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WO2017035733A1 - 美金刚与牛蒡子苷元的缀合物及其组合物和用途 - Google Patents

美金刚与牛蒡子苷元的缀合物及其组合物和用途 Download PDF

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WO2017035733A1
WO2017035733A1 PCT/CN2015/088585 CN2015088585W WO2017035733A1 WO 2017035733 A1 WO2017035733 A1 WO 2017035733A1 CN 2015088585 W CN2015088585 W CN 2015088585W WO 2017035733 A1 WO2017035733 A1 WO 2017035733A1
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substituted
unsubstituted
group
conjugate
compound
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PCT/CN2015/088585
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English (en)
French (fr)
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孙海丰
刘军
燕炜
张定
阳靖
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深圳青雅启瑞生物科技有限公司
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Priority to PCT/CN2015/088585 priority Critical patent/WO2017035733A1/zh
Priority to CN201580082720.XA priority patent/CN108024990B/zh
Priority to US15/756,342 priority patent/US10441565B2/en
Publication of WO2017035733A1 publication Critical patent/WO2017035733A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • 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

Definitions

  • the invention relates to the field of medicinal chemistry and disease treatment.
  • the present invention relates to a conjugate of memantine and arctigenin, a pharmaceutical composition comprising the same, and a treatment thereof for a disease associated with an amyloid beta (A ⁇ ) or Tau protein pathway Use, especially in the treatment of neurodegenerative diseases such as Alzheimer's disease (AD) or Parkinson's disease.
  • a ⁇ amyloid beta
  • AD Alzheimer's disease
  • Parkinson's disease a complex regional pain syndrome
  • AD is an age-related, progressive central nervous system degenerative disease.
  • the early clinical manifestations include memory and cognition such as recent memory loss, aphasia, misuse, and loss of recognition, executive dysfunction, and abnormal personality changes.
  • the mid-term clinical manifestations are irritability, panic, sleep disorders, hallucinations, and other personality and behavioral changes; Late clinical manifestations are lack of logical thinking, bedridden, and life cannot take care of themselves.
  • AD patients there are currently about 30 million AD patients in the world, and with the aging of the world's population, by 2050, the number of AD patients worldwide will exceed 100 million. AD patients will not be able to live independently in the middle and late stages, and need medical staff care. According to statistics, the annual cost of caring for AD patients in the United States amounts to more than $300 billion (US, Alzheimer's Association). According to the latest data released by the National Bureau of Statistics of China, as of the end of 2014, the number of elderly people aged 60 and over in China has reached 210.42 million, accounting for 15.5% of the total population. The population aged 65 and over is 137.55 million, accounting for 10.1% of the total population. At present, the number of AD patients in China has exceeded 8 million. As China's population ages, the number of AD patients will also increase dramatically. It is estimated that by 2050, the number of AD patients in China will reach nearly 30 million, so AD has become an important burden for our society and family.
  • AD patients have two important histopathological features: a large number of senile plaques (SP) formed by A ⁇ aggregation in brain tissue related to learning and memory in the cerebral cortex, hippocampus, forebrain basal ganglia and thalamus; Entanglement of nerve fibers due to hyperphosphorylation of Tau protein.
  • SP senile plaques
  • Oligomers which cause changes in oxidative stress, inflammation, and hyperphosphorylation of Tau protein in the brain, ultimately leading to neuronal death. Therefore, A ⁇ , as a leading factor in the pathological changes of AD, plays a crucial role in the pathological process of AD patients.
  • AD model mice with high expression of A ⁇ it was also found that A ⁇ increased earlier than memory impairment, and if AD model mice were knocked out of BACE1 (the rate-limiting enzyme produced by A ⁇ ), the A ⁇ was significantly reduced. Memory impairment and neuronal apoptosis also showed significant reversal. Therefore, A ⁇ has become an important target for new anti-AD therapeutic drugs, and AD model mice with high expression of A ⁇ have also become accepted models for the evaluation of the efficacy of such anti-AD therapeutic drugs.
  • BACE1 the rate-limiting enzyme produced by A ⁇
  • APP/PS1 double transgenic AD model mice (B6C3 transgenic mice, APPswe, PS1dE9) can highly express the embedded mutant and mouse/human Swedish mutant APP (Mo/HuAPP695swe) and humans to delete the presenilin of the 9th exon. 1 protein (presenilin, PS1-dE9). Both of these gene mutations are thought to be the major causative mutations that cause familial AD.
  • a ⁇ deposition began to appear in about 6 months, and memory damage occurred in about 7 months.
  • APP/PS1 transgenic mice became model mice suitable for pharmacodynamic evaluation in the development of anti-AD therapeutic drugs.
  • Memantine is currently a clinically used drug for the treatment of AD. However, memantine can only improve the symptoms of AD, but not its pathological process (Areosa SA. et al., Memantine for dementia. (2005) Cochrane Database Syst Rev. (3): CD003154). It is urgent to develop drugs that can improve the symptoms of AD while blocking its pathological process.
  • the invention provides a conjugate comprising memantine and arctigenin,
  • the conjugate may be a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or prodrug thereof, wherein linker 1 is as defined below,
  • the conjugates are useful for treating diseases associated with the A[beta] or Tau protein pathway.
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a conjugate of the invention and one or more pharmaceutically acceptable carriers, and optionally further comprising one or more treatments associated with an A[beta] or Tau protein pathway Other drugs for the disease.
  • a further aspect of the invention provides a method of treating a disease associated with an A[beta] or Tau protein pathway comprising administering to a subject in need thereof a therapeutically effective amount of a conjugate or pharmaceutical composition of the invention, and optionally comprising The individual is additionally administered another drug that treats diseases associated with the A[beta] or Tau protein pathway.
  • a further aspect of the invention provides the use of a conjugate of the invention in the manufacture of a medicament for the treatment of a disease associated with the A[beta] or Tau protein pathway.
  • Figure 1 is a genetic representation of Drosophila.
  • Figure 2 shows the salvage effect of memantine (Mem) and conjugate A04 on memory damage of AD Drosophila.
  • Figure 3 shows the effect of conjugate A04 on reversing memory impairment in transgenic AD model mice.
  • the invention provides a conjugate comprising memantine and arctigenin.
  • the conjugate of the invention is a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or prodrug thereof:
  • Linker 1 is selected from: -C(O)-, -C(O)L 1 C(O)-, -C(O)OL 1 C(O)-, -C(O)OL 1 OC(O)- , -C(O)OQ 1 L 2 Q 2 -, -C(O)Q 1 L 2 Q 2 N(R 1 )C(O)-, -C(O)Q 1 L 2 Q 2 OC(O )-, -C(O)Q 1 L 2 Q 2 C(O)-, -C(O)OQ 1 L 2 Q 2 OC(O)-, -C(O)OQ 1 L 1 Q 2 N( R 1 )C(O)-, -C(O)OQ 1 L 2 Q 2 N(R 1 )C(O)- and -C(O)OQ 1 L 2 Q 2 C(O)-;
  • L 1 is a direct bond or is selected from: -O-, -S-, -NR 2 -, substituted or unsubstituted C1-C6 straight or branched alkylene, substituted or unsubstituted C2-C6 straight chain Or branched alkenylene, substituted or unsubstituted C2-C6 straight or branched alkynylene, substituted or unsubstituted C3-C10 cycloalkylene, substituted or unsubstituted C3-C10 non-aromatic hetero a cycloalkyl, substituted or unsubstituted C6-C14 arylene group, a substituted or unsubstituted C6-C14 heteroarylene group, and a substituted or unsubstituted C6-C20 aralkylene group;
  • L 2 is a direct bond or is selected from: -NR 2 -, -O-, -C(O)-, -N(R 3 )C(O)-, -C(O)N(R 3 )-, -C(O)O-, -OC(O)-, -N(R 3 )Q 3 O-, -N(R 3 )C(O)Q 3 O-, -N(R 3 )C(O ) Q 3 C(O)-, -N(R 3 )C(O)Q 3 N(R 3 )-, -N(R 3 )C(O)Q 3 C(O)N(R 3 )- , -N(R 3 )C(O)Q 3 N(R 3 )C(O)-, -N(R 3 )C(O)Q 3 N(R 3 )C(O)-, -N(R 3 )C(O)Q 3 N(R 3 )C(O)-
  • Q 1 , Q 2 and Q 3 are each independently selected from: a substituted or unsubstituted C1-C6 straight or branched alkylene group, a substituted or unsubstituted C3-C10 cycloalkylene group, a substituted or unsubstituted C2 -C6 straight or branched alkenylene, substituted or unsubstituted C2-C6 straight or branched alkynylene, substituted or unsubstituted C3-C10 non-aromatic heterocyclylene, substituted or unsubstituted C6 a C14 arylene group, a substituted or unsubstituted C6-C14 heteroarylene group, and a substituted or unsubstituted C6-C20 aralkylene group;
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of: H and C1-C6 alkyl.
  • Linker 1 is selected from the group consisting of: -C(O)-, -C(O)L 1 C(O)-, -C(O)OL 1 C(O)-, -C(O) OL 1 OC(O)-, -C(O)OQ 1 L 2 Q 2 -, -C(O)OQ 1 L 2 Q 2 OC(O)-, -C(O)OQ 1 L 1 Q 2 N (R 1 )C(O)-, -C(O)OQ 1 L 2 Q 2 N(R 1 )C(O)- and -C(O)OQ 1 L 2 Q 2 C(O)-.
  • L 1 is a direct bond or is selected from the group consisting of methylene, ethylene, propylene, pyrrolidinyl, piperidinyl, piperazinyl, phenylene, and benzidine. Or a pyridylene group, which group is optionally substituted by one or more substituents selected from cyano, amino, halogen or C1-C6 alkyl.
  • L 2 is a direct bond or is selected from the group consisting of: -NR 2 -, -C(O)-, -C(O)N(R 3 )-, -C(O)O-, - OC(O)-, -N(R 3 )Q 3 O-, -N(R 3 )C(O)Q 3 C(O)-, -N(R 3 )C(O)Q 3 C(O N(R 3 )-, -OQ 3 N(R 3 )-, -OC(O)Q 3 -, -OC(O)Q 3 C(O)O-, -OC(O)Q 3 N( R 3 )-, -OC(O)Q 3 N(R 3 )L 1 O-, -C(O)OQ 3 -, -C(O)OQ 3 O-.
  • Q 1 , Q 2 and Q 3 are each independently selected from the group consisting of methylene, ethylene, propylene, cyclohexylene, pyrrolidinyl, piperidinyl, and piperazine.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of: H and a C1-C4 alkyl group, such as a methyl group.
  • the present invention encompasses a conjugate of the formula (I) obtained by any combination of the above preferred groups.
  • the conjugate of the invention is a compound of formula (II), a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or prodrug thereof:
  • Linker 2 is selected from: -L 1 -, - L 1 O -, - Q 1 L 1 Q 2 N (R 1) -, - Q 1 L 2 Q 2 N (R 1) -, - Q 1 L 2 Q 2 O- or -Q 1 L 2 Q 2 -;
  • L 1 is selected from: a substituted or unsubstituted C1-C6 straight or branched alkylene group, a substituted or unsubstituted C2-C6 straight or branched alkenylene group, a substituted or unsubstituted C2-C6 straight chain or Branched alkynylene, substituted or unsubstituted C3-C10 cycloalkylene, substituted or unsubstituted C3-C10 non-aromatic heterocyclylene, substituted or unsubstituted C6-C14 arylene, substituted or not a substituted C6-C14 heteroarylene group, and a substituted or unsubstituted C6-C20 aralkylene group;
  • L 2 , Q 1 , Q 2 , Q 3 , R 1 , R 2 and R 3 are as defined above for the general formula (I).
  • the conjugate of the invention is a compound of formula (III), a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or prodrug thereof:
  • Linker 3 is a direct bond or is selected from: -C(O)Q 3 N(R 3 )Q 2 -, -C(O)Q 3 N(R 3 )Q 2 N(R 1 )-, -C( O) Q 2 O-, -C(O)Q 2 N(R 1 )-, -C(O)Q 3 N(R 3 )L 1 OQ 2 N(R 1 )-, and -C(O) Q 3 Q 2 N(R 1 )-;
  • L 1 , Q 2 , Q 3 , R 1 and R 3 are as defined above for formula (II);
  • R is selected from the group consisting of: H or a C1-C6 alkyl group.
  • the two groups are not homogeneous groups. That is, when any two groups of L 1 , Q 1 , Q 2 or Q 3 are directly bonded, the two groups are not simultaneously an alkylene group, a cycloalkylene group, an alkenylene group or an alkynylene group.
  • conjugates of the invention are selected from, but are not limited to, the conjugates in the table below:
  • alkyl preferably denotes a saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec. Butyl or tert-butyl.
  • alkylene preferably denotes a saturated divalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.
  • alkenylene preferably denotes a divalent hydrocarbon group containing one or more double bonds, such as a vinylidene group, a propylene group or an allylene group.
  • alkynylene preferably denotes a divalent hydrocarbon radical containing one or more triple bonds, such as ethynylene or propynylene.
  • cycloalkylene preferably denotes a saturated divalent monocyclic or bicyclic hydrocarbon ring, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, A cyclononylene group, a cyclopentylene group or a silylene naphthalene ring.
  • the heterocyclylene group may be, for example but not limited to, a 4-membered ring such as a sulfylene group or a sulfoxy group; a 5-membered ring such as a tetrahydrofuranyl group or a dioxetane.
  • arylene preferably denotes a divalent aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring such as phenylene, biphenylene or naphthylene.
  • heteroarylene preferably denotes a divalent monocyclic, bicyclic or tricyclic aromatic ring system comprising at least one hetero atom which may be the same or different, said hetero atom being, for example, oxygen, nitrogen or sulfur, such as thiophene. , furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isoisothiazolyl, pyridylene, pyridazinyl, pyrimidine Base, pyrazine group, triazine base.
  • aralkylene preferably denotes an arylene substituted alkylene group wherein the arylene group and the alkylene group are as defined herein.
