl acylamino, alkylamino, arylamino, arylalkylamino, di
  • alkylene is obtained by removing two hydrogen atoms from a single carbon atom or two carbon atoms of an alkane structure having 1 to 20 carbon atoms, preferably 1 to 7 or 1 to 4 carbon atoms.
  • alkenyl refers to a straight or branched chain hydrocarbon radical having from 2 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, most preferably from 2 to 8 carbon atoms, and having from 1 to 4 double bonds.
  • substituted alkenyl refers to an alkenyl group substituted by 1-2 substituents such as halogen, nitro, cyano, aryl, substituted aryl, heteroaryl, substituted Heteroaryl,
  • alkynyl refers to a straight or branched chain hydrocarbon radical having from 2 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, most preferably from 2 to 8 carbon atoms, and having from 1 to 4 triple bonds.
  • substituted alkynyl refers to an alkynyl group substituted by a substituent such as halo, nitro, cyano, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Hydroxy, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines wherein the two amino substituents are described Selected from alkyl, aryl or arylalkyl).
  • a substituent such as halo, nitro, cyano, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Hydroxy, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines wherein the two amino substituents are described Selected from alkyl
  • aryl refers to a monocyclic or bicyclic aromatic hydrocarbon group having from 6 to 12 carbon atoms in the ring portion.
  • the aryl group includes a bicyclic group including a ring fused to a saturated or partially unsaturated aromatic ring, or an aromatic carbocyclic or heterocyclic ring.
  • aryl groups include, but are not limited to, the following groups: benzene, naphthalene, anthracene, biphenyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like.
  • substituted aryl refers to an aryl group substituted with from 1 to 4 substituents such as halogen, halogen, nitro, cyano, ureido, carboxy, trifluoromethoxy, trifluoro.
  • cycloalkyl refers to a non-aromatic, saturated or partially unsaturated cyclic hydrocarbon group which may be optionally substituted with one or more substituents described herein, which have 3- 30 carbon atoms become a monocyclic ring, or 7-12 carbon atoms become a bicyclic or tricyclic ring.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopenta-3 Alkenyl, cyclohexyl, 1-cyclohex-1-enyl, cycloheptyl, cyclooctyl.
  • Exemplary bridged bicyclic cycloalkyl groups include, but are not limited to, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] decane, adamantyl.
  • cycloalkylene is derived by removing two hydrogen atoms from a single carbon atom or two carbon atoms of a cyclic hydrocarbon structure.
  • the cyclic hydrocarbon has from 3 to 30 carbon atoms, preferably from 3 to 10 carbon atoms including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2- Alkenyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2 ] Octane, bicyclo [3.2.2] decane, adamantyl.
  • heterocycle refers to an optionally substituted, fully saturated or unsaturated, aromatic or non-aromatic ring group, for example it may be 4-7.
  • Each ring of the hetero atom-containing heterocyclic group may have 1, 2 or 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • heterocyclic group may be optionally substituted by one or more substituents described herein, and examples of “heterocyclic group” include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, Ortholinal, thiomorpholino, piperazinyl, homopiperazinyl, propylene oxide, imidazolidinyl, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[4.1. 0] heptyl, azabicyclo[2.2.2]hexane, N-pyridylurea, pyrimidinone and 1,1-dioxo-thiomorpholinyl.
  • heteroaryl refers to a monovalent aromatic group of a 5-, 6-, 7-, 8, 9, or 10-membered ring, and includes a fused system of 5-20 atoms, containing one or more selected Heteroatoms from nitrogen, oxygen, phosphorus and sulfur may be optionally substituted by one or more substituents described herein.
  • heteroaryl include, but are not limited to, pyridyl, imidazolyl, imidazopyridyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, thiazolyl , quinolyl, fluorenyl and the like.
  • sulfonamido refers to -SO 2 NH 2 group.
  • substituted carbamoyl means that at least one hydrogen of the amide, sulfonamide or carbamate is selected from the group consisting of alkyl, substituted alkyl, chain Alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl groups Replace.
  • acceptable salt refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the invention.
  • Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, acid sulfates, isonicotites, lactates Salicylate, acid citrate, succinate, maleate, fumarate, gluconate, formate, methanesulfonate and bamoate.
  • An "acceptable salt” can involve the inclusion of another molecule such as a maleate or other counterion. The counter ion stabilizes the charge in the parent compound.
  • An "acceptable salt” can have more than one charged atom, and a plurality of charged atoms can have multiple counterions.
  • the desired “acceptable salt” can be prepared by a suitable method, for example, treating the free base with the following inorganic acid: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or as follows Organic acids: acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, salicylic acid, pyranoside acid such as glucuronic acid or galacturonic acid, ⁇ -hydroxy acid Tannic acid or tartaric acid, an amino acid such as glutamic acid, an aromatic acid such as benzoic acid or cinnamic acid, a sulfonic acid such as methanesulfonic acid or p-toluenesulfonic acid.
  • inorganic acid hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid
  • Organic acids acetic acid, maleic acid, succinic acid, mandelic acid, fumaric
  • the desired "acceptable salt” can be prepared by a suitable method, for example, by treating the free acid with an inorganic base or an organic base: an amine, an alkali metal hydroxide or an alkaline earth metal hydroxide. Wait.
  • suitable salts include, but are not limited to, organic salts derived from amino acids, salts of primary, secondary, and tertiary amines, and salts of cyclic amines such as piperidine, morpholine, and piperazine, and sodium, calcium, potassium.
  • Inorganic salts obtained from magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • solvate is meant a combination or complex of one or more solvent molecules with a compound of the invention.
  • solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.
  • the compounds of the invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, so the invention will include both solvated and unsolvated forms.
  • the compounds of the invention may contain asymmetric centers or chiral centers, and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, including, but not limited to, diastereomers, enantiomers and hindered isomers, as well as mixtures thereof, such as racemic mixtures, will form part of the present invention. Herein, when the stereochemistry of any particular chiral atom is not determined, all stereoisomers are considered. Furthermore, the invention relates to all geometric and positional isomers. The compounds of the invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. All stereoisomers of the compounds of the invention are intended to include the form of the mixture or the pure or substantially pure form. Pure optical isomers can be prepared by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or by HPLC preparative column, chiral preparative column resolution.
  • the conditions for the resolution of optical isomers by the HPLC preparation column used in the present invention are as follows:
  • ELSD detector atomization temperature is 55 ° C; carrier gas flow rate: 2.4 L / min.
  • Preparative column selected from Waters Xbridge C18 5 ⁇ m 10*250mm, Waters Xbridge C18 5 ⁇ m OBD30*150mm, Waters Xbridge C18 5 ⁇ m OBD50*150mm, Waters Xbridge C18 5 ⁇ m OBD50*250mm;
  • the mobile phase was water and acetonitrile, linear gradient elution procedure: 0-30 min, 14% water ⁇ 5% water; flow rate 3.0 mL/min.
  • the mobile phase was subjected to ultrasonic degassing before use; the injection volume was 800 ul.
  • Preparative column selected from Daicel ⁇ chiral preparation column CHIRALPAK AD-H 5 ⁇ m 20*250mm, CHIRALPAK AD-H 5 ⁇ m 30*250mm, CHIRALPAK AD 5 ⁇ m 20*250mm, CHIRALPAK AS-H 5 ⁇ m 20*250mm, CHIRALCEL OD-H 5 ⁇ m 20*250mm,
  • the mobile phase was n-hexane and isopropanol at a flow rate of 3.0 mL/min.
  • the mobile phase was subjected to ultrasonic degassing before use; the injection volume was 600 ul.
  • triphosgene dissolved in 20 ml of DCM, and 1.2 g of 3 ⁇ -aminosaponin was dissolved in 20 ml of DCM, and then slowly added dropwise to the reaction system.
  • 0.85 ml of triethylamine was dissolved in 20 ml of DCM, and then slowly added dropwise to the reaction system.
  • the solvent was evaporated under reduced pressure and the residue was evaporated mjjjjj
  • a solution of 0.28 ml of the amine II in 30 ml of DCM was slowly added dropwise to the reaction mixture, and the solvent was evaporated under reduced pressure.
  • the crude product was subjected to silica gel column chromatography to give 60 mg of the product 3-cyclohexylureidosaponin as a mixture of compound C-11 and compound C-12 (mass ratio of about 6:4).
  • the 3-aminosaponin used (a mixture of the two conformations of alpha and beta) was prepared from the preparation of Example 3.
  • Example 10 60 mg of 3-cyclohexylureidosaponin prepared by silica gel column chromatography was subjected to HPLC preparative column resolution to obtain a pure optical isomer, and 30 mg of the compound C-11 was obtained to obtain a compound.
  • C-12 has 20mg.
  • Compound C-23 was prepared by referring to the preparation method of the above examples.
  • the substrate (1 mmol) was dissolved in 30 ml of DCM, EDCI ⁇ HCl (2 mmol), DMAP (3 mmol) was weighed in the reaction system, and then R b COOH (2 mmol) was added to the reaction system, stirred at room temperature overnight, and diluted with DCM. The solution was washed with saturated sodium bicarbonate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate.
  • the substrate (1 mmol), triazole (1.5 mmol), triphenylphosphine (1.5 mmol) was dissolved in 30 mL of THF, and DIAD (2 mmol) was slowly dropped. Stir at room temperature overnight, spin dry THF, silica gel column chromatography, yield 20%.
  • the first step of the urea-forming reaction to give an intermediate can be synthesized by reference to the compound C-34.
  • the substrate (1 mmol) is dissolved in DCM, EtOAc (8 mmol) EtOAc.
  • the target compound was obtained in vacuo to yield 65%.
  • the substrate (1 mmol) was dissolved in 30 ml of DCM, EDCI ⁇ HCl (2 mmol), DMAP (3 mmol) was weighed in the reaction system, and then R b COOH (2 mmol) was added to the reaction system, stirred at room temperature overnight, and diluted with DCM. The solution was washed with saturated sodium bicarbonate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate.
  • the amidation reaction was carried out with reference to the synthesis of the compound C-47 to C-52, followed by the Boc reaction with reference to the synthesis of the compound C-46.
  • the product was obtained in a yield: 50%.
  • the synthetic synthesis of the compound C-83 to C-88 can be synthesized by exhibiting the following synthetic route.
  • the substrate (1 mmol) was dissolved in 30 ml of DCM, and EDCI ⁇ HCl (2 mmol), DMAP (3 mmol) was weighed in the reaction system, and then the carboxylic acid RCOOH (2 mmol) was added to the reaction system, stirred at room temperature overnight, and diluted with DCM. The solution was washed with saturated sodium hydrogen sulfate, washed with saturated sodium After the intermediate was added to DCM, EtOAc (EtOAc) (EtOAc) The title compound was obtained by silica gel column chromatography.
  • the carboxylic acid RCOOH is selected from:
  • the intermediate 2 (1 mmol) was dissolved in 30 ml of DCM, and EDCI ⁇ HCl (2 mmol), DMAP (3 mmol) was weighed in the reaction system, and N,N-dimethylglycine (2 mmol) was added to the reaction system. After stirring at room temperature, the reaction mixture was diluted with EtOAc EtOAc.
  • the substrate (1 mmol) was dissolved in 30 ml of DCM, and EDCI ⁇ HCl (2 mmol), DMAP (3 mmol) was weighed in the reaction system, and then the carboxylic acid RCOOH (2 mmol) was added to the reaction system, stirred at room temperature overnight, and diluted with DCM. The solution was washed with saturated sodium hydrogen sulfate, washed with saturated sodium After the intermediate was added to DCM, EtOAc (EtOAc)EtOAc. The title compound was obtained by silica gel column chromatography.
  • the carboxylic acid RCOOH is selected from:
  • RNH 2 is selected from
  • NHR 2 R 3 is selected from the following amines:
  • the medicinal herbs contain a large amount of saponin compounds, and the structures related to the compounds of the present invention are mainly spiro saponins and timosaponins (ie, saponins), such as timosaponin A1, and timosaponin A3.
  • the structural feature of these saponin compounds is that the 3-position substituent is a glycosyl group, for example, timosaponin A1 is a 3-position monosaccharide-substituted saponin; and timosaponin A3 is a 3-position disaccharide-substituted saponin.
  • the compound of the present invention is characterized in that a chemical synthesis means is used at the 3-position to bond other types of substituents.
  • Animal forced swimming test (FST) and tail suspension test (TST) are two classic antidepressant screening models.
  • the compounds of the present invention primarily employ both models for screening for antidepressant activity.
  • FLX represents fluoxetine and Fluoxetine represents fluoxetine.
  • mice Male ICR mice were used in the experiment.
  • the body weight (20 ⁇ 2) g was purchased from the Experimental Animal Center of Shanghai Institute of Materia Medica, Chinese Academy of Sciences, free access to drinking water, room temperature (23 ⁇ 2) ° C, natural light. All mice were randomly divided into a blank control group and a test group, with 10 rats in each group and 5 cages/cage. The experiment was started after 3 days of adaptation in the breeding environment. The rats were fasted for 12 hours before the experiment and the drinking water was free.
  • the specific administration method was intragastric administration, and the administration dose of the administration group was 10 mg/Kg, and the blank control group was given an equal volume of 0.5% CMC-Na.
  • mice continuous administration for 6 days, and testing 1 hour after the last administration.
  • the spontaneous activity of the mice was measured by the open field method, that is, the mice were individually placed in a cylindrical glass jar, timed for 4 minutes, and the number of lifting arms within 2 minutes after recording was recorded. The mice were then individually placed in a cylindrical glass jar 20 cm high and 14 cm in diameter with a water depth of 10 cm and a water temperature of 23 ° C to 25 ° C. Timed from the time the mice entered the water for 6 minutes, the cumulative immobility time within 4 minutes after recording (determination of immobility criteria: the mice stopped struggling in the water, or floating, only small limb movements to keep the head floating on the water) . Each group of mice was operated in parallel.
  • Experimental data processing Experimental results are expressed as mean ⁇ standard error (x ⁇ SD). Statistical analysis was performed using the t test to determine whether it was significant. First, the t-test was performed on the index of autonomic activity, and P>0.05 indicated that the autonomous post-movement of the mice had no effect, so as to avoid the interference of the central stimulant. Then, the t-test was performed on the experimental index of forced swimming to determine whether it had antidepressant effect.
  • the experimental results of the compound C-23 are shown in Table 7. Compared with the blank group, the compound C-23 can reduce the immobility time of the forced swimming test in mice and has certain antidepressant activity.
  • TST Suspension test
  • mice Male ICR mice were used in the experiment.
  • the body weight (20 ⁇ 2) g was purchased from the Experimental Animal Center of Shanghai Institute of Materia Medica, Chinese Academy of Sciences, free access to drinking water, room temperature (23 ⁇ 2) ° C, natural light. All mice were randomly divided into a blank control group and a test group, with 10 rats in each group and 5 cages/cage. The experiment was started after 3 days of adaptation in the breeding environment. The rats were fasted for 12 hours before the experiment and the drinking water was free.
  • the specific administration method was intragastric administration, and a group of the blank control group was given an equal volume of 0.5% CMC-Na at a dose of 10 mg/Kg.
  • mice spontaneous activity of the mice was measured by the open field method, that is, the mice were individually placed in a cylindrical glass jar, timed for 4 minutes, and the number of lifting arms within 2 minutes after recording was recorded. Then use the tape to stick the tail of the mouse to the horizontal bar 2 cm from the tip of the tail, and isolate the animal's line of sight with the plate around.
  • the horizontal bar is about 25 cm from the ground, so that the mouse is about 10 cm from the ground, and the time is 6 min. The accumulated time was accumulated in minutes, and each group of mice was operated in parallel.
  • Experimental data processing Experimental results are expressed as mean ⁇ standard error (x ⁇ SD). Statistical analysis was performed using the t test to determine whether it was significant. First, the t-test was performed on the index of autonomic activity, and P>0.05 indicated that the autonomous post-movement of the mice had no effect, so as to avoid the interference of the central stimulant. Then, the t-test was performed on the hanging tail experimental index to determine whether it has an anti-depressant effect.
  • timosaponin A1 and saponin could not significantly reduce the time of mouse tail suspension in the mouse tail suspension model, and there was no statistically significant difference.
  • the timosaponin A3, 3-cyclohexylureidosaponin (Example 20), Compound C-11, and Compound C-12 all significantly reduced the immobility time of the mouse tail suspension experiment.
  • timosaponin A3, 3-cyclohexylureidosaponin (Example 20) and Compound C-12 have significant antidepressant activity (P ⁇ 0.05); Compound C-11 has extremely significant antidepressant activity. (P ⁇ 0.01).
  • the experimental results of the compound C-7 are shown in Table 11. Compared with the blank group, the compound C-7 can reduce the immobility time of the mouse tail suspension experiment and has certain antidepressant activity.
  • the experimental results of the compound C-5 and the compound C-20 are shown in Table 11. Compared with the blank group, the compound C-5 and the compound C-20 can reduce the immobility time of the mouse tail suspension experiment and have certain antidepressant activity.
  • the experimental results of the compound C-19 are shown in Table 13. Compared with the blank group, the compound C-19 can reduce the immobility time of the mouse tail suspension experiment and has certain antidepressant activity.
  • timosaponin A1 and saponin spirostrobin-type timosaponins known as timosaponin A1 and saponin in nature have no antidepressant effect on both animal models; Anthraquinone saponin A3 is only effective in the tail-hanging model, but has no effect on the forced swimming model. It can be seen that the natural product, timosaponin A3, is not potent and has significant toxicity (Acta Pharmacologica Sinica 2014; 35 (9): 1188-1198.).
  • the compounds of the invention showed significant antidepressant activity in both animal models.
  • the compound C-12 and 3-cyclohexylureidosaponin (Example 20) of the present invention all showed significant antidepressant activity (P ⁇ 0.05), and the compound C-11 had a pole.
  • the compound C-12 and 3-cyclohexylureidosaponin (Example 20) of the present invention all showed significant antidepressant activity (P ⁇ 0.05), and the compound C-11 was extremely remarkable.
  • the compounds of the invention C-13, compound C-23, compound C-5, compound C-7, compound C-19, compound C-20 also have significant or certain Antidepressant activity.
  • Compound C-49 of the present invention showed significant antidepressant activity (P ⁇ 0.05) in the forced swimming model.
  • both the compound C-35 and the compound C-49 of the present invention showed significant antidepressant activity (P ⁇ 0.05).
  • Compound C-49 showed significant antidepressant activity in both animal models.
  • mice 24 hours before the administration, the mice were placed in a cylindrical cylinder to accommodate the underwater environment for 15 min.
  • animals were dosed twice and administered orally 4 h and 1 h before the behavioral test.
  • the mice were individually placed in a cylindrical glass jar, timed for 6 minutes, and the number of lifts was recorded within 2 minutes after recording.
  • the mice were then placed in a cylindrical glass jar 30 cm high and 20 cm in diameter.
  • the water depth in the cylinder was 15 cm (the rat water depth was 20 cm), so that the animal could not escape the glass jar, and the feet and tail did not.
  • mice The 6-minute video of the mice after entering the water, since most animals are very active at the beginning of two minutes, the immobility time is calculated 4 minutes after the calculation (determination of the standard: the mice stop struggling in the water, do not move and maintain balance or present Small limb movements in a floating state). Each group of mice was operated in parallel.
  • mice On the day of the behavioral test, animals were dosed twice and administered orally 4 h and 1 h before the behavioral test. During the experiment, the tail of the mouse was about 1 cm away from the end with a tape or a clip, and was hung on a suspension test stand about 15 cm away from the ground. The mice struggled to overcome the abnormal posture, but after a period of activity, intermittent Do not move, showing disappointment, each group of experimental time is 6 minutes. Since most of the mice struggled with excitement for the first two minutes, the remaining time was 4 minutes.
  • Rats were placed in a cylindrical cylinder for 15 min in the water environment 24 hours before administration. On the day of the behavioral test, animals were dosed twice and administered orally 4 h and 1 h before the behavioral test. The rats were individually placed in a cylindrical glass jar, timed for 6 minutes, and the number of lifts was recorded within 2 minutes after recording. Then the rats were placed in a cylindrical glass jar with a height of 30 cm and a diameter of 20 cm. The water depth in the cylinder was 20 cm, so that the animal could not escape the glass cylinder, and the feet and tail did not touch the bottom of the cylinder. °C-25 °C. The 6-minute video of the rats after entering the water was taken.
  • the immobility time was calculated 4 minutes after the calculation (determination of immobility criteria: the state of the rat in the water was classified as immobility, swimming (swimming) and climbing (climbing) three states, counting the equal scores of these three states, counting every 5 seconds, a total of 5 minutes, a total of 60 times).
  • mice were dosed twice and administered orally 4 h and 1 h before the behavioral test.
  • the tail of the rat was about 1 cm away from the end with a tape or a clip, and was hung on a suspension test stand about 15 cm away from the ground.
  • the rat struggled to overcome the abnormal position, but after a period of activity, intermittent Do not move, showing disappointment, each group of experimental time is 6 minutes. Since the rats were mostly struggling with excitement in the first two minutes, the remaining time was not measured for 4 minutes.
  • CD-1 Male CD-1, which has passed 4-6 months of childbearing age, is raised separately, allowing it to eat freely and adapt to the environment for a week or so. 8-20 weeks old male C57 was used to screen for aggressive CD-1 mice. C57-screened mice were placed directly in the cage of CD-1, exposed to it for 3 minutes, and CD-1 began to show The offensive latency was followed by removal of C57 screening mice. For each CD-1 mouse, the same C57-screened mice were repeated three times a day, and different C57-selected mice were selected every day for a total of three days of screening. Selective offensive mice based on each CD-1 exhibiting an aggressive latency: CD-1 mice must exhibit an attack in at least two consecutive sessions within three 3-minute exposure sessions of each day of the day.
  • each C57 test mouse was exposed to different CD-1 aggressive mice daily for 10 minutes for 10 consecutive days. During transient exposure, all test mice exhibited stress and compliance characteristics including vocalization, escape response, and compliance posture. After 10 minutes of contact, the test mice were isolated from the invaders. Test mice and aggressive mice were placed in adjacent sections of the same squirrel cage, separated by a porous transparent plastic baffle, allowing test mice to be exposed to threatening chronic stress for the next 24 hours. stimulate. Control mice were placed in cages of the same structure, but the other side of the baffle was placed on other mice of the same line that were replaced daily.
  • SI ratio time in the interaction area when the aggressor exists / time in the interaction area when the aggressor is absent. If the SI ratio is less than 1, it indicates that the test mice have less time in the interactive area in the presence of the invader than in the absence of the aggressor and are used as criteria and thresholds for identifying susceptible mice. All selected test mice and control mice were then housed individually for 3 weeks.
  • mice were randomly divided into three groups: DEFEAT depression model group was given 0.5% CMC-Na per day, C- 11 The administration group was intragastrically administered with 10 mg/kg C-11 every day, and the FLX administration group was given 10 mg/kg fluoxetine intraperitoneally every day. Vehicles in the Vehicle group were given 0.5% CMC-Na intragastrically daily. The SI ratio is assessed once a week.
  • the test results are shown in Figure 5.
  • A illustrates the pharmacodynamic evaluation of a socially depressed depression mouse model, and the mouse social time is calculated.
  • the results showed that C-11 significantly increased the social time of the mice during the second week of dosing, while fluoxetine did not work during the third week of dosing.
  • B shows the social proportion of mice, the larger the value indicates the better the social behavior of the animals.
  • C-11 can effectively increase the social activity of mice in the first week of dosing, while fluoxetine administration has not been effective for three weeks.
  • C shows the results of the open field experiment, and there is no significant change in the moving distance between the animals in each group, suggesting that there is no difference in the exercise ability of each group of animals, and it will not affect social behavior.
  • the specific experimental procedures are as follows: healthy male SD rats weighing about 270 g, fasting for 10 h before administration, and free drinking water.
  • C-49 CMC-Na solvent suspension
  • the tail vein was injected with C-49 (10% ethanol/15% Tween 80/75% normal saline to prepare a solution) at a dose of 1 mg/kg rat body weight.
  • the time point of blood collection from the eyelid was 5 min, 10 min, 30 min, 1 h.
  • the drug time curve is shown in Figure 6, and the drug action parameters are shown in Table 16 below.
  • the anti-depressant activity of spirostrobin-type timosaponins and their aglycones is weak, and the bioavailability is relatively low.
  • the compounds C-11, C-49 and the like obtained in the present application have better antidepressant activity than the lead compound saponins.
  • the bioavailability of the compound C-49 was 11.1%, which was also greatly improved.
  • Learning memory is an advanced function of the human and animal brains.
  • this screening test by comparing the passive avoidance behavior of the administered mice and memory-impaired mice, it is possible to initially evaluate whether the candidate drugs have a learning and memory effect.
  • ethanol-induced memory reproduction disorder in mice was used to explore the role of candidate drug C-49 in promoting learning and memory.
  • the experimental principle is that ethanol has a central inhibitory effect, which can inhibit the neurological activity of the cerebral cortex and significantly interfere with the reproduction of memory. Before the retesting after training, the mouse ethanol solution can block the memory reproduction process of the animal, resulting in memory reproduction disorder.
  • mice 16-18 g, were purchased from Shanghai Xipuer-Bikai Experimental Animal Co., Ltd.
  • Animal feeding Animals are fed standard sterilized rat feed, animal drinking water is supplied by drinking water bottle, and animals are free to drink water.
  • Animal feeding 10 animals per cage. The animals were set at room temperature of 20 ° C to 22 ° C, humidity of 40% to 70%, and light and dark for 12 hours. The litter is replaced at least twice a week, and the feeding box is replaced at the same time. When there is an abnormal situation, the feeding box can be replaced at any time. Disinfect the drinking water bottle and stopper every day and disinfect the cage once every two weeks. All the washed cages are autoclaved after washing.
  • mice Forty male mice were divided into 4 groups by Excel, and 10 animals in each group.
  • Group 1 mice (blank group)
  • group 2 mice (model group) were given oral drinking water by oral gavage (ig) every day
  • group 3 mice (positive drug group) ig were given donepezil 1.6 mg/kg
  • the mice in each group were intragastrically administered with the corresponding C-49 solution at a dose of 15 mg/kg.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Veterinary Medicine (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种菝葜皂苷元衍生物及其制备方法和应用，该衍生物的结构如式I所示，其中各取代基的定义如说明书和权利要求书所述。本发明的衍生物可以用于防护、处理、治疗或减轻抑郁症等多种疾病、病症。

