WO2024027845A1 - 双四氢呋喃类化合物作为α-突触核蛋白聚集体形成抑制剂的用途、包含其的药物组合物 - Google Patents

双四氢呋喃类化合物作为α-突触核蛋白聚集体形成抑制剂的用途、包含其的药物组合物 Download PDF

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WO2024027845A1
WO2024027845A1 PCT/CN2023/111505 CN2023111505W WO2024027845A1 WO 2024027845 A1 WO2024027845 A1 WO 2024027845A1 CN 2023111505 W CN2023111505 W CN 2023111505W WO 2024027845 A1 WO2024027845 A1 WO 2024027845A1
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saturated
group
partially unsaturated
substituted
ring
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French (fr)
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叶阳
冯林音
姚胜
王晴
柯昌强
张玉
唐春萍
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中国科学院上海药物研究所
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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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicinal chemistry, and more specifically, relates to the use of ditetrahydrofuran compounds as ⁇ -synuclein ( ⁇ -synuclein) aggregate formation inhibitors, pharmaceutical compositions containing the same, and the treatment of Parkinson's and other diseases.
  • Drugs for Neurodegenerative Diseases are included in the field of medicinal chemistry, and more specifically, relates to the use of ditetrahydrofuran compounds as ⁇ -synuclein ( ⁇ -synuclein) aggregate formation inhibitors, pharmaceutical compositions containing the same, and the treatment of Parkinson's and other diseases.
  • Parkinson's disease is a type of neurodegenerative disease that mostly occurs in middle-aged and elderly people. Its clinical symptoms are mainly movement disorders, which are divided into two categories: one is tremor, muscle rigidity, involuntary movements, etc. A behavior rarely seen in healthy people; another category is bradykinesia and impaired postural reflexes. Bradykinesia leads to difficulty walking, lack of facial expression (mask face), and impaired postural reflexes make it difficult for patients to maintain a normal posture and have difficulty standing. Further deterioration will lead to impaired speech function and even difficulty chewing and swallowing, seriously affecting the patient's quality of life. With the extension of the average life span and aging of the population, the incidence of PD has shown a significant upward trend.
  • the incidence rate of PD is 0.3%, rising to 1% in people over 60 years old, and as high as 4% in people over 80 years old. It is expected that the incidence of Parkinson's disease will double by 2050. .
  • Current treatments for Parkinson's disease mainly include levodopa, dopamine reuptake inhibitors and a series of enzyme inhibitors. These drugs mainly target the motor symptoms of PD, have no effect on non-motor symptoms, and cannot prevent the progression of the disease. Therefore, developing a new generation of PD treatment drugs has huge social significance and economic benefits.
  • PD is the second most common neurodegenerative disease in the world.
  • SNpc dopaminergic neurons in the substantia nigra pars compacta
  • 80% of the dopaminergic neurons in the putamen have also been reduced.
  • the death of the vast majority of neurons has resulted in the loss of the disease.
  • the optimal therapeutic window for treatment The gene encoding ⁇ -Synuclein ( ⁇ -synuclein), SNCA, was the first gene found to be related to PD.
  • ⁇ -Synuclein is a disordered protein with random helical extension. Its natural conformation is generally a stable-state monomer and a tetramer mediated by the KTKEGV repeat sequence in its nitrogen-terminal region.
  • Alpha-synuclein is capable of transitioning between many different conformations, including monomers, tetramers, higher-level oligomers (soluble conformation), fibers (highly ordered structures characterized by a beta-sheet conformation) Insoluble conformation) and aggregates, ⁇ -synuclein protein misfolding causes disorder of the nervous system environment, damages dopaminergic neurons, and promotes the occurrence and development of PD. Under pathological conditions, excessive ⁇ -synuclein and its oligomers and other aggregates are distributed on cell bodies and processes, and damage cell functions.
  • ⁇ -Synuclein aggregates are one of the core components of Lewy bodies and play an important role in the early occurrence and development of PD. Its mutation and overexpression are considered to be the driving factors for the onset of PD. Research in recent years has found that abnormal aggregation of ⁇ -Synuclein appears ten to fifteen years earlier than the typical symptoms of PD. Blocking the aggregation of ⁇ -Synuclein should slow down the progression of PD and improve symptoms. Therefore, inhibiting the formation of ⁇ -synuclein aggregates is one of the current hot research directions for PD drugs. In the process of PD, the aggregation of ⁇ -synuclein is a key factor. Reducing the aggregation of ⁇ -synuclein can delay the course of PD.
  • the inventor used a complementary analysis method based on luciferase and fluorescent protein fragments. According to existing literature reports, the Gaussia luciferase or Venus fluorescent protein was split into two protein fragments and combined with A53T mutant ⁇ -synapse respectively.
  • nucleoprotein to explore the effect of ditetrahydrofuran-type lignans with different substitutions (the specific structure is shown in Figure 1) on the depolymerization or degradation of ⁇ -synuclein oligomers, and discovered a class of compounds with this type of activity
  • the present invention provides bistetrahydrofuran compounds represented by formula (I) or pharmaceutically acceptable salts, esters, optical isomers, stereoisomers, polymorphs, and solvates thereof , N-oxides, isotopically labeled compounds, metabolites, chelates, complexes, inclusion compounds or prodrugs as inhibitors of alpha-synuclein aggregate formation,
  • ring A and ring B independently represent a substituted or unsubstituted C6-10 aromatic ring, or a substituted or unsubstituted C5-14 heteroaromatic ring, preferably a benzene ring, a pyridine ring, or a pyrrole ring;
  • X 1 and X 2 are each independently NRC , O or S, preferably O or S, more preferably O,
  • Each R C is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocycle base, C6-10 aryl group, 5-14 membered heteroaryl group or C6-12 aralkyl group, preferably H, C1-6 alkyl group;
  • Each R d is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocycle group, C6-10 aryl, C5-14 heteroaryl or C6-12 aralkyl, multiple R d can be connected to each other and form a ring together with the atoms constituting ring A, provided that at least one of the multiple R d is H,
  • Substituted in “substituted or unsubstituted” here means optionally substituted by 1-3 halogens, C1-C3 alkyl, C1-C3 alkoxy, C1-C6 cycloalkyl, C1-C6 cycloalkyl Oxygen or C1-C3 haloalkyl substitution, cyano group, nitro, hydroxyl, amino, phosphinyl, sulfonyl, sulfonamido group, the expression of the ring structure crossed by "—" indicates that the connection site is at Any position on the ring structure that can form a bond.