  • the arylene group can have from 6 to 14 carbon atoms and the alkylene group can have up to 6 carbon atoms.
  • Exemplary aralkylene groups include, but are not limited to, benzylidene, phenyleneethyl, phenylenepropyl, phenylenebutyl.
  • substituted means that one or more hydrogens on the designated atom are replaced by a substituent, provided that the normal valence of the specified atom in the present case is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • the substituent may be selected from a hydroxyl group, an amino group, a halogen, a cyano group, a nitro group, a carboxyl group, a C1-C6 alkyl group or a C6-C14 aryl group.
  • halogen or "halo” preferably denotes any of fluorine, chlorine, bromine, and iodine.
  • the conjugate of formula ( ⁇ ), (II) or (III) may also comprise one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H (D or ⁇ ) and 3 H (T or ⁇ );
  • C may be in any isotopic form, including 12 C, 13 C and 14 C;
  • O can be any isotopic form, including 16 O and 18 O;
  • stereoisomer denotes an isomer formed by at least one asymmetric center. In compounds having one or more asymmetric centers, they can produce racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the conjugates of the invention may exist as a mixture (generally referred to as a tautomer) of two or more different forms in a rapidly balanced structure. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait.
  • any general structure also encompasses all conformational isomers, regioisomers, and tautomers that may result from a particular set of substituents.
  • the invention encompasses all possible crystalline forms or polymorphs of the conjugates of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • solvate is defined as the form of the conjugate of the invention by complexing with a solvent molecule to form a complex in a solid or liquid state. Hydrates are a special form of solvates in which complexation occurs with water. In the present invention, a hydrate is a preferred solvate.
  • Salts of the conjugates of the invention can be conveniently prepared, purified and/or treated.
  • Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Parmaceutically Acceptable Salts.” J. Pharm. Sci. Vol. 66, pp. 1-19.
  • the conjugate is an anion or a functional group having ionizable anionic (e.g. -COOH may be ionised into -COO -), then the conjugate can be a suitable salt-forming cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions (e.g., Na + and K + ), alkaline earth metal ions (e.g., Ca 2+ and Mg 2+ ), and other cations (e.g., Al 3 + ).
  • Suitable organic cations include, but are not limited to, ammonium ions (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 (R) 2 + , NH(R) 3 + , N(R) 4 + ).
  • Suitable substituted ammonium ions include, but are not limited to, those derived from the following organic amines: ethylamine, ethylenediamine, dicyclohexylamine, triethylamine, butylamine, cyclohexanediamine, ethanolamine, diethanolamine, piperidine Oxazine, benzylamine, phenylbenzylamine, choline and tromethamine, and amino acids (such as lysine and arginine).
  • a representative example of a quaternary ammonium is N(CH 3 ) 4 + .
  • the conjugate having cationic or ionizable functional groups may be cationic (e.g. -NH 2 may be ionized as -NH 3 +), then the conjugate can be a suitable salt anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetoxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, lysine Acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalenecarboxylic acid, isethionic acid, lactic acid, lactobionic acid , lauric acid, maleic acid, malic acid, methanesulfonic acid, mucic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic acid, phenylacetic acid, benzenesulfonic acid, propionic acid, pyruvic acid, salicylic acid, Stearic acid
  • compositions and methods of treatment are provided.
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a conjugate of the invention and one or more pharmaceutically acceptable carriers.
  • a further aspect of the invention provides a method of treating a disease associated with an A[beta] or Tau protein pathway comprising administering to a subject in need thereof a therapeutically effective amount of a conjugate or pharmaceutical composition of the invention.
  • compositions and methods of the invention are useful for treating, for example, neurodegenerative diseases, particularly AD or Parkinson's disease.
  • “Pharmaceutically acceptable carrier” in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, Propylene glycol, water, ethanol, and the like.
  • the composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed.
  • Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the invention may act systemically and/or locally.
  • they may be administered in a suitable route, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, It is administered in the form of an ophthalmic preparation or by inhalation.
  • compositions of the invention may be administered in a suitable dosage form.
  • the dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups.
  • the pharmaceutical composition may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oily suspension.
  • a sterile injectable aqueous or oily suspension This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as Tween 80) and suspending agents.
  • the sterile injectable preparation may also be formulated in a pharmaceutically acceptable diluent or solvent, for example, 1,3-butanediol, mannitol, water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils can be conventionally employed as a solvent or suspension medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • olive oil or castor oil especially in the form of their polyoxyethylation.
  • Other commonly used surfactants such as Tween or Span and/or other similar emulsifiers or bioavailability enhancers (which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms) may also be used for formulation purposes. .
  • the pharmaceutical composition of the present invention can be orally administered in any orally acceptable dosage form, the dosage form
  • the dosage form include, but are not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
  • carriers commonly used include lactose and corn starch.
  • a lubricant such as magnesium stearate is also usually added.
  • effective diluents include lactose and corn starch.
  • compositions of this invention may also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a conjugate of the invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and thus will melt in the rectum to release the activity
  • suitable non-irritating excipient such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.
  • Topical administration of the pharmaceutical compositions of the invention is useful when the desired treatment comprises topical application to an area or organ that is readily accessible.
  • the pharmaceutical compositions should be formulated into a suitable ointment containing the active component suspended or dissolved in the vehicle.
  • Carriers for topical administration of the conjugates of the invention include, but are not limited to, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene polyoxypropylene polymers, emulsifying waxes, and water.
  • the pharmaceutical compositions may be formulated as a suitable lotion or cream containing active conjugates suspended or dissolved in a vehicle with a suitable emulsifier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • the pharmaceutical compositions of the invention may also be topically applied to the lower intestinal tract by rectal suppositories or suitable enemas. Topical transdermal patches are also included in the present invention.
  • compositions of the present invention can be administered by an aerosol or an inhalant.
  • Such compositions can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and/or Other solubilizers or dispersants known in the art.
  • treating refers to reducing, inhibiting, attenuating, alleviating, preventing or stabilizing the progression or progression of a disease/disease, reducing the severity or amelioration of a disease/disease and symptoms associated with the disease/patient.
  • an amount or "therapeutically effective amount” of a conjugate that is effective to treat a disease refers to the amount of conjugate that is effectively treated or cured after administration to a subject in single or multiple doses. Relieve, alleviate or ameliorate individuals with disease.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include having a disease A human individual (referred to as a patient) or a normal individual (such as the disease described herein).
  • “Non-human animals” in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).
  • compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents, such as one or more additional agents that treat diseases associated with the A[beta] or Tau protein pathway, such as acetylcholine.
  • additional therapeutic or prophylactic agents such as one or more additional agents that treat diseases associated with the A[beta] or Tau protein pathway, such as acetylcholine.
  • Esterase inhibitors such as donepezil, Huperzine A, Tacrine, etc.).
  • the pharmaceutical composition of the invention comprises a combination of a conjugate of the invention and one or more additional therapeutic or prophylactic agents
  • the conjugate and additional therapeutic or prophylactic agent should be in a monotherapy regimen
  • a dosage level of from about 1% to 100%, and more preferably from about 5% to 95%, of the dosage administered will generally be present in the combination therapy.
  • Additional therapeutic or prophylactic agents can be administered separately from the conjugates of the invention as part of a multiple dose regimen. Alternatively, those agents can be part of a single dosage form, mixed with a conjugate of the invention in a single composition.
  • the conjugates of the invention may be administered at a dose of from about 0.5 to about 1000 mg/kg body weight, or from about 1 to about 100 mg/kg body weight, every 4 to 120 hours, or as required by the particular drug.
  • the methods described herein comprise administering an effective amount of a conjugate of the invention or a composition thereof to achieve the desired effect.
  • the pharmaceutical compositions of this invention are administered from about 1 to about 6 times per day, or alternatively, as a continuous infusion. This administration can be used as a chronic or acute treatment.
  • the amount of active ingredient which may be combined with carrier materials in a single dosage form will vary depending upon the subject being treated and the particular route of administration.
  • a representative formulation contains from about 5% to about 95% active conjugate (w/w). Alternatively, such formulations contain from about 20% to about 80% active conjugate.
  • the conjugates of the invention may need to be used at lower or higher doses than those listed above.
  • the specific dosage and treatment regimen of any particular individual will depend on a variety of factors, including the activity of the particular conjugate employed, age, weight, general health, sex, diet, time of administration, rate of excretion, combination of drugs, disease, The severity of the condition or symptom, the individual's treatment of the disease, condition or symptom, and the judgment of the treating physician.
  • a maintenance dose of the conjugate, composition or combination of the invention can be administered if desired. Subsequently, when the symptoms have been alleviated to the desired level, the dose or frequency of administration or both can be reduced to achieve a level that maintains an improved condition. However, the individual has anti-disease symptoms Intermittent treatment may be required at time.
  • Conjugate A02 was prepared according to Route 1.
  • Reagents and conditions a) toluene, triphosgene, pyridine, room temperature; b) N-Boc-serine benzyl alcohol ester, triethylamine; c) palladium / carbon, hydrogen, methanol; d) p-nitrophenyl chloroformic acid Ester, triethylamine, 2-aminoethanol; e) 1-ethyl-(3-dimethylaminopropyl)carbodiimide, 4-dimethylaminopyridine, triethylamine, dichloromethane; a solution of HCl in dioxane.
  • triphosgene (1.6 eq.) was dissolved in toluene, cooled to 0 ° C, and pyridine (6.0 eq.) was slowly added dropwise, followed by the addition of memantine hydrochloride (1.0 eq.) to the above reaction mixture at room temperature. Next night reaction. To the above reaction mixture, ice water was added, and the mixture was extracted twice with ethyl acetate, and the organic phase was combined, dried over sodium sulfate and concentrated to give a liquid product which was purified without further purification.
  • the compound 1 obtained in the step a) was dissolved in dry tetrahydrofuran, and N-Boc-serine benzyl alcohol ester (0.8 equivalent) and triethylamine (1 equivalent) were added. The reaction was carried out at 50 ° C for 24 hours. TLC showed disappearance of the starting material D-type serine, and the reaction mixture was concentrated to give a product, which was purified by column chromatography to give a pure product.
  • the compound 2 obtained in the step b) was dissolved in methanol, 10% palladium on carbon was added, the reaction was heated to 50 ° C, and hydrogenation was carried out under a pressure of 40 psi for 3 hours.
  • the palladium/carbon was removed by filtration, the filtrate was concentrated, and the concentrate was used directly in the next reaction without purification.
  • the arctigenin (1.0 eq.) and p-nitrophenyl chloroformate (1.0 eq.) were dissolved in dichloromethane, and triethylamine (2.0 eq.) was added to the mixture. The reaction was carried out for 3 hours at room temperature. 2-Aminoethanol (1.1 eq.) and triethylamine (2.0 eq.) were added. After reacting at room temperature overnight, the reaction solution was concentrated and purified by column chromatography to give a product.
  • the compound 5 obtained in the step e) was added to a reaction flask, and a solution of an appropriate amount of HCl in dioxane was added, and the mixture was stirred at room temperature overnight.
  • the reaction mixture was concentrated, EtOAc EtOAc m.
  • Conjugate A04 was prepared according to Route 2.
  • Reaction reagents and conditions a) triphosgene, toluene, pyridine, room temperature, N-tert-butoxycarbonyl-1,2-ethanediamine; b) solution of HCl in dioxane; c) 1-ethyl- (3-Dimethylaminopropyl)carbonyldiimide, 4-dimethylaminopyridine, triethylamine, dichloromethane; d) a solution of HCl in dioxane.
  • Compound 6 was prepared in a similar manner to the preparation of Compound 2 from memantine hydrochloride in the steps a) and b) of Example 1.
  • the compound 6 obtained in the step a) was added to a reaction flask, and a suitable amount of a solution of HCl in dioxane was added thereto, and the reaction was carried out overnight at room temperature.
  • the reaction mixture was concentrated, dried with EtOAc EtOAc EtOAc
  • Conjugate A10 was prepared according to Route 3.
  • Reaction reagents and conditions a) 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide, 4-dimethylaminopyridine, triethylamine, dichloromethane; b) p-nitrophenyl chloride Formate, triethylamine, (S,S)-2-aminocyclohexanol; c) potassium carbonate, methanol; d) a solution of HCl in dioxane.
  • the compound 11 obtained in the step c) was added to a reaction flask, and a suitable amount of a solution of HCl in dioxane was added thereto, and the mixture was allowed to react at room temperature overnight.
  • the reaction mixture was concentrated, and EtOAc (EtOAc m.
  • Reaction reagents and conditions a) potassium carbonate, acetone, bromoethanol, reflux; b) 1-ethyl-(3-dimethylaminopropyl)carbodiimide, 4-dimethylaminopyridine, triethylamine , methylene chloride; c) a solution of HCl in dioxane.
  • the burdock aglycone (1 eq.) is dissolved in an appropriate amount of acetone, potassium carbonate (1.5 eq.) is added, bromoethanol (1.5 eq.) is added with stirring, the reaction mixture is refluxed until the starting material disappears, the solid is filtered, and the filtrate is concentrated. Purification yielded the desired product.
  • the compound 13 obtained in the step b) was added to a reaction flask, and a suitable amount of a solution of HCl in dioxane was added thereto, and the mixture was allowed to react at room temperature overnight. Concentrate the reaction solution, add appropriate amount of ether to beat, filter The hydrochloride salt of the conjugate was obtained, which was crystallised eluted eluted eluted eluted
  • Conjugate A01 was prepared in a similar manner to the preparation of conjugate A02 of Example 1.
  • Conjugate A03 was prepared in a similar manner to the preparation of conjugate A02 of Example 1.
  • Conjugate A15 was prepared in a similar manner to the preparation of conjugate A04 of Example 2.
  • Conjugate A17 was prepared in a similar manner to the preparation of conjugate A04 of Example 2.