Description

一种菝葜皂苷元衍生物及其制备方法和应用 技术领域
本发明涉及药物领域，具体涉及一种菝葜皂苷元衍生物或其药学上可接受的盐、溶剂化合物、光学异构体和立体异构体，及其制备方法和应用。
背景技术
抑郁症是危害人类健康的常见病和多发病。在我国，情感性精神病的发病率为0.76％。抑郁症的发病率很高，但现在对它的发病原因仍不十分清楚。传统观点认为，抑郁症的发病机理与脑内单胺类神经递质异常有关，其中包括5-羟色氨、乙酰胆碱和儿茶酚胺类，去甲肾上腺素和肾上腺素。临床上当前应用较为常用的抗抑郁药物有：三环和四环类抗抑郁药、单胺氧化酶抑制剂、选择性5-HT重吸收抑制剂(SSRI)、非典型抗抑郁药和锂盐等。中医认为，抑郁症多因忧思过度，劳伤心脾为病，治疗应以宁心安神，养血滋阴为主。因此，在大部分用于中医治疗抑郁症的处方中，知母也是一味较为常用的中药材。
阿尔兹海默病(Alzheimer’s Disease,AD)是老年痴呆症的主要类型。AD的临床主要表现为进行性的认知衰退及情绪紊乱的加重等一系列症状，包括短时记忆、言语功能、生活习惯及注意力等。目前AD的发病机制不清，因此，迄今为止，可供选择的AD药物治疗手段是十分有限的，且用于治疗AD的药物主要针对认识行为症状的改善，其中主要包括：(1).改善胆碱能神经传递，其中主要是胆碱酯酶抑制剂；(2).N-甲基-D-天冬氨酸(NMDA)受体拮抗剂：如美金刚。临床一线非常缺乏有效治疗AD的药物。
中药材知母主要的化学成分有甾体皂苷、双苯吡喃酮类、多糖类和木质素类等，如：知母皂苷(甙)(timosaponin)A-Ⅰ、A-Ⅱ、A-Ⅲ、A-Ⅳ、B-Ⅰ、B-Ⅱ和B-Ⅲ，其中，知母皂苷A-Ⅱ、A-Ⅳ结构尚不明；以及知母皂苷(amemarsaponin)A2，即马尔考皂苷元-3-O-β-D-吡喃葡萄糖基(1→2)-β-D-吡喃半乳糖苷B(marlogenin-3-O-β-D-glucopyranosy(1→2)-β-D-galactopyranoside B)、去半乳糖替告皂苷(desgalactotigonin)、F-芰脱皂苷(F-gitonin)和异菝葜皂苷(smilageninoside)等。此外，还含有知母多糖(anemaran)A/B/C/D、顺-扁柏树脂酚(cis-hinokiresinol)、单甲基-顺-扁柏树脂酚(monomethyl-cis-hinokiresinol)、氧化-顺-扁柏树脂酚(oxy-cis-himokiresinol)、2,6,4'-三羟基-4-甲氧基二苯甲酮(2,6,4'-trihydroxy-4-methoxy benzophenone)、对-羟苯基巴豆油酸(p-hydroxyphenyl crotonic acid)、二十五烷酸乙烯脂(pentacosyl vinyl ester)、β-谷甾醇(β-sitosterol)、芒果苷(mangiferin)、烟酸(nicotinic acid)、烟酰胺(nicotinamide)及泛酸(pantothenic acid)等。
近来相关研究还表明，知母皂苷在抗老年痴呆症状、抗衰老、抗抑郁等方面有一定的作用。知母总皂在多种抑郁模型上具有抗抑郁作用，可能与其增强去甲肾上腺素能及5-羟色胺能神经系统有关(中药新药与临床药理，2007，18，29)。通过动物实 验验证，知母中所含有的菝葜皂苷元对小鼠实验性抑郁有一定作用，可以影响小鼠脑内多巴胺和单胺氧化酶的活性，而使该类皂苷元具有抗抑郁活性(Biol.Pharm.Bull.,2006,29,2304-2306)。伊佳等人的研究发现，知母皂苷B-Ⅱ具有抗抑郁活性，其作用机制可能与增强脑内5-HT和DA神经系统作用有关(CN101214253A；药学实践杂志，2010，28，283-287)。
本领域还需要对抗抑郁化合物进行深入研究和开发。
发明内容
本发明的目的在于提供一种菝葜皂苷元衍生物及其药学上可接受的盐。
本发明的第一方面，提供一种式I所示的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体、立体异构体或它们的混合物，
Figure PCTCN2018124690-appb-000001
所述式I所示的化合物由以下片段A和片段B连接而成，
Figure PCTCN2018124690-appb-000002
其中，R 1、R 2、R 3各自独立地选自氢、烷基、取代的烷基、芳基烷基、取代的芳基烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环，
或者R 1、R 2、R 3中的任两个与相连的N形成含有1-3个N、0-2个O和/或0-2个S原子的3-7元饱和或不饱和杂环，所述“杂环”未取代或者被以下基团单取代或者多取代：氢、烷基、取代的烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、 炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环基、取代的杂环基、烷酰基、取代的烷酰基、烷氧基羰基、芳基烷氧基羰基、烷基磺酰基、烷基亚磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基、羧基、酰胺、取代的酰胺、磺酰胺基、取代的磺酰胺基，
Figure PCTCN2018124690-appb-000003
表示单键或者双键
R 6a、R 6b、R 6c、R 6d、R 6e、R 6f、R 7a、R 7b、R 8a、R 8b、R 9a、R 9b、R 10a、R 10b各自独立地选自无、氢、卤素、烷基、取代的烷基、羟基、巯基、烷基巯基、烷氧基、取代的烷氧基、氨基、取代的氨基、烷基氨基、取代的烷基氨基、二取代的氨基、烷基酰氧基、芳基酰氧基、杂芳基酰氧基、糖基，或者R 6a、R 6b两两之间和/或R 7a、R 7b两两之间和/或R 8a、R 8b两两之间和/或R 9a、R 9b两两之间和/或R 10a、R 10b两两之间合并成羰基；
X 1为O、S或NR 5，R 5选自氢、烷基、氰基、羟基、烷氧基，
Figure PCTCN2018124690-appb-000004
表示单键或者无；
当
Figure PCTCN2018124690-appb-000005
为单键时，X 2为O或NH，R 4a、R 4b各自独立地选自氢、羟基、烷基、取代的烷基、链烯基、取代的链烯基、炔基、取代的炔基，或者R 4a、R 4b与相连的C形成含有0-3个N、0-2个O和/或0-2个S原子的3-7元饱和或不饱和杂环，所述“杂环”未取代或者被以下基团单取代或者多取代：氢、羟基、烷基、取代的烷基、链烯基、取代的链烯基、炔基、取代的炔基；
当
Figure PCTCN2018124690-appb-000006
为无时，X 2为OR h、N(R i)(R j)，R 4a、R 4b与连接的碳共同形成-X aR k，Xa为CH 2或者C＝O，R h、R i、R j、R k各自独立选自氢、烷基、取代的烷基、环烷基、取代的环烷基、烷酰基、取代的烷酰基、烷氧基羰基、烷氧基羰基、烷胺基羰基、芳基烷氧基羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基、羧基、酰胺、取代的酰胺；
各*独立地表示消旋、S或R构型。
在另一优选例中，R 2为氢时，R 3为烷基、取代的烷基、环烷基、取代的环烷基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环基；或者R 2、R 3与相连的N形成以下结构：
Figure PCTCN2018124690-appb-000007
其中，X 3为C＝O、CH 2、O或NR 11，R 11选自烷基、取代的烷基、芳基烷基、取代的芳基烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环、烷酰基、取代的烷酰基、烷氧基羰基、芳基烷氧基羰基、氨基甲酰基、取代的氨基甲酰基、羧基、烷基磺酰基、烷基亚磺酰基、芳基磺酰基、芳基烷基磺酰基、酰胺、取代的酰胺、磺酰胺基、取代的磺酰胺基；
n＝0、1或2。
在另一优选例中，R 2、R 3各自独立地选自氢、环烷基、取代的环烷基、杂环基、取代的杂环基、芳基、取代的芳基、-MX 3PX 5Q，其中，
M为亚烷基、取代的亚烷基、亚环烷基、取代的亚环烷基，
X 3选自O、S、(CH 2) r、NRa或者无，Ra选自氢、烷基、取代的烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环，r＝1、2、3、4或5；
P为C＝O、C＝S、C＝NR b、C＝C(R c)(R d)或者无，R b选自氢、羟基、烷氧基、氰基、硝基，R c、R d独立选自氢、烷基、羟基、烷氧基、氰基、硝基，
X 5选自O、S、(CH 2) m、NRe或者无，Re选自氢、烷基、取代的烷基，m＝1、2、3、4或5，
Q为氢、羟基、烷氧基、芳氧基、NR fR g、烷基、取代的烷基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环基、取代的杂环基，R f、R g相互独立，为氢、羟基、烷基、烷氧基、取代的烷基、链烯基、取代的链烯基、炔基、取代的炔基、烷氧基羰基，或者R f、R g两两之间形成含有0-3个N、0-2个O和/或0-2个S原子的3-7元饱和或不饱和杂环，此“杂环”未取代或者被以下基团单取代或者多取代：氢、羟基、氨基、烷基、取代的烷基、链烯基、取代的链烯基、炔基、取代的炔基。
在另一优选例中，所述片段B选自下组：片段B1-片段B20，式中，X 4为CH 2OR 12、CH 2N(R 13)(R 14)、醛基、COOR 12、CON(R 13)(R 14)，R 12、R 13、R 14相互独立，选自氢、烷基、取代的烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环、烷酰基、取代的烷酰基、烷氧基羰基、芳基烷氧基羰基、烷基磺酰基、烷基亚磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基；X 6为OR 15、N(R 16)(R 17)，R 15、R 16、R 17相互独立，选自氢、烷基、取代的烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环、烷酰基、取代的烷酰基、烷氧基羰基、芳基烷氧基羰基、烷基磺酰基、烷基亚磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基，X 7为CH 2或者C＝O。
在另一优选例中，R 1、R 2、R 3各自独立地选自氢、C3-C8环烷基、C6-C10芳基、C3-C8的饱和杂环基、C1-C4烷基，其中环烷基、芳基、饱和杂环基、烷基任选地被选自下组的基团单取代、二取代或三取代：卤素、羟基、C1-C4烷基、C6-C10芳基、-C(＝O)-O-C1-C4烷基；或者R 2、R 3与相连的N形成含有1-3个N、0-2个O和/或0-2个S原子的3-7元饱和或不饱和杂环，所述“杂环”未取代或者被以下基团单取代或者多取代：氢、C1-C4烷基、C1-C4烷氧基、C2-C4烯基、C2-C4炔基、羟基；
R 4a、R 4b各自独立地选自氢、羟基、取代或未取代的C1-C6烷基，所述取代是指具有选自下组的一个、两个或三个取代基：卤素、羟基、C1-C4烷基、C1-C4烷氧基；或者R 4a、R 4b与相连的C形成含有1-2个O和/或1-2个S原子的3-7元饱和或不饱 和杂环，所述“杂环”未取代或者被以下基团单取代或者多取代：氢、C1-C4烷基、C1-C4烷氧基、C2-C4烯基、C2-C4炔基、羟基；
X 1为O、S、NR 5，R 5选自氢、烷基、羟基，
R 6a、R 6b、R 6c、R 6d、R 6e、R 6f、R 7a、R 7b、R 8a、R 8b、R 9a、R 9b、R 10a、R 10b为无、氢、烷基、取代的烷基、羟基或巯基，或者R 6a、R 6b两两之间和/或R 7a、R 7b两两之间和/或R 8a、R 8b两两之间和/或R 9a、R 9b两两之间和/或R 10a、R 10b两两之间合并成羰基，
Figure PCTCN2018124690-appb-000008
表示单键或者双键。
在另一优选例中，X 1为O。
在另一优选例中，R 2、R 3各自独立地选自氢、C3-C12环烷基、C6-C10芳基、C3-C8的饱和杂环基、C1-C4烷基，其中环烷基、芳基、饱和杂环基、烷基任选地被选自下组的基团单取代、二取代或三取代：卤素、羟基、羧基、C1-C4烷基、C6-C10芳基、3-8元杂芳基、-C(＝O)-OC1-C4烷基、3-7元饱和或不饱和杂环、-NR f1R g1、-C(＝O)NR f1R g1、-O-C(＝O)(C1-C4亚烷基)NR f1R g1、-O-C(＝O)(3-8元杂芳基)、-NHCO(C1-C4亚烷基)N R f1R g1、-NHCON R f1R g1，
各R f1、各R g1相互独立选自：氢、C1-C4烷基、-C(＝O)C1-C6烷基、-C(＝O)(3-8元杂芳基)、-C(＝O)(C1-C4亚烷基)(3-8元杂芳基)，其中烷基为未取代的或被选自下组的基团取代：羟基、氨基、羧基、N(C1-C4烷基)(C1-C4烷基)；或者R f1与R g1与相连的N形成3-8元的饱和杂环，任选被以下基团取代：C1-C4烷基、C1-C4烷氧基、卤素、羟基、氨基；
或者R 2、R 3与相连的N形成含有1-3个N、0-2个O和/或0-2个S原子的3-7元饱和或不饱和杂环；
所述“杂环”未取代或者被以下基团单取代或者多取代：氢、C1-C4烷基、C1-C4烷氧基、羟基、3-8元杂芳基。
在另一优选例中，R 3为苯基、环己基、环戊基、金刚烷基、C1-C4烷基，C3-C8的饱和杂环，上述基团任选被选自下组的基团取代：羟基、C1-C4烷基、卤素、苯基、-C(＝O)-OC1-C4烷基。
在另一优选例中，R 2为氢或取代或未取代的C1-C4烷基，取代基选自下组：羟基、氨基、-NHCO(C1-C4亚烷基)N R f1R g1，其中各R f1、各R g1相互独立选自：氢、C1-C4烷基。
在另一优选例中，当
Figure PCTCN2018124690-appb-000009
为无时，X 2为羟基、氨基或-OCOCH 3；R 4a、R 4b与连接的碳共同形成-X aR k，X a为CH 2、CHOH或者C＝O，R k为取代或未取代的C1-C8的烷基，取代基选自下组：羟基、羧基、氨基、C3-C6环烷基。
在另一优选例中，X 1为O；
R 1为氢；
R 6a、R 6b、R 6c、R 6d、R 6e、R 6f、R 7a、R 7b、R 8a、R 8b、R 9a、R 9b、R 10a、R 10b均为氢；
R 2、R 3各自独立地选自氢、C3-C8环烷基、C6-C10芳基、C3-C8的饱和杂环基、C1-C4烷基，其中环烷基、芳基、饱和杂环基、烷基任选地被选自下组的基团单取代、二取代或三取代：卤素、羟基、C1-C4烷基、C6-C10芳基、-C(＝O)-OC1-C4烷基；或者R 2、R 3与相连的N形成含有1-3个N、0-2个O和/或0-2个S原子的3-7元饱和或不饱和杂环，所述“杂环”未取代或者被以下基团单取代或者多取代：氢、C1-C4烷基、C1-C4烷氧基、羟基。
在另一优选例中，片段B为片段B1-片段B8中的任一片段。
在另一优选例中，R 1为H、R 2为H、R 3为环己基。在另一优选例中，片段B为片段B1、片段B3、片段B5或片段B7。
在另一优选例中，X 1为O；
R 1为氢；
R 6a、R 6b、R 6c、R 6d、R 6e、R 6f、R 7a、R 7b、R 8a、R 8b、R 9a、R 9b、R 10a、R 10b均为氢；
R 2为环己基、环戊基、金刚烷基；
片段B为
Figure PCTCN2018124690-appb-000010
R 3为-MX 3PX 5Q，其中，
M选自C1-C4亚烷基，
X 3选自O、NRa或者无，Ra选自氢、烷基，
P为C＝O或者无，
X 5选自O、(CH 2)m、NRe或者无，Re选自氢、烷基、取代的烷基，m＝0,1,2,3,
Q为氢、羟基、烷氧基、氨基、烷基、取代的烷基、NR fR g，R f、R g相互独立，为氢、烷基、取代的烷基，或者R f、R g两两之间形成含有0-3个N、0-2个O和/或0-2个S原子的3-7元饱和或不饱和杂环，此“杂环”未取代或者被以下基团单取代或者多取代：氢、羟基、氨基、烷基、取代的烷基、链烯基、取代的链烯基、炔基、取代的炔基。
在另一优选例中，所述化合物为实施例中制备的任一化合物。
在另一优选例中，所述化合物为：
Figure PCTCN2018124690-appb-000011
Figure PCTCN2018124690-appb-000012
Figure PCTCN2018124690-appb-000013
Figure PCTCN2018124690-appb-000014
Figure PCTCN2018124690-appb-000015
在另一优选例中，所述化合物为实施例中制备的任一化合物。
在另一优选例中，片段A为
Figure PCTCN2018124690-appb-000016
其中，R 3a选自环己烷基、环戊烷基、环丁烷基、苯基；
R 3b选自氢、(C1-C6)烷氧基羰基、羧基；
R 2a选自氢以及
Figure PCTCN2018124690-appb-000017
R 2b选自氢、羟基、氨基、-OC(＝O)R 2c、-NHC(＝O)R 2c、-NHC(＝O)NHR 2c，R 2c选自
Figure PCTCN2018124690-appb-000018
Figure PCTCN2018124690-appb-000019
q＝0，1，2或3；
片段B选自下组：
Figure PCTCN2018124690-appb-000020
在另一优选例中，所述化合物为：
Figure PCTCN2018124690-appb-000021
Figure PCTCN2018124690-appb-000022
在另一优选例中，片段A为
Figure PCTCN2018124690-appb-000023
其中
R 3c选自环己烷基、环戊烷基、环丁烷基、氢、甲基、苯基或者取代的苯基，取代基选自氟、氯、溴、碘、氰基、羟基、甲氧基、三氟甲基、三氟甲氧基；
D选自
Figure PCTCN2018124690-appb-000024
或者D与R 3c相连形成含有1个N的3-7元饱和杂环，
R 3d选自
Figure PCTCN2018124690-appb-000025
Figure PCTCN2018124690-appb-000026
片段B选自下组：
Figure PCTCN2018124690-appb-000027
在另一优选例中，所述化合物为：
Figure PCTCN2018124690-appb-000028
Figure PCTCN2018124690-appb-000029
Figure PCTCN2018124690-appb-000030
在另一优选例中，片段A为
Figure PCTCN2018124690-appb-000031
其中
R 3e选自环己烷基、环戊烷基、环丁烷基、氢、甲基、苯基或者取代的苯基，取代基选自氟、氯、溴、碘、氰基、羟基、甲氧基、三氟甲基、三氟甲氧基，
R dd为O或NH；
D选自
Figure PCTCN2018124690-appb-000032
或者与R 3e相连形成含有1个N的3-7元饱和杂环，
R 3f选自下组：氢、氨基、C1-C6烷基氨基、取代的C1-C6烷基氨基、C3-C6环烷基氨基、取代的C3-C6环烷基氨基、C1-C6烷基、取代的C1-C6烷基、C3-C6环烷基、取代的C3-C6环烷基、
Figure PCTCN2018124690-appb-000033
Figure PCTCN2018124690-appb-000034
片段B选自下组：
Figure PCTCN2018124690-appb-000035
在另一优选例中，所述化合物选自下组：
Figure PCTCN2018124690-appb-000036
Figure PCTCN2018124690-appb-000037
Figure PCTCN2018124690-appb-000038
Figure PCTCN2018124690-appb-000039
Figure PCTCN2018124690-appb-000040
Figure PCTCN2018124690-appb-000041
Figure PCTCN2018124690-appb-000042
本发明的第二方面，提供第一方面所述的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体或立体异构体的制备方法，所述制备方法包括以下步骤：
Figure PCTCN2018124690-appb-000043
(a)3-氨基甾体配基与异氰酸酯反应得到第一方面所述的化合物，其中R 1和R 2为氢，其他取代基的定义如第一方面所述。
上述3-氨基甾体配基可以为光学纯手性化合物或者各种比例混合的光学纯手性化合物。当为各种比例混合的光学纯手性化合物时，所述制备方法还包括对步骤a)得到的第一方面所述的化合物进行拆分得到光学纯手性化合物的步骤。
本发明的第三方面，提供第一方面所述的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体或立体异构体的制备方法，所述制备方法包括以下步骤：
Figure PCTCN2018124690-appb-000044
Figure PCTCN2018124690-appb-000045
(i)由3-氨基甾体配基制备3-异氰酸酯甾体化合物；
(ii)3-异氰酸酯甾体化合物与NHR 2R 3反应生成权利要求1所述的化合物，其中R 1为氢，其他取代基的定义如第一方面所述。
在另一优选例中，所述制备方法还包括以下步骤：
(iii)所得到的产物可以经过进一步的化学反应得到新化合物，-NHBoc取代基脱除Boc反应得到-NH 2，-COOCH 3取代基水解得到-COOH。
上述3-氨基甾体配基可以为光学纯手性化合物或者各种比例混合的光学纯手性化合物。当为各种比例混合的光学纯手性化合物时，所述制备方法还包括对步骤ii)得到的第一方面所述的化合物进行拆分得到光学纯手性化合物的步骤。
在另一优选例中，本发明化合物采用以下路线合成：