  • the compound has the structure of the following formula (II),
  • R 1 to R 4 are independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 yuan Heterocyclyl, C6-10 aryl, C5-14 heteroaryl or C6-12 aralkyl, preferably H, C1-6 alkyl, R 1 and R 2 can be connected and connected to the atoms in the benzene ring Together to form a ring, R 3 and R 4 can be connected and together form a ring with the atoms in the benzene ring to which they are connected,
  • R 5 and R 6 are each independently H, hydroxyl, saturated or partially unsaturated C1-6 hydrocarbon group, saturated or partially unsaturated C1-6 hydrocarbon group -O-, saturated or partially unsaturated C3-10 cyclic hydrocarbon group, Saturated or partially unsaturated C3-10 cycloalkyl -O-, saturated or partially unsaturated C3-10 cycloalkyl -NH-, substituted saturated or partially unsaturated C1-6 alkyl, substituted saturated or partially unsaturated One of the C3-10 cyclic hydrocarbon groups, preferably H, hydroxyl group,
  • Substituted in “substituted or unsubstituted” here means optionally substituted by 1-3 halogens, C1-C3 alkyl, C1-C3 alkoxy, C1-C6 cycloalkyl, C1-C6 cycloalkyl Oxygen or C1-C3 haloalkyl substitution, cyano group, nitro, hydroxyl, amino, phosphinyl, sulfonyl, sulfonamido group, the expression of the ring structure crossed by "—" indicates that the connection site is at Any position on the ring structure that can form a bond.
  • the compound has a structure represented by the following formula (III),
  • R 1 to R 4 are independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cyclic hydrocarbon group, R 1 and R 2 can be connected and together form a ring with the atoms in the benzene ring to which it is connected, R 3 and R 4 can be connected and together form a ring with the atoms in the benzene ring to which it is connected,
  • R 5 and R 6 are each independently H, hydroxyl, saturated or partially unsaturated C1-6 hydrocarbon group, saturated or partially unsaturated C1-6 hydrocarbon group -O-, saturated or partially unsaturated C3-10 cyclic hydrocarbon group, Saturated or partially unsaturated C3-10 cyclic hydrocarbon group -O-, preferably H.
  • R 1 to R 4 are independently selected from H, methyl, ethyl, and propyl.
  • R 1 and R 2 can be connected to form methylene or ethylene, and R 3 and R 4 can be connected. Become methylene, ethylene,
  • R 5 and R 6 are each independently H, hydroxyl, methoxy, or ethoxy.
  • three or more of R 1 to R 4 are H.
  • the compound is selected from the following specific compounds, but is not limited to the following compounds:
  • the present invention also provides the application of the compound represented by formula (I) in the preparation of medicines for treating Parkinson's disease, and the compound represented by formula (I) has anti-Parkinson activity, which activity may be related to that of ⁇ -synuclein.
  • the activity of the aggregate formation inhibitor is directly related, and may also be based on other independent mechanisms.
  • the anti-Parkinson activity of the compound represented by formula (I) does not depend on the correctness of the mechanism speculation in the present invention.
  • the present invention also provides the compound represented by (I) itself. Preferred embodiments of the compound represented by (I) are also the same as above.
  • the present invention also provides a pharmaceutical composition, which contains a preventive or therapeutically effective amount of the above-mentioned compound of the present invention or its pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, polymorph, Solvates, N-oxides, isotopically labeled compounds, metabolites, chelates, complexes, inclusion compounds or prodrugs, and pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, Semi-solid preparations, liquid preparations or gaseous preparations.
  • the dosage form of the pharmaceutical composition is an oral dosage form or an injection, and the oral dosage form includes tablets, capsules, films, and granules.
  • the present invention is a method for treating neurodegenerative diseases, which includes administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, polyisomer thereof to a person in need of such treatment.
  • Crystalline forms, solvates, N-oxides, isotopically labeled compounds, metabolites, chelates, complexes, clathrates or prodrugs or the above-mentioned pharmaceutical compositions of the present invention.
  • the compound of the present invention is structurally original.
  • the compound (I) of the present invention can be used in the preparation of drugs for diseases related to the formation of ⁇ -synuclein aggregates, and can also be used in the preparation of drugs for the treatment of Parkinson's and other neurodegenerative diseases. Used in medicines as other neurodegenerative diseases Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), different types of spinocerebellar ataxia (SCA), Pick's disease
  • AD Alzheimer's disease
  • HD Huntington's disease
  • ALS amyotrophic lateral sclerosis
  • SCA spinocerebellar ataxia
  • alkylene refers to a saturated divalent hydrocarbon radical, preferably a saturated divalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • an alkyl group has 1 to 12, such as 1 to 6 carbon atoms.
  • C 1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl base, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents
  • halogen substitution in this case, the group is called "haloalkyl" (for example, CH 2 F, CHF 2 , CF 3 , CCl 3 , C 2 F 5 , C 2 Cl 5
  • C1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon radical containing one double bond and having 2 to 6 carbon atoms (“C 2-6 alkenyl”).
  • the alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2 -Hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • the compound of the present invention contains an alkenyl group, the compound may exist in pure E (ent ought) form, pure Z (zusammen) form, or any mixture thereof.
  • alkynyl means a monovalent hydrocarbon radical containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cyclononyl, or bicyclo, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.)), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cyclonon
  • the cycloalkyl group has 3 to 15 carbon atoms.
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl or cycloalkyl). hexyl), optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example methyl-substituted cyclopropyl.
  • cycloalkylene As used herein, the terms “cycloalkylene”, “cycloalkyl” and “hydrocarbon ring” refer to having, for example, 3 to 10 (suitably 3 to 8, more suitably 3 to 6) ring carbons.
  • heterocyclyl As used herein, the terms “heterocyclyl”, “heterocyclylene” and “heterocycle” mean, for example, 3-10 (suitably 3-8, more suitably 3-6) Ring atoms, in which at least one ring atom is a heteroatom selected from N, O, and S and the remaining ring atoms are C saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., have one or more double bond and/or triple bond) cyclic group.
  • 3-10 suitably 3-8, more suitably 3-6
  • Ring atoms in which at least one ring atom is a heteroatom selected from N, O, and S and the remaining ring atoms are C saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., have one or more double bond and/or triple bond) cyclic group.
  • a “3-10 membered (ylidene)heterocycle(yl)” has 2-9 (such as 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and is independently selected from N , a saturated or partially unsaturated (sub)heterocyclic ring (base) with one or more (eg 1, 2, 3 or 4) heteroatoms of O and S.
  • heterocyclylene and heterocycl(yl) include, but are not limited to: ()oxirylene, ()aziridinyl, (azetidinyl), (ylidene) Heterocyclobutyl (oxetanyl), (ylidene) tetrahydrofuranyl, (ylidene) dioxolinyl (dioxolinyl), (ylidene) pyrrolidinyl, (ylidene) pyrrolidonyl, (ylidene) imidazolidinyl, (ylidene) )Pyrazolidinyl, (ylidene) pyrrolinyl, (ylidene) tetrahydropyranyl, (ylidene) piperidyl, (ylidene) morpholinyl, (ylidene) dithianyl (dithianyl), (ylidene) Thiomorpholinyl, (ylidene)piperazinyl
  • the groups also encompass bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azaspiro[5.5]undecan, Heterobicyclo[2.2.2]octane, etc.).
  • Heterocyclylene and heterocycl(yl) groups may be optionally substituted with one or more (eg 1, 2, 3 or 4) suitable substituents.