  • Example 9 Preparation of conjugates A05-A09, A11-A14, A16, A18-A30 and A32-A34
  • Reaction reagents and conditions a) 1-chloroethyl chloroformate, 4-dimethylaminopyridine, dichloromethane, 0 ° C; b) N-methylmorpholine, 2,2-dimethyl-3-hydroxyl Propionic acid, tetrahydrofuran, 50 ° C; c) 2,2,6,6-tetramethylpiperidine-1-oxide, trichloro-s-triazine, dichloromethane; d) sodium triacetoxyborohydride, 1 , 2-dichloroethane.
  • Reaction reagents and conditions a) N-Boc-D-valine, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, 4-dimethylaminopyridine, dichloromethane; b) a solution of HCl in dioxane; c) sodium triacetoxyborohydride, 1,2-dichloroethane.
  • N-Boc-D-proline (1 equivalent) was dissolved in an appropriate amount of dichloromethane, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide (1.2 equivalents) and 4-di were added.
  • Methylaminopyridine (5 equivalents), after stirring at room temperature for 15 minutes, was added with arctigenin (1 equivalent) and continued to react at room temperature overnight. An appropriate amount of water was added to the reaction mixture, and the organic phase was separated, washed with EtOAc EtOAc m.
  • Conjugate A36 was prepared in a similar manner to the preparation of conjugate A35 in step 10) of Example 10.
  • Conjugate A37 was prepared in a similar manner to the preparation of conjugate A36 of Example 11.
  • Conjugate A38 was prepared in a similar manner to the preparation of conjugate A36 in Example 11.
  • Conjugates A39-A52 were prepared according to methods similar to those described above in Example 10 and Example 11.
  • Reaction reagents and conditions a) monoethyl oxalate, 1-ethyl-(3-dimethylaminopropyl) carbodiimide, 4-dimethylaminopyridine, dichloromethane; b) aqueous sodium hydroxide solution, Ethanol; c) arctigenin, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, 4-dimethylaminopyridine, dichloromethane.
  • Conjugate A54 was prepared in a similar manner to Example 15.
  • Reaction reagents and conditions a) glycolic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, triethylamine, dichloromethane; b) triethylamine, tetrahydrofuran.
  • glycolic acid (1 equivalent) was dissolved in an appropriate amount of dichloromethane, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide (1.2 equivalents) and triethylamine (1.2 equivalents) were added at room temperature. After stirring for 5 minutes, burdock aglycone (1.1 eq.) was added and the reaction was continued at room temperature overnight. An appropriate amount of water is added to the reaction mixture, and the organic phase is separated, washed with dilute hydrochloric acid, saturated sodium hydrogen sulfate and brine, dried over sodium sulfate,
  • the present invention employs an Alzheimer's disease fruit fly model that overexpresses human A?42 (the model has significant learning and memory deficits), and evaluates the ability of the conjugate A04 to rescue the model Drosophila from learning and memory.
  • the Pavlovian olfactory memory platform is from the literature (Tully, T. et al., Classical conditioning and retention in normal and mutant Drosophila melanogaster. (1985) J. Comp. Physiol. A 157:, 263-277; Tully, T (Genesis dissection of consolidated memory in Drosophila. (1994) Cell 79: 35-47; Yin, JC et al, Induction of a dominant negative CREB transgene specific blocks long-term memory in Drosophila. (1994) Cell 79: 49-58.) The improvement was obtained.
  • the learning and memory test was carried out in a constant temperature and humidity chamber at 25 ° C and 70% relative humidity. The experiment consists of two phases:
  • Training phase Approximately 100 fruit flies are placed in a training tube with a copper mesh. These flies will smell two odors (octanol (OCT) and methylcyclohexanol (MCH)). Each scent lasted for 1 minute and was followed by a 45 second fresh air access. Fruit flies receive a one-minute electric shock penalty only when they smell the first smell. Such a process constitutes a training cycle. In order to avoid the natural preference of fruit flies for odor, in each data point, 1 tube of fruit flies will first smell OCT and receive electric shock, while the other tube will first smell MCH and receive electric shock, 2 tubes of fruit fly test value The average is one data point.
  • OCT octanol
  • MCH methylcyclohexanol
  • the parental fruit flies were housed in a standard environment of 24 ° C, 40 to 60% relative humidity, 12 hours of light per day. From the day after eclosion (DAE 2) of the fruit fly, the control male flies (+/Y; UAS-A ⁇ 42/+) and the experimental group of male flies were selected under the microscope (elav/ Y; UAS-A ⁇ 42/+), 100 per tube. The picked fruit flies were transferred to 29 ° C and subjected to subsequent feeding and drug treatment under conditions of 40 ⁇ 15% relative humidity.
  • Both the conjugate mother liquor and the control compound Meman (Mem) (10 mM) were stored in a -20 ° C refrigerator.
  • the mother liquor was diluted to 100 ⁇ M in a 4% sucrose working solution and then stored in a -20 ° C refrigerator.
  • the sucrose working solution has no effect on the learning and memory ability of Drosophila.
  • Pavlovian olfactory memory method was used to detect the salvage effect of the compound on memory damage of Drosophila. Seven data points were obtained for each drug, and each data point was the average of 2 floristic olfactory memories.
  • 2U*H29.3 was the genetic control group (healthy fruit fly), and P35*H29.3 was the AD control group (only the solvent was administered, ie, the negative control).
  • Mem and conjugate A04 are data for feeding the corresponding drugs to the AD experiment. The results of each drug contained 7 data points and were subordinate to three independent experiments. Among them, the PI of the AD negative control group was 41 (required less than 45), and the difference between the genetic control group and the AD negative group was 19 (to be The ratio is greater than 15), the positive drug Mem has a PI value of 55, the salvage effect is greater than 50% (the negative control group has a rescue effect of 0%, and the genetic control group is 100%), and all meet the experimental establishment criteria. The experimental data is shown in Figure 2.
  • the conjugate A04 is administered to the APP/PS1 transgenic AD model mouse by gavage, and then the effect of the conjugate A04 on the memory impairment of the transgenic AD model mouse is detected by the classical Morris water maze test.
  • mice 1) Identification of APP/PS1 double transgenic AD model mice: The mouse was tail-tailed, and then the mouse APP/PS1 gene sequence was identified by PCR. Wild type C57 (B6C3) mice were used as negative control mice. Mice were housed under standard conditions (12/12 hour light and dark cycle, sufficient water and food, 22 ° C constant temperature, 60% humidity).
  • transgenic AD model mice 30 mice of transgenic AD model were randomly divided into 3 groups at the age of 6 months (Control-AD: transgenic solvent group; A04: 50 mg administered to transgenic mice) /kg conjugate A04 group; Mem: 50 mg/kg memantine hydrochloride group was administered to transgenic mice), and 10 non-transgenic mice were used as a negative control group (Control-WT).
  • the conjugate A04 and memantine hydrochloride were dissolved with 0.9% NaCl + 0.5% Tween 80, and administered orally for 60 days, and then the Morris water maze test was started.
  • each mouse was swam 4 times a day to find a platform. The interval is the same between 1 hour and 2 hours. If the mouse fails to find the platform within 60 seconds, the time for the mouse to find the platform is considered to be 60 seconds.
  • the mouse's motion trajectory and speed are automatically recorded by Anymaze and matching cameras. The average time to find the platform in four tests per day is recorded as the day of the platform (latency). All animal experiments are strictly in accordance with the Regulations for the Control of Laboratory Animals.