Figure PCTCN2018124690-appb-000046
本发明的第四方面，提供一种药物混合物，所述药物混合物包含选自下组的两种或三种以上的化合物：第一方面所述的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体、立体异构体。
在另一优选例中，所述药物混合物是化合物C-1至化合物C-32中任意两种或三种以上化合物的混合物。
本发明中药物混合物中的组分可以以任意质量比例进行混合。例如，当药物混合物是化合物C-1至化合物C-32中任意两种化合物的混合物时，质量比例为0.01:0.99-0.99:0.01，较佳为1:9-9:1、2:8-8:2、3:7-7:3或4:6-6:4。
本发明的第五方面，提供一种药物组合物，所述药物组合物包含第一方面所述的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体或立体异构体，或第四方面所述的药物混合物；以及药学上可接受的载体。
在另一优选例，药物组合物可以更进一步地包含附加治疗剂，这些附加治疗剂选自：抗抑郁药、抗躁狂药、帕金森病治疗药、阿尔兹海默病治疗药或它们的组合。
在另一优选例，药物组合物可以更进一步地包含附加治疗剂，所述的附加治疗剂是吗氯贝胺、托洛沙酮、氟西汀、帕罗西汀、西酞普兰、舍曲林、文拉法辛、曲米帕明、曲唑酮、丙咪嗪、地昔帕明、氯米帕明、阿米替林、去甲替林、多塞平、马普替林、洛沙平、阿莫沙平、米氮平、丁螺环酮、氯美扎酮、坦度螺酮、碳酸锂、他克林、石杉碱甲、加兰他敏、多奈哌齐、力帆斯的明、美金刚、普拉克索、他利克索、罗匹罗尼，或它们的组合。
本发明的化合物可以单独使用，或者与其他治疗剂联合使用。联合治疗可以提供协同作用，即当活性成分一起使用时达到的效果，大于分别使用所述化合物所产生效果的加和。所述联合治疗可以以同时或连续的方案施用。当连续施用时，所述组合可以以两种或多种用法来施用。化合物可以再单一的药物组合中一起施用，或分开施用，且当分开施用时，可以同时地或以任意次序先后地进行。
本发明化合物可以通过适宜所治疗病况的任何途径施用。适宜的途径包括但是不局限于口腔、胃肠外(包括皮下、肌内、静脉内、动脉内、皮内)、阴道、腹膜内、肺内和鼻内。应当理解，优选的途径可以因例如病人的病况变化。当所述化合物经口施用时，可以将其与药学上可接受的载体或赋形剂配制成丸剂、胶囊剂、片剂等。当所述化合物配制成胃肠外时，其可以与药学上可接受的胃肠外载体配制。
本发明可以以任意方便的制剂形式施用化合物，本发明所称的“制剂”是指含有本发明通式I化合物的有利于给药(drug delivery)的剂型，如：但不仅限于，水溶液注射剂、粉针剂、丸剂、散剂、片剂、贴剂、栓剂、乳剂、霜剂、凝胶剂、颗粒剂、胶囊剂、气雾剂、喷雾剂、粉雾剂、缓释剂和控释剂等。这些药用辅料既可以是各种制剂中常规使用的，如：但不仅限于，等渗剂、缓冲液、矫味剂、赋形剂、填充剂、粘合剂、崩解剂和润滑剂等；也可以是为了与所述物质相适应而选择使用的，如：乳化剂、增溶剂、抑菌剂、止痛剂和抗氧剂等，这类辅料能有效提高组合物所含化合物 的稳定性和溶解性或改变化合物的释放速率和吸收速率等，从而改善本发明化合物在生物体内的代谢，进而增强给药效果。此外，还可以为实现特定的给药目的或方式，如：缓释给药、控释给药和脉冲给药等，而使用的辅料，如：但不仅限于，明胶、白蛋白、壳聚糖、聚醚和聚酯类高分子材料，如：但不仅限于，聚乙二醇、聚氨酯、聚碳酸酯及其共聚物等。所称的“有利于给药”的主要表现有：但不仅限于提高治疗效果、提高生物利用度、降低毒副作用和提高患者顺应性等。
本发明的第六方面，提供第一方面所述的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体或立体异构体，第四方面所述的药物混合物物或第五方面所述的药物组合物的用途，用于制备防护、处理、治疗或减轻患者疾病、病症或病状的药物的用途，所述的疾病、病症或病状选自抑郁症、焦虑症、帕金森病、阿尔兹海默病、亨廷顿病、精神分裂症、躁狂症、癌症、瘤转移、高血糖、高血脂、病毒性病症、细菌感染病症、血管生成性病症、自体免疫疾病、炎症性病症、与器官移植相关联的病状。
在另一优选例中，所述的疾病、病症或病状选自抑郁症、焦虑症、帕金森病、阿尔兹海默病、亨廷顿病、精神分裂症、躁狂症。
在另一优选例中，所述的疾病、病症或病状选自抑郁症、焦虑症、帕金森病、阿尔兹海默病、躁狂症。
在另一优选例中，所述的疾病、病症或病状选自抑郁症。
本发明的第七方面，提供一种预防和/或治疗抑郁症的方法，包括将第一方面所述的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体或立体异构体，第四方面所述的药物混合物物或第五方面所述的药物组合物给予有需要的患者。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为实施例29灌胃给药对ICR小鼠强迫游泳不动时间的影响结果图(“*”表示P＜0.05；“**”表示P＜0.01)。
图2为实施例29灌胃给药对ICR小鼠悬尾不动时间的影响结果图(“*”表示P＜0.05；“**”表示P＜0.01)。
图3为实施例30灌胃给药对大鼠强迫游泳不动时间的影响结果图(“*”表示P＜0.05；“**”表示P＜0.01)
图4为实施例30灌胃给药对大鼠悬尾不动时间的影响结果图(“*”表示P＜0.05；“**”表示P＜0.01)
图5为实施例31灌胃给药化合物C-11对社交失败抑郁动物模型的影响结果图(“*”表示P＜0.05；“**”表示P＜0.01)。
图6为大鼠分别口服和尾静脉注射C-49后药时曲线图。
图7为体重增长图。
具体实施方式
本申请的发明人经过广泛而深入地研究，首次研发出一种结构新颖的化合物，由脲基和甾体配基连接而成，结构如式I所示。本发明的化合物，可以用于防护、处理、治疗或减轻抑郁症等多种疾病、病症。在此基础上，完成了本发明。
术语
下面是本说明书中所用术语的定义。除非另外指出，本文所提供的基团或术语的初始定义适用于本书明说中单独地或作为其他基团的一部分的基团或者术语。
术语“取代的”是指本发明说明书中提到的任一取代基，包括但不限于，卤素、硝基、氰基、羧基、氧代基、烷基、取代的烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环、羟基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷酰基氨基、芳酰基氨基、芳基烷基酰基氨基、杂芳基烷基酰基氨基、氨基烷基酰基氨基、烷基氨基烷基酰基氨基、二烷基氨基烷基酰基氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)、烷酰基、取代的烷酰基、芳酰基、杂芳酰基、羧基、烷氧基羰基、芳氧基羰基、烷氨基羰基、芳氨基羰基、芳基烷氧基羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基、取代烷基氨基甲酰基、酰胺、取代的酰胺、磺酰胺基、取代的磺酰胺基。
术语“卤素”或“卤”是指氟、氯、溴、碘。
术语“烷基”是指直链或者支链未取代的具有1-20个碳原子、优选1-7个碳原子的烃基团。“烷基”的实例包括但是不要局限于甲基、乙基、1-丙基、2-丙基、1-丁基、2-丁基等等。
术语“取代的烷基”是指由1-4个取代基取代的烷基，所述的取代基诸如：卤素、硝基、氰基、羧基、氧代基、烷基、取代的烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环、羟基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷酰基氨基、芳酰基氨基、芳基烷基酰基氨基、杂芳基烷基酰基氨基、氨基烷基酰基氨基、烷基氨基烷基酰基氨基、二烷基氨基烷基酰基氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)、烷酰基、取代的烷酰基、芳酰基、杂芳酰基、羧基、烷氧基羰基、芳氧基羰基、烷氨基羰基、芳氨基羰基、芳基烷氧基羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基、取代烷基氨基甲酰基、酰胺、取代的酰胺、磺酰胺基、取代的磺酰胺基。
术语“亚烷基”其通过从具有1-20个碳原子、优选1-7或1-4个碳原子的烷烃结构的单个碳原子或者两个碳原子上除去两个氢原子得到。
术语“链烯基”是指具有2-20个碳原子、优选2-15个碳原子、最优选2-8个碳原子，且具有1-4个双键的直链或支链烃基团。
术语“取代的链烯基”是指由1-2个取代基取代的链烯基，所述取代基例如：卤素、硝基、氰基、芳基、取代的芳基、杂芳基、取代的杂芳基、
烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)。
术语“炔基”是指具有2-20个碳原子、优选2-15个碳原子、最优选2-8个碳原子，且具有1-4个三键的直链或支链烃基团。
术语“取代的炔基”是指由以下取代基取代的炔基，所述取代基例如：卤素、硝基、氰基、芳基、取代的芳基、杂芳基、取代的杂芳基、羟基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)。
术语“芳基”是指在环部分中具有6-12个碳原子的单环或双环芳烃基团。芳基包括二环基团，该二环将基团中包括稠合至饱和的或部分不饱和的芳族环，或者芳族碳环或杂环的环。通常芳基基团包括但是不局限于以下的基团：苯、萘、蒽、联苯基、1,2-二氢萘、1,2,3,4-四氢萘基等等。
术语“取代的芳基”是指由1-4个取代基取代的芳基，所述取代基例如：卤素、卤素、硝基、氰基、脲基、羧基、三氟甲氧基、三氟甲基、烷基、取代的烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环、羟基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)，烷酰基、取代的烷酰基、烷氧基羰基、芳基烷氧基羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基、酰胺、取代的酰胺、磺酰胺基、取代的磺酰胺基。
术语“环烷基”是指非芳族的、饱和的或部分不饱和的环烃基团，所述环烷基可以任意地被一个或多个本申请所述的取代基取代，其具有3-30个碳原子成为单环的环，或者7-12个碳原子成为二环、三环的环。单环环烷基的实例包括但是不局限于环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、环庚基、环辛基。示例性的成桥二环环烷基包括但是不局限于二环[2.2.1]庚烷、二环[2.2.2]辛烷、二环[3.2.2]壬烷、金刚烷基。
术语“亚环烷基”其通过从环烃结构的单个碳原子或者两个碳原子上除去两个氢原子得到。环烃具有3-30个碳原子，优选3-10个碳原子包括但不限于环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、环庚基、环辛基、二环[2.2.1]庚烷、二环[2.2.2]辛烷、二环[3.2.2]壬烷、金刚烷基。
术语“杂环”、“杂环的”和“杂环基”是指任选取代的、完全饱和的或不饱和的、芳族或非芳族环基团，例如它可以是4-7元单环、7-11元双环或10-15元三环体系，其在至少一个含碳原子的环中具有至少一个杂原子。含杂原子的杂环基的每个环可以具有1、2或3个选自氮原子、氧原子和硫原子的杂原子。所述“杂环基”可以任意地被一个或多个本申请所述的取代基取代，“杂环基”的实例包括但是不局限于吡咯烷基、四氢呋喃基、四氢吡喃基、吗啉代、硫吗啉代、哌嗪基、高哌嗪基、环氧丙烷基、咪唑烷基、3-氮杂二环[3.1.0]己烷基、3-氮杂二环[4.1.0]庚烷基、氮杂二环[2.2.2]己烷基、N-吡啶基脲、嘧啶酮基和1,1-二氧代-硫吗啉基。
术语“杂芳基”是指5-、6-、7-、8、9或10-元环的一价芳香基团，并且包括5-20个原子的稠合系统，含有一个或多个选自氮、氧、磷和硫的杂原子，可以任意地被一个或多个本申请所述的取代基取代。“杂芳基”的实例包括但是不局限于吡啶基、咪唑基、咪唑并吡啶基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、噻唑基、喹啉基、吲哚基等等。
术语“氧代基”代表二价基＝O。
术语“氨基甲酰基”是指-OC(＝O)NH 2基团。
术语“酰胺”是指-C(＝O)NH 2基团。
术语“磺酰胺基”是指-SO 2NH 2基团。
术语“取代的氨基甲酰基”、“取代的酰胺”、“取代的磺酰胺基”是指酰胺、磺酰胺或氨基甲酸酯分别至少有一个氢被选自烷基、取代的烷基、链烯基、取代的链烯基、环烷基、取代的环烷基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环基、取代的杂环基的基团所取代。
术语“可接受的盐”，是指本发明化合物的药学上可接受有机或无机盐。示例性的盐包括但是不局限于硫酸盐、枸橼酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、酸式硫酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式枸橼酸盐、琥珀酸盐、马来酸盐、延胡索酸盐、葡萄糖酸盐、甲酸盐、甲磺酸盐和巴莫酸盐。“可接受的盐”可涉及包括另一分子例如马来酸盐或其他平衡离子。平衡离子在母体化合物中稳定电荷。“可接受的盐”可以有多于一个的荷电原子，多个荷电原子可具有多个平衡离子。
如果本发明化合物是碱，需要的“可接受的盐”可通过适宜的方法制备，例如，用以下的无机酸处理该游离碱：盐酸、氢溴酸、硫酸、硝酸、磷酸；或者用如下的有机酸：乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、水杨酸、吡喃糖苷基酸如葡萄糖醛酸或半乳糖醛酸、α-羟基酸如枸橼酸或酒石酸、氨基酸如谷氨酸、芳香族酸如苯甲酸或肉桂酸、磺酸如甲磺酸或对甲苯磺酸。
如果本发明化合物是酸，需要的“可接受的盐”可通过适宜的方法制备，例如，用如下的无机碱或者有机碱处理该游离酸：胺、碱金属氢氧化物或碱土金属氢氧化物等。适宜的盐的示例性的示例包括但是不限于由氨基酸得到的有机盐，伯、仲、叔胺盐，以及环状胺例如哌啶、吗啉和哌嗪的盐，以及由钠、钙、钾、镁、锰、铁、铜、锌、铝和锂得到的无机盐。
溶剂合物是指一个或多个溶剂分子与本发明化合物的结合物或络合物。形成溶剂合物的溶剂的示例包括但是不局限于水、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸和乙醇胺。本发明化合物可以以非溶剂化形式存在，也可以与药学上可接受的溶剂如水、乙醇等以溶剂化形式存在，所以本发明将包括溶剂化和非溶剂化的形式。
本发明的化合物可以含有不对称中心或手性中心，并且因此存在不同的立体异构体形式。本发明化合物的所有立体异构体形式，包括但不局限于，非对映体、对映体和位阻异构体，以及它们的混合物例如外消旋混合物，将形成本发明的一部分。在本文中，当任何特定手性原子的立体化学未确定时，所有立体异构体均被考虑。此外，本发明涉及所有的几何和位置异构体。本发明化合物可以以不同的互变异构体形式存在，并且所有这些形式均包括在本发明范围内。本发明化合物的所有立体异构体预期包括混合物形式或纯的或基本上纯的形式。可以通过物理方法例如分步结晶、非对映体衍生物的分离或结晶、或者通过HPLC制备柱、手性制备柱拆分制备纯的光学异构体。
本发明所用的HPLC制备柱拆分光学异构体的条件如下：
分析色谱条件如下：
柱子：Waters Xbridge C18 5μm 4.6*250mm；柱温为30℃；流速为1mL/min；流动相：乙腈(A)-水(B)：86％A-95％A 30min；
ELSD检测器：雾化温度为55℃；载气流量：2.4L/min。
制备用色谱条件1如下：
制备色谱柱：选自美国沃特斯Waters Xbridge C18 5μm 10*250mm、Waters Xbridge C18 5μm OBD30*150mm、Waters Xbridge C18 5μm OBD50*150mm、Waters Xbridge C18 5μm OBD50*250mm；
流动相为水和乙腈，线性梯度洗脱程序:0～30min,14％水→5％水；流速为3.0mL/min。流动相在使用前需经,超声脱气；进样量为800ul。
或者制备用色谱条件2如下：
制备色谱柱：选自大赛璐手性制备柱CHIRALPAK AD-H 5μm 20*250mm、CHIRALPAK AD-H 5μm 30*250mm、CHIRALPAK AD 5μm 20*250mm、CHIRALPAK AS-H 5μm 20*250mm、CHIRALCEL OD-H 5μm 20*250mm，
流动相为正己烷和异丙醇，流速为3.0mL/m in。流动相在使用前需经,超声脱气；进样量为600ul。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以被任何提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常 按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数，所有温度均以摄氏度给出，试剂从商业供应商购置或者定制，例如国药、韶远、安耐吉、TCI、Sigma等等。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1
3α-氨基菝葜皂苷元的制备
Figure PCTCN2018124690-appb-000047
称取菝葜皂苷元1.2g，加入30mlDCM溶解，加入2ml吡啶，室温搅拌溶解。冰浴条件下，缓慢滴加0.5ml甲磺酰氯，滴加完毕后，继续在冰浴条件下搅拌0.5h，再慢慢回复到室温继续反应4h。向反应液加入冰水搅拌30min，用DCM萃取，合并有机相无水硫酸钠干燥，硅胶柱层析得到产物1g。将其再次溶解于40mlDMF中，加入800mg的NaN 3，60℃下搅拌12h。冷却到室温，加入冰水搅拌30min，有白色固体析出，过滤，水洗，干燥后硅胶柱层析得到550mg的3α-叠氮基菝葜皂苷元。将其溶解于20mlTHF/2ml水中，加入三苯基膦600mg，60℃下搅拌过夜。减压除去溶剂，剩余物经过硅胶柱层析纯化得到350mg的3α-氨基菝葜皂苷元。
1H NMR(300MHz,CDCl 3):δ4.40(1H,dd,J＝6.0,12.0Hz,H-16),3.95(1H,dd,J＝3.0,9.0Hz,H-26a),2.70(1H,m,H-3),3.30(1H,d,J＝6.0Hz,H-26b),1.08(3H,d,J＝6.0Hz,H-21),0.99(3H,d,J＝6.0Hz,H-27),0.93(3H,s,H-19),0.75(3H,s,H-18). 13C NMR(300MHz,CDCl 3):δ157.3(C＝O),109.8(C-22),81.1(C-16),65.2(C-26),62.1(C-17),56.6(C-14),51.5(C-3),42.5(C-5),42.2(C-20),40.7(C-13),40.6(C-9),40.4(C-12),37.6(C-4),36.2(C-1),35.6(C-8),34.8(C-10),31.8(C-15),31.4(C-2),27.3(C-6),27.2(C-23),26.8(C-7),26.0(C-25),25.9(C-24),23.7(C-19),20.7(C-11),16.6(C-18),16.2(C-27),14.4(C-21).LC-MS，计算(C 27H 45NO 2，M)为415.3450，发现[M+H] +：416.3528.
实施例2 3β-氨基菝葜皂苷元的制备
Figure PCTCN2018124690-appb-000048
称取3g菝葜皂苷元溶解于80mlTHF中，加入三苯基膦2.6g，再加入DIAD4.3ml，最后加入对硝基苯乙酸1.6g，室温搅拌过夜。减压除去溶剂，残余物直接硅胶柱层析，得到产物1.2g。将其再溶解在20mlTHF/5mlH 2O中，加入氢氧化钠400mg，室温搅拌过夜。减压除去溶剂，加入DCM和水，分出DCM层，水层用DCM萃取，合并有机相，1M盐酸洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析，洗脱剂P/E＝5:1，得到3α-羟基菝葜皂苷元，其数据如下所示：
1H NMR(300MHz,CDCl 3):δ4.40(1H,dd,J＝6.0,12.0Hz,H-16),3.95(1H,dd,J＝3.0,9.0Hz,H-26a),2.70(1H,m,H-3),3.30(1H,d,J＝6.0Hz,H-26b),1.08(3H,d,J＝6.0Hz,H-21),0.99(3H,d,J＝6.0Hz,H-27),0.93(3H,s,H-19),0.75(3H,s,H-18). 13C NMR(300MHz,CDCl 3):δ157.3(C＝O),109.8(C-22),81.1(C-16),65.2(C-26),62.2(C-17),56.5(C-14),71.8(C-3),42.2(C-5),42.1(C-20),40.7(C-13),40.6(C-9),40.4(C-12),36.5(C-4),35.5(C-1),35.6(C-8),34.8(C-10),31.9(C-15),30.6(C-2),27.3(C-6),27.2(C-23),26.8(C-7),26.0(C-25),25.9(C-24),23.5(C-19),20.7(C-11),16.6(C-18),16.2(C-27),14.4(C-21).LC-MS，计算(C 27H 44O 3，M)为416.3290，实测[M+H] +：417.3334。
称取菝葜皂苷元1.2g，加入30mlDCM溶解，加入2ml吡啶，室温搅拌溶解。冰浴条件下，缓慢滴加0.5ml甲磺酰氯，滴加完毕后，继续在冰浴条件下搅拌0.5h，再慢慢回复到室温继续反应4h。向反应液加入冰水搅拌30min，用DCM萃取，合并有机相无水硫酸钠干燥，硅胶柱层析得到产物900mg。将其再次溶解于40mlDMF中，加入800mg的NaN 3，60℃下搅拌12h。冷却到室温，加入冰水搅拌30min，有白色固体析出，过滤，水洗，干燥后硅胶柱层析得到450mg的3β-叠氮基菝葜皂苷元。将其溶解于20mlTHF/2ml水中，加入三苯基膦600mg，60℃下搅拌过夜。减压除去溶剂，剩余物经过硅胶柱层析纯化得到250mg的3β-氨基菝葜皂苷元。