  • (arylene) and “aromatic ring” refer to all-carbon monocyclic or fused-ring polycyclic aromatic radicals having a conjugated pi electron system.
  • C 6-10 ()arylene” and “C 6-10 aromatic ring” mean aromatic groups containing 6 to 10 carbon atoms, such as ()phenylene (Benzene ring) or (phenylene) naphthyl (naphthalene ring).
  • the ()arylene groups and aromatic rings are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.) .
  • heteroarylene and “heteroaryl ring” refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and it contains at least one heteroatom which may be the same or different (the heteroatoms are for example oxygen, nitrogen or sulfur), and, in each case, may additionally be benzo-fused.
  • (ylene)heteroaryl or “heteroaryl ring” is selected from (ylene)thienyl, (ylene)furyl, (ylene)pyrrolyl, (ylene)oxazolyl, (ylene)thiazolyl, (Imidazolyl), (pyrazolylene), (isoxazolyl), (isothiazolylene), (ylidene) oxadiazolyl, (ylidene) triazolyl, (ylidene) thiadiazolyl etc., as well as their benzo derivatives; or (pyridylidene), (pyridylene) pyridazinyl, (pyrimidinyl), (ylidene) pyrazinyl, (ylidene) triazinyl, etc., and their benzo derivatives derivative.
  • aralkyl preferably means an aryl- or heteroaryl-substituted alkyl group, wherein aryl, heteroaryl and alkyl are as defined herein.
  • the aryl group may have 6 to 14 carbon atoms
  • the heteroaryl group may have 5 to 14 ring atoms
  • the alkyl group may have 1 to 6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • Alkyl refers to a saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms , or a saturated linear or branched chain monovalent hydrocarbon group of 1-2 carbon atoms, wherein the alkyl group can be independently optionally substituted by one or more substituents described in the present invention.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1 ,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2 -Dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-di Methylbutyl etc. Alkyl groups may be optionally substituted or unsubstituted.
  • Alkenyl refers to a linear or branched monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, in which at least one CC is sp 2 double bond, in which the alkenyl group can be independently optionally substituted by one or more substituents described in the present invention. Specific examples include, but are not limited to, vinyl, allyl and alkenyl. Dinky and more. Alkenyl groups may be optionally substituted or unsubstituted.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring includes 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl. Cycloalkyl groups may be optionally substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one carbon atom (called a spiro atom) with each other, and the ring contains 1 or more An aromatic system with double bonds but in which no ring has fully conjugated ⁇ electrons. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl group is divided into single spiro, double spiro or polyspiral cycloalkyl, preferably single spiro and double spiro cycloalkyl, preferably 4-membered/5-membered, 4-membered Yuan/6 Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan.
  • spirocycloalkyl include, but are not limited to:
  • Condensed cycloalkyl refers to an all-carbon polycyclic group with 5 to 18 members and containing two or more cyclic structures sharing a pair of carbon atoms with each other.
  • One or more rings may contain one or more double bonds.
  • aromatic systems in which none of the rings have fully conjugated ⁇ electrons are preferably 6 to 12 members, and more preferably 7 to 10 members.
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed ring alkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl groups.
  • Non-limiting examples of "fused cycloalkyl” include, but are not limited to:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetralin base, benzocycloheptyl, etc.
  • Heterocyclyl “heterocycle” or “heterocyclic” are used interchangeably in this application. They are used interchangeably in this application and all refer to a saturated or partially unsaturated monocyclic ring containing 3-12 ring atoms. , bicyclic or tricyclic non-aromatic heterocyclic groups, in which at least one ring atom is a heteroatom, such as oxygen, nitrogen, sulfur atom, etc. Preference is given to a 5- to 7-membered monocyclic ring or a 7 to 10-membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine base, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and Piperazinyl.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring attached to the parent structure is heterocyclyl.
  • Heterocyclyl groups may be optionally substituted or unsubstituted.
  • Condensed heterocyclyl refers to an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclyl include, but are not limited to:
  • “Bridged heterocyclyl” refers to a polycyclic group with 5 to 18 members, containing two or more cyclic structures, sharing two atoms that are not directly connected to each other.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl include, but are not limited to:
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner.
  • aryl includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferred aryl groups are C 6 -C 10 aryl groups, more preferred aryl groups are phenyl and naphthyl, and most preferred are phenyl groups.
  • Aryl groups may be substituted or unsubstituted.
  • the "aryl” can be fused with a heteroaryl, heterocyclyl or cycloalkyl group, where an aryl ring is attached to the parent structure. Non-limiting examples include, but are not limited to:
  • Heteroaryl refers to an aromatic 5 to 6 membered monocyclic ring or 9 to 10 membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzobis Oxolenyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl,
  • Heteroaryl groups may be optionally substituted or unsubstituted.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring.
  • Non-limiting examples include, but are not limited to:
  • Alkoxy refers to the group (alkyl-O-). Among them, alkyl group is as defined in this article. C 1 -C 6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.
  • Haloalkyl refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as described herein.
  • haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.
  • Halogen refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO 2 .
  • Benzyl refers to -CH2 -phenyl.
  • Carboxy refers to -C(O)OH.
  • Alcohol refers to -C(O) CH3 or Ac.
  • Carboxylate group refers to -C(O)O (alkyl) or (cycloalkyl), where alkyl and cycloalkyl are as defined above.
  • halo or halogen group is defined to include F, Cl, Br or I.
  • substituted means that one or more (e.g., one, two, three or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is present in the case of normal valence and the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the substituent lists, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together Optional substituent substitutions of choice. If the nitrogen of a substituent is described as optionally substituted with one or more of the substituents listed, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected as optional. substitution of substituents.
  • each substituent is selected independently of the other.
  • each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.
  • the point of attachment of a substituent may be from any suitable position on the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of the present invention except that one or more atoms are substituted with the same atomic number but an atomic mass or mass number different from the atomic mass that predominates in nature. or atomic substitution of mass number.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g. , 11C , 13C , and 14C ) ; Isotopes of chlorine (e.g. 36 Cl); Isotopes of fluorine (e.g.
  • Isotopes of iodine e.g. 123 I and 125 I
  • Isotopes of nitrogen e.g. 13 N and 15 N
  • Isotopes of oxygen e.g. 15 O , 17 O and 18 O
  • isotopes of phosphorus such as 32 P
  • isotopes of sulfur such as 35 S.
  • Certain isotopically labeled compounds of the invention eg, those incorporating radioactive isotopes
  • the radioactive isotopes tritium (i.e. 3H ) and carbon-14 (i.e. 14C) are particularly useful for this purpose because they are easy to incorporate and detect.
  • positron emitting isotopes eg 11 C, 18 F, 15 O and 13 N
  • PTT positron emission tomography
  • Isotopically labeled compounds of the invention may be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using appropriate isotopically labeled reagents in place of the previously employed non-labeled reagents.
  • Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, for example, D2O , acetone- d6 or DMSO- d6 .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art is able to determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • the term "pediatric patient” as used herein refers to a patient who is under 16 years of age at the time of diagnosis or treatment.