  • A04 indicates a transgenic AD model mouse administration group (a dose of 50 mg/kg/day of conjugate A04);
  • Control-Ad indicates a transgenic AD model mouse solvent group (0.9% NaCl + 0.5% Tween 80)
  • Control-Wt represents a non-transgenic mouse solvent group (0.9% NaCl + 0.5% Tween 80)
  • Mem represents a transgenic AD model mouse memantine hydrochloride administration group (dosage 50 mg/kg/day of memantine hydrochloride).
  • the latency of the Morris water maze experimental training experiment showed that the latency of the transgenic AD model mice was significantly longer than that of the non-transgenic normal mice; the transgenic AD model mice were administered with the conjugate A04 (50 mg/kg/day) for 60 days. The incubation period was significantly lower than that of solvent-treated transgenic mice. The above results indicated that the memory of the transgenic AD model mice was damaged, and the conjugate A04 could significantly improve the memory damage of transgenic mice.
  • the latency of the memantine hydrochloride administration group was not significantly different from that of the transgenic AD model mice group, indicating that memantine hydrochloride did not reverse the memory impairment of AD transgenic mice.
  • This study investigated the pharmacokinetics of arctigenin (ATG) and conjugate A04 in rats. After ATG and A04 were administered to rats by intragastric administration, whole blood samples were taken at different time points, plasma was separated, and the concentration of ATG in plasma was determined by LC-MS.
  • Rats were fasted for 12 h before the test, and they were given free access to water. The rats were fed uniformly 2 h after administration.
  • Blood collection time 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 12 h after intragastric administration.
  • venous blood was taken from the posterior venous plexus of the rat eye, placed in a heparinized test tube, centrifuged at 11,000 rpm for 5 min, plasma was separated, and it was frozen in a refrigerator at -20 °C.
  • acetonitrile 200 ⁇ L was added to 100 ⁇ L of plasma sample, vortexed for 1 min, centrifuged for 5 min (11000 rpm), and all the supernatant was taken out in a 10 mL tube and blown dry under a stream of air at 40 ° C in 100 ⁇ L of acetonitrile-water (1:9, v/ Dissolve in v) and take 10 ⁇ L for UPLC/Q-TOF MS analysis.
  • the ATG plasma concentration (ng/mL) in rats after intragastric administration of 20 mg/kg conjugate A04 to rats was as shown in Table 1.

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Abstract

美金刚与牛蒡子苷元的缀合物，包含所述缀合物的药物组合物。所述缀合物可治疗与Aβ或者Tau蛋白通路相关的疾病，例如阿尔茨海默病或帕金森氏病。

Description

美金刚与牛蒡子苷元的缀合物及其组合物和用途 技术领域
本发明涉及药物化学和疾病治疗领域。具体而言，本发明涉及美金刚与牛蒡子苷元的缀合物、包含其的药物组合物及其在与β-淀粉样肽(Amyloid beta，Aβ)或者Tau蛋白通路相关的疾病的治疗中的用途，尤其是在诸如阿尔茨海默病(Alzheimer’s disease,AD)或帕金森氏症等神经退行性疾病的治疗中的用途。
背景技术
AD是一种与年龄高度相关，进行性的中枢神经系统退行性疾病。其早期临床表现为近期记忆丢失、失语、失用、失认等记忆和认知、执行功能障碍及个性变化异常等；中期临床表现为易怒、恐慌、睡眠失常、幻觉等人格和行为改变；晚期临床表现为逻辑思维缺失、卧床不起、生活不能自理等。
统计结果显示，目前全世界大约有三千万AD患者，并且随着全世界人口的老龄化，到2050年，全世界AD患者数目将超过一亿。AD患者到中后期将不能独立生活，需要医护人员护理。据统计目前美国每年花费在AD患者照顾中的费用达到三千多亿美元(美国，阿尔茨海默病协会)。中国国家统计局公布的最新数据显示，截至2014年底，中国60岁及以上老年人口已达2.1242亿，占总人口的15.5％，65岁及以上人口为1.3755亿人，占总人口的10.1％。目前我国AD患者数目已经超过800万。随着我国人口老龄化，AD患者人数也会出现急剧增加。预计到2050年，我国AD患者人数将达到近三千万，因而AD已经成为我国社会和家庭的重要负担。
AD患者具有两个重要的组织病理学特征：在大脑皮质、海马、前脑基底神经核和丘脑等与学习记忆相关的大脑组织中有大量由Aβ聚集形成的老年斑(senile plaque，SP)；以及由于Tau蛋白的高度磷酸化导致的神经纤维缠结。研究发现当AD患者脑内Aβ增多时，Aβ蛋白聚集形成高度神经毒性 的寡聚体，从而导致脑内出现氧化应激、炎症以及Tau蛋白高度磷酸化等变化，最终诱导神经元死亡。因此Aβ作为AD病理变化的起始因子在AD患者的病理进程中起着至关重要的作用。
不管是家族性AD患者还是非家族性的散在的AD患者脑内，Aβ均在AD症状出现之前就出现了明显的增多，这表明Aβ为导致AD的病理改变的起始因子。另外，在高表达Aβ的AD模型小鼠中也发现Aβ增多早于记忆力损伤出现，同时如果将AD模型小鼠敲除BACE1(Aβ产生的限速酶)，则在Aβ显著性减少的同时，其记忆力损伤和神经元凋亡也出现明显逆转。因此Aβ成为新型抗AD治疗药物的重要靶标，并且高表达Aβ的AD模型小鼠也成为此类抗AD治疗药物药效评价的公认模型。APP/PS1双转基因的AD模型小鼠(B6C3转基因小鼠，APPswe，PS1dE9)可高表达嵌和鼠/人的瑞典突变APP(Mo/HuAPP695swe)和人源删除第9个外显子的早老素1蛋白(presenilin，PS1-dE9)。这两个基因突变都被认为是导致家族性AD的主要致病突变基因。这类APP/PS1转基因AD模型小鼠会在6个月左右开始出现Aβ沉积，并在7个月左右出现记忆力的损害。因而，APP/PS1转基因小鼠成为适用于在抗AD治疗药物开发中进行药效学评价的模型小鼠。
美金刚是目前临床上使用的治疗AD的药物。但是美金刚只能改善AD的症状，而不能阻断其病理进程(Areosa SA.等人，Memantine for dementia.(2005)Cochrane Database Syst Rev.(3):CD003154)。研发能够改善AD的症状同时能够阻断其病理进程的药物是迫切需要的。
中国专利申请CN 103467417A报道了牛蒡子苷元具有抑制Aβ生成的作用，其是通过激动AMPK的磷酸化和减少AKT的磷酸化，抑制mTOR通路，导致细胞自噬增加，从而增加Aβ的清除，进而起到治疗AD的作用。然而，本申请发明人进一步研究发现，牛蒡子苷元的口服生物利用度较差，因而不能用于口服给药。研发具有改善的口服生物利用度的牛蒡子苷元衍生物对于改善患者顺应性具有极大益处。
发明内容
本发明一方面提供缀合物，其包含美金刚与牛蒡子苷元，
Figure PCTCN2015088585-appb-000001
所述缀合物可为通式(I)的化合物、其药学上可接受的盐、立体异构体、多晶型物、溶剂合物或前药，其中linker 1如下文中所定义，
Figure PCTCN2015088585-appb-000002
所述缀合物可用于治疗与Aβ或者Tau蛋白通路相关的疾病。
本发明另一方面提供药物组合物，其包含本发明的缀合物以及一种或多种药学上可接受的载体，并任选地进一步包含一种或多种治疗与Aβ或者Tau蛋白通路相关的疾病的其它药物。
本发明再一方面提供治疗与Aβ或者Tau蛋白通路相关的疾病的方法，其包括向需要其的个体给药治疗有效量的本发明的缀合物或药物组合物，并任选地包括向需要其的个体另外给药治疗与Aβ或者Tau蛋白通路相关的疾病的其它药物。
本发明再一方面提供本发明的缀合物在制备治疗与Aβ或者Tau蛋白通路相关的疾病的药物中的用途。
附图说明
图1为果蝇的遗传图示。
图2显示美金刚(Mem)与缀合物A04对AD果蝇记忆损伤的挽救效果。
图3显示缀合物A04逆转转基因AD模型小鼠记忆力损伤的效果。
具体实施方式
缀合物
本发明一方面提供缀合物，其包含美金刚与牛蒡子苷元。
在一个实施方案中，本发明的缀合物为通式(I)的化合物、其药学上可接受的盐、立体异构体、多晶型物、溶剂合物或前药：
Figure PCTCN2015088585-appb-000003
其中：
Linker 1选自：-C(O)-、-C(O)L1C(O)-、-C(O)OL1C(O)-、-C(O)OL1OC(O)-、-C(O)OQ1L2Q2-、-C(O)Q1L2Q2N(R1)C(O)-、-C(O)Q1L2Q2OC(O)-、-C(O)Q1L2Q2C(O)-、-C(O)OQ1L2Q2OC(O)-、-C(O)OQ1L1Q2N(R1)C(O)-、-C(O)OQ1L2Q2N(R1)C(O)-和-C(O)OQ1L2Q2C(O)-；
L1为直接键，或者选自：-O-、-S-、-NR2-、取代或未取代的C1-C6直链或支链亚烷基、取代或未取代的C2-C6直链或支链亚烯基、取代或未取代的C2-C6直链或支链亚炔基、取代或未取代的C3-C10亚环烷基、取代或未取代的C3-C10非芳族亚杂环基、取代或未取代的C6-C14亚芳基、取代或未取代的C6-C14亚杂芳基，以及取代或未取代的C6-C20亚芳烷基；
L2为直接键，或者选自：-NR2-、-O-、-C(O)-、-N(R3)C(O)-、-C(O)N(R3)-、-C(O)O-、-OC(O)-、-N(R3)Q3O-、-N(R3)C(O)Q3O-、-N(R3)C(O)Q3C(O)-、-N(R3)C(O)Q3N(R3)-、-N(R3)C(O)Q3C(O)N(R3)-、-N(R3)C(O)Q3N(R3)C(O)-、-N(R3)C(O)Q3C(O)O-、-N(R3)C(O)Q3OC(O)-、-C(O)N(R3)Q3C(O)N(R3)-、-C(O)N(R3)Q3C(O)O-、-C(O)N(R3)Q3N(R3)C(O)-、-C(O)N(R3)Q3OC(O)-、-N(R3)Q3C(O)N(R3)-、-N(R3)Q3C(O)O-、-N(R3)Q3N(R3)C(O)-、-N(R3)Q3OC(O)-、-OQ3N(R3)-、-OQ3C(O)N(R3)-、-OQ3C(O)O-、-OQ3N(R3)C(O)-、-OQ3OC(O)-、-OC(O)Q3-、-OC(O)Q3C(O)N(R3)-、-OC(O)Q3C(O)O-、-OC(O)Q3N(R3)-、-OC(O)Q3N(R3)C(O)-、-OC(O)Q3N(R3)L1O-、-OC(O)Q3OC(O)-、-C(O)OQ3-、-C(O)OQ3O-、-C(O)OQ3C(O)N(R3)-、-C(O)OQ3C(O)O-、-C(O)OQ3N(R3)C(O)-或 -C(O)OQ3OC(O)-；
Q1、Q2和Q3各自独立地选自：取代或未取代的C1-C6直链或支链亚烷基、取代或未取代的C3-C10亚环烷基、取代或未取代的C2-C6直链或支链亚烯基、取代或未取代的C2-C6直链或支链亚炔基、取代或未取代的C3-C10非芳族亚杂环基、取代或未取代的C6-C14亚芳基、取代或未取代的C6-C14亚杂芳基，以及取代或未取代的C6-C20亚芳烷基；并且
R1、R2和R3各自独立地选自：H和C1-C6烷基。
在优选的实施方案中，Linker 1选自：-C(O)-、-C(O)L1C(O)-、-C(O)OL1C(O)-、-C(O)OL1OC(O)-、-C(O)OQ1L2Q2-、-C(O)OQ1L2Q2OC(O)-、-C(O)OQ1L1Q2N(R1)C(O)-、-C(O)OQ1L2Q2N(R1)C(O)-和-C(O)OQ1L2Q2C(O)-。
在优选的实施方案中，L1为直接键，或者选自：亚甲基、亚乙基、亚丙基、亚吡咯烷基、亚哌啶基、亚哌嗪基、亚苯基、亚苄基或亚吡啶基，所述基团任选地被一个或多个选自氰基、氨基、卤素或C1-C6烷基的取代基取代。
在优选的实施方案中，L2为直接键，或者选自：-NR2-、-C(O)-、-C(O)N(R3)-、-C(O)O-、-OC(O)-、-N(R3)Q3O-、-N(R3)C(O)Q3C(O)-、-N(R3)C(O)Q3C(O)N(R3)-、-OQ3N(R3)-、-OC(O)Q3-、-OC(O)Q3C(O)O-、-OC(O)Q3N(R3)-、-OC(O)Q3N(R3)L1O-、-C(O)OQ3-、-C(O)OQ3O-。
在优选的实施方案中，Q1、Q2和Q3各自独立地选自：亚甲基、亚乙基、亚丙基、亚环己基、亚吡咯烷基、亚哌啶基、亚哌嗪基、亚苯基、亚苄基或亚吡啶基，所述基团任选地被一个或多个选自氰基、氨基、卤素或C1-C6烷基的取代基取代。
在优选的实施方案中，R1、R2和R3各自独立地选自：H和C1-C4烷基，如甲基。
本发明涵盖上述优选基团任意组合所得的通式(I)的缀合物。
在优选的实施方案中，本发明的缀合物为通式(II)的化合物、其药学上可接受的盐、立体异构体、多晶型物、溶剂合物或前药：
Figure PCTCN2015088585-appb-000004
其中：
Linker 2选自：-L1-、-L1O-、-Q1L1Q2N(R1)-、-Q1L2Q2N(R1)-、-Q1L2Q2O-或-Q1L2Q2-；
L1选自：取代或未取代的C1-C6直链或支链亚烷基、取代或未取代的C2-C6直链或支链亚烯基、取代或未取代的C2-C6直链或支链亚炔基、取代或未取代的C3-C10亚环烷基、取代或未取代的C3-C10非芳族亚杂环基、取代或未取代的C6-C14亚芳基、取代或未取代的C6-C14亚杂芳基，以及取代或未取代的C6-C20亚芳烷基；并且
L2、Q1、Q2、Q3、R1、R2和R3如上文中对于通式(I)所定义。
在另一优选的实施方案中，本发明的缀合物为通式(III)的化合物、其药学上可接受的盐、立体异构体、多晶型物、溶剂合物或前药：
Figure PCTCN2015088585-appb-000005
其中：
Linker 3为直接键，或者选自：-C(O)Q3N(R3)Q2-、-C(O)Q3N(R3)Q2N(R1)-、-C(O)Q2O-、-C(O)Q2N(R1)-、-C(O)Q3N(R3)L1OQ2N(R1)-，以及-C(O)Q3Q2N(R1)-；
L1、Q2、Q3、R1和R3如上文中对于通式(II)所定义；并且
R选自：H或C1-C6烷基。
在另一优选的实施方案中，当L1、Q1、Q2或Q3中的任意两个基团直接连接时，所述两个基团不为同类基团。即，当L1、Q1、Q2或Q3中的任意两 个基团直接连接时，所述两个基团不同时为亚烷基、亚环烷基、亚烯基、亚炔基、非芳族亚杂环基、亚芳基、亚杂芳基或亚芳烷基。
在另外的实施方案中，本发明的缀合物选自但不限于下表中的缀合物：
Figure PCTCN2015088585-appb-000006
Figure PCTCN2015088585-appb-000007
Figure PCTCN2015088585-appb-000008
Figure PCTCN2015088585-appb-000009
Figure PCTCN2015088585-appb-000010
Figure PCTCN2015088585-appb-000011