实施例3 3-氨基菝葜皂苷元(混合物)的制备
Figure PCTCN2018124690-appb-000049
称取菝葜皂苷元1g，加入无水DCM20ml溶解，在冰浴条件下缓慢加入PCC800mg，然后缓慢升至室温反应，TLC点板追踪反应结束。向反应体系中加入DCM和水，分出有几层，水层用DCM萃取，合并有机相，水洗，无水硫酸钠干燥，减压旋出溶剂，硅胶柱层析分离，得到产物菝葜皂苷元氧化产物790mg。
称取氧化产物700mg，加入无水甲醇40ml溶解，加入乙酸铵1.3g，室温搅拌1h，加入氰基硼氢化钠120mg继续搅拌24h，点板追踪反应结束。减压旋出溶剂，向残留物中加入DCM和水，分出有机层，水层用DCM萃取，合并有机层，用NaOH水溶液洗涤，饱和氯化钠洗涤，无水硫酸钠干燥，减压旋出有机溶剂，粗产品经过硅胶柱层析分离得到350mg产物，为非对映异构体3α-氨基菝葜皂苷元和3β-氨基菝葜皂苷元的混合物。
实施例4
HPLC制备柱拆分实施例3的3-氨基菝葜皂苷元(混合物)制备光学纯3α-氨基菝葜皂苷元和3β-氨基菝葜皂苷元
Figure PCTCN2018124690-appb-000050
取实施例3中经过硅胶柱层析分离得到的3-氨基菝葜皂苷元(混合物)350mg，经过HPLC制备柱拆分制备得到纯的光学异构体，得到3α-氨基菝葜皂苷元150mg；3β-氨基菝葜皂苷元130mg。
实施例5
化合物C-7的制备
Figure PCTCN2018124690-appb-000051
称取三光气840mg溶解于20ml DCM中，3α-氨基菝葜皂苷元1.2g溶解于20mlDCM中，然后缓慢滴加入到反应体系中，三乙胺0.85ml溶解于20mlDCM，然后缓慢滴加入反应体系中，减压旋尽溶剂，将残留物溶于DCM50ml中。胺Ⅱ0.28ml于30mlDCM的溶液缓慢滴加入反应体系中，减压旋尽溶剂，残留物柱层析分离，得到890mg化合物C-7。
LC-MS，计算(C 32H 53N 3O 4，M)为543.4036，发现[M+H] +：544.4190.
化合物C-5的制备
Figure PCTCN2018124690-appb-000052
制备方法同以上化合物C-7的制备方法。LC-MS，计算(C 34H 56N 2O 4，M)为556.4240，发现[M+H] +：557.4298.
实施例6
化合物C-13的制备
Figure PCTCN2018124690-appb-000053
称取三光气2.8g溶解于90ml DCM中，3α-氨基菝葜皂苷元3.9g溶解于60mlDCM中，然后缓慢滴加入到反应体系中，三乙胺(2.2eq)溶解于60mlDCM，然后缓慢滴加入反应体系中，减压旋尽溶剂，将残留物溶于DCM120ml中。苯胺(2eq)于120mlTHF的溶液缓慢滴加入反应体系中，加入DCM稀释反应液，1M盐酸洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，得到2.5g化合物C-13。
1H NMR(300MHz,CDCl 3):δ7.30(2H,m,H-2’,H-6’),7.25(2H,m,H-3’,H-5’),7.01(1H,d,J＝6.0Hz,H-4’),4.40(1H,dd,J＝6.0,9.0Hz,H-16),3.95(1H,dd,J＝3.0,9.0Hz,H-26a),3.61(1H,m,H-3),3.30(1H,d,J＝9.0Hz,H-26b),1.08(3H,d,J＝6.0Hz,H-21),1.00(3H,d,J＝6.0Hz,H-27),0.89(3H,s,H-19),0.74(3H,s,H-18). 13C NMR(300MHz,CDCl 3):δ155.8(C＝O),132.9(C-1’),120.4(C-2’,C-6’),129.3(C-3’,C-5’),123.3(C-4’),109.9(C-22),81.2(C-16),65.3(C-26),62.2(C-17),56.4(C-14),50.4(C-3),42.5(C-5),42.2(C-20),40.7(C-9),40.7(C-13),40.3(C-12),36.1(C-4), 35.5(C-8),34.8(C-1),34.4(C-10),31.9(C-15),28.6(C-2),27.2(C-6),27.1(C-23),26.8(C-7),26.1(C-25),25.9(C-24),23.7(C-19),20.7(C-11),16.6(C-18),16.2(C-27),14.5(C-21).LC-MS，计算(C 34H 50N 2O 3，M)为534.3821，发现[M+H] +：535.3879.
实施例7
HPLC制备柱拆分制备化合物C-13和化合物C-14
Figure PCTCN2018124690-appb-000054
称取三光气300mg溶解于10ml DCM中，3-氨基菝葜皂苷元(两种构象的混合物)400mg溶解于10ml DCM中，然后缓慢滴加入到反应体系中，2.2当量的三乙胺溶解于10mlDCM，然后缓慢滴加入反应体系中，减压旋尽溶剂，将残留物溶于DCM 30ml中。2当量的苯胺于20mlTHF的溶液缓慢滴加入反应体系中，减压旋尽溶剂，残留物DCM溶解，1M盐酸洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥，粗产品经过硅胶柱层析分离，再经过HPLC制备柱拆分制备得到纯的光学异构体，得到化合物C-13有90mg，化合物C-14有80mg。所用的3-氨基菝葜皂苷元(α和β两种构象的混合物)来自实施例3的制备。
实施例8
化合物C-11的制备
Figure PCTCN2018124690-appb-000055
称取三光气800mg溶解于50ml DCM中，3α-氨基菝葜皂苷元1g于20mlDCM的溶液缓慢滴加入到反应体系中，三乙胺1ml缓慢滴加入反应体系中，减压旋尽溶剂，将残留物溶于DCM 150ml中。2当量的环己胺于20ml DCM的溶液缓慢滴加入反应体系中，减压旋尽溶剂，残留物DCM溶解，1M盐酸洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥，粗产品经过硅胶柱层析分离，洗脱剂P/E＝3:1～2:1，得到产物750mg化合物C-11。
1H NMR(300MHz,CDCl 3):δ4.40(1H,dd,J＝6.0,12.0Hz,H-16),3.95(1H,dd,J＝3.0,9.0Hz,H-26a),3.49(1H,m,H-3),3.47(1H,m,H-1’),3.30(1H,d,J＝9.0Hz,H-26b), 1.08(3H,d,J＝6.0Hz,H-21),0.99(3H,d,J＝6.0Hz,H-27),0.94(3H,s,H-19),0.75(3H,s,H-18). 13C NMR(300MHz,CDCl 3):δ157.2(C＝O),109.9(C-22),81.1(C-16),65.3(C-26),62.2(C-17),56.6(C-14),50.4(C-3),49.1(C-1’),42.5(C-5),42.2(C-20),40.8(C-9),40.8(C-13),40.4(C-12),36.2(C-4),35.5(C-8),34.9(C-1),34.7(C-10),34.1(C-2’,C-6’),31.9(C-15),28.8(C-2),27.2(C-6),27.1(C-23),26.8(C-7),26.1(C-25),25.9(C-24),25.7(C-4’),25.1(C-3’,C-5’),23.7(C-19),20.7(C-11),16.6(C-18),16.2(C-27),14.4(C-21).LC-MS，计算(C 34H 56N 2O 3，M)为540.4291，发现[M+H] +：541.4353.
实施例9
化合物C-12的制备
Figure PCTCN2018124690-appb-000056
称取三光气800mg溶解于50ml DCM中，3β-氨基菝葜皂苷元1g于20mlDCM的溶液缓慢滴加入到反应体系中，三乙胺1ml缓慢滴加入反应体系中，减压旋尽溶剂，将残留物溶于DCM 150ml中。2当量的环己胺于20ml DCM的溶液缓慢滴加入反应体系中，减压旋尽溶剂，残留物DCM溶解，1M盐酸洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥，粗产品经过硅胶柱层析分离，洗脱剂P/E＝3:1～2:1，得到产物700mg化合物C-12。
1H NMR(300MHz,CDCl 3):δ4.40(1H,dd,J＝6.0,9.0Hz,H-16),3.95(1H,m,H-26a),3.94(1H,m,H-3),3.52(1H,m,H-1’),3.30(1H,d,J＝6.0Hz,H-26b),1.08(3H,d,J＝6.0Hz,H-21),0.99(3H,d,J＝6.0Hz,H-27),0.96(3H,s,H-19),0.75(3H,s,H-18). 13C NMR(300MHz,CDCl 3):δ157.2(C＝O),109.8(C-22),81.1(C-16),65.2(C-26),62.2(C-17),56.5(C-14),45.8(C-3),49.1(C-1’),42.5(C-20),40.3(C-9),40.8(C-13),40.0(C-12),37.9(C-5),35.4(C-10),35.3(C-8),31.5(C-4),31.3(C-1),34.1(C-2’,C-6’),31.8(C-15),26.9(C-7),27.2(C-23),26.6(C-7),26.1(C-25),25.9(C-24),25.8(C-4’),25.6(C-6),25.1(C-3’,C-5’),24.2(C-19),20.9(C-11),16.6(C-18),16.2(C-27),14.4(C-21).LC-MS，计算(C 34H 56N 2O 3，M)为540.4291，发现[M+H] +：541.4331.
实施例10
3-环己基脲基菝葜皂苷元的制备(化合物C-11和化合物C-12的混合物)
Figure PCTCN2018124690-appb-000057
称取三光气80mg溶解于5ml DCM中，3-氨基菝葜皂苷元(两种构象的混合物)100mg于2mlDCM的溶液缓慢滴加入到反应体系中，三乙胺85ul缓慢滴加入反应体 系中，减压旋尽溶剂，将残留物溶于DCM 5ml中。2当量的环己胺于2mlTHF的溶液缓慢滴加入反应体系中，减压旋尽溶剂，残留物DCM溶解，1M盐酸洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥，粗产品经过硅胶柱层析分离，得到产物3-环己基脲基菝葜皂苷元60mg，为化合物C-11以及化合物化学C-12的混合物(质量比约为6:4)。所用的3-氨基菝葜皂苷元(α和β两种构象的混合物)来自实施例3的制备。
实施例11
HPLC制备柱拆分实施例10的3-环己基脲基菝葜皂苷元制备化合物C-11和化合物C-12
Figure PCTCN2018124690-appb-000058
实施例10中经过硅胶柱层析分离制备的3-环己基脲基菝葜皂苷元60mg，再经过HPLC制备柱拆分制备得到纯的光学异构体，得到化合物C-11有30mg，得到化合物C-12有20mg。
实施例12
化合物C-11的制备
Figure PCTCN2018124690-appb-000059
称取2g 3α-氨基菝葜皂苷元溶解于80mlDCM中，加入环己基异氰酸酯2ml，室温搅拌过夜。加入DCM稀释反应液，1M盐酸洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析，洗脱剂P/E＝3:1～2:1，得到产物1.5g化合物C-11。
实施例13
化合物C-12的制备
Figure PCTCN2018124690-appb-000060
称取2g 3β-氨基菝葜皂苷元溶解于80mlDCM中，加入环己基异氰酸酯2ml，室温搅拌过夜。加入DCM稀释反应液，1M盐酸洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析，洗脱剂P/E＝3:1～2:1，得到产物1.5g化合物C-12。
参考以上实施例的制备方法制备化合物C-23。
实施例14 化合物C-33的合成
Figure PCTCN2018124690-appb-000061
称取三光气(1mmol)溶解于60ml DCM中，3α-氨基菝葜皂苷元(1mmol)溶解于30mlDCM中，然后缓慢滴加入到反应体系中，三乙胺(2.2mmol)溶解于30mlDCM，然后缓慢滴加入反应体系中，减压旋尽溶剂，将残留物溶于DCM60ml中，将环戊胺(2mmol)于30mlDCM的溶液缓慢滴加入反应体系中，过夜反应。1M盐酸洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，得到化合物，产率60％。
1H NMR(400MHz,Chloroform-d)δ4.53(d,J＝7.2Hz,2H),4.47–4.36(m,2H),3.96(ddd,J＝13.1,8.7,5.9Hz,3H),3.55(s,1H),3.31(d,J＝10.9Hz,1H),1.27(s,4H),1.09(d,J＝7.0Hz,4H),1.00(d,J＝6.8Hz,3H),0.95(s,4H),0.76(s,3H).
LC-MS，理论值(C 33H 55N 2O 3，[M+H] +)为527.4213，实测值：527.4185.
实施例15 化合物C-34的合成
Figure PCTCN2018124690-appb-000062
称取三光气(1mmol)溶解于60ml DCM中，3α-氨基菝葜皂苷元(1mmol)溶解于30mlDCM中，然后缓慢滴加入到反应体系中，三乙胺(2.2mmol)溶解于30mlDCM，然后缓慢滴加入反应体系中，减压旋尽溶剂，将残留物溶于DCM60ml中，将金刚烷胺盐酸盐(2mmol)和三乙胺(2mmol)于30mlDCM的溶液缓慢滴加入反应体系中， 过夜反应。1M盐酸洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，得到化合物，产率70％。
1H NMR(400MHz,Chloroform-d)δ4.42(q,J＝7.4Hz,1H),4.15(s,2H),3.97(dd,J＝11.0,2.7Hz,1H),3.47(td,J＝10.9,5.6Hz,1H),3.32(d,J＝10.9Hz,1H),1.09(d,J＝7.1Hz,4H),1.01(d,J＝6.7Hz,3H),0.95(s,4H),0.76(s,3H).
LC-MS，理论值(C 38H 61N 2O 3，[M+H] +)为593.4682，实测值：593.4668.
实施例16 取代环己胺的合成
方法1：还原胺化反应
Figure PCTCN2018124690-appb-000063
环己酮(3eq)与胺(1eq)溶解在甲醇中，加入0.2eq的乙酸，氰基硼氢化钠(1.2eq)进行还原，减压除去溶剂，加入饱和氯化钠与乙酸乙酯，分出有机层，硅胶快速柱层析，得到化合物直接投入下一步反应。按此方法可以得到如下的化合物：
Figure PCTCN2018124690-appb-000064
方法2：亲核取代反应
Figure PCTCN2018124690-appb-000065
环己胺(5mmol)与2-氯甲基酰胺(5.5mmol)溶于30mlDMF中，在体系加入碳酸钾(15mmol)，过夜反应。乙酸乙酯每次200ml萃取三次，后用饱和氯化钠洗涤乙酸乙酯层3次，分出有机层，硅胶快速柱层析，得到化合物直接投入下一步反应。
实施例17 化合物C-35～C-39的合成
Figure PCTCN2018124690-appb-000066
称取三光气(1mmol)溶解于60ml DCM中，3α-氨基菝葜皂苷元(1mmol)溶解于30mlDCM中，然后缓慢滴加入到反应体系中，三乙胺(2.2mmol)溶解于30mlDCM，然后缓慢滴加入反应体系中，减压旋尽溶剂，将残留物溶于DCM60ml中，将环己胺衍生物(2mmol)于30mlDCM的溶液缓慢滴加入反应体系中，过夜反应。1M盐酸洗涤， 饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，得到化合物如表1所示。
表1 化合物C-35～C-39的化学结构及数据
Figure PCTCN2018124690-appb-000067
Figure PCTCN2018124690-appb-000068
实施例18 化合物C-40～C-41的合成
Figure PCTCN2018124690-appb-000069
1H NMR(400MHz,Chloroform-d)δ5.13(d,J＝23.8Hz,1H),4.43(q,J＝7.2Hz,1H),3.97(dd,J＝11.2,2.7Hz,1H),3.89(s,1H),3.68(s,1H),3.32(d,J＝10.9Hz,1H),3.12(t,J＝7.8Hz,2H),2.40(t,J＝6.1Hz,2H),1.45(s,2H),1.10(d,J＝6.9Hz,4H),1.01(d,J＝6.5Hz,3H),0.96(s,3H),0.78(s,3H).
LC-MS，理论值(C 38H 63N 2O 5，[M+H] +)为627.4737，实测值：627.4675。
实施例19 化合物C-42～C-43的合成
Figure PCTCN2018124690-appb-000070
将底物(1mmol)溶解于30mlDCM中，称取EDCI·HCl(2mmol)，DMAP(3mmol)于反应体系中，再取R bCOOH(2mmol)于反应体系中，室温搅拌过夜，加入DCM稀释反应液，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥，硅胶柱层析，得到化合物如表2所示。
表2 化合物C-42～C-43的化学结构及数据
Figure PCTCN2018124690-appb-000071
Figure PCTCN2018124690-appb-000072
实施例20 化合物C-44的合成
Figure PCTCN2018124690-appb-000073
将底物(1mmol)、三氮唑(1.5mmol)、三苯基膦(1.5mmol)溶于30mlTHF，缓慢滴入DIAD(2mmol)。室温搅拌过夜，旋干THF，硅胶柱层析，产率20％。
1H NMR(400MHz,Chloroform-d)δ10.62(d,J＝7.2Hz,1H),8.23(s,2H),4.89(s,1H),4.72(t,J＝8.4Hz,2H),4.41(d,J＝7.0Hz,1H),3.96(dd,J＝11.2,2.8Hz,1H),3.83(t,J＝8.4Hz,2H),3.55(d,J＝32.4Hz,2H),3.33(d,J＝11.0Hz,1H),2.30(q,J＝12.6Hz,1H),1.04(dd,J＝38.5,6.8Hz,6H),0.94(s,3H),0.73(s,3H).
LC-MS，理论值(C 38H 62N 5O 3，[M+H] +)为636.4853，实测值：636.4813。
实施例21 化合物C-45～C-46的合成
Figure PCTCN2018124690-appb-000074
第一步的成脲反应得到中间体可以参照化合物C-34的合成，底物(1mmol)溶解于DCM中，加入HCl(8mmol)的乙酸乙酯溶液，室温搅拌过夜，减压除去溶剂，烘干得到目标化合物，产率65％。
1H NMR(400MHz,Chloroform-d)δ4.40(q,J＝7.4,6.8Hz,1H),4.00–3.89(m,1H),3.62(d,J＝10.6Hz,4H),3.47(s,2H),3.29(d,J＝10.8Hz,1H),3.24–3.08(m,3H),1.08(d,J＝7.0Hz,3H),0.99(d,J＝6.7Hz,3H),0.95(s,4H),0.75(s,3H).
13C NMR(100MHz,Chloroform-d)δ157.60,109.72,81.01,77.26,65.12,57.27,56.21,51.91,42.51,42.10,40.63,40.52,40.18,35.97,35.49,34.75,34.02,31.76,30.80,28.25,27.06,26.69,25.95,25.72,25.10,23.52,20.64,16.44,16.04,14.35.
LC-MS，理论值(C 36H 62N 3O 3，[M+H] +)为584.4791，实测值：584.4751。
实施例22 化合物C-47～C-52的合成
Figure PCTCN2018124690-appb-000075
将底物(1mmol)溶解于30mlDCM中，称取EDCI·HCl(2mmol)，DMAP(3mmol)于反应体系中，再取R bCOOH(2mmol)于反应体系中，室温搅拌过夜，加入DCM稀释反应液，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥，硅胶柱层析，得到化合物如表3所示。
表3 化合物C-47～C-52的化学结构及数据
Figure PCTCN2018124690-appb-000076
Figure PCTCN2018124690-appb-000077
Figure PCTCN2018124690-appb-000078
实施例23 化合物C-55的合成
Figure PCTCN2018124690-appb-000079
酰胺化反应参照化合物C-47～C-52的合成，后脱Boc反应参照化合物C-46的合成.可以得到产物，产率：50％。
1H NMR(400MHz,Chloroform-d)δ7.84(d,J＝5.9Hz,1H),4.46–4.35(m,1H),3.96(dd,J＝11.0,2.7Hz,1H),3.81(d,J＝11.2Hz,1H),3.70–3.58(m,1H),3.42(s,2H),3.35–3.27(m,3H),3.23(dd,J＝7.9,5.3Hz,2H),2.28–2.23(m,3H),1.44(s,3H),1.09(d,J＝7.1Hz,4H),1.00(d,J＝6.8Hz,3H),0.95(s,3H),0.76(s,3H).