  • the word "child” can also be divided into the following subcategories: newborn (from birth to the first month of life); infant (1 month to 2 years old); child (2 years to 12 years old); adolescent (12 years old) to 21 years of age (up to but not including the 22nd birthday)).
  • Berhman RE Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Edition. New York: McGrow-Hill, 2002; and Avery MD, 1st LR. Pediatric Medicine, 2nd ed. Baltimore: Williams &Wilkins; 1994.
  • an "effective amount" of a compound refers to an amount sufficient to negatively regulate or agonize the formation of A-synuclein aggregates.
  • a "therapeutically effective dose" of a compound refers to an amount sufficient to ameliorate or reduce symptoms in some manner, halt or reverse disease progression, or negatively regulate or stimulate the formation of A-synuclein aggregates. This dose can be taken as a single dose or as part of a regimen to be effective.
  • treatment means to ameliorate or otherwise modify in any manner the symptoms or pathology of a patient's condition, disorder, or disease.
  • amelioration of the symptoms of a particular disease by the use of a particular compound or pharmaceutical composition means any reduction, whether permanent or temporary, attributable to or associated with the use of the composition sexual, permanent or temporary.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist as different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention. part.
  • Diastereomers can be separated into individual diastereomers on the basis of their physical and chemical differences by methods such as chromatography, crystallization, distillation or sublimation.
  • Enantiomers can be converted into diastereomeric mixtures by separation of chiral isomeric mixtures by reaction with a suitable optically active compound, such as a chiral auxiliary agent such as a chiral alcohol or Mosher's acid chloride. , separate diastereomers, and convert individual diastereomers into the corresponding pure enantiomers.
  • a suitable optically active compound such as a chiral auxiliary agent such as a chiral alcohol or Mosher's acid chloride.
  • the intermediates and compounds of the invention may also exist in different tautomeric forms, and all such forms are included within the scope of the invention.
  • racemic mixture A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during a chemical reaction.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomers that lacks optical activity.
  • Tautomers or “tautomeric forms” refer to isomers of structures with different energies that can be converted into each other through a low energy barrier.
  • proton tautomers i.e., proton-shifting tautomers
  • tautomers by proton migration such as keto-enol and imine-enamine isomerizations.
  • Valence (valency) tautomers include recombination of bonding electrons.
  • the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): for example, the R, S configuration containing an asymmetric center, Double bond (Z), (E) isomers, and (Z), (E) conformational isomers. Therefore, individual stereochemical isomers or mixtures of enantiomers, diastereomers, or geometric isomers of the compounds of the present invention are within the scope of the present invention.
  • “Pharmaceutically acceptable salts” refer to salts of compounds of the present invention that are safe and effective when administered to humans or animals. Salts of the compounds can be obtained by using a sufficient amount of base or acid in pure solution or in a suitable inert solution to obtain the corresponding addition salts.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts, etc.
  • Pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts.
  • the inorganic acids and organic acids include Hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, butadione, Phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid and methanesulfonic acid, etc. (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)).
  • Solid lines may be used in this article solid wedge or virtual wedge Draw the chemical bonds of the compounds of the invention.
  • the use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, a specific enantiomer, a racemic mixture, etc.).
  • the use of solid or imaginary wedges to depict bonds to asymmetric carbon atoms is intended to demonstrate that the stereoisomers shown exist. When present in a racemic mixture, solid and imaginary wedges are used to define relative stereochemistry rather than absolute stereochemistry.
  • the compounds of the present invention are intended to exist as stereoisomers (which includes cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, They exist in the form of geometric isomers, rotamers, conformational isomers, atropisomers and mixtures thereof).
  • the compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (eg, racemic mixtures and pairs of diastereoisomers).
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.
  • compositions of the present invention may exist in free form for therapeutic use, or, where appropriate, as pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, chelates, complexes, clathrates or Prodrugs, upon their administration to a patient in need thereof, can directly or indirectly provide a compound of the invention or a metabolite or residue thereof. Therefore, when reference is made herein to "a compound of the invention", it is also intended to encompass the various derivative forms of the compound described above.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof, including but not limited to salts containing hydrogen bonds or coordination bonds.
  • Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate , citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphoric acid Salt, hypobenate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleic acid Salt, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmi
  • Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinate salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, Potassium salt, sodium salt, tromethamine salt and zinc salt.
  • esters means esters derived from compounds of each general formula herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the present invention). compound).
  • the compounds of the present invention may themselves be esters.
  • the compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise as structural elements of the crystal lattice of the compounds a polar solvent, in particular such as water, methanol or ethanol.
  • a polar solvent in particular such as water, methanol or ethanol.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • nitrogen-containing heterocycles are capable of forming N-oxides; those skilled in the art will recognize that nitrogen-containing heterocycles are capable of forming N-oxides. Nitrogen-containing heterocycle. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocyclic and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyldioxirane are used to oxidize heterocyclic and tertiary amines.
  • MCPBA m-chloroperoxybenzoic acid
  • hydrogen peroxide alkyl Hydroperoxides
  • alkyl Hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate and dioxirane such as dimethyldioxirane
  • metabolites of the compounds of the invention ie substances formed in the body upon administration of the compounds of the invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound.
  • the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce metabolites thereof.
  • the invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity when administered into or onto the body. can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound that are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs of the present invention may be prepared, for example, by using certain moieties known to those skilled in the art as "pro-moiety" (e.g. as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)) Prepared by substituting appropriate functional groups present in the compounds of the invention.
  • pro-moiety e.g. as described in "Design of Prodrugs", H. Bund
  • the invention also encompasses compounds of the invention containing protecting groups.
  • protecting groups In any process for preparing the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecules, thereby forming chemically protected forms of the compounds of the invention. This can be accomplished by conventional protecting groups, for example, those described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference.
  • the protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
  • Typical compounds of the present invention include but are not limited to the compounds in the table above.
  • the naming of the compounds in the present invention follows systematic naming, or is named using ChemDraw software.
  • bistetrahydrofuran compound represented by the general formula 1 of the present invention can be obtained by a known method, for example, synthesized by a known organic synthesis method.
  • An exemplary synthetic route is given below, but those in the art can also obtain it through other known methods.
  • Compound D1 (commonly known as forsythin) and compound D2 (commonly known as sesamin) in the examples described later in the present invention are common natural products, which are also extracted and isolated from the commonly used traditional Chinese medicines Xinyi, Magnolia officinalis, Forsythia suspensa, Eucommia ulmoides, and sesame. such compounds.
  • the biological activities of this type of compounds have been reported one after another, including anti-tumor, liver protection, antioxidant, anti-inflammatory, and immunosuppression.
  • Compound D1 and compound D2 are commercially available.
  • compositions and methods of treatment are provided.
  • the invention provides a pharmaceutical composition, which contains an effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, polymorph, solvate, N-oxidation thereof substances, isotope-labeled compounds, metabolites, chelates, complexes, inclusion compounds or prodrugs, and pharmaceutically acceptable carriers.