Figure PCTCN2015088585-appb-000012
Figure PCTCN2015088585-appb-000013
Figure PCTCN2015088585-appb-000014
Figure PCTCN2015088585-appb-000015
Figure PCTCN2015088585-appb-000016
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
术语“烷基”优选表示具有1、2、3、4、5或6个碳原子的饱和一价烃基，例如甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基或叔丁基。
术语“亚烷基”优选表示具有1、2、3、4、5或6个碳原子的饱和二价烃基，例如亚甲基、亚乙基、亚丙基或亚丁基。
术语“亚烯基”优选表示包含一个或多个双键的二价烃基，例如亚乙烯基、亚丙烯基或亚烯丙基。
术语“亚炔基”优选表示包含一个或多个三键的二价烃基，例如亚乙炔基或亚丙炔基。
术语“亚环烷基”优选表示饱和的二价单环或双环烃环，例如亚环丙基、亚环丁基、亚环戊基、亚环己基、亚环庚基、亚环辛基、亚环壬基、亚环癸基或者亚十氢化萘环。
术语“亚杂环基”优选表示含有一个或多个选自C(＝O)、O、S、S(＝O)、S(＝O)2、NRa的杂原子的饱和或不饱和二价环系，其中Ra表示氢原子或者C1-C6烷基或亚烷基；所述亚杂环基可以通过任意的环原子或者通过环原子中的任一个和Ra的碳原子(当Ra表示C1-C6亚烷基时)与分子的其余部分连接。所述亚杂环基可以是例如但不限于：4元环，如亚氮杂环丁烷基、亚氧杂环丁烷基；5元环，如亚四氢呋喃基、亚二氧杂环戊烯基(dioxolinyl)、亚吡咯烷基、亚吡咯烷酮基、亚咪唑烷基、亚吡唑烷基、亚吡咯啉基；或6元环，如亚四氢吡喃基、亚哌啶基、亚吗啉基、亚哌嗪基。
术语“亚芳基”优选表示二价芳香性的单环、双环或三环烃环，例如亚苯基、亚联苯基或亚萘基。
术语“亚杂芳基”优选表示包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫)的二价单环、双环或三环芳族环系，例如亚噻吩基、亚呋喃基、亚吡咯基、亚噁唑基、亚噻唑基、亚咪唑基、亚吡唑基、亚异噁唑基、亚异噻唑基、亚吡啶基、亚哒嗪基、亚嘧啶基、亚吡嗪基、亚三嗪基。
术语“亚芳烷基”优选表示亚芳基取代的亚烷基，其中所述亚芳基和所述亚烷基如本文中所定义。通常，所述亚芳基可具有6-14个碳原子，并且所述亚烷基可具有至多6个碳原子。示例性亚芳烷基包括但不限于亚苄基、亚苯基乙基、亚苯基丙基、亚苯基丁基。
术语“取代”指所指定的原子上的一个或多个氢被取代基代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。所述取代基可选自羟基、氨基、卤素、氰基、硝基、羧基、C1-C6烷基或C6-C14芳基。
术语“卤素”或“卤代”优选表示氟、氯、溴、碘中任何一种。
通式(Ι)、(II)或(III)的缀合物还可以包含一个或多个同位素置换。例如，在所述化合物中，H可是任何同位素形式，包括1H、2H(D或氘)和3H(T或氚)；C可是任何同位素形式，包括12C、13C和14C；O可是任何同位素形式，包括16O和18O；等。
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个不对称中心的化合物中，其可产生外消旋体、外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的缀合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。
对于本文公开的任意具体缀合物，任意一般结构也涵盖所有构象异构体、区域异构体(regioisomer)和可能由于一组特定的取代基产生的互变异构体。
除非另外说明，当所公开的化合物的命名或结构中没有明确说明其立体化学并且具有一个或多个不对称中心时，应该理解代表所述化合物的所有可能的立体异构体。
本发明涵盖本发明的缀合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
术语“溶剂合物”定义为通过与溶剂分子络合形成固体或液体状态的络合物的本发明的缀合物的形式。水合物为溶剂合物的特殊形式，其中络合作用与水发生。在本发明中，水合物为优选的溶剂合物。
可便捷地制备、纯化和/或处理本发明的缀合物的盐，例如药学上可接受的盐。药学上可接受的盐的实例在下列文献中讨论：Berge等人,1977,“Parmaceutically Acceptable Salts.”J.Pharm.Sci.Vol.66,pp.1-19。
例如，如果缀合物是阴离子或具有可以电离为阴离子的官能团(例如-COOH可以电离为-COO-)，则所述缀合物可以和合适的阳离子形成盐。合适的无机阳离子的实例包括但不限于碱金属离子(例如Na+和K+)、碱土金属 离子(例如Ca2+和Mg2+)以及其它阳离子(例如Al3 +)。合适的有机阳离子的实例包括但不限于铵离子(即NH4 +)和取代的铵离子(例如NH3R+、NH2(R)2 +、NH(R)3 +、N(R)4 +)。合适的取代的铵离子的实例包括但不限于衍生自下列有机胺的那些：乙胺、乙二胺、二环己胺、三乙胺、丁胺、环己二胺、乙醇胺、二乙醇胺、哌嗪、苄胺、苯基苄胺、胆碱和氨基丁三醇，以及氨基酸(例如赖氨酸和精氨酸)。季铵的代表性实例是N(CH3)4 +。
如果缀合物是阳离子或具有可以电离为阳离子的官能团(例如-NH2可以电离为-NH3 +)，则所述缀合物可以和合适的阴离子形成盐。合适的无机阴离子的实例包括但不限于衍生自下列无机酸的那些：盐酸、氢溴酸、氢碘酸、硫酸、亚硫酸、硝酸、亚硝酸、磷酸和亚磷酸。合适的有机阴离子的实例包括但不限于衍生自下列有机酸的那些：2-乙酰氧基苯甲酸、乙酸、抗坏血酸、天冬氨酸、苯甲酸、樟脑磺酸、肉桂酸、柠檬酸、依地酸、乙二磺酸、乙磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、羟乙酸、羟基马来酸、羟基萘羧酸、羟乙磺酸、乳酸、乳糖酸、月桂酸、马来酸、苹果酸、甲磺酸、粘酸、油酸、草酸、棕榈酸、双羟萘酸、泛酸、苯乙酸、苯磺酸、丙酸、丙酮酸、水杨酸、硬脂酸、琥珀酸、磺胺酸、酒石酸、甲苯磺酸和戊酸。合适的聚合物有机阴离子的实例包括但不限于衍生自下列聚合物的那些：鞣酸或羟甲基纤维素。
除非另外明确说明，涉及的具体化合物也包括其盐的形式。
药物组合物和治疗方法
本发明另一方面提供药物组合物，其包含本发明的缀合物以及一种或多种药学上可接受的载体。
本发明再一方面提供治疗与Aβ或者Tau蛋白通路相关的疾病的方法，其包括向需要其的个体给药治疗有效量的本发明的缀合物或药物组合物。
本发明的药物组合物和方法可用于治疗例如神经退行性疾病，特别是AD或帕金森氏症。
本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体，如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。
本发明的组合物可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过注射、静脉内、动脉内、皮下、腹膜内、肌内或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
对于这些给药途径，可以适合的剂型给药本发明的组合物。
所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂。
所述药物组合物可以是无菌可注射制剂的形式，例如，无菌可注射的含水或油状混悬剂。该混悬剂可按照本领域已知的技术，使用适合的分散剂或湿润剂(如吐温80)和助悬剂配制。无菌可注射制剂还可以在药学上可接受的稀释剂或溶剂中配制，例如1,3-丁二醇、甘露醇、水、林格氏溶液和等渗氯化钠溶液。此外，无菌的不挥发油可常规地用作溶剂或悬浮介质。就该目的而言，可使用任何温和的不挥发油，包括合成的甘油单酯或甘油二酯。例如橄榄油或蓖麻油，特别是以它们聚氧乙基化的形式。其它常用的表面活性剂如吐温或司盘和/或其它相似的乳化剂或生物利用度增强剂(它们通常用于制造药学上可接受的固体、液体或其它剂型)也可用于配制的目的。
本发明的药物组合物可以任何口服可接受的剂型口服给药，所述剂型 包括但不限于胶囊剂、片剂、乳剂和含水混悬剂、分散体和溶液剂。就口服使用的片剂而言，通常使用的载体包括乳糖和玉米淀粉。通常还加入润滑剂，如硬脂酸镁。对于以胶囊剂形式口服给药来说，有效的稀释剂包括乳糖和玉米淀粉。口服给药含水混悬剂和/或乳剂时，可将活性成分悬浮或溶于油相中。如果需要，可加入某些甜味剂和/或调味剂和/或着色剂。
本发明的药物组合物还可以栓剂形式用于直肠给药。这些组合物可通过将本发明缀合物与适宜的无刺激性赋形剂混合而制备，其在室温下是固体，但在直肠温度下是液体，且因此会在直肠中融化，从而释放活性组分，这类材料包括但不限于可可脂、蜂蜡和聚乙二醇。
当期望的治疗包含局部施用于可容易地接近的区域或器官时，本发明的药物组合物的局部给药是有用的。就局部施用于皮肤而言，应当将药物组合物配制成含有悬浮或溶解于载体中的活性组分的合适软膏剂。用于局部给药本发明的缀合物的载体包括但不限于矿物油、液体石油、丙二醇、聚氧乙烯聚氧丙烯聚合物、乳化蜡和水。作为另外的选择，可以将药物组合物配制成合适的洗剂或乳膏剂，其含有用合适的乳化剂悬浮或溶解于载体中的活性缀合物。合适的载体包括但不限于矿物油、脱水山梨醇单硬脂酸酯、聚山梨醇酯60、十六烷基酯、鲸蜡醇(cetearyl alcohol)、2-辛基十二烷醇、苄醇和水。通过直肠栓剂或合适的灌肠剂，也可以将本发明的药物组合物局部地施用于下肠道。局部透皮贴剂也包括在本发明中。
本发明的药物组合物可通过气雾剂或吸入剂给药。这类组合物可根据药物制剂领域中熟知的技术制备且可在盐水中制备成溶液，其中使用苄醇或其它适宜的防腐剂、提高生物利用度的吸收促进剂、碳氟化合物和/或本领域已知的其它增溶剂或分散剂。
本文中所使用“治疗”是指减少、抑制、削弱、减轻、阻止或稳定疾病/疾病的发展或恶化、减轻疾病/病患的严重程度或改善和疾病/病患有关症状。
如本文中所使用的，有效地治疗疾病的缀合物的量或“治疗有效量”是指这样的缀合物的量，在单或多剂量给药至个体后，其有效地治疗或治愈、缓解、减轻或改善患有疾病的个体。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病 (例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
在一些实施方案中，本发明的药物组合物还可以包含一种或多种另外的治疗剂或预防剂，例如一种或多种治疗与Aβ或者Tau蛋白通路相关的疾病的其它药物，例如乙酰胆碱酯酶抑制剂(如多奈哌齐、石杉碱甲、他克林等)。
当本发明的药物组合物包含本发明的缀合物和一种或多种另外的治疗剂或预防剂的组合时，所述缀合物和另外的治疗剂或预防剂应以单一疗法方案中通常给予的剂量的约1％至100％，且更优选约5％至95％的剂量水平存在于组合疗法中。另外的治疗剂或预防剂可作为多剂量方案的一部分与本发明的缀合物分开给药。作为另外的选择，那些药剂可以是单一剂型的一部分，与本发明的缀合物共同混合于单一组合物中。
本发明的缀合物可以约0.5至约1000mg/kg体重，或者约1至约100mg/kg体重的剂量每隔4-120小时给药，或者按照具体药物的要求给药。本文中所述方法包括给药有效剂量的本发明的缀合物或其组合物，以得到期望的作用。通常，本发明的药物组合物以每天约1至约6次给药，或者作为另外的选择，以连续输注的形式给药。这种给药可用作慢性或急性治疗。可与载体物质混合制备为单剂量形式的活性成分的量将根据所治疗的个体和特定的给药途径而变化。代表性的制剂含有约5％至约95％的活性缀合物(w/w)。作为另外的选择，这样的制剂含有约20％至约80％活性缀合物。
本发明的缀合物可能需要以比上面列举那些更低或更高的剂量使用。任何具体个体的具体剂量和治疗方案会取决于多种因素，包括所用具体缀合物的活性、个体年龄、体重、一般健康状态、性别、饮食、给药时间、排泄速率、药物组合、疾病、病况或症状的严重程度、个体对疾病、病况或症状的处置和治疗医师的判断。
个体的病况改善后，如果需要，可给药本发明的缀合物、组合物或组合的维持剂量。随后，当症状已经减轻到希望的水平时，可减少给药剂量或频率或二者，以达到保持改善的病况的水平。然而，个体在疾病症状反 复时可能需要间歇治疗。
在以下的实施例中将进一步举例说明本发明。这些实施例仅用于说明本发明，但不以任何方式限制本发明。
实施例
在下列实施例中，所用原料或试剂如无特殊说明，均来自商业购买，并且在无进一步纯化下使用。
实施例1：缀合物A02的制备
按照路线1制备缀合物A02。
Figure PCTCN2015088585-appb-000017
反应试剂与条件：a)甲苯、三光气、吡啶、室温；b)N-Boc-丝氨酸苄醇酯、三乙胺；c)钯/碳、氢气、甲醇；d)对硝基苯氯甲酸酯、三乙胺、2-氨基乙醇；e)1-乙基-(3-二甲基氨基丙基)碳酰二亚胺、4-二甲氨基吡啶、三乙胺、二氯甲烷；f)HCl在二氧六环中的溶液。
步骤a).化合物1的制备：
在N2气氛下，将三光气(1.6当量)在甲苯中溶解，冷却至0℃，将吡啶(6.0当量)缓慢滴入，接着将盐酸美金刚(1.0当量)加入上述反应混合物中，在室温下过夜反应。向上述反应混合物中加入冰水，用乙酸乙酯萃取2次，合并有机相，并用硫酸钠干燥，浓缩得到液体产品，未进行纯化，直接进 行下一步反应。
1H NMR(400MHz,DMSO-d6)δ:2.11(dt,J＝6.3,3.1Hz,1H),1.70(d,J＝1.4Hz,2H),1.51(q,J＝12.1Hz,4H),1.37-1.21(m,4H),1.12(dd,J＝3.8,1.8Hz,2H),0.84(s,6H)。
步骤b).化合物2的制备：
将步骤a)中得到的化合物1在干燥的四氢呋喃中溶解，加入N-Boc-丝氨酸苄醇酯(0.8当量)以及三乙胺(1当量)。反应在50℃下进行24小时，TLC显示原料D型丝氨酸消失，将反应液浓缩得到产品，柱色谱纯化得纯产物。
1H NMR(400MHz,DMSO-d6)δ:7.44-7.30(m,5H),7.22(d,J＝8.1Hz,1H),6.88(s,1H),5.14(s,2H),4.34-4.10(m,2H),2.05(s,1H),1.66(s,2H),1.55-1.20(m,18H),1.07(s,2H),0.80(s,6H)。
步骤c).化合物3的制备：
将步骤b)中得到的化合物2溶于甲醇，加10％的钯/碳，将反应物加热至50℃，并在40psi压力下通入氢气进行氢化，持续3小时。过滤移除钯/碳，将滤液浓缩，将浓缩物在未进行纯化下直接用于下一步反应。
1H NMR(400MHz,DMSO-d6)δ:6.98-6.75(m,2H),4.21-3.98(m,3H),2.06(m,1H),1.66(m,2H),1.49(s,4H),1.42-1.19(m,13H),1.08(s,2H),0.81(s,6H)。
步骤d).化合物4的制备：
将牛蒡子苷元(1.0当量)和对硝基苯氯甲酸酯(1.0当量)溶解于二氯甲烷中，向上述混合物中加入三乙胺(2.0当量)。反应在室温进行3小时。加入2-氨基乙醇(1.1当量)和三乙胺(2.0当量)。室温反应过夜，将反应液浓缩并通过柱色谱法纯化，得到产品。
1H NMR(400MHz,CDCl3)δ:7.02(d,J＝8.0Hz,1H),6.78(m,2H),6.68(dd,J＝8.0,1.6Hz,1H),6.57(dd,J＝8.1,1.7Hz,1H),6.52(d,J＝1.8Hz,1H),5.57(s,1H),4.18(dd,J＝9.0,7.2Hz,1H),3.93–3.79(m,10H),3.44(m,2H),2.98(d,J＝5.9Hz,2H),2.72–2.48(m,4H),1.97(s,3H).
步骤e).化合物5的制备：
将步骤c)中得到的化合物3(1.0当量)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(1.5当量)、4-二甲氨基吡啶(0.2当量)以及三乙胺(1.5当量)溶于二氯 甲烷中。将反应物在室温下搅拌15分钟，加入步骤d)中得到的化合物4(1.0当量)，并将上述反应物在室温下搅拌过夜。向反应物加入适量水，分离有机相，将水相用二氯甲烷萃取一次，合并有机相并用稀盐酸洗1次，用饱和食盐水洗有机相，用硫酸钠干燥，浓缩、柱色谱纯化得到产品。
1H NMR(400MHz,CDCl3)δ:7.32–7.25(m,1H),7.02(d,J＝8.0Hz,1H),6.85–6.76(m,2H),6.68(d,J＝8.0Hz,1H),6.55(dd,J＝13.0,5.0Hz,2H),5.91(s,1H),5.43(d,J＝7.8Hz,1H),4.82(s,1H),4.65-4.44(m,2H),4.22(dd,J＝23.0,11.0Hz,2H),3.85(dd,J＝21.6,13.6Hz,9H),3.55(d,J＝5.3Hz,1H),3.36-3.27(m,3H),3.01-2.93(m,2H),2.72-2.50(m,4H),2.09(s,1H),1.95(dd,J＝8.0,5.1Hz,3H),1.55-1.43(m,10H),1.28(dd,J＝12.2,4.9Hz,6H),1.10(s,2H),0.81(s,6H).
步骤f).缀合物A02的制备：
将步骤e)中得到的化合物5加入到反应瓶中，加入适量HCl在二氧六环中的溶液，将反应物在室温下搅拌过夜。浓缩反应物，加入适量乙醚打浆，过滤得到缀合物的盐酸盐，用饱和碳酸氢钠水溶液处理得到游离缀合物，并用乙酸乙酯萃取、用硫酸钠干燥，浓缩得到目标产品。
1H NMR(400MHz,CD3OD)δ:6.98(d,J＝8.0Hz,1H),6.87-6.84(m,2H),6.75-6.64(m,3H),4.61-4.29(m,5H),4.23-4.14(m,1H),3.97(t,J＝8.5Hz,1H),3.84-3.74(m,9H),3.52(t,J＝5.0Hz,2H),3.01-2.89(m,2H),2.79-2.73(m,1H),2.58(m,3H),2.08(m,1H),1.76(d,J＝1.9Hz,2H),1.60-1.47(m,4H),1.35-1.26(m,6H),1.11(s,2H),0.82(s,6H).