13C NMR(100MHz,Chloroform-d)δ173.30,157.57,109.74,81.05,77.23,65.14,62.14,56.32,54.32,51.14,44.42,42.61,40.65,40.59,40.27,36.24,35.53,34.84,34.35,31.77,31.53,28.37,27.09,26.91,26.74,25.97,25.76,25.54,23.64,20.67,16.46,16.03,14.32.
LC-MS，理论值(C38H65N4O4，[M+H] +)为641.5006，实测值：641.4984。
实施例24 化合物C-55和化合物C-56的合成
Figure PCTCN2018124690-appb-000080
称取三光气(1mmol)溶解于60ml DCM中，底物(1mmol)溶解于30mlDCM中，然后缓慢滴加入到反应体系中，三乙胺(2.2mmol)溶解于30mlDCM，然后缓慢滴加入反应体系中，减压旋尽溶剂，将残留物溶于DCM60ml中，将R cNH(2mmol)于30mlDCM的溶液缓慢滴加入反应体系中，过夜反应。1M盐酸洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，得到化合物如表4所示。
表4 化合物C-55～C-56的化学结构及数据
Figure PCTCN2018124690-appb-000081
实施例25 化合物C-57的合成
Figure PCTCN2018124690-appb-000082
将1g化合物C-11溶于干燥DCM中，冰浴，在氮气保护下加入2.4ml三氟化硼乙醚和3.1ml乙酸酐。10分钟后加入冰水搅拌过夜。用饱和碳酸氢钠洗涤、饱和食盐水洗涤，硅胶柱层析得到0.4g化合物C-57。
1H NMR(400MHz,Chloroform-d)δ4.98(s,1H),4.20(d,J＝55.5Hz,3H),3.48(s,2H),3.43(d,J＝5.3Hz,1H),2.98(dd,J＝10.9,6.8Hz,1H),2.72(dt,J＝17.9,7.1Hz,1H),2.53–2.20(m,2H),1.98(s,2H),1.95–1.87(m,3H),1.71(d,J＝12.3Hz,2H),1.26(d,J＝10.3Hz,2H),1.15(d,J＝7.5Hz,3H),0.85(s,3H).
13C NMR(101MHz,CDCl 3)δ214.01,170.00,157.22,77.39,77.07,76.76,75.87,67.33,55.35,53.94,50.08,48.87,43.47,42.36,42.28,40.50,40.12,38.46,35.98,35.43,35.25,34.82,34.60,34.52,33.96,28.67,26.94,26.32,25.64,24.96,23.52,21.19,20.54,16.90,16.73,13.42，
LC-MS，理论值(C 36H 61N 2O 5，[M+H]+)为601.4502，发现[M+H] +：601.4619.
实施例26 化合物C-58的合成
Figure PCTCN2018124690-appb-000083
将1.6g 3-氨基知母皂苷元于乙醇中与36g锌粉加热回流，滴入32ml浓盐酸。30分钟后，冷却，旋干乙醇，加入200ml DCM，和同体积含16gNaOH的水溶液。产生大量白色沉淀，硅藻土过滤得到DCM和水的混合液，分液得到DCM层，旋干得到产物，产物加入环己基异氰酸酯0.55ml、三乙胺0.08ml，30min后得到终产物化合物C-58，硅胶柱层析纯化得到0.22g。
1H NMR(400MHz,Chloroform-d)δ4.40–4.30(m,1H),4.08(t,J＝8.0Hz,2H),3.60–3.38(m,5H),2.24(dt,J＝13.0,7.6Hz,1H),1.76–1.67(m,2H),1.49–1.37(m,2H),1.13(ddd,J＝14.4,10.1,5.8Hz,6H),1.06(s,1H),0.87(s,3H).
LC-MS，理论值(C 34H 61N 2O 3，[M+H]+)为545.4604，发现[M+H] +：545.4638.
实施例27 化合物C-59的合成
Figure PCTCN2018124690-appb-000084
将1.6g 3-氨基知母皂苷元于乙醇中与36g锌粉加热回流，滴入32ml浓盐酸。30分钟后，冷却，旋干乙醇，加入200ml DCM，和同体积含16gNaOH的水溶液。产生大量白色沉淀，硅藻土过滤得到DCM和水的混合液，分液得到DCM层，旋干得到产物，产物在DCM中加入CDI 1.2eq，30min后加入2eq环己胺衍生物，过夜反应后得到终产物化合物C-59，硅胶柱层析纯化得到0.2g。
1H NMR(400MHz,Chloroform-d)δ4.86(s,1H),4.35(td,J＝7.3,4.2Hz,1H),4.06(s,1H),3.71(q,J＝4.0Hz,2H),3.64(d,J＝8.9Hz,1H),3.55(s,2H),3.56–3.40(m,2H),3.36(t,J＝4.9Hz,2H),2.25(dt,J＝12.9,7.6Hz,1H),2.05–1.95(m,1H),1.58(s,1H),1.50–1.39(m,2H),0.87(s,3H).
13C NMR(101MHz,CDCl 3)δ159.26,72.57,68.26,65.00,61.67,55.61,54.37,50.90,45.07,42.60,42.48,40.62,36.63,35.85,35.38,34.63,34.54,33.57,31.29,29.83,28.72,26.42,25.95,25.51,23.75,23.57,20.52,18.22,16.75,13.27.
LC-MS，理论值(C 36H 65N 2O 4，[M+H]+)为589.4866，发现[M+H] +:589.4985。
实施例28 化合物C-65的合成
Figure PCTCN2018124690-appb-000085
将0.14g化合物C-57溶于DCM，加入催化量DMAP和2eq乙酸酐，过夜反应。1M盐酸洗涤、饱和碳酸氢钠洗涤、饱和食盐水洗涤得到0.1g化合物C-65。
LC-MS，理论值(C 38H 63N 2O 6，[M+H]+)为643.4608,发现[M+H] +：643.4684
实施例29 化合物C-66与化合物C-67的合成
Figure PCTCN2018124690-appb-000086
250mg化合物C-57溶于50mlDMF，加入2gPDC，5天后，旋去部分DMF，加入饱和食盐水，用乙酸乙酯萃取，硅胶柱层析得到0.03g化合物C-66与0.06g化合物C-67。
化合物C-66，LC-MS，理论值(C 36H 59N 2O 6，[M+H]+)为615.4295，发现[M+H] +：615.4403
化合物C-67，LC-MS，理论值(C 36H 59N 2O 5，[M+H]+)为599.4346,发现[M+H] +：599.4450
实施例30 化合物C-69与化合物C-70的合成
Figure PCTCN2018124690-appb-000087
将580mg化合物C-57溶于10ml甲醇，加入46.6微升乙酸，加热至55摄氏度，投入1.2g硼氢化钠，旋去甲醇，溶于DCM，饱和氯化铵洗涤，饱和碳酸氢钠洗涤、饱和食盐水洗涤，硅胶柱层析得到0.1g化合物C-69与0.06g化合物C-70。
化合物C-69数据 1H NMR(400MHz,Methanol-d 4)4.31(t,J＝6.6Hz,1H),4.25(td,J＝7.8,4.6Hz,1H),3.84(ddd,J＝9.8,4.0,1.9Hz,1H),3.47(tdd,J＝12.1,6.8,3.3Hz,3H),3.40–3.35(m,1H),0.99(s,3H),0.98(d,J＝1.9Hz,3H),0.96(d,J＝1.6Hz,3H),0.92(s,3H).
13C NMR(101MHz,MeOD)δ167.87,158.48,73.43,71.29,66.81,65.26,58.92,54.24,49.73,48.39,48.27,48.05,47.84,47.63,47.42,47.20,46.99,42.71,42.65,40.47,36.42,35.82,35.75,35.44,34.33,34.05,33.41,30.34,30.02,28.13,26.89,26.27,25.38,24.74,22.76,20.32,18.89,16.24,12.72,12.31,11.90.
LC-MS，理论值(C 36H 63N 2O 5，[M+H]+)603.4659，发现[M+H] +：603.4738
化合物C-70数据，
1H NMR(400MHz,Methanol-d 4)4.36(td,J＝7.7,4.6Hz,1H),3.73(ddd,J＝9.1,3.3,1.7Hz,1H),3.47(ddd,J＝16.5,9.4,4.8Hz,3H),3.37(dd,J＝10.6,6.5Hz,1H),2.22(dt,J＝12.8,7.6Hz,1H),0.99(s,3H),0.96(d,J＝2.6Hz,3H),0.91(s,3H).
13C NMR(101MHz,MeOD)δ167.87,158.47,74.38,71.28,67.08,65.26,57.37,54.35,49.73,48.39,48.28,48.07,47.92,47.86,47.64,47.43,47.22,47.00,42.65,42.36,40.49,40.40,36.00,35.83,35.52,35.46,35.11,34.34,34.06,33.42,30.75,30.35,30.02,29.41,28.15,26.92,26.28,25.40,24.74,22.79,20.32,18.90,15.81,13.10,12.74,12.37.
LC-MS，理论值(C 36H 63N 2O 5，[M+H]+)603.4659，发现[M+H] +：603.4742
实施例31 化合物C-71合成
Figure PCTCN2018124690-appb-000088
将540mg化合物C-11在氮气保护下加入10ml乙酸酐和0.29g无水氯化锌。5小时后加入冰水搅拌过夜。用饱和碳酸氢钠洗涤、饱和食盐水洗涤，硅胶柱层析得到0.3g化合物C-71。
LC-MS，理论值(C 38H 61N 2O 5，[M+H]+)为625.4502，发现[M+H] +：625.4584。
实施例32 化合物C-72合成
Figure PCTCN2018124690-appb-000089
将1g化合物C-11溶于干燥DCM中，在氮气保护下加入2.4ml三氟化硼乙醚和3.1ml乙酸酐。60分钟后加入冰水搅拌过夜。用饱和碳酸氢钠洗涤、饱和食盐水洗涤，硅胶柱层析得到0.1g化合物C-72。
1H NMR(400MHz,Chloroform-d)δ5.14(td,J＝7.6,3.7Hz,1H),4.13(dt,J＝11.4,6.4Hz,3H),4.05(d,J＝9.6Hz,1H),3.49(s,3H),3.38(t,J＝10.5Hz,1H),2.23(s,3H),2.08(s,2H),0.96–0.88(m,3H),0.74(s,2H).
LC-MS，理论值(C 38H 61N 2O 5，[M+H]+)为625.4502，发现[M+H] +：625.4834
实施例33 化合物C-83～C-88的合成
化合物C-83～C-88的合成的合成可以参展下面的合成路径进行合成得到。
Figure PCTCN2018124690-appb-000090
将底物(1mmol)溶解于30mlDCM中，称取EDCI·HCl(2mmol)，DMAP(3mmol)于反应体系中，再取羧酸RCOOH(2mmol)于反应体系中，室温搅拌过夜，加入DCM稀释反应液，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥，硅胶柱层析，浓缩洗脱液得到中间体。中间体加入DCM溶解后，加入三氟乙酸(5eq)搅拌过夜，加入DCM和饱和碳酸钠溶液，分出有机层，饱和氯化钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，得到目标化合物。
羧酸RCOOH选自：
Figure PCTCN2018124690-appb-000091
实施例34 化合物C-75、化合物C-91、化合物C-93-C-101、化合物C-105、化合物C-106的合成
Figure PCTCN2018124690-appb-000092
称取三光气(1mmol)溶解于60ml DCM中，3α-氨基菝葜皂苷元(1mmol)溶解于30mlDCM中，然后缓慢滴加入到反应体系中，三乙胺(2.2mmol)溶解于30mlDCM，然后缓慢滴加入反应体系中，减压旋尽溶剂，将残留物溶于DCM60ml中，将有机胺衍生物(2mmol，II)于30mlDCM的溶液缓慢滴加入反应体系中，过夜反应。1M盐酸洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，浓缩洗脱液得到中间体1；
中间体1加入DCM溶解后，加入三氟乙酸(5eq)搅拌过夜，加入DCM和饱和碳酸钠溶液，分出有机层，饱和氯化钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，得到中间体2；
将中间体2(1mmol)溶解于30mlDCM中，称取EDCI·HCl(2mmol)，DMAP(3mmol)于反应体系中，再取羧酸N,N-二甲基甘氨酸(2mmol)于反应体系中，室温搅拌过夜，加入DCM稀释反应液，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥，硅胶柱层析，浓缩洗脱液得到目标化合物。
有机胺选自
Figure PCTCN2018124690-appb-000093
实施例35 化合物C-104、化合物C-107、化合物C-108的合成
化合物C-104、C-107、C-108的合成的合成可以参展下面的合成路径进行合成得到。
Figure PCTCN2018124690-appb-000094
将底物(1mmol)溶解于30mlDCM中，称取EDCI·HCl(2mmol)，DMAP(3mmol)于反应体系中，再取羧酸RCOOH(2mmol)于反应体系中，室温搅拌过夜，加入DCM稀释反应液，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥，硅胶柱层析，浓缩洗脱液得到中间体。中间体加入DCM溶解后，加入三氟乙酸(5eq)搅拌过夜， 加入DCM和饱和碳酸钠溶液，分出有机层，饱和氯化钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，得到目标化合物。
羧酸RCOOH选自：
Figure PCTCN2018124690-appb-000095
实施例36 化合物C-113～C-114、C-130～C-132的合成
Figure PCTCN2018124690-appb-000096
称取三光气(1mmol)溶解于60ml DCM中，底物(1mmol)溶解于30mlDCM中，然后缓慢滴加入到反应体系中，三乙胺(2.2mmol)溶解于30mlDCM，然后缓慢滴加入反应体系中，减压旋尽溶剂，将残留物溶于DCM60ml中，将有机胺RNH 2(2mmol)于30mlDCM的溶液缓慢滴加入反应体系中，过夜反应。1M盐酸洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥硅胶柱层析，浓缩洗脱液得到中间体。中间体加入DCM溶解后，加入三氟乙酸(5eq)搅拌过夜，加入DCM和饱和碳酸钠溶液，分出有机层，饱和氯化钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，得到目标化合物。
RNH 2选自
Figure PCTCN2018124690-appb-000097
实施例37 化合物C-133～C-143的合成
Figure PCTCN2018124690-appb-000098
称取三光气(1mmol)溶解于60ml DCM中，3α-氨基菝葜皂苷元(1mmol)溶解于30mlDCM中，然后缓慢滴加入到反应体系中，三乙胺(2.2mmol)溶解于30mlDCM，然后缓慢滴加入反应体系中，减压旋尽溶剂，将残留物溶于DCM60ml中，将有机胺衍生物(2mmol，II)于30mlDCM的溶液缓慢滴加入反应体系中，过夜反应。1M盐酸洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，浓缩洗脱液得到中间体1；
中间体1加入DCM溶解后，加入三氟乙酸(5eq)搅拌过夜，加入DCM和饱和碳酸钠溶液，分出有机层，饱和氯化钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，得到中间体2；
称取中间体2(1eq)，DCM溶解，加入N,N'-羰基二咪唑(CDI，1eq)以及三乙胺(2eq)，室温搅拌0.5h，加入N,N-二甲基乙二胺(2eq)，室温搅拌过夜。饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，浓缩洗脱液得到目标化合物。
有机胺选自
Figure PCTCN2018124690-appb-000099
实施例38 化合物C-144～C-154的合成
Figure PCTCN2018124690-appb-000100
称取三光气(1mmol)溶解于60ml DCM中，3α-氨基菝葜皂苷元(1mmol)溶解于30mlDCM中，然后缓慢滴加入到反应体系中，三乙胺(2.2mmol)溶解于30mlDCM，然后缓慢滴加入反应体系中，减压旋尽溶剂，将残留物溶于DCM60ml中，将有机胺衍生物(2mmol，II)于30mlDCM的溶液缓慢滴加入反应体系中，过夜反应。1M盐酸洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，浓缩洗脱液得到中间体1；
中间体1加入DCM溶解后，加入三氟乙酸(5eq)搅拌过夜，加入DCM和饱和碳酸钠溶液，分出有机层，饱和氯化钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，得到中间体2；
称取中间体2(1eq)，DCM溶解，加入N,N'-羰基二咪唑(CDI，1eq)以及三乙胺(2eq)，室温搅拌0.5h，加入N-Boc-1,2-乙二胺(2eq)，室温搅拌过夜。饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，浓缩洗脱液得到中间体3；
中间体3加入DCM溶解后，加入三氟乙酸(5eq)搅拌过夜，加入DCM和饱和碳酸钠溶液，分出有机层，饱和氯化钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，得到目标化合物。
有机胺选自
Figure PCTCN2018124690-appb-000101
实施例39 化合物C-73～C-75、化合物C-91、化合物C-93-C-101、化合物C-105、化合物C-106、化合物C-133～C-143的合成
Figure PCTCN2018124690-appb-000102
称取三光气(1mmol)溶解于60ml DCM中，3α-氨基菝葜皂苷元(1mmol)溶解于30mlDCM中，然后缓慢滴加入到反应体系中，三乙胺(2.2mmol)溶解于30mlDCM，然后缓慢滴加入反应体系中，减压旋尽溶剂，将残留物溶于DCM60ml中，将有机胺衍生物(2mmol，II)于30mlDCM的溶液缓慢滴加入反应体系中，过夜反应。1M盐酸洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，无水硫酸钠干燥。硅胶柱层析分离，浓缩洗脱液得到目标化合物。
NHR 2R 3选自下列的胺：
Figure PCTCN2018124690-appb-000103
Figure PCTCN2018124690-appb-000104
Figure PCTCN2018124690-appb-000105
Figure PCTCN2018124690-appb-000106
本发明其他化合物可以参照以上合成路径进行合成。
药理实施例
知母药材中含有大量的皂苷类化合物，与本发明化合物结构相关的主要是螺甾烷型皂苷及知母皂苷元(即菝葜皂苷元)，如知母皂苷A1、知母皂苷A3等。这些皂苷类化合物的结构特征是3位取代基为糖基，比如知母皂苷A1是3位单糖取代皂苷；知母皂苷A3是3位双糖取代皂苷。而本发明的化合物，其结构特征在于，在3位上采用化学合成手段，连接其他类型取代基。
动物强迫游泳试验(FST)和悬尾试验(TST)为两种经典的抗抑郁药效筛选模型。本发明的化合物主要采用这两种模型来进行抗抑郁活性的筛选。
下文表中或者图中出现的一些代号的解释如下所示：
FLX表示氟西汀，Fluoxetine表示氟西汀，
化合物知母皂苷A1、知母皂苷A3、菝葜皂苷元的化学结构如下所示：
Figure PCTCN2018124690-appb-000107
实施例40
强迫游泳试验(FST)考察本发明部分化合物及部分天然产物的抗抑郁活性
实验选用雄性ICR小鼠，体重(20±2)g，购自中科院上海药物所实验动物中心，自由摄食饮水，室温(23±2)℃，自然光照。所有小鼠随机分组分为空白对照组和试验组，每组10只，5只/笼，于饲养环境中适应3天后开始实验，实验前禁食12小时，饮水自由。具体给药方法为灌胃给药，给药组的给药剂量都是10mg/Kg，空白对照组给予等体积的0.5％CMC-Na。
具体操作：连续给药6天，末次给药后1小时进行测试。首先利用开野法测定小鼠的自主活动，即将小鼠单独置于圆柱型玻璃缸内，计时4分钟，记录后2分钟内的抬臂次数。然后将小鼠单独放入高20厘米、直径14厘米的圆柱型玻璃缸中，缸内水深10厘米，水温23℃-25℃。从小鼠入水后计时6分钟，记录后4分钟内的累计不动时间(判定不动标准：小鼠在水中停止挣扎，或呈漂浮状态，仅有细小的肢体运动以保持头部浮在水面)。各组小鼠平行操作。