  • the pharmaceutical composition is preferably a solid preparation, semi-solid preparation, liquid preparation or Gaseous preparations.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle that is administered with a therapeutic agent and is suitable for contact with humans and/or within the scope of reasonable medical judgment. Tissues from other animals without undue toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that may 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, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous glucose and glycerol solutions may also be used as liquid carriers, particularly for injections.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol etc.
  • the compositions may also, if desired, contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents.
  • 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 described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the invention may act systemically and/or locally.
  • they may be administered by a suitable route, for example by injection (eg intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, transdermal Nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.
  • compositions of the present invention can be administered in suitable dosage forms.
  • the dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, and aqueous suspensions. , injectable solutions, elixirs, syrups.
  • the pharmaceutical composition of the present invention can be used to prevent and/or treat neurodegenerative diseases.
  • it can also be used at the same time selected from the group consisting of Madopar, Tasoteda, Senfro, Xining, and Anxiety. Medications in selegiline, rasagiline, and tolcapone.
  • the pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutically acceptable carrier or excipient include (but are not limited to): one or more of saline, buffer, glucose, water, glycerol, ethanol, powder, etc.
  • the drug formulation should match the mode of administration.
  • the pharmaceutical composition of the present invention can be prepared in the form of an injection, for example, prepared by conventional methods using physiological saline or an aqueous solution containing glucose and other adjuvants.
  • Pharmaceutical compositions, such as tablets and capsules can be prepared by conventional methods.
  • Pharmaceutical compositions such as injections, solutions, tablets and capsules are preferably manufactured under sterile conditions.
  • the pharmaceutical composition of the present invention can also be made into powder for aerosol inhalation.
  • the dosage of the active ingredient is a therapeutically effective amount, for example, about 1 microgram/kg body weight to about 50 mg/kg body weight per day; preferably, about 5 micrograms/kg body weight to about 10 mg/kg body weight; further preferably, About 10 micrograms/kg body weight - about 5 mg/kg body weight. Additionally, the compounds of the present invention may be used with other therapeutic agents.
  • composition of the present invention can be administered to desired subjects (such as humans and non-human mammals) by conventional means.
  • desired administration methods include (but are not limited to): oral administration, injection, aerosol inhalation, etc.
  • a safe and effective amount of the drug is administered to the mammal, wherein the safe and effective amount is usually at least about 10 micrograms/kg of body weight, and in most cases no more than about 50 mg/kg of body weight, preferably , the dose is about 10 micrograms/kg body weight - about 20 mg/kg body weight.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
  • an "effective amount” of a compound refers to an amount of a compound that, when administered, alleviates to a certain extent one or more symptoms of the condition being treated.
  • an "effective amount” of a compound refers to an amount sufficient to negatively regulate or promote the formation of A-synuclein aggregates.
  • a “therapeutically effective dose” of a compound refers to an amount sufficient to ameliorate or reduce symptoms in some manner, halt or reverse disease progression, or negatively regulate or stimulate the formation of A-synuclein aggregates. This dose can be taken as a single dose or as part of a regimen to be effective.
  • Dosage regimens can be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dosage may be proportionally reduced or increased as the exigencies of the therapeutic situation indicate. It is noted that dosage values may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that, for any particular individual, specific dosage regimens should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.
  • treatment means to ameliorate or otherwise modify in any manner the symptoms or pathology of a patient's condition, disorder, or disease.
  • aboration of the symptoms of a particular disease by the use of a particular compound or pharmaceutical composition means any reduction, whether permanent or temporary, attributable to or associated with the use of the composition sexual, permanent or temporary.
  • “Individual” as used herein includes humans or non-human animals.
  • Exemplary human subjects include human subjects (referred to as patients) suffering from a disease, such as those described herein, or normal subjects.
  • non-human animals include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (such as sheep, dogs , cats, cows, pigs, etc.).
  • compositions of the present invention may also include one or more additional therapeutic or prophylactic agents.
  • Figure 1 shows the results of cell viability testing and Gaussia luciferase activity testing results
  • Figure 2 is a diagram showing the effect of compound 03A10 on preventing ⁇ -synuclein protein aggregation
  • Figure 3 is a diagram showing that compound 03A10 improves the damage effect of ⁇ -synuclein protein aggregates on cells;
  • Figure 4 is a diagram showing that compound 03A10 improves the ROS damage effect of ⁇ -synuclein protein aggregates on cells;
  • Figure 5 shows that 03A10 shortens the downswing time of MPTP/p PD mice
  • Figure 6 shows that 03A10 increases the rotarod residence time of MPTP/p PD mice
  • Figure 7 shows that 03A10 improves the damage of dopamine neurons in the substantia nigra and striatum of MPTP/p PD mice.
  • the mass spectrum was measured using an LC/MS instrument, and the ionization method was ESI.
  • High performance liquid chromatography model Agilent 1260, Thermo Fisher U3000; chromatographic column model: Waters xbrige C18 (4.6*150mm, 3.5 ⁇ m); mobile phase: A: ACN, B: Water (0.1% H 3 PO 4 ); Flow rate: 1.0mL/min; Gradient: 5%A for 1min, increase to 20%A within 4min, increase to 80%A within 8min, 80%A for 2min, back to 5%A within 0.1min; Wavelength: 220nm; Column temperature oven: 35°C.
  • Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.2mm-0.3mm.
  • the specifications used for thin layer chromatography separation and purification products are 0.4mm. -0.5mm.
  • the hydrogen atmosphere refers to the reaction bottle connected to a hydrogen balloon with a volume of about 1L.
  • the solution in the reaction refers to an aqueous solution.
  • the reaction temperature is room temperature, which is 20°C-30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the developing agent used in the reaction, the column chromatography eluent system or the thin layer chromatography developing agent system used to purify the compound include: A: Petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents can also be added Adjust, such as acetic acid or triethylamine, etc.
  • Sesamin (717mg, 2.03mmol) was dissolved in anhydrous benzene (30ml) at room temperature, 1.35g of lead (IV) acetate (3.04mmol, 1.5eq.,) was added, and the temperature was raised to 80°C overnight. After the reaction solution was cooled to room temperature, 75 ml of ethyl acetate was added to dilute it. The diluted solution was washed three times with distilled water (50 ml) and then once with saturated brine (50 ml). The organic phase was dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the organic solvent.
  • Example 3 Discovery of the activity of natural and synthetic ditetrahydrofuran-type lignans in preventing ⁇ -synuclein aggregation
  • This experiment used the luciferase protein fragment complementation analysis method to remove the secretion sequence of luciferase so that the luciferase is only expressed within the cell.
  • This artificially modified luciferase Human Gaussiaprinceps Luciferase
  • As a reporter protein its N-terminus and C-terminus are fused to ⁇ -syn protein respectively, and the ⁇ -syn aggregation in cells is determined by detecting luciferase activity.