LC-MS(ESI)752.4[M+H]+。
实施例2：缀合物A04的制备
按照路线2制备缀合物A04。
Figure PCTCN2015088585-appb-000018
反应试剂与条件：a)三光气、甲苯、吡啶、室温、N-叔丁氧羰基-1,2-乙二胺；b)HCl在二氧六环中的溶液；c)1-乙基-(3-二甲基氨基丙基)碳酰二亚胺、4-二甲氨基吡啶、三乙胺、二氯甲烷；d)HCl在二氧六环中的溶液。
步骤a).化合物6的制备：
以与实施例1步骤a)和步骤b)由盐酸美金刚制备化合物2类似的方法制备化合物6。
1H NMR(400MHz,CDCl3)δ:6.96(d,J＝8.0Hz,1H),6.73(m,2H),6.63(dd,J＝8.0,1.6Hz,1H),6.49(m,2H),5.46(s,1H),4.84(s,1H),4.19-4.10(m,1H),3.91-3.68(m,10H),3.39-3.25(m,4H),2.94(d,J＝5.8Hz,2H),2.66-2.43(m,4H),1.43(s,9H)。
步骤b).化合物7的制备：
将步骤a)中得到的化合物6加入到反应瓶中，加入适量HCl在二氧六环中的溶液，在室温下过夜反应。浓缩反应液，用饱和碳酸氢钠水溶液使产物游离，并用乙酸乙酯萃取、用硫酸钠干燥，浓缩得到目标产品。
1H NMR(400MHz,CDCl3)δ7.00(d,J＝7.9Hz,1H),6.76(m,2H),6.66(d,J＝7.8Hz,1H),6.58-6.49(m,2H),5.56(s,1H),4.20-4.13(m,1H),3.85(m,11H),3.47(s,2H),2.96(d,J＝5.8Hz,2H),2.70-2.45(m,4H)。
步骤c).化合物8的制备：
以与实施例1步骤e)制备化合物5类似的方法制备化合物8。
1H NMR(400MHz,CDCl3)δ:6.94(s,1H),6.68(m,3H),6.51(m,2H), 5.36-5.17(m,2H),4.32-3.98(m,7H),3.92-3.69(m,10H),2.92(m,2H),2.71-2.46(m,4H),2.12-1.95(m,6H),1.41(m,13H),0.77(s,6H)。
步骤d).缀合物A04的制备：
将步骤c)中得到的化合物8加入到反应瓶中，加入适量HCl在二氧六环中的溶液，在室温下过夜反应。浓缩反应液，加入适量乙醚打浆，过滤得到缀合物A04的盐酸盐，用饱和碳酸氢钠水溶液使缀合物A04游离，并用乙酸乙酯萃取、用硫酸钠干燥，浓缩得到目标产品。
1H NMR(400MHz,CD3OD)δ:6.98(d,J＝8.0Hz,1H),6.85(m,2H),6.73(d,J＝8.0Hz,1H),6.71-6.63(m,2H),4.38(m,2H),4.21(t,J＝8.1Hz,1H),4.11(s,1H),3.97(t,J＝8.5Hz,1H),3.86-3.66(m,10H),3.50(m,1H),3.33(m,4H),2.99-2.87(m,2H),2.76(m,1H),2.65-2.51(m,3H),2.10(s,1H),1.76(s,2H),1.55(m,4H),1.32(m,6H),1.13(s,2H),0.83(s,6H).
LC-MS(ESI)751[M+H]+。
实施例3：缀合物A10的制备
按照路线3制备缀合物A10。
Figure PCTCN2015088585-appb-000019
反应试剂与条件：a)1-乙基-(3-二甲基氨基丙基)碳酰二亚胺、4-二甲氨基吡啶、三乙胺、二氯甲烷；b)对硝基苯氯甲酸酯、三乙胺、(S,S)-2-氨基环己醇；c)碳酸钾、甲醇；d)HCl在二氧六环中的溶液。
步骤a).化合物9的制备：
将实施例1步骤c)中得到的化合物3(1.0当量)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺(1.5当量)、4-二甲氨基吡啶(0.2当量)以及三乙胺(1.5当量)溶于二氯甲烷中，将反应液在室温下搅拌15分钟，加入2-溴乙醇(1.0当量)，将所得的反应液在室温下搅拌过夜。向反应液加入适量水，分离二氯甲烷层，将水相用二氯甲烷萃取一次，合并有机相并用稀盐酸洗1次，用饱和 食盐水洗有机相，用硫酸钠干燥，浓缩、柱色谱纯化得到产品。
LC-MS(ESI)518[M+H]+。
步骤b).化合物10的制备：
将牛蒡子苷元(1.0当量)和对硝基苯氯甲酸酯(1.0当量)溶解于二氯甲烷中，向上述混合物中加三乙胺(2.0当量)，在室温下反应3小时，加入(S,S)-2-氨基环己醇(1.1当量)和三乙胺(2.0当量)，在室温下反应过夜，将反应液浓缩并通过柱色谱法纯化，得到产品。
LC-MS(ESI)514[M+H]+。
步骤c).化合物11的制备：
将步骤a)中得到的化合物9(1当量)和步骤b)中得到的化合物10(1当量)溶解于甲醇中，加碳酸钾(2.0当量)，回流过夜，TLC显示原料反应完成，浓缩反应液，加入适量水及适量二氯甲烷，搅拌10分钟，将有机相用饱和食盐水洗，硫酸钠干燥、浓缩、柱色谱纯化得产品。
LC-MS(ESI)951[M+H]+。
步骤d).缀合物A10的制备：
将步骤c)中得到的化合物11加入到反应瓶中，加入适量HCl在二氧六环中的溶液，在室温下过夜反应。浓缩反应液，加入适量乙醚打浆，过滤得到缀合物A10的盐酸盐，用饱和碳酸氢钠水溶液处理得到游离缀合物A10，并用乙酸乙酯萃取、用硫酸钠干燥，浓缩得到目标产品。
LC-MS(ESI)851[M+H]+。
实施例4：缀合物A31的制备
按照路线4制备缀合物A31。
Figure PCTCN2015088585-appb-000020
反应试剂与条件：a)碳酸钾、丙酮、溴乙醇，回流；b)1-乙基-(3-二甲基氨基丙基)碳酰二亚胺、4-二甲氨基吡啶、三乙胺、二氯甲烷；c)HCl在二氧六环中的溶液。
步骤a).化合物12的制备：
将牛蒡子苷元(1当量)溶解于适量丙酮中，加入碳酸钾(1.5当量)，搅拌下加入溴乙醇(1.5当量)，将反应混合物回流至原料消失，过滤掉固体，浓缩滤液，柱色谱纯化得到目标产物。
1H NMR(400MHz,DMSO)δ:6.89-6.77(m,3H),6.72-6.57(m,3H),4.82(t,J＝5.5Hz,1H),4.13-4.06(m,1H),3.96-3.85(m,3H),3.70(m,11H),2.89-2.70(m,3H),2.48(m,3H)。
步骤b).化合物13的制备：
以与实施例1步骤e)制备化合物5类似的方法制备化合物13。
1H NMR(400MHz,DMSO)δ:8.68(br,2H),6.91-6.52(m,7H),4.50-4.06(m,6H),3.95-3.84(m,2H),3.73-3.67(m,9H),2.88-2.71(m,3H),2.49-2.42(m,2H),2.04(m,1H),1.66(m,2H),1.54-1.38(m,13H),1.32-1.16(m,6H),1.09(m,2H),0.79(s,6H).LC-MS(ESI)809[M+H]+。
步骤c).缀合物A31的制备：
将步骤b)中得到的化合物13加入到反应瓶中，加入适量HCl在二氧六环中的溶液，在室温下过夜反应。浓缩反应液，加入适量乙醚打浆，过滤 得到缀合物的盐酸盐，用饱和碳酸氢钠水溶液处理得到游离缀合物，并用乙酸乙酯萃取、用硫酸钠干燥，浓缩得到目标产品。
1H NMR(400MHz,DMSO)δ:8.69(br,2H),6.92-6.53(m,7H),4.50-4.06(m,6H),3.94-3.83(m,2H),3.73-3.68(m,9H),2.88-2.70(m,3H),2.49-2.42(m,2H),2.04(m,1H),1.66(m,2H),1.54-1.38(m,4H),1.33-1.17(m,6H),1.07(m,2H),0.78(s,6H).
LC-MS(ESI)709[M+H]+。
实施例5：缀合物A01的制备
按照与实施例1制备缀合物A02类似的方法制备缀合物A01。
1H NMR(400MHz,CDCl3)δ:7.00(d,J＝8.0Hz,1H),6.86–6.74(m,2H),6.69(d,J＝8.0Hz,1H),6.60–6.45(m,2H),5.12(d,J＝13.1Hz,1H),4.56–4.24(m,4H),4.16(m,1H),3.91–3.58(m,12H),3.17(s,1H),3.07(s,2H),2.98(d,J＝5.7Hz,2H),2.73–2.43(m,8H),2.11(s,1H),1.54–1.46(m,3H),1.37–1.27(m,4H),0.83(s,6H).LRMS(ESI)766[M+H]+。
实施例6：缀合物A03的制备
按照与实施例1制备缀合物A02类似的方法制备缀合物A03。
1H NMR(400MHz,CDCl3)δ:8.85(s,2H),7.10-6.49(m,6H),5.99(m,2H),4.40(m,6H),3.81(m,9H),3.31(m,7H),2.74-2.48(m,3H),2.06-1.90(m,3H),1.76-1.42(m,5H),1.25(m,7H),0.78(s,6H).LRMS(ESI)766[M+H]+。
实施例7：缀合物A15的制备
按照与实施例2制备缀合物A04类似的方法制备缀合物A15。
1H NMR(400MHz,CDCl3)δ:6.99(d,J＝8.0Hz,1H),6.77(m,2H),6.66(d,J＝7.8Hz,1H),6.58–6.48(m,2H),4.41(m,2H),4.16(m,1H),3.92–3.75(m,12H),3.22(s,1H),2.96(s,2H),2.70–2.13(m,8H),1.75–1.53(d,J＝21.5Hz,7H),1.34–1.14(m,4H),0.84(m,9H).
LC-MS(ESI)791[M+H]+。
实施例8：缀合物A17的制备
按照与实施例2制备缀合物A04类似的方法制备缀合物A17。
1H NMR(400MHz,CDCl3)δ:8.42(s,1H),6.96(d,J＝7.5Hz,1H),6.73(m,2H),6.64(t,J＝7.2Hz,1H),6.60-6.44(m,2H),4.71-4.09(m,4H), 3.89-3.70(m,12H),3.36(s,1H),2.91(d,J＝5.3Hz,2H),2.75-2.45(m,4H),2.13-1.42(m,13H),1.27(dd,J＝29.8,11.4Hz,6H),1.09(s,2H),0.80(s,6H).
LC-MS(ESI)791[M+H]+。
实施例9：缀合物A05-A09、A11-A14、A16、A18-A30和A32-A34的制备
依据与上述实施例1类似的方法制备缀合物A05-A09、A11-A14、A16、A18-A30和A32-A34，其表征数据如下。
Figure PCTCN2015088585-appb-000021
实施例10：缀合物A35的制备
Figure PCTCN2015088585-appb-000022
反应试剂与条件：a)氯甲酸-1-氯乙酯、4-二甲氨基吡啶、二氯甲烷，0℃；b)N-甲基吗啡啉、2,2-二甲基-3-羟基丙酸、四氢呋喃，50℃；c)2,2,6,6-四甲基哌啶-1-氧化物、三氯均三嗪、二氯甲烷；d)三乙酰氧基硼氢化钠、1,2-二氯乙烷。
步骤a).化合物14的制备：
将盐酸美金刚(1当量)在二氯甲烷中的悬浮液冷却至0℃，并加入催化量的4-二甲氨基吡啶以及三乙胺(3当量)，缓慢滴加氯甲酸-1-氯乙酯(1.1当量)在二氯甲烷中的溶液，将反应液在室温下搅拌过夜。向反应混合物中加入适量水，分离有机层，将水相用二氯甲烷萃取，合并有机相，并分别用稀盐酸、饱和碳酸氢钠以及饱和食盐水洗有机相，用硫酸钠干燥，浓缩，未经纯化直接进行下一步反应。
1H NMR(400MHz,CDCl3)δ:6.54-6.46(m,1H),4.72(m,1H),2.18(m,1H),1.88-1.70(m,4H),1.66-1.49(m,4H),1.43–1.24(m,5H),1.16(d,J＝7.3Hz,2H),0.88(s,6H).
步骤b).化合物15的制备：
将步骤a)中得到的化合物14(1当量)和N-甲基吗啡啉(1.2当量)溶解于适量四氢呋喃中，向上述反应液中加入2,2-二甲基-3-羟基丙酸(1当量)，将反应液加热至50℃，直到TLC显示反应完成。浓缩反应液，将浓缩物加入适量稀盐酸，分离有机相，并用饱和碳酸氢钠水溶液及饱和食盐水洗有机相，硫酸钠干燥、浓缩得到产品。
1H NMR(400MHz,CDCl3)δ:6.72-6.63(m,1H),4.69(m,1H),4.07(s,1H),3.66(d,J＝11.4Hz,1H),3.43(d,J＝11.4Hz,1H),2.15(m,1H),1.86-1.51(m,7H),1.46(t,J＝5.7Hz,2H),1.40-1.21(m,8H),1.19-1.10(m,4H),0.86(s,6H).