实验数据处理：实验结果以均值±标准误差(x±SD)表示。采用t检验进行统计分析，判断是否具有显著性意义。首先对其自主活动指标进行t检验，其P﹥0.05说明小鼠的自主后动没有影响，以避免中枢兴奋药的干扰。然后对强迫游泳实验指标进行t检验，判断是否具有抗抑郁作用。
实验相关结果如表5、表6、表7、表8和表9所示。
表5 本发明部分化合物及部分天然产物对ICR小鼠强迫游泳不动时间的影响
Figure PCTCN2018124690-appb-000108
“*”表示P＜0.05；“**”表示P＜0.01。
3-环己基脲基菝葜皂苷元(即实施例20的产物)、化合物C-11、化合物C-12的实验结果如表5所示，并且与天然产物知母皂苷A1、知母皂苷A3、菝葜皂苷元进行了比较。结果表明，与空白组比较，自然界存在的化合物知母皂苷A1、知母皂苷A3、菝葜皂苷元，在小鼠强迫游泳模型上，不能显著降低小鼠强迫游泳不动时间，统计学无显著性差异。3-环己基脲基菝葜皂苷元(实施例20)、化合物C-11、化合物C-12均可显著减少小鼠强迫游泳实验不动时间。其中，3-环己基脲基菝葜皂苷元(实施例20)和化合物C-12具有显著的抗抑郁活性(P＜0.05)；化合物C-11具有极显著的抗抑郁活性(P＜0.01)。
表6 化合物C-13对ICR小鼠强迫游泳不动时间的影响
组别 TST累计不动时间(mean±SD,s)
空白对照组 154.7±18.8
化合物C-13 131.1±28.1*
化合物C-13的实验结果如表6所示，与空白组比较，化合物C-13可显著减少小鼠强迫游泳实验不动时间，具有显著的抗抑郁活性(P＜0.05)。
表7 化合物C-23对ICR小鼠强迫游泳不动时间的影响
组别 TST累计不动时间(mean±SD,s)
空白对照组 118.4±37.3
化合物C-23 94.7±29.8 (P＝0.062)
化合物C-23的实验结果如表7所示，与空白组比较，化合物C-23可减少小鼠强迫游泳实验不动时间，具有一定的抗抑郁活性。
表8 化合物C-49对ICR小鼠强迫游泳不动时间的影响
组别 TST累计不动时间(mean±SD,s)
空白对照组 134.3±25.3
氟西汀阳性对照 100.7±24.1*
菝葜皂苷元 127.0±44.4
化合物C-49 110.8±20.5*
“*”表示P＜0.05；“**”表示P＜0.01。
化合物C-49的实验结果如表8所示，结果表明，与空白组比较，菝葜皂苷元，在小鼠强迫游泳模型上，不能显著降低小鼠强迫游泳不动时间，统计学无显著性差异；而化合物C-49可显著减少小鼠强迫游泳实验不动时间(P＜0.05)，统计学有显著性差异。
表9 化合物C-58、C-72对ICR小鼠强迫游泳不动时间的影响
Figure PCTCN2018124690-appb-000109
与空白组比较，化合物C-58可显著减少小鼠累计不动时间(p<0.05)，显示出显著的抗抑郁活性；化合物C-72可明显减少小鼠累计不动时间(p＝0.06)，显示出一定的抗抑郁活性。
实施例41
悬尾试验(TST)考察本发明部分化合物及部分天然产物的抗抑郁活性
实验选用雄性ICR小鼠，体重(20±2)g，购自中科院上海药物所实验动物中心，自由摄食饮水，室温(23±2)℃，自然光照。所有小鼠随机分组分为空白对照组和试验组，每组10只，5只/笼，于饲养环境中适应3天后开始实验，实验前禁食12小时，饮水自由。具体给药方法为灌胃给药，空白对照组一组给予等体积的0.5％CMC-Na，给药剂量都是10mg/Kg。
具体操作：连续给药6天，末次给药后1小时进行测试。首先利用开野法测定小鼠的自主活动，即将小鼠单独置于圆柱型玻璃缸内，计时4分钟，记录后2分钟内的抬臂次数。然后用胶带将小鼠尾在距尾尖2厘米处粘在横杠上，四周以板隔离动物视 线，横杠距地面约25厘米，使小鼠距地面约10厘米，计时6min，记录后4分钟内累计不动时间，各组小鼠平行操作。
实验数据处理：实验结果以均值±标准误差(x±SD)表示。采用t检验进行统计分析，判断是否具有显著性意义。首先对其自主活动指标进行t检验，其P﹥0.05说明小鼠的自主后动没有影响，以避免中枢兴奋药的干扰。然后对悬尾实验指标进行t检验，判断是否具有抗抑郁作用。
实验相关结果如表10-15所示。
3-环己基脲基菝葜皂苷元(实施例20)、化合物C-11、化合物C-12的实验结果如表10所示，并且与天然产物知母皂苷A1、知母皂苷A3、菝葜皂苷元进行了比较：
表10 本发明部分化合物及部分天然产物对ICR小鼠悬尾不动时间的影响
Figure PCTCN2018124690-appb-000110
“*”表示P＜0.05；“**”表示P＜0.01。
结果表明，与空白组比较，自然界存在的化合物知母皂苷A1、菝葜皂苷元，在小鼠悬尾模型上，不能显著降低小鼠悬尾不动时间，统计学上无显著性差异。知母皂苷A3、3-环己基脲基菝葜皂苷元(实施例20)、化合物C-11、化合物C-12均可显著减少小鼠悬尾实验不动时间。其中，知母皂苷A3、3-环己基脲基菝葜皂苷元(实施例20)和化合物C-12具有显著的抗抑郁活性(P＜0.05)；化合物C-11具有极显著的抗抑郁活性(P＜0.01)。
表11 化合物C-7对ICR小鼠悬尾不动时间的影响
组别 TST累计不动时间(mean±SD,s)
空白对照组 91.2±38.5
化合物C-7 54.7±44.9 (P＝0.067)
化合物C-7的实验结果如表11所示，与空白组比较，化合物C-7可减少小鼠悬尾实验不动时间，具有一定的抗抑郁活性。
表12 化合物C-5、化合物C-20对ICR小鼠悬尾不动时间的影响
组别 TST累计不动时间(mean±SD,s)
空白对照组 104.7±24.3
化合物C-5 81.1±26.2 (P＝0.051)
化合物C-20 79.6±29.5 (P＝0.053)
化合物C-5、化合物C-20的实验结果如表11所示，与空白组比较，化合物C-5、化合物C-20可减少小鼠悬尾实验不动时间，具有一定的抗抑郁活性。
表13 化合物C-19对ICR小鼠悬尾不动时间的影响
组别 TST累计不动时间(mean±SD,s)
空白对照组 105.3±34.8
化合物C-19 74.1±30.6 (P＝0.079)
化合物C-19的实验结果如表13所示，与空白组比较，化合物C-19可减少小鼠悬尾实验不动时间，具有一定的抗抑郁活性。
表14 本发明部分化合物对ICR小鼠悬尾不动时间的影响
组别 TST累计不动时间(mean±SD,s)
空白对照组 126.2±21.8
氟西汀 89.5±28.9*
菝葜皂苷元 116.6±29.4
化合物C-35 81.3±47.7*
化合物C-42 116.9±43.3
化合物C-46 118.0±28.4
化合物C-49 82.4±43.6*
“*”表示P＜0.05；“**”表示P＜0.01。
化合物C-49等的实验结果如表14所示。结果表明，与空白组比较，菝葜皂苷元，在小鼠悬尾模型上，不能显著降低小鼠强迫游泳不动时间，统计学无显著性差异；而化合物C-35以及化合物C-49在小鼠悬尾模型上可显著减少小鼠悬尾实验不动时间(P＜0.05)，统计学有显著性差异。
表15 本发明化合物C-58、C-72小鼠悬尾不动时间的影响
Figure PCTCN2018124690-appb-000111
“*”表示P＜0.05；“**”表示P＜0.01。
与空白组比较，化合物C-72可显著减少小鼠累计不动时间(p<0.05)，显示出显著的抗抑郁活性；化合物C-58可明显减少小鼠累计不动时间(p＝0.07)，显示出一定的抗抑郁活性。
本发明部分化合物与部分天然产物的抗抑郁比较试验结果表明，自然界中存在的螺甾烷型知母皂苷类化合物知母皂苷A1、菝葜皂苷元在两种动物模型上都没有抗抑郁效果；知母皂苷A3仅在悬尾模型有效，但是在强迫游泳模型上没有效果，可见天然产物知母皂苷A3的抗抑郁药效不强，而且知母皂苷A3具有明显毒性(Acta Pharmacologica Sinica 2014；35(9):1188-1198.)。
在与上述天然产物比较的同批动物药效筛选中，本发明化合物在两种动物模型上都显示了显著的抗抑郁活性。在强迫游泳模型中，本发明中的化合物C-12、3-环 己基脲基菝葜皂苷元(实施例20)都显示出显著的抗抑郁活性(P＜0.05)，化合物C-11具有极显著的抗抑郁活性(P＜0.01)。在悬尾模型中，本发明中化合物C-12、3-环己基脲基菝葜皂苷元(实施例20)都显示出显著的抗抑郁活性(P＜0.05)，化合物C-11具有极显著的抗抑郁活性(P＜0.01)。本发明化合物C-11、12以及3-环己基脲基菝葜皂苷元(实施例20)未发现明显毒性。
在其他批次动物抗抑郁药效筛选中，本发明化合物C-13、化合物C-23、化合物C-5、化合物C-7、化合物C-19、化合物C-20也都具有显著或者一定的抗抑郁活性。
与空白组对比，在强迫游泳模型中，本发明中的化合物C-49显示出显著的抗抑郁活性(P＜0.05)。在悬尾模型中，本发明中化合物C-35与化合物C-49都显示出显著的抗抑郁活性(P＜0.05)。而且化合物C-49在两种动物模型上都显示出显著的抗抑郁活性。
实施例42
化合物C-11与氟西汀在小鼠模型抗抑郁活性比较
强迫游泳试验
在给药前24小时，小鼠放入圆柱型缸内适应水中环境15min。行为测试当天，动物给药两次，分别在行为测试前4h和1h口服给药。将小鼠单独置于圆柱型玻璃缸内，计时6分钟，记录后2分钟内的抬臂次数。然后将小鼠单独放入高30厘米、直径20厘米的圆柱型玻璃缸中，缸内水深为15厘米(大鼠水深20厘米)，使动物既不能逃出玻璃缸，其脚和尾部又不接触到缸底，水温23℃-25℃。拍摄小鼠入水后的6分钟视频，由于大多数动物在开始两分钟十分活跃，因此计算后4分钟不动时间(判定不动标准：小鼠在水中停止挣扎，不动和为保持平衡或呈漂浮状态的细小的肢体运动)。各组小鼠平行操作。
悬尾实验
行为测试当天，动物给药两次，分别在行为测试前4h和1h口服给药。实验时将小鼠尾部距末端约1cm处用胶带或夹子，倒吊于距地面15cm左右的悬尾试验架上，小鼠为克服不正常体位而挣扎活动，但活动一段时间后，出现间断性不动，显示失望状态，各组实验时间为6分钟。由于前两分钟小鼠大多因兴奋而挣扎频繁，统计其后4分钟不动时间。
实验结果表明，小鼠游泳实验以及小鼠悬尾实验，化合物C-11可显著减少小鼠强迫游泳试验累计不动时间(p<0.05)，以及可显著减少小鼠悬尾不动时间(p<0.05)，显示出抗抑郁活性。而且化合物C-11的起效剂量明显低于阳性药氟西汀，化合物C-11的起效剂量仅为氟西汀的一半。
小鼠游泳试验结果如图1所示。与空白组比较，化合物C-11可显著减少小鼠强迫游泳试验累计不动时间(p<0.05)，显示出抗抑郁活性。而且，化合物C-11起效剂量明显低于阳性药氟西汀，起效剂量仅为氟西汀的一半。
小鼠悬尾试验结果如图2所示：与空白组比较，化合物C-11可显著减少小鼠悬尾试验累计不动时间(p<0.05)，显示出抗抑郁活性。而且，化合物C-11起效剂量明显低于阳性药氟西汀，起效剂量仅为氟西汀的一半。
实施例43
化合物C-11与氟西汀在大鼠模型抗抑郁活性比较
强迫游泳试验
实验操作：在给药前24小时，大鼠放入圆柱型缸内适应水中环境15min。行为测试当天，动物给药两次，分别在行为测试前4h和1h口服给药。将大鼠单独置于圆柱型玻璃缸内，计时6分钟，记录后2分钟内的抬臂次数。然后将大鼠单独放入高30厘米、直径20厘米的圆柱型玻璃缸中，缸内水深为20厘米，使动物既不能逃出玻璃缸，其脚和尾部又不接触到缸底，水温23℃-25℃。拍摄大鼠入水后的6分钟视频，由于大多数动物在开始两分钟十分活跃，因此计算后4分钟不动时间(判定不动标准：把大鼠在水中的状态分为静止(immobility)、游泳(swimming)和爬壁(climbing)三种状态，统计这三种状态的等分数，每隔5秒计一次，一共5分钟，合计60次)。
悬尾实验
实验操作：行为测试当天，动物给药两次，分别在行为测试前4h和1h口服给药。实验时将大鼠尾部距末端约1cm处用胶带或夹子，倒吊于距地面15cm左右的悬尾试验架上，大鼠为克服不正常体位而挣扎活动，但活动一段时间后，出现间断性不动，显示失望状态，各组实验时间为6分钟。由于前两分钟大鼠大多因兴奋而挣扎频繁，统计其后4分钟不动时间。
实验结果表明，大鼠游泳实验以及大鼠悬尾实验，化合物C-11可显著减少大鼠强迫游泳试验累计不动时间(p<0.05)，以及显著减少大鼠悬尾不动时间(p<0.05)，显示出抗抑郁活性。而且，在大鼠模型上，化合物C-11的起效剂量明显低于阳性药氟西汀。
大鼠游泳试验结果如图3所示。在大鼠的强迫游泳实验中，化合物C-11的抗抑郁活性得到进一步的验证，而且化合物C-11的起效剂量明显低于阳性药氟西汀：氟西汀在给药剂量为6.92mg/kg才可以显著影响大鼠的不动时间和爬壁行为，而1.73mg/kg和3.46mg/kg剂量对这两种抑郁样行为均无影响；与之相比，C-11剂量明显减小，1.73mg/kg和3.46mg/kg剂量均可以显著减少大鼠强迫游泳的不动时间，3.46mg/kg的口服剂量显著增加爬壁时间(*p<0.05,**p<0.01与Vehicle组比较)。
大鼠悬试验结果如图4所示。在大鼠的悬尾实验中，化合物C-11的抗抑郁活性也得到了进一步的验证，而且，化合物C-11的起效剂量明显低于阳性药氟西汀：氟西汀在给药剂量为6.92mg/kg才可以显著影响大鼠悬尾试验累计不动时间，而1.73mg/kg和3.46mg/kg剂量对这两种抑郁样行为均无影响；与之相比，C-11剂量 减小，3.46mg/kg剂量可以显著减少大鼠悬尾试验累计不动时间(*p<0.05,**p<0.01与Vehicle组比较)。
实施例44
社交失败抑郁动物模型(social defeated stress，SDS)考察本发明化合物的抗抑郁活性
试验结果表明，化合物C-11在这个模型上，皆显示优于氟西汀的抗抑郁活性。
具体实验操作如下：
采用4-6个月已过育龄的雄性CD-1单独饲养，让其自由饮食并适应环境一周左右。8-20周不同周龄雄性C57用来筛选具有攻击性的CD-1小鼠，将C57筛选小鼠直接放在CD-1的笼子内，与其接触3分钟，并记录CD-1开始表现出进攻性的潜伏期，随后移出C57筛选小鼠。对每一只CD-1小鼠，一天中用同一只C57筛选小鼠重复三次实验，每天选取不同的C57筛选小鼠，共进行三天的筛选。根据每只CD-1表现出进攻性的潜伏期来选择具有进攻性的小鼠:在一天中每次3分钟的三次接触环节内，CD-1小鼠必须至少在两个连续环节内表现出攻击行为，并且在每一次的3分钟接触时间内，其表现出进攻性的潜伏期必须小于1分钟。在筛选出用于造模的CD-1侵略性小鼠后，每只C57测试小鼠每天暴露于不同的CD-1侵略性小鼠10分钟，连续进行10天。在短暂的暴露中，所有的测试小鼠都表现出具有压力和依顺性的特征，包括发声、逃避反应以及顺从性姿势。在10分钟的接触后，测试小鼠与侵略者分离。测试小鼠与侵略性小鼠被安排在同一个鼠笼内的相邻部分，中间用一个多孔的透明塑料挡板隔开，使得测试小鼠在接下来的24小时暴露于威胁性的慢性压力刺激。对照组小鼠则被安排在同样结构的鼠笼内，但挡板另一边放置每天更换的同种系的其它小鼠。在最后一天实验结束后的24小时之后，根据之前相关报道,我们评估CSDS诱导的社交行为学改变并挑选出所有的易感型小鼠。社交互动比例(social interaction ratio,SI ratio)按照以下公式计算:SI ratio＝侵略者存在时在互动区域的时间/侵略者缺席时在互动区域的时间。如果SI ratio小于1，说明测试小鼠在侵略者存在时在互动区域的时间比侵略者缺席时少,被用作鉴别易感型小鼠的判断标准和阈值。随后所有被挑选出的测试小鼠以及对照组小鼠单独饲养3周，在此期间，易感型小鼠被随机分成三组:DEFEAT抑郁模型组每天灌胃给予0.5％CMC-Na，C-11给药组每天灌胃给予10mg/kg C-11，FLX给药组每天腹腔注射给予10mg/kg fluoxetine。Vehicle组小鼠每天灌胃给予0.5％CMC-Na。SI ratio每周评估一次。
所有数据分析采用spss 22(for mac)数据处理软件完成。使用双因素方差分析(two-way ANOVA)，采用LSD法多重比较校验结果。数据用Mean±sem表示。p<0.05时标记一个星号；p<0.01时标记两个星号。
试验结果如图5所示。A图示社交失败抑郁小鼠模型的药效评估，计算小鼠社交时间。结果显示C-11在给药的第二周就可以显著提高小鼠的社交时间，而氟西汀在给药的第三周仍未起效。B图示小鼠的社交比例，该值越大表示动物的社交行为越好。 结果进一步提示C-11在给药的第一周就可有效的提高小鼠的社交活动，而氟西汀给药三周仍未起效。C图示旷场实验结果，各组间动物的移动距离均无明显变化，提示各组动物的运动能力无差异，不会对社交行为造成影响。这些结果提示口服化合物C-11的1-2周可有效缓解抑郁症状，且药物起效时间明显比氟西汀快。
实施例45
化合物C-49生物利用度考察
具体实验步骤如下：健康雄性SD大鼠，体重270g左右，给药前禁食10h，自由饮水。灌胃C-49(CMC-Na溶剂混悬)，剂量为100mg/kg大鼠体重，眼眶取血的时间点为给药后眼眶取血的时间点为30min,1h,2h,4h,6h,8h,10h,24h，48h(n＝5)。尾静脉注射C-49(10％乙醇/15％吐温80/75％生理盐水配制成溶液)，剂量为1mg/kg大鼠体重，眼眶取血的时间点为5min,10min,30min,1h,2h,4h,8h(n＝4)。将血浆置于涂有肝素的离心试管中，离心10min(8000r)后取上清液。置于-80℃冰箱中保存。经过乙腈沉淀处理后，进HPLC-QQQ进行检测。药动学参数通过WinNonlin(Pharsight6.2,NC,USA)的非房室模型进行计算每只老鼠的PK参数。所有的参数用Mean±S.D.表示。生物利用度(F)＝(AUC 口服/Dose 口服)/(AUC 尾静脉/Dose 尾静脉)
药时曲线如图6所示，药动参数如下表16所示。
表16 大鼠口服、尾静脉注射C-49的药代动力学参数
Figure PCTCN2018124690-appb-000112
由实验可知，大鼠口服C-49(100mg/kg)，血药浓度较高，C max和AUC分别为250.8ng/mL和3115.3h*ng/mL，T 1/2和MRT分别为9.7和13.6h。大鼠尾静脉注射C-49(1mg/kg)后，血药浓度比较低，C max和AUC分别为284.7ng/mL和293.0h*ng/mL，T 1/2和MRT分别为9.7和13.6h。通过比较大鼠口服和尾静脉注射的C-49的AUC/Does，计算出C-49的生物利用度为11.1％。
自然界中，螺甾烷型知母皂苷及其苷元的抗抑郁活性较弱，而且生物利用度也比较低。经过对菝葜皂苷元进行结构修饰，本申请得到的化合物C-11、C-49等，相对于先导化合物菝葜皂苷元，具有更好的抗抑郁活性。而且，化合物C-49的生物利用度为11.1％，也有了较大幅度的提高。
实施例46
化合物C-49对小鼠学习记忆促进作用的药效学筛选研究
学习记忆是人类和动物大脑的高级功能。在本次筛选试验中，通过比较给药小鼠及记忆障碍小鼠的被动回避行为则可初步评估候选药物是否具有促学习记忆作用。在本次实验中，选用乙醇诱导小鼠的记忆再现障碍，对候选药物C-49的促进学习记忆作用进行了初步探索。其实验原理为：乙醇具有中枢抑制作用，可抑制大脑皮层的神经功能活动，明显干扰记忆的再现。训练后重测前，给予小鼠乙醇溶液，可阻断动物的记忆再现过程，造成记忆再现障碍。
实验选用雄性ICR小鼠，16-18g，购自上海西普尔-毕凯实验动物有限公司。
动物喂养：动物均喂以标准灭菌鼠饲料，动物饮用水采用饮水瓶供应，动物自由饮水。动物饲养：每笼饲养动物10只。动物设定室温20℃～22℃，湿度40％～70％，光照12小时明暗交替。垫料每周至少更换2次，同时更换饲养盒，遇有异常情况时随时更换饲养盒。每天更换消毒饮水瓶和瓶塞，每两周消毒1次笼架。所有换洗的笼具清洗后均采用高压灭菌。
40只雄性小鼠由Excel完全随机分组法分为4组，每组10只动物。第1组小鼠(空白组)、第2组小鼠(模型组)每天经口灌胃(i.g.)给予饮用水，第3组小鼠(阳性药组)i.g.给予多奈哌齐1.6mg/kg，第4组小鼠分别按相应C-49药液灌胃给药，给药剂量15mg/kg。每日1次，0.2mL/10g体重/次，连续给药3周。
给药满3周后，末次给药后1h，以避暗法训练一次。将小鼠放入避暗箱内，背朝洞口放入明室，同时启动视频分析装置，动物穿过洞口进入暗室受到电击，计时自动停止。取出小鼠，视屏分析将记录每鼠从放入明室至进入暗室遇到电击所需的时间，此即潜伏期。24h后进行测试，测试前30min经口灌胃给予45％的乙醇溶液(0.1ml/10g)，视频分析系统将摄制并自动记录动物所有相关数据。数据以平均值±标准差
Figure PCTCN2018124690-appb-000113
表示，数据差异统计采用单因素方差分(ANOVA)或X 2检验，组间差异以P<0.05判断。
实验结果表明，经口灌胃给予15mg/kg的C-49，给药后未观察到小鼠有异常状态出现。期间每周称体重并记录。给药期21d内，所有动物体重增长未见异常。动物体重的增长情况见(图7)。候选药物C-49灌胃连续三周对乙醇造成的记忆再现障碍小鼠的实验结果如表17所示。
表17.C-49连续i.g.给药3周对乙醇所致小鼠记忆再现障碍的影响(
Figure PCTCN2018124690-appb-000114
n＝10)
Figure PCTCN2018124690-appb-000115
**P<0.01；*P<0.05，与模型组相比
表17实验结果表明，训练后24h，给予小鼠45％乙醇可致明显记忆再现障碍(与空白组比较，均出现统计学显著差异)，证明造模成功。与模型组小鼠比较，1.6mg/kg多奈哌齐和15mg/kg剂量C-49连续给药三周，可显著延长小鼠进入暗室的潜伏期，并降低5min内小鼠受电击总次数，同时显著减少受电击的动物数(P<0.01或0.05)。实验表明C-49(15mg/kg)对乙醇诱导的记忆再现障碍小鼠有显著促学习记忆作用。同时，在该剂量下连续三周给药对小鼠未出现明显的毒性作用。针对乙醇诱导的动物记忆障碍模型，C-49在实验中表现良好的安全性及显著的药效作用。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (17)