  • SH-SY5Y human neuroblastoma cells were purchased from ATCC;
  • Human neuroblastoma SH-SY5Y cells (purchased from ATCC) were cultured in MEM/F-12 medium containing 10% FBS, and incubated and grown in a constant temperature incubator at 37°C and 5% CO2 .
  • SH-SY5Y cells were seeded in a 96-well plate at a density of 1 ⁇ 10 5 cells/ml, placed in a 37°C, 5% CO 2 cell culture incubator, and incubated for 24 hours until the cells completely adhered to the wall.
  • the medium was changed for plasmid transfection.
  • the dyeing procedure was carried out according to the instructions of Fugene HD (Promega). After incubation in the incubator for 12 hours, add 10 ⁇ M of the test compound to each well, continue administration and culture for 24 hours, and then detect the biological activity of Gaussia luciferase in the cells according to the instructions of the Renilla Luciferase Assay System (Promega), and normalize the results. deal with.
  • Cell viability was determined using the tetramethylazolium salt (Thiazoly Blue, MTT) detection method: add MTT (final concentration: 0.5 mg/mL) to the cells, continue culturing at 37°C for 4 hours, then aspirate the supernatant, and add dimethyl oxide. sulfone (DMSO), place it on a shaker, and after the crystals are fully dissolved, measure the absorbance value at 595nm with a NovoStar microplate reader. Cell viability is calculated as the percentage of the absorbance value of cells in the treatment group relative to the absorbance value of cells in the control group. Three duplicate wells were made for each experimental treatment group, and the experiments were repeated at least three times independently.
  • MTT tetramethylazolium salt
  • Example 4 Compound 03A10 prevents the increase of large molecular weight aggregate proteins and reduces THT readings
  • Thioflavin was first reported in 1959. It is a fluorescent marker commonly used to detect protein aggregates. It can bind to the ⁇ -sheets that appear during the protein aggregation process and measure the fluorescence value in a microplate reader. The degree of aggregation of the reaction protein and the absorption and emission wavelengths of the fluorescent dye are 450nm and 485nm respectively. ThT experiment was used to explore whether 03A10 can prevent the aggregation of ⁇ -synuclein protein.
  • ThT was purchased from sigma
  • the ⁇ -synuclein protein solution helps to form fibrous aggregates as the polymerization treatment time (37°C, 1000rpm incubation) increases.
  • the results show that compound 03A10 can reduce the aggregation of ⁇ -synuclein at a concentration of 10 ⁇ M.
  • Example 5 Electron microscopy results show that compound 03A10 prevents the increase of large molecular weight aggregate proteins
  • Transmission electron microscopy uses high-energy electron beams as the illumination source and uses the electron beams transmitted from the lower surface of the sample to image. It has high resolution and is often used to observe protein samples, nanomaterials, etc.
  • the electron microscope sample was negatively stained.
  • the protein sample was dropped on the copper grid and fixed, it was blotted dry with filter paper.
  • 10 ⁇ L of uranium formate dye solution was added dropwise. Aspirate while adding, and then a drop of uranium formate dye solution was added. , let it stand for 1 minute and then blot it dry with filter paper. After drying the copper mesh, carefully place it in the sample rod. After checking that the sample rod has no visible impurities such as lint and hair, push it into the sample stage and wait until the system is fully evacuated before proceeding. , observe the protein sample.
  • 120kv transmission electron microscope is commonly used to detect negatively stained protein samples and observe protein morphology. After incubating ⁇ -synuclein protein solution and 10 ⁇ M compound 03A10 in a metal bath for 72 hours (37°C, 1000 rpm), take an appropriate amount of protein samples for negative staining. After sample preparation, it was observed under a transmission electron microscope that the protein in the blank control group appeared in the form of fibrillar aggregation, while the protein in the histone co-incubated with Compound 03A10 (10 ⁇ M) appeared in the form of non-fiber aggregation ( Figure 2B).
  • Example 6 Compound 03A10 improves cell damage caused by fiber aggregates
  • PC12 cells were purchased from ATCC, and a PC12 stably transfected cell line overexpressing ⁇ -synuclein protein was constructed and set aside for use.
  • Thiazolyl blue is a yellow powdered chemical reagent commonly used to detect the survival of living cells.
  • the succinate dehydrogenase in the mitochondria of living cells can reduce exogenous MTT into water-insoluble blue-violet crystals - formazan. oxidized and deposited in cells.
  • For the treated 96-well plate cells add MTT with a final concentration of 0.5mg/ml to each well. After continuing to culture in the cell culture incubator for 4 hours, carefully remove the supernatant, add 100ul DMSO, shake and mix, and use PerkinElmer The multi-well plate instrument measures the absorbance value at a wavelength of 490 nm and calculates the cell survival rate. There were 3 replicate wells for each treatment group, and the experiment was repeated 3 times.
  • B. MTT detection after co-treatment of compound 03A10 and protein aggregates. Data are expressed as mean ⁇ SEM, and the number of independent repeated experiments is n 3. *p ⁇ 0.05, **p ⁇ 0.01.
  • Example 7 Compound 03A10 improves oxidative stress caused by fiber aggregates and subsequently causes cell damage.
  • PC12 cells were purchased from ATCC, and a PC12 stably transfected cell line overexpressing ⁇ -synuclein protein was constructed and set aside for use.
  • Reactive oxygen species (Reactive oxygen assay, ROS) is detected through the fluorescent probe DCFH-DA.
  • the specific operation follows the fluorescent probe DCFH-DA (Thermo Fisher scientific), which is briefly described as follows: Add the DCFH-DA probe into the cells to be detected. , after continuing to culture in the incubator for 30 minutes, wash the cells twice with PBS, collect the cells after digestion, filter and detect with FACS Calibur flow cytometer, collect the data and analyze it with FlowJo software.
  • Example 8 03A10 improves the behavioral disorders of PD animals and reduces the damage of dopamine neurons in the substantia nigra of the midbrain.
  • MPTP can cause the death of dopaminergic neurons in the midbrain and decrease motor coordination. It is a good modeling agent for simulating PD patients. MPTP combined with probenecid (MPTP/p) chronic PD model can slow down the metabolism of MPTP in vivo and show more pathological characteristics, such as neuroinflammation, ⁇ -synuclein deposition, abnormal increase in extracellular glutamate, etc. . This model explores PD-like symptoms in mice through rotating rod experiments, pole climbing experiments, etc.
  • mice The animal model of MPTP/p-induced Parkinson's disease uses male C57/BL6J mice, purchased from Shanghai Slack Experimental Animal Co., Ltd. The mice weigh about 25g.
  • the animal feeding conditions are as follows: the maximum breeding density of male mice is 6 per cage, alternating 12 hours of light (7:00-19:00) and 12 hours of darkness (19:00-7:00 the next day) every day, and the feeding temperature is 22 ⁇ 2°C, humidity 35 ⁇ 5%, and provide sufficient food and clean drinking water. After raising for more than 7 days, they were used for experiments.
  • the experimental use and operation have been approved by the Experimental Animal Welfare and Ethics Committee of Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and their operating regulations are strictly followed.