步骤c).化合物16的制备：
将步骤b)中得到的化合物15(1当量)及三氯均三嗪(1.5当量)溶解于适量二氯甲烷中，并加入催化量的2,2,6,6-四甲基哌啶-1-氧化物，将反应混合物在室温下搅拌至原料反应完毕。加入适量饱和硫代硫酸钠，将有机相分别用饱和碳酸氢钠及饱和食盐水洗，用硫酸钠干燥，浓缩、柱色谱法纯化得到目标化合物16。
LC-MS：366[M+H]+。
步骤d).缀合物A35的制备：
将实施例2步骤b)中得到的化合物7(1当量)与本实施例中步骤c)中得到的化合物16(1当量)溶解于适量的1,2-二氯乙烷中，加入适量三乙酰氧基硼氢化钠，在室温下反应至TLC显示原料反应完毕。加入适量饱和氯化铵水溶液，分离有机层，水相用二氯甲烷萃取一次，合并有机相并用饱和食盐水洗一次，硫酸钠干燥，浓缩、柱色谱分离得到目标产物缀合物A35。
1H NMR(400MHz,CDCl3)δ:7.03(d,J＝8.0Hz,1H),6.83-6.64(m,4H),6.60-6.51(m,2H),6.04(m,1H),4.84(m,1H),4.17(dd,J＝9.0,7.2Hz,1H),4.06(s,1H),3.93-3.77(m,10H),3.51(m,2H),3.04–2.49(m,9H),2.10(s,1H),1.75(s,2H),1.52(m,6H),1.38–1.10(m,12H),0.83(m,6H).
实施例11：缀合物A36的制备
Figure PCTCN2015088585-appb-000023
反应试剂与条件：a)N-Boc-D-缬氨酸、1-乙基-(3-二甲氨基丙基)碳酰二亚胺、4-二甲氨基吡啶、二氯甲烷；b)HCl在二氧六环中的溶液；c)三乙酰氧基硼氢化钠、1,2-二氯乙烷。
步骤a).化合物17的制备：
将N-Boc-D-缬氨酸(1当量)溶解于适量二氯甲烷中，加入1-乙基-(3-二甲氨基丙基)碳酰二亚胺(1.2当量)以及4-二甲氨基吡啶(5当量)，在室温下搅拌15分钟后，加入牛蒡子苷元(1当量)，继续在室温下反应过夜。向反应液中加入适量水，分离有机相，并将其用稀盐酸、饱和碳酸氢钠以及饱和食盐水洗，用硫酸钠干燥，浓缩、柱色谱法纯化得到化合物17。
1H NMR(400MHz,CDCl3)δ:6.97(d,J＝8.0Hz,1H),6.79(m,2H),6.69(dd,J＝8.0,1.6Hz,1H),6.54(m,2H),5.10(d,J＝9.0Hz,1H),4.53(dd,J＝9.2,4.2Hz,1H),4.21-4.15(m,1H),3.97-3.70(m,10H),3.00(d,J＝5.8Hz,2H),2.72–2.32(m,5H),1.49(s,9H),1.12(d,J＝6.9Hz,3H),1.05(d,J＝6.9Hz,3H).
步骤b).化合物18的制备：
将步骤a)中得到的化合物17(1当量)加入到反应瓶中，向其中加入适量HCl在二氧六环中的溶液，将反应液在室温下搅拌直到原料消失，浓缩得到化合物18。
1H NMR(400MHz,DMSO)δ:8.73(m,3H),7.08(dd,J＝8.0,2.6Hz,1H),7.03(s,1H),6.84(m,2H),6.66(d,J＝1.7Hz,1H),6.63-6.58(m,1H), 4.15(dd,J＝15.3,7.2Hz,2H),3.93(dd,J＝17.1,9.1Hz,1H),3.79–3.67(m,10H),2.96(m,1H),2.82(m,2H),2.36(m,1H),1.11(m,6H).
步骤c).缀合物A36的制备：
按照与实施例10步骤d)制备缀合物A35类似的方法制备缀合物A36。
1H NMR(400MHz,CDCl3)δ:6.93(m,1H),6.80(m,3H),6.69(m,1H),6.59-6.51(m,2H),4.66(d,J＝28.6Hz,1H),4.19(m,1H),3.98-3.74(m,11H),3.15(dd,J＝21.8,6.3Hz,1H),2.98(m,3H),2.74–2.47(m,5H),2.12(s,2H),1.74(m,3H),1.53(m,8H),1.26-1.18(m,6H),1.15–1.02(m,8H),0.84(m,6H)。
LC-MS(ESI)821[M+H]+。
实施例12：缀合物A37的制备
按照与实施例11制备缀合物A36类似的方法制备缀合物A37。
1H NMR(400MHz,CDCl3)δ:6.99-6.92(m,1H),6.85-6.76(m,3H),6.71-6.50(m,3H),4.68(d,J＝17.8Hz,1H),4.21-4.13(m,1H),3.89(m,11H),3.03-2.46(m,9H),2.13(s,1H),1.80-1.12(m,24H),0.84(m,6H)。
LC-MS(ESI)793[M+H]+。
实施例13：缀合物A38的制备
按照与实施例11制备缀合物A36类似的方法制备缀合物A38。
1H NMR(400MHz,CDCl3)δ:8.05(d,J＝8.1Hz,2H),7.42(d,J＝8.1Hz,2H),6.96(d,J＝8.0Hz,1H),6.78-6.58(m,4H),6.43(s,1H),4.59(s,1H),4.09(dd,J＝9.2,6.5Hz,1H),3.91-3.64(m,12H),2.93(d,J＝4.6Hz,2H),2.75-2.52(m,6H),2.07-1.99(m,1H),1.73-1.23(m,16H),1.14(d,J＝6.1Hz,6H),0.79-0.70(m,6H).
LC-MS(ESI)855[M+H]+。
实施例14：缀合物A39-A52的制备
依据与上述实施例10和实施例11类似的方法制备缀合物A39-A52。
Figure PCTCN2015088585-appb-000024
实施例15：缀合物A53的制备
Figure PCTCN2015088585-appb-000025
反应试剂与条件：a)草酸单乙酯、1-乙基-(3-二甲氨基丙基)碳酰二亚胺、4-二甲氨基吡啶、二氯甲烷；b)氢氧化钠水溶液、乙醇；c)牛蒡子苷元、1-乙基-(3-二甲氨基丙基)碳酰二亚胺、4-二甲氨基吡啶、二氯甲烷。
步骤a).化合物19的制备
将草酸单乙酯(1当量)溶解于适量二氯甲烷中，加入1-乙基-(3-二甲氨基丙基)碳酰二亚胺(1.2当量)以及4-二甲氨基吡啶(5当量)，在室温下搅拌15分钟后，加入美金刚(1当量)，继续在室温下反应过夜。向反应液中加入适量水，分离有机相，并将其用稀盐酸、饱和碳酸氢钠以及饱和食盐水洗，用硫酸钠干燥，浓缩、柱色谱法纯化得到化合物19。LC-MS 280[M+H]+。
步骤b).化合物20的制备
将化合物19溶解于适量乙醇中，加入适量的氢氧化钠水溶液，在室温下搅拌过夜。以稀盐酸中和反应液至酸性，将固体过滤，得到目标物20，未纯化直接用于下一步反应。1H NMR(400MHz,CD3OD)δ:2.14(dt,J＝6.4,3.2Hz,1H),1.72(d,J＝1.6Hz,2H),1.52(q,J＝12.4Hz,4H),1.38-1.22(m,4H),1.12(dd,J＝3.6,2.0Hz,2H),0.87(s,6H)。
步骤c).缀合物A53的制备
将化合物20(1当量)溶解于适量二氯甲烷中，加入1-乙基-(3-二甲氨基丙基)碳酰二亚胺(1.2当量)以及4-二甲氨基吡啶(5当量)，在室温下搅拌15分钟后，加入牛蒡子苷元(1当量)，继续在室温下反应过夜。向反应液中加入适量水，分离有机相，并将其用稀盐酸、饱和碳酸氢钠以及饱和食盐水洗，用硫酸钠干燥，浓缩、柱色谱法纯化得到缀合物A53。
1H NMR(400MHz,CD3OD)δ:6.89–6.77(m,3H),6.72–6.57(m,3H),4.82(t,J＝5.5Hz,1H),4.13–4.06(m,1H),3.84(s,3H),3.81(s,6H),2.89-2.70(m,4H),2.57-2.47(m,2H),2.11(dt,J＝6.4,3.2Hz,1H),1.71(d,J＝1.6Hz,2H),1.50(q,J＝12.4Hz,4H),1.36-1.21(m,4H),1.12(dd,J＝3.6,2.0 Hz,2H),0.83(s,6H)。
实施例16：缀合物A54的制备
按照与实施例15类似的方法制备缀合物A54。
1H NMR(400MHz,CD3OD)δ:6.89-6.78(m,3H),6.73-6.58(m,3H),4.83(t,J＝5.5Hz,1H),4.15-4.07(m,1H),3.84(s,3H),3.82(s,6H),3.52(s,2H),2.90-2.71(m,4H),2.58-2.47(m,2H),2.13(dt,J＝6.4,3.2Hz,1H),1.72(d,J＝1.6Hz,2H),1.51(q,J＝12.4Hz,4H),1.36-1.22(m,4H),1.12(dd,J＝3.6,2.0Hz,2H),0.84(s,6H)。
实施例17：缀合物A55的制备
Figure PCTCN2015088585-appb-000026
反应试剂与条件：a)羟基乙酸、1-乙基-(3-二甲氨基丙基)碳酰二亚胺、三乙胺、二氯甲烷；b)三乙胺、四氢呋喃。
步骤a).化合物21的制备
将羟基乙酸(1当量)溶解于适量二氯甲烷中，加入1-乙基-(3-二甲氨基丙基)碳酰二亚胺(1.2当量)以及三乙胺(1.2当量)，在室温下搅拌5分钟后，加入牛蒡子苷元(1.1当量)，继续在室温下反应过夜。向反应液中加入适量水，分离有机相，并将其用稀盐酸、饱和碳酸氢钠以及饱和食盐水洗，用硫酸钠干燥，浓缩、柱色谱法纯化得到化合物21。
LC-MS 430[M-H]-。
步骤b).缀合物A55的制备
将实施例1步骤a)中得到的化合物1(1当量)在干燥的四氢呋喃中溶解，加入化合物21(0.8当量)以及三乙胺(1当量)。反应在50℃下进行24小时，TLC显示化合物21消失，将反应液浓缩得到产品，柱色谱法纯化得缀合物A55。
1H NMR(400MHz,CD3OD)δ:6.87-6.76(m,3H),6.72-6.57(m,3H), 5.02(s,2H),4.81(t,J＝5.5Hz,1H),4.14-4.06(m,1H),3.83(s,3H),3.81(s,6H),2.88-2.70(m,4H),2.54-2.46(m,2H),2.11(dt,J＝6.4,3.2Hz,1H),1.71(d,J＝1.6Hz,2H),1.50(q,J＝12.4Hz,4H),1.34-1.21(m,4H),1.10(dd,J＝3.6,2.0Hz,2H),0.82(s,6H)。
生物学实验：
测试例1
缀合物A04挽救AD模型果蝇的记忆力损伤的作用
本发明采用过表达人源Aβ42的阿尔兹海默症果蝇模型(该模型果蝇具有显著的学习记忆缺陷)，评价缀合物A04挽救该模型果蝇学习记忆的能力。
1、实验原理
巴普洛夫式嗅觉记忆平台是从文献(Tully,T.等人，Classical conditioning and retention in normal and mutant Drosophila melanogaster.(1985)J.Comp.Physiol.A 157:,263-277；Tully,T.等人，Genetic dissection of consolidated memory in Drosophila.(1994)Cell 79:35-47；Yin,J.C.等人，Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila.(1994)Cell 79:49-58.)中改进得到。学习记忆测试是在25℃，70％相对湿度的恒温恒湿行为房中进行。实验包括两阶段：
训练阶段：将约一百只果蝇装入一个内铺有铜网的训练管，这些果蝇会先后闻到两种气味(辛醇(OCT)与甲基环己醇(MCH))。每种气味持续1分钟，并在结束之后都跟随有45秒的新鲜空气的通入。果蝇只有在闻到第一种气味时会接受持续1分钟的电击惩罚。这样的一遍流程构成一个训练周期。为了避免果蝇对气味的天然偏好，每个数据点中，1管果蝇会先闻到OCT并接受电击，而另1管则会先闻到MCH并接受电击，2管果蝇测试值的平均值为一个数据点。
测试阶段：果蝇在训练后立刻转移到T型迷宫的选择点，然后在两分钟内，使其在两种气味容器之间进行选择。2分钟后，分别统计处于不同容器的果蝇的数目，并计算行为指数(PI)。若果蝇在两个容器中呈50:50分布，则PI＝0，这表明果蝇无法记忆电击与气味的联系；而PI＝100则表示100％的果蝇都会记住气味和电击的联系，会根据气味信息去回避电击。
2、实验材料与方法
1)果蝇品系
本实验中使用的所有果蝇均经过至少5代的回交，使之均处于w1118(isoCJ1)的遗传背景下，以避免不同遗传背景对结果的影响。因此，w1118(isoCJ1)品系果蝇(简称“2U”)是本次所有实验的原始对照组。为避免长期、跨代表达Aβ42蛋白对果蝇品系产生的潜在不利影响，使用载有可调控人源Aβ42基因的果蝇(简称“H29.3”)，其只有在与启动Aβ42基因表达的果蝇elav-GAL4c155(简称“P35”)杂交后，其子代才会在神经系统中表达Aβ42蛋白。将H29.3与遗传背景果蝇2U杂交，其子代果蝇则不会表达Aβ42蛋白，为遗传对照组。学习测试则是在上述子代上进行的。本测试例中使用的果蝇如图1中所示得到。
2)果蝇饲养、给药及检测
将亲本果蝇均饲养在24℃，40～60％相对湿度，每天12小时光照的标准环境中。子代果蝇羽化后的第二日(day after eclosion，DAE 2)起，在显微镜下挑选出对照雄果蝇(+/Y；UAS-Aβ42/+)与实验组的雄果蝇(elav/Y；UAS-Aβ42/+)，每管100只。将挑得的果蝇转移至29℃,40±15％相对湿度的条件下进行后继饲养和药物处理。