  1. 一种式I所示的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体、立体异构体或它们的混合物，
    Figure PCTCN2018124690-appb-100001
    所述式I所示的化合物由以下片段A和片段B连接而成，
    Figure PCTCN2018124690-appb-100002
    其中，R 1、R 2、R 3各自独立地选自氢、烷基、取代的烷基、芳基烷基、取代的芳基烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环基、取代的杂环基，
    或者R 1、R 2、R 3中的任两个与相连的N形成含有1-3个N、0-2个O和/或0-2个S原子的3-7元饱和或不饱和杂环，所述“杂环”未取代或者被以下基团单取代或者多取代：氢、烷基、取代的烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环基、取代的杂环基、烷酰基、取代的烷酰基、烷氧基羰基、芳基烷氧基羰基、烷基磺酰基、烷基亚磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基、羧基、酰胺、取代的酰胺、磺酰胺基、取代的磺酰胺基，
    Figure PCTCN2018124690-appb-100003
    表示单键或者双键
    R 6a、R 6b、R 6c、R 6d、R 6e、R 6f、R 7a、R 7b、R 8a、R 8b、R 9a、R 9b、R 10a、R 10b各自独立地选自无、氢、卤素、烷基、取代的烷基、羟基、巯基、烷基巯基、烷氧基、取代的烷氧基、氨基、取代的氨基、烷基氨基、取代的烷基氨基、二取代的氨基、烷基 酰氧基、芳基酰氧基、杂芳基酰氧基、糖基，或者R 6a、R 6b两两之间和/或R 7a、R 7b两两之间和/或R 8a、R 8b两两之间和/或R 9a、R 9b两两之间和/或R 10a、R 10b两两之间合并成羰基；
    X 1为O、S或NR 5，R 5选自氢、烷基、氰基、羟基、烷氧基，
    Figure PCTCN2018124690-appb-100004
    表示单键或者无；
    当
    Figure PCTCN2018124690-appb-100005
    为单键时，X 2为O或NH，R 4a、R 4b各自独立地选自氢、羟基、烷基、取代的烷基、链烯基、取代的链烯基、炔基、取代的炔基，或者R 4a、R 4b与相连的C形成含有0-3个N、0-2个O和/或0-2个S原子的3-7元饱和或不饱和杂环，所述“杂环”未取代或者被以下基团单取代或者多取代：氢、羟基、烷基、取代的烷基、链烯基、取代的链烯基、炔基、取代的炔基；
    当
    Figure PCTCN2018124690-appb-100006
    为无时，X 2为OR h、N(R i)(R j)，R 4a、R 4b与连接的碳共同形成-X aR k，Xa为CH 2、CHOH或者C＝O，R h、R i、R j、R k各自独立选自氢、烷基、取代的烷基、环烷基、取代的环烷基、烷酰基、取代的烷酰基、烷氧基羰基、烷氧基羰基、烷胺基羰基、芳基烷氧基羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基、羧基、酰胺、取代的酰胺；
    各*独立地表示消旋、S或R构型。
  2. 根据权利要求1所述的化合物，其特征在于，R 2、R 3各自独立地选自氢、环烷基、取代的环烷基、杂环基、取代的杂环基、芳基、取代的芳基、-MX 3PX 5Q，其中，
    M为亚烷基、取代的亚烷基、亚环烷基、取代的亚环烷基，
    X 3选自O、S、(CH 2) r、NRa或者无，Ra选自氢、烷基、取代的烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环，r＝1、2、3、4或5；
    P为C＝O、C＝S、C＝NR b、C＝C(R c)(R d)或者无，R b选自氢、羟基、烷氧基、氰基、硝基，R c、R d独立选自氢、烷基、羟基、烷氧基、氰基、硝基，
    X 5选自O、S、(CH 2) m、NRe或者无，Re选自氢、烷基、取代的烷基，m＝1、2、3、4或5，
    Q为氢、羟基、烷氧基、芳氧基、NR fR g、烷基、取代的烷基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环基、取代的杂环基，R f、R g相互独立，为氢、羟基、烷基、烷氧基、取代的烷基、链烯基、取代的链烯基、炔基、取代的炔基、烷氧基羰基，或者R f、R g两两之间形成含有0-3个N、0-2个O和/或0-2个S原子的3-7元饱和或不饱和杂环，此“杂环”未取代或者被以下基团单取代或者多取代：氢、羟基、氨基、烷基、取代的烷基、链烯基、取代的链烯基、炔基、取代的炔基。
  3. 根据权利要求1所述的化合物，其特征在于，R 2为氢时，R 3为烷基、取代的烷基、环烷基、取代的环烷基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环基；或者R 2、R 3与相连的N形成以下结构：
    Figure PCTCN2018124690-appb-100007
    其中，X 3为C＝O、CH 2、O或NR 11，R 11选自烷基、取代的烷基、芳基烷基、取代的芳基烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环、烷酰基、取代的烷酰基、烷氧基羰基、芳基烷氧基羰基、氨基甲酰基、取代的氨基甲酰基、羧基、烷基磺酰基、烷基亚磺酰基、芳基磺酰基、芳基烷基磺酰基、酰胺、取代的酰胺、磺酰胺基、取代的磺酰胺基；
    n＝0、1或2。
  4. 根据权利要求1所述的化合物，其特征在于，所述片段B选自下组：
    Figure PCTCN2018124690-appb-100008
    Figure PCTCN2018124690-appb-100009
    各式中，X 4为CH 2OR 12、CH 2N(R 13)(R 14)、醛基、COOR 12、CON(R 13)(R 14)，R 12、R 13、R 14相互独立，选自氢、烷基、取代的烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂 环、取代的杂环、烷酰基、取代的烷酰基、烷氧基羰基、芳基烷氧基羰基、烷基磺酰基、烷基亚磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基；
    X 6为OR 15、N(R 16)(R 17)，R 15、R 16、R 17相互独立，选自氢、烷基、取代的烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环、烷酰基、取代的烷酰基、烷氧基羰基、芳基烷氧基羰基、烷基磺酰基、烷基亚磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基；
    X 7为CH 2或者C＝O。
  5. 根据权利要求1所述的化合物，其特征在于，R 1、R 2、R 3各自独立地选自氢、C3-C8环烷基、C6-C10芳基、C3-C8的饱和杂环基、C1-C4烷基，其中环烷基、芳基、饱和杂环基、烷基任选地被选自下组的基团单取代、二取代或三取代：卤素、羟基、C1-C4烷基、C6-C10芳基、-C(＝O)-O-C1-C4烷基；或者R 2、R 3与相连的N形成含有1-3个N、0-2个O和/或0-2个S原子的3-7元饱和或不饱和杂环，所述“杂环”未取代或者被以下基团单取代或者多取代：氢、C1-C4烷基、C1-C4烷氧基、C2-C4烯基、C2-C4炔基、羟基；
    R 4a、R 4b各自独立地选自氢、羟基、取代或未取代的C1-C6烷基，所述取代是指具有选自下组的一个、两个或三个取代基：卤素、羟基、C1-C4烷基、C1-C4烷氧基；或者R 4a、R 4b与相连的C形成含有1-2个O和/或1-2个S原子的3-7元饱和或不饱和杂环，所述“杂环”未取代或者被以下基团单取代或者多取代：氢、C1-C4烷基、C1-C4烷氧基、C2-C4烯基、C2-C4炔基、羟基；
    X 1为O、S、NR 5，R 5选自氢、烷基、羟基，
    R 6a、R 6b、R 6c、R 6d、R 6e、R 6f、R 7a、R 7b、R 8a、R 8b、R 9a、R 9b、R 10a、R 10b为无、氢、烷基、取代的烷基、羟基或巯基，或者R 6a、R 6b两两之间和/或R 7a、R 7b两两之间和/或R 8a、R 8b两两之间和/或R 9a、R 9b两两之间和/或R 10a、R 10b两两之间合并成羰基，
    Figure PCTCN2018124690-appb-100010
    表示单键或者双键。
  6. 根据权利要求1或4所述的化合物，其特征在于，
    X 1为O；
    R 1为氢；
    R 6a、R 6b、R 6c、R 6d、R 6e、R 6f、R 7a、R 7b、R 8a、R 8b、R 9a、R 9b、R 10a、R 10b均为氢；
    R 2、R 3各自独立地选自氢、C3-C8环烷基、C6-C10芳基、C3-C8的饱和杂环基、C1-C4烷基，其中环烷基、芳基、饱和杂环基、烷基任选地被选自下组的基团单取代、二取代或三取代：卤素、羟基、C1-C4烷基、C6-C10芳基、-C(＝O)-OC1-C4烷基；或者R 2、R 3与相连的N形成含有1-3个N、0-2个O和/或0-2个S原子的3-7元饱和或不饱和杂环，所述“杂环”未取代或者被以下基团单取代或者多取代：氢、C1-C4烷基、C1-C4烷氧基、羟基。
  7. 根据权利要求1所述的化合物，其特征在于，所述化合物为：
    Figure PCTCN2018124690-appb-100011
    Figure PCTCN2018124690-appb-100012
    Figure PCTCN2018124690-appb-100013
    Figure PCTCN2018124690-appb-100014
    Figure PCTCN2018124690-appb-100015
  8. 根据权利要求1所述的化合物，其特征在于，
    片段A为
    Figure PCTCN2018124690-appb-100016
    其中，R 3a选自环己烷基、环戊烷基、环丁烷基、苯基；
    R 3b选自氢、烷氧基羰基、羧基；
    R 2a选自氢以及
    Figure PCTCN2018124690-appb-100017
    R 2b选自氢、羟基、氨基、-OC(＝O)R 2c、-NHC(＝O)R 2c、-NHC(＝O)NHR 2c，R 2c选自
    Figure PCTCN2018124690-appb-100018
    Figure PCTCN2018124690-appb-100019
    q＝0，1，2或3；
    片段B选自下组：
    Figure PCTCN2018124690-appb-100020
  9. 根据权利要求8所述的化合物，其特征在于，所述化合物为：
    Figure PCTCN2018124690-appb-100021
    Figure PCTCN2018124690-appb-100022
  10. 根据权利要求1所述的化合物，其特征在于，
    片段A为
    Figure PCTCN2018124690-appb-100023
    其中
    R 3c选自环己烷基、环戊烷基、环丁烷基、氢、甲基、苯基或者取代的苯基，取代基选自氟、氯、溴、碘、氰基、羟基、甲氧基、三氟甲基、三氟甲氧基；
    D选自
    Figure PCTCN2018124690-appb-100024
    或者D与R 3c相连形成含有1个N的3-7元饱和杂环，
    R 3d选自
    Figure PCTCN2018124690-appb-100025
    Figure PCTCN2018124690-appb-100026
    片段B选自下组：
    Figure PCTCN2018124690-appb-100027
  11. 根据权利要求10所述的化合物，其特征在于，所述化合物为：
    Figure PCTCN2018124690-appb-100028
    Figure PCTCN2018124690-appb-100029
    Figure PCTCN2018124690-appb-100030
  12. 根据权利要求1所述的化合物，其特征在于，
    片段A为
    Figure PCTCN2018124690-appb-100031
    其中
    R 3e选自环己烷基、环戊烷基、环丁烷基、氢、甲基、苯基或者取代的苯基，取代基选自氟、氯、溴、碘、氰基、羟基、甲氧基、三氟甲基、三氟甲氧基，
    R dd为O或NH；
    D选自
    Figure PCTCN2018124690-appb-100032
    或者与R 3e相连形成含有1个N的3-7元饱和杂环，
    R 3f选自下组：氢、氨基、C1-C6烷基氨基、取代的C1-C6烷基氨基、C3-C6环烷基氨基、取代的C3-C6环烷基氨基、C1-C6烷基、取代的C1-C6烷基、C3-C6环烷 基、取代的C3-C6环烷基、
    Figure PCTCN2018124690-appb-100033
    Figure PCTCN2018124690-appb-100034
    片段B选自下组：
    Figure PCTCN2018124690-appb-100035
  13. 根据权利要求12所述的化合物，其特征在于，所述化合物选自下组：
    Figure PCTCN2018124690-appb-100036
    Figure PCTCN2018124690-appb-100037
    Figure PCTCN2018124690-appb-100038
    Figure PCTCN2018124690-appb-100039
    Figure PCTCN2018124690-appb-100040
    Figure PCTCN2018124690-appb-100041
    Figure PCTCN2018124690-appb-100042
  14. 根据权利要求1所述的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体或立体异构体的制备方法，其特征在于，所述制备方法包括以下步骤：
    Figure PCTCN2018124690-appb-100043
    (a)3-氨基甾体配基与异氰酸酯反应得到权利要求1所述的化合物，其中R 1和R 2为氢，其他取代基的定义如权利要求1所述；
    或者所述制备方法包括以下步骤：
    Figure PCTCN2018124690-appb-100044
    (i)由3-氨基甾体配基制备3-异氰酸酯甾体化合物；
    (ii)3-异氰酸酯甾体化合物与NHR 2R 3反应生成权利要求1所述的化合物，其中R 1为氢，其他取代基的定义如权利要求1所述。
  15. 一种药物混合物，其特征在于，所述药物混合物包含选自下组的两种或三种以上的化合物：权利要求1-13任一项所述的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体、立体异构体。
  16. 一种药物组合物，其特征在于，所述药物组合物包含权利要求1-13任一项所述的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体或立体异构体，或权利要求15所述的药物混合物；以及药学上可接受的载体。
  17. 如权利要求1-13任一项所述的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体或立体异构体、权利要求15所述的药物混合物物或权利要求16所述的药物组合物的用途，其特征在于，用于制备防护、处理、治疗或减轻患者疾病、病症或病状的药物的用途，所述的疾病、病症或病状选自抑郁症、焦虑症、帕金森病、阿尔兹海默病、亨廷顿病、精神分裂症、躁狂症。
PCT/CN2018/124690 2017-12-29 2018-12-28 一种菝葜皂苷元衍生物及其制备方法和应用 WO2019129176A1 (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201711482896 2017-12-29
CN201711482896.1 2017-12-29
CN201810664219.XA CN109988218B (zh) 2017-12-29 2018-06-25 一种菝葜皂苷元衍生物及其制备方法和应用
CN201810664219.X 2018-06-25