  • C57/BL6J mice were purchased from Beijing Huafukang Biotechnology Co., Ltd. The mice were randomly divided into 5 groups: saline control group (control), MPTP/probenecid (MPTP/p) model group (model), 03A10 0.3mg/kg dosage group, 03A101mg/kg dosage group, 03A10 5mg/kg dosage group. Modeling was done every 3.5 days, for a total of 10 times (5 weeks). 100 mg/kg probenecid was dissolved in 5% sodium bicarbonate. The model group was injected intraperitoneally with probenecid, and the control group was intraperitoneally injected with normal saline.
  • the model group was injected subcutaneously with MPTP, and the control group was injected subcutaneously with normal saline.
  • the control group and model group were given physiological saline by gavage, and the medication group was given different concentrations of 03A10 by gavage.
  • the rod-climbing experiment and rod-rotating experiment were conducted to conduct behavioral testing.
  • the rotarod test is widely used to assess motor coordination and ability.
  • MPTP/p chronic mouse model behavioral testing was conducted after the 5th week of modeling. Place the mouse on the rotary rod. Before modeling, train the mouse at a rotation speed of 5-30 rpm for 200 seconds every day for three days. During the test, record the mouse residence time on the rod at a rotation speed of 5-30 rpm for a total time of 200 seconds. If it exceeds 200 seconds, the 200s record. Each mouse was tested three times, with an interval of no less than 0.5 h.
  • the pole test is used to detect bradykinesia, a typical behavioral symptom in PD. Mice were trained to climb the pole three times a day for three days before the start of drug administration. Behavioral testing was conducted after the 5th week of modeling. Gently place the mouse head upward on the top of a rough rod (diameter 10 mm, height 55 cm). The time from when the mouse moves its head upward to when its head is completely downward is recorded as the latency period (T-turn), and the time from when the mouse moves downward to when all limbs reach the bottom of the rod is recorded as the down-lever time (T-LA). If it exceeds 30 seconds, it will be counted as 30 seconds. Recording, each mouse was tested three times.
  • T-turn latency period
  • T-LA down-lever time
  • Tyrosine hydroxylase (TH) immunohistochemistry detects the loss of dopaminergic neurons and nerve fibers
  • mice were anesthetized with Serta, and then perfused with 4% paraformaldehyde and the brains were removed.
  • the brain tissue was post-fixed with 4% paraformaldehyde for 24 hours, and then the sample was transferred to 30% sucrose solution to dehydrate until the sample sank to the bottom.
  • Coronal sections were made in a -20°C freezing microtome.
  • the thickness of the mouse brain section was 20 ⁇ m.
  • the primary antibody was monoclonal mouse anti-TH (1:1000, CHEMICON) and incubated at room temperature for 2.5 hours. After washing three times with TBST, HPR-labeled secondary antibody was used and incubated at room temperature for 1 hour. DAB color development, ethanol gradient dehydration, xylene transparency, and neutral gum sealing.
  • Result analysis Image-pro plus software was used to analyze the stained sections.
  • the total optical density of TH positive staining in the substantia nigra was used as the parameter for the number of dopanergic positive neurons in the substantia nigra.
  • the average optical density of TH positive staining in the striatum was used as the parameter for the number of striatal TH positive neurons.
  • Statistics were performed on the parameters of the number of dopanergic nerve fibers in the body.
  • mice in the control group are expressed as mean ⁇ SEM
  • the present invention uses the above examples to illustrate the use of a ditetrahydrofuran compound of the present invention as an ⁇ -synuclein aggregate formation inhibitor, a pharmaceutical composition containing the same, and the treatment of Parkinson's and other neurodegeneration.
  • Disease agents but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented.
  • Those skilled in the art should understand that any improvements to the present invention, equivalent replacement of raw materials of the product of the present invention, addition of auxiliary ingredients, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