将缀合物母液与对照化合物美金刚(Mem)(10mM)均存储于-20℃冰箱中。喂药开始前一天，将母液在4％蔗糖工作液中稀释至100μM，然后存放于-20℃冰箱中。蔗糖工作液对果蝇的学习记忆能力没有影响。从第2天到第8天(共7天)，向每组果蝇每天给药4小时，在新鲜食物存在下休息20小时。通过果蝇给药装置，每天向每管果蝇给药50μl的药物或对照化合物。
然后采用巴甫洛夫式嗅觉记忆方法检测化合物对果蝇记忆损伤的挽救效果。每个药物获得7个数据点，每个数据点是2管果蝇嗅觉记忆的平均值。
3、实验结果
2U*H29.3为遗传对照组(健康果蝇)，P35*H29.3为AD对照组(仅给药溶剂，即阴性对照)。Mem与缀合物A04为AD实验喂食相对应药物的数据。每个药物的结果包含了7个数据点，隶属于三次独立的实验。其中，AD阴性对照组PI为41(要求小于45)，遗传对照组与AD阴性组的PI差异为19(要 求大于15)，阳性药物Mem的PI值为55，挽救效果大于50％(阴性对照组挽救效果为0％，遗传对照组为100％)，均满足实验成立标准。实验数据如图2所示。数据表明缀合物A04具有比Mem更强的对AD果蝇记忆损伤的挽救效果(采用T-test统计学方法，对应于AD模型果蝇组(P35*H29.3)；*，p<0.05；**，p<0.01；***，p<0.001)。
测试例2
缀合物A04逆转APP/PS1转基因AD模型小鼠记忆力损伤的作用
本发明将缀合物A04通过灌胃方式向APP/PS1转基因AD模型小鼠给药，然后通过经典的Morris水迷宫实验检测缀合物A04对转基因AD模型小鼠记忆力损伤的影响。
1、实验原理
本实验采用APP/PS1双转基因AD模型小鼠，其在6个月左右大时出现Aβ沉积，在7个月左右大时出现空间记忆力的损害。因而本实验进一步通过水迷宫测试，观察小鼠空间记忆能力的损伤情况，同时评价缀合物A04对损伤的记忆是否有治疗或者改善的效果。
2、实验材料与方法
1)APP/PS1双转基因AD模型小鼠的鉴定：对小鼠剪尾，然后PCR鉴定小鼠的APP/PS1的基因序列。采用野生型C57(B6C3)小鼠作为阴性对照小鼠。将小鼠在标准条件下(12/12小时明暗循环，足够水和食物，22℃的恒温，60％的湿度)饲养。
2)转基因AD模型小鼠给药：在小鼠6个月大小时，将30只转基因AD模型小鼠随机分为3组(Control-AD：转基因溶剂组；A04：向转基因小鼠给药50mg/kg缀合物A04的组；Mem：向转基因小鼠给药50mg/kg盐酸美金刚的组)，10只非转基因小鼠作为阴性对照组(Control-WT)。将缀合物A04和盐酸美金刚用0.9％NaCl+0.5％Tween 80溶解，将其灌胃给药60天，然后开始Morris水迷宫实验。
3)Morris水迷宫实验：每天实验时均在直径120厘米的白色圆形水池中注入温度为19-20℃的水和新鲜牛奶混合物。将一个直径15厘米的圆形平台放置在圆形四个象限的某个象限的中心处，且平台低于水面2厘米。在水池的四个象限上壁都贴有形状不同的标记物，其为小鼠通过标记物定 位水下平台的位置提供线索。在实验的第零天(即适应期)，如果小鼠未能在60秒内找到平台，则需人工将小鼠放置在平台上停留5秒，帮助小鼠认识到平台的存在及位置。在实验的第一天到第八天中，使每只小鼠每天游4次，让其寻找平台。每次之间间隔相同的1个小时到2个小时。若小鼠在60秒内未能找到平台，则认为小鼠寻找平台的时间为60秒。小鼠的行动轨迹及速度由Anymaze及匹配的摄像头自动记录。每天四次测试中找到平台的平均时间记为当天的寻找平台时间(潜伏期)。所有的动物实验操作都严格遵守《实验动物管理条例》。
3、实验结果
在图3中，A04表示转基因AD模型小鼠给药组(剂量为50mg/kg/日的缀合物A04)；Control-Ad表示转基因AD模型小鼠溶剂组(0.9％NaCl+0.5％Tween 80)；Control-Wt表示非转基因小鼠溶剂组(0.9％NaCl+0.5％Tween 80)，Mem表示转基因AD模型小鼠盐酸美金刚给药组(剂量50mg/kg/日的盐酸美金刚)。Morris水迷宫实验训练实验中潜伏期的测定结果表明转基因AD模型小鼠潜伏期明显长于非转基因正常小鼠；被给药缀合物A04(50mg/kg/日)持续60天后的转基因AD模型小鼠的潜伏期明显低于溶剂处理转基因小鼠；以上实验结果说明转基因AD模型小鼠记忆力出现损伤，而缀合物A04能够明显改善转基因小鼠的记忆力损伤。盐酸美金刚给药组的潜伏期与转基因AD模型小鼠组比没有明显的变化，这说明盐酸美金刚没有逆转AD转基因小鼠记忆力损伤的作用。
该测试表明缀合物A04具有逆转转基因AD模型小鼠记忆力损伤的效果，而盐酸美金刚不能逆转转基因AD模型小鼠记忆力损伤。
测试例3
本试验研究牛蒡子苷元(ATG)和缀合物A04在大鼠体内的药物代谢动力学。向大鼠灌胃给药ATG和A04后，在不同时间点采集全血样品，分离血浆，用LC-MS测定血浆中ATG的浓度。
1、实验方案
健康SD大鼠6只，雄性，体重200-220g，给药方案见下表：
组别 动物数目 化合物 给药途径 给药剂量(mg/kg) 给药体积(ml/kg)
1 3 A04 灌胃 20 10
2 3 ATG 灌胃 20 10
试验前将大鼠禁食12h，自由饮水，给药后2h使大鼠统一进食。
采血时间点：灌胃给药后0.5、1.0、2.0、4.0、6.0、8.0和12h。
在以上设定时间点经大鼠眼球后静脉丛取静脉血0.5mL，将其置于肝素化试管中，在11000rpm下离心5min，分离血浆，将其于-20℃冰箱中冷冻。
向100μL血浆样品中加入200μL乙腈，涡流混合1min，离心5min(11000rpm)，取出全部上清液置于10mL试管中，在40℃空气流下吹干，在100μL乙腈-水(1:9,v/v)中溶解，取10μL进行UPLC/Q-TOF MS分析。
2、结果
向大鼠灌胃给药20mg/kg ATG后，在血浆中未检测到ATG(血浆浓度低于检测下限1.0ng/ml)。
向大鼠灌胃给药20mg/kg缀合物A04后，大鼠中的ATG血浆浓度(ng/mL)如表1中所示。
表1.
Figure PCTCN2015088585-appb-000027
尽管本发明通过之前的具体实施例得到说明，但应当理解，不应将其解释为受此限制。本发明涵盖之前公开的一般方面，并且本领域技术人员可在不背离本发明的精神和范围的情况下进行多种修饰或改变本发明的各种细节。因此，本说明书仅为说明的目的，而非为限制的目的。

Claims (11)

  1. 缀合物，其包含美金刚与牛蒡子苷元。
  2. 权利要求1的缀合物，其为通式(I)的化合物、其药学上可接受的盐、立体异构体、多晶型物、溶剂合物或前药：
    Figure PCTCN2015088585-appb-100001
    其中：
    Linker 1选自：-C(O)-、-C(O)L1C(O)-、-C(O)OL1C(O)-、-C(O)OL1OC(O)-、-C(O)OQ1L2Q2-、-C(O)Q1L2Q2N(R1)C(O)-、-C(O)Q1L2Q2OC(O)-、-C(O)Q1L2Q2C(O)-、-C(O)OQ1L2Q2OC(O)-、-C(O)OQ1L1Q2N(R1)C(O)-、-C(O)OQ1L2Q2N(R1)C(O)-和-C(O)OQ1L2Q2C(O)-；
    L1为直接键，或者选自：-O-、-S-、-NR2-、取代或未取代的C1-C6直链或支链亚烷基、取代或未取代的C2-C6直链或支链亚烯基、取代或未取代的C2-C6直链或支链亚炔基、取代或未取代的C3-C10亚环烷基、取代或未取代的C3-C10非芳族亚杂环基、取代或未取代的C6-C14亚芳基、取代或未取代的C6-C14亚杂芳基，以及取代或未取代的C6-C20亚芳烷基；
    L2为直接键，或者选自：-NR2-、-O-、-C(O)-、-N(R3)C(O)-、-C(O)N(R3)-、-C(O)O-、-OC(O)-、-N(R3)Q3O-、-N(R3)C(O)Q3O-、-N(R3)C(O)Q3C(O)-、-N(R3)C(O)Q3N(R3)-、-N(R3)C(O)Q3C(O)N(R3)-、-N(R3)C(O)Q3N(R3)C(O)-、-N(R3)C(O)Q3C(O)O-、-N(R3)C(O)Q3OC(O)-、-C(O)N(R3)Q3C(O)N(R3)-、-C(O)N(R3)Q3C(O)O-、-C(O)N(R3)Q3N(R3)C(O)-、-C(O)N(R3)Q3OC(O)-、-N(R3)Q3C(O)N(R3)-、-N(R3)Q3C(O)O-、-N(R3)Q3N(R3)C(O)-、-N(R3)Q3OC(O)-、-OQ3N(R3)-、-OQ3C(O)N(R3)-、-OQ3C(O)O-、-OQ3N(R3)C(O)-、-OQ3OC(O)-、-OC(O)Q3-、-OC(O)Q3C(O)N(R3)-、 -OC(O)Q3C(O)O-、-OC(O)Q3N(R3)-、-OC(O)Q3N(R3)C(O)-、-OC(O)Q3N(R3)L1O-、-OC(O)Q3OC(O)-、-C(O)OQ3-、-C(O)OQ3O-、-C(O)OQ3C(O)N(R3)-、-C(O)OQ3C(O)O-、-C(O)OQ3N(R3)C(O)-或-C(O)OQ3OC(O)-；
    Q1、Q2和Q3各自独立地选自：取代或未取代的C1-C6直链或支链亚烷基、取代或未取代的C3-C10亚环烷基、取代或未取代的C2-C6直链或支链亚烯基、取代或未取代的C2-C6直链或支链亚炔基、取代或未取代的C3-C10非芳族亚杂环基、取代或未取代的C6-C14亚芳基、取代或未取代的C6-C14亚杂芳基，以及取代或未取代的C6-C20亚芳烷基；并且
    R1、R2和R3各自独立地选自：H和C1-C6烷基。
  3. 权利要求2的缀合物，其为通式(II)的化合物、其药学上可接受的盐、立体异构体、多晶型物、溶剂合物或前药：
    Figure PCTCN2015088585-appb-100002
    其中：
    Linker 2选自：-L1-、-L1O-、-Q1L1Q2N(R1)-、-Q1L2Q2N(R1)-、-Q1L2Q2O-或-Q1L2Q2-；
    L1选自：取代或未取代的C1-C6直链或支链亚烷基、取代或未取代的C2-C6直链或支链亚烯基、取代或未取代的C2-C6直链或支链亚炔基、取代或未取代的C3-C10亚环烷基、取代或未取代的C3-C10非芳族亚杂环基、取代或未取代的C6-C14亚芳基、取代或未取代的C6-C14亚杂芳基，以及取代或未取代的C6-C20亚芳烷基；并且
    L2、Q1、Q2、Q3、R1、R2和R3如权利要求2中所定义。
  4. 权利要求3的缀合物，其为通式(III)的化合物、其药学上可接受的 盐、立体异构体、多晶型物、溶剂合物或前药：
    Figure PCTCN2015088585-appb-100003
    Linker 3为直接键，或者选自：-C(O)Q3N(R3)Q2-、-C(O)Q3N(R3)Q2N(R1)-、-C(O)Q2O-、-C(O)Q2N(R1)-、-C(O)Q3N(R3)L1OQ2N(R1)-，以及-C(O)Q3Q2N(R1)-；
    L1、Q2、Q3、R1和R3如权利要求3中所定义；并且
    R选自：H或C1-C6烷基。
  5. 权利要求2的缀合物，其选自缀合物A01至A55及其药学上可接受的盐、立体异构体、多晶型物、溶剂合物或前药：
    Figure PCTCN2015088585-appb-100004
    Figure PCTCN2015088585-appb-100005
    Figure PCTCN2015088585-appb-100006
    Figure PCTCN2015088585-appb-100007
    Figure PCTCN2015088585-appb-100008
    Figure PCTCN2015088585-appb-100009
    Figure PCTCN2015088585-appb-100010
    Figure PCTCN2015088585-appb-100011
    Figure PCTCN2015088585-appb-100012
    Figure PCTCN2015088585-appb-100013
    Figure PCTCN2015088585-appb-100014
    Figure PCTCN2015088585-appb-100015
  6. 药物组合物，其包含权利要求1-5中任一项的缀合物以及一种或多种药学上可接受的载体。
  7. 权利要求6的药物组合物，其进一步包含一种或多种治疗与Aβ或者Tau蛋白通路相关的疾病的其它药物。
  8. 治疗与Aβ或者Tau蛋白通路相关的疾病的方法，其包括向需要其的个体给药治疗有效量的权利要求1-5中任一项的缀合物或权利要求6-7中任一项的药物组合物。
  9. 权利要求8的方法，其中所述疾病为神经退行性疾病，特别是阿尔茨海默病或帕金森氏症。
  10. 权利要求8的方法，其还包括向需要其的个体另外给药治疗与Aβ或者Tau蛋白通路相关的疾病的其它药物。
  11. 权利要求7的药物组合物或权利要求10的方法，其中所述治疗与Aβ或者Tau蛋白通路相关的疾病的其它药物为乙酰胆碱酯酶抑制剂(如多奈哌齐、石杉碱甲、他克林等)。
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