Publications (1)

Publication Number Publication Date
WO2019129176A1 true WO2019129176A1 (zh) 2019-07-04

Family

ID=67066581

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/124690 WO2019129176A1 (zh) 2017-12-29 2018-12-28 一种菝葜皂苷元衍生物及其制备方法和应用

Country Status (1)

Country Link
WO (1) WO2019129176A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3564253A4 (en) * 2016-12-30 2020-07-29 Shanghai Institute of Materia Medica, Chinese Academy of Sciences ANTIDEPRESSIVE PREPARATION AND PRODUCTION METHOD AND USE THEREOF
EP3858849A4 (en) * 2018-09-29 2022-07-13 Phytovent Biopharma DERIVATIVE BASED ON A COMMON STRUCTURE OF SARSASAPOGENIN FROM RHIZOME OF ANEMARRHENAE, PHARMACEUTICAL COMPOSITION AND USE

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102924559B (zh) * 2012-11-16 2015-10-28 沈阳药科大学 菝葜皂苷元衍生物及其制备和应用
US20170129915A1 (en) * 2014-04-25 2017-05-11 Resilio Company Limited Therapeutic agent for diseases associated with nerve axon dysfunction, including therapeutic agent for alzheimer's disease
WO2018121770A1 (zh) * 2016-12-30 2018-07-05 中国科学院上海药物研究所 一种抗抑郁化合物及其制备方法和应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102924559B (zh) * 2012-11-16 2015-10-28 沈阳药科大学 菝葜皂苷元衍生物及其制备和应用
US20170129915A1 (en) * 2014-04-25 2017-05-11 Resilio Company Limited Therapeutic agent for diseases associated with nerve axon dysfunction, including therapeutic agent for alzheimer's disease
WO2018121770A1 (zh) * 2016-12-30 2018-07-05 中国科学院上海药物研究所 一种抗抑郁化合物及其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
REMERO-HERNANDEZ, L. L. ET AL.: "Diosgenin-based thio(seleno)ureas and triazolyl glycoconjugates as hybrid drugs. Antioxidant and antiproliferative profile", EUROPEAN JOUR-NALPHAL OF MEDICINAL CHEMISTRY, vol. 99, 31 December 2015 (2015-12-31), pages 67 - 81, XP029222662, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2015.05.018 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3564253A4 (en) * 2016-12-30 2020-07-29 Shanghai Institute of Materia Medica, Chinese Academy of Sciences ANTIDEPRESSIVE PREPARATION AND PRODUCTION METHOD AND USE THEREOF
US11142543B2 (en) 2016-12-30 2021-10-12 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Antidepressant compound and preparation method and application thereof
EP3858849A4 (en) * 2018-09-29 2022-07-13 Phytovent Biopharma DERIVATIVE BASED ON A COMMON STRUCTURE OF SARSASAPOGENIN FROM RHIZOME OF ANEMARRHENAE, PHARMACEUTICAL COMPOSITION AND USE

Similar Documents

Publication Publication Date Title
WO2018121770A1 (zh) 一种抗抑郁化合物及其制备方法和应用
US9884844B2 (en) Heterocyclic compounds and methods of use thereof
TWI357327B (en) Pyrazoline compounds
US20040072867A1 (en) NK1 antagonists
JP2016065085A (ja) モノアミン再取り込み阻害薬としてのフェニル置換シクロアルキルアミン
KR20220131520A (ko) 아릴시클로헥실아민 유도체 및 정신장애 치료에서의 이의 용도
US20190083420A1 (en) Methods of using (2r, 6r)-hydroxynorketamine and (2s, 6s)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, fatigue, suicidal ideation, and post traumatic stress disorders
JP6078059B2 (ja) 置換シンナムアミド誘導体、その製造方法及び使用
WO2019192602A1 (zh) 芳香类化合物及其制备方法和用途
JP6697808B2 (ja) 感覚有毛細胞の死を防ぐまたは処置するための化合物と方法
WO2019129176A1 (zh) 一种菝葜皂苷元衍生物及其制备方法和应用
CA3017342A1 (en) Dopamine d3 receptor selective antagonists/partial agonists; method of making; and use thereof
CN109988218B (zh) 一种菝葜皂苷元衍生物及其制备方法和应用
TW200843748A (en) New combination 629
EA003991B1 (ru) Производные 2-аминопиридинов, способ ингибирования синтазы оксида азота, фармацевтические композиции и способы лечения
EP2784077B1 (en) Norepinephrine and selective serotonin receptor blocker and use thereof
WO1995026187A1 (en) Anxiolytic agent
CN114728920B (zh) 一种沃替西汀前药及其应用
WO2023165575A1 (zh) 新型氨基酮类化合物及其制备方法和用途
JP2018521090A (ja) 疼痛に対する多様な活性を有するアミド誘導体
JP2008001596A (ja) ナトリウムチャネル阻害剤
WO2020259612A1 (zh) 一种抗抑郁甾体化合物
CA3232914A1 (en) Lsd derivatives, synthesis &amp; method for treatment of diseases and disorders
JPH04128224A (ja) クマリン環を有する脳循環代謝改善薬
US20140213647A1 (en) Compound useful for preventing or treating irritable bowel syndrome and composition including same

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18895813

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18895813

Country of ref document: EP

Kind code of ref document: A1