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Abstract

本发明提供了以下化合物（I）或者其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，以及含有本发明的化合物的药物组合物，还提供本发明化合物的α-突触核蛋白聚集体形成抑制剂的用途，以及在减轻和/或消除PD（帕金森症）方面的应用，还提供本发明化合物在制备神经退行性疾病中的应用，本发明还提供与α-突触核蛋白聚集体形成相关疾病的治疗方法。

Description

双四氢呋喃类化合物作为α-突触核蛋白聚集体形成抑制剂的用途、包含其的药物组合物 技术领域
本发明属于药物化学领域，更具体而言，涉及双四氢呋喃类化合物作为α-突触核蛋白(α-synuclein)聚集体形成抑制剂的用途、包含其的药物组合物，以及治疗帕金森和其他神经退行性疾病的药物。
背景技术
帕金森病(Parkinson`s disease,PD)是一类多发于中老年的神经退行性疾病，临床症状主要以运动障碍为主，分为两类：一类是震颤、肌肉强直、不自主运动等在健康人中很少出现的行为；另一类为运动迟缓和姿势反射受损。运动迟缓导致行走困难，缺乏面部表情(面具脸)，姿势反射受损则会使患者难以维持正常的姿态，站立困难。进一步恶化则会导致语言功能受损，甚至咀嚼，吞咽困难，严重影响患者的生活质量。随着人口平均寿命的延长和老龄化的出现，PD的发病率呈明显上升趋势。据统计，在发达国家，PD的发病率为0.3％，60岁以上人群发病率上升到1％，80岁以上高达4％，预计至2050年帕金森病的发病数将增至目前的一倍。根据2016年的统计数据，全球现有PD病人约450万，而我国已超过220万，全世界一半的PD病人在中国。因此，对PD的防治刻不容缓。目前针对帕金森病的治疗药物主要是左旋多巴、多巴胺再摄取抑制剂以及一系列酶抑制剂。这些药物主要针对PD的运动症状，对于非运动症状没有作用，并且不能阻止病情的恶化。因此研制新一代的PD治疗药物有巨大的社会意义和经济效益。
PD是世界上第二大神经退行性疾病，临床上以路易小体形成和黑质致密部多巴胺能神经元丢失作为PD确诊的重要指征。当病人出现典型的运动症状时，黑质致密部(SNpc)多巴胺能神经元已丢失60％以上，而壳核处多巴胺能神经元也已减少80％，绝大多数神经元的死亡丧失了疾病治疗的最佳治疗窗。编码α-Synuclein(α-突触共核蛋白)的基因SNCA是第一个发现与PD相关的基因。α-突触核蛋白是一个随机螺旋伸展的无序蛋白，天然构象一般是稳定状态的单体和由其氮末端区的KTKEGV重复序列介导形成的四聚物。α-突触核蛋白能够在多种不同的构象之间转变，包括单体、四聚体、较高水平的寡聚物(可溶性构象)、纤维(以β片层构象为特征的高度有序的不溶性构象)和聚集体，α-突触核蛋白蛋白错误折叠引起神经系统环境紊乱，损伤多巴胺能神经元，促进PD的发生发展。病理状态下，过多的α-突触核蛋白以及它的寡聚体等聚集体分布在细胞胞体以及突起上，并损伤细胞功能。
α-突触核蛋白聚集体是路易小体(Lewy bodies)核心成分之一，在PD的早期发生、发展过程中发挥重要作用，它的突变和过度表达被认为是PD发病的驱动因素。近几年的研究发现α-Synuclein异常聚集出现早于PD典型症状显现十至十五年，阻断α-Synuclein的聚集应能减缓PD病程发展和改善症状。因此，抑制α-突触核蛋白聚集体的形成是当前PD药物的热点研究方向之一。在PD发生形成的过程中，α-突触核蛋白的聚集是一个关键因素，减少α-突触核蛋白的聚集形成能够延缓PD病程。
发明内容
为开发治疗帕金森和其他神经退行性疾病的新药，发明人进行了深入研究，结果发现如下述式(I)所示的双四氢呋喃类化合物及其衍生物具α-突触核蛋白聚集体形成抑制剂活性，该用途意味着其治疗帕金森和其他神经退行性疾病用途。
发明人采用了基于萤光素酶和荧光蛋白片段互补分析方法，根据已有文献报道，将Gaussia萤光素酶或者Venus荧光蛋白拆分成两个蛋白片段，分别结合A53T突变型α-突触核蛋白，探究具有不同取代的双四氢呋喃型木脂素类化合物(具体结构如图1所示)对于α-突触核蛋白寡聚体解聚或者降解的作用，发现了一类具有该类活性的化合物，具体而言，本发明提供式(I)所示的双四氢呋喃类化合物或者其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药作为α-突触核蛋白聚集体形成抑制剂的用途，
式(I)中，环A和环B分别独立地表示取代或未取代的C6-10芳香环、或者取代或未取代的C5-14杂芳香环，优选苯环、吡啶环、吡咯环；
X1和X2分别独立地为NRC、O或S，优选为O或S，更优选为O，
各RC独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基或者C6-12芳烷基，优选为H、C1-6烷基；
Ra和Rb各自独立地为选自卤素、氨基、氰基、硝基、C1-6烷基、C1-6烷氧基、饱和或部分不饱和的C3-6环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、葡萄糖基、-C(＝O)Rd、-OC(＝O)Rd、-C(＝O)ORd、-ORd、-SRd、-S(＝O)Rd、-S(＝O)2Rd、-S(＝O)2N(Rd)2、-N(Rd)2、-C(＝O)N(Rd)2、-NRd-C(＝O)Rd、-NRd-C(＝O)ORd、-NRd-S(＝O)2-Rd、-NRd-C(＝O)-N(Rd)2、-C1-6亚烷基-N(Rd)2、-C1-6亚烷基-ORd、-C1-6亚烯基-OR8和-O-C1-6亚烷基-N(R8)2，m和n分别独立地为1～4的整数，优选为2～3的整数，进一步优选为2；条件是，Ra中至少2个为-ORd基团，Rb中至少2个为-ORd基团，
各Rd独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、C5-14杂芳基或者C6-12芳烷基，多个Rd之间可以连接并与构成环A的原子共同形成环，条件是多个Rd中至少一个为H，
Y和Z分别独立地表示选自H、卤素、NH2、OH、SH、C1-6烷基取代氨基、取代或未取代的C1-10的脂肪族烃基、取代或未取代的饱和或部分不饱和的C3-10的杂环基、取代或未取代的C6-10芳基、或者取代或未取代的C5-14的杂芳基、-C(＝O)RX、-OC(＝O)RX、-C(＝O)ORX、-ORX、-SRX、-S(＝O)RX、-S(＝O)2RX、-S(＝O)2N(RX)2、-N(RX)2、-C(＝O)N(RX)2、-NRX-C(＝O)RX、-NRX-C(＝O)ORX、-NRX-S(＝O)2-RX、C(＝O)-N(RX)2、-C1-6亚烷基-N(RX)2、-C1-6亚烷基-ORX、-C1-6亚烯基-ORX和-O-C1-6亚烷基-N(RX)2；其中，RX为H、胍基、C1～C6烷基、饱和或部分不饱和的C 3-6环烃基、饱和或部分不饱和的3-10元杂环基或者C6-10芳基；Y和Z分别独立地优选为H、卤素、甲基、乙基、OH、甲氧基；
此处“取代或未取代”中的“取代”是指任选地被1-3个卤素、C1-C3烷基、C1-C3烷氧基、C1-C6环烷基、C1-C6环烷氧基或C1-C3卤代烷基取代、氰基、硝基、羟基、氨基、氧膦基、磺酰基、磺酰胺基所取代，“—”划过的环结构的表达方式，表示连接位点于该环结构上任意能够成键的位置。
在优选的实施方式中，所述化合物具有下述式(II)的结构，
在式II中，X1和X2表达的意思与权利要求1中相同，
R1～R4独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、C5-14杂芳基或者C6-12芳烷基，优选为H、C1-6烷基，R1和R2可以连接并与其连接的苯环中的原子共同形成环，R3和R4可以连接并与其连接的苯环中的原子共同形成环，
R5、R6各自独立地为H、羟基、饱和或部分不饱和的C1-6烃基、饱和或部分不饱和的C1-6烃基-O-、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的C3-10环烃基-O-、饱和或部分不饱和的C3-10环烃基-NH-、取代的饱和或部分不饱和的C1-6烃基、取代的饱和或部分不饱和的C3-10环烃基中的一种，优选为H、羟基，
Y和Z分别独立地表示选自H、卤素、NH2、OH、SH、C1-6烷基取代氨基、取代或未取代的C1-10的脂肪族烃基、取代或未取代的饱和或部分不饱和的C3-10的杂环基、取代或未取代的C6-10芳基、或者取代或未取代的C5-14的杂芳基、-C(＝O)RX、-OC(＝O)RX、-C(＝O)ORX、-ORX、-SRX、-S(＝O)RX、-S(＝O)2RX、-S(＝O)2N(RX)2、-N(RX)2、-C(＝O)N(RX)2、-NRX-C(＝O)RX、-NRX-C(＝O)ORX、-NRX-S(＝O)2-RX、C(＝O)-N(RX)2、-C1-6亚烷基-N(RX)2、-C1-6亚烷基-ORX、-C1-6亚烯基-ORX和-O-C1-6亚烷基-N(RX)2；其中，RX为H、胍基、C1～C6烷基、饱和或部分不饱和的C 3-6环烃基、饱和或部分不饱和的3-10元杂环基或者C6-10芳基；Y和Z分别独立地优选为H、卤素、甲基、乙基、OH、甲氧基；
此处“取代或未取代”中的“取代”是指任选地被1-3个卤素、C1-C3烷基、C1-C3烷氧基、C1-C6环烷基、C1-C6环烷氧基或C1-C3卤代烷基取代、氰基、硝基、羟基、氨基、氧膦基、磺酰基、磺酰胺基所取代，“—”划过的环结构的表达方式，表示连接位点于该环结构上任意能够成键的位置。
在优选的实施方式中，所述化合物具有下述式(III)所示的结构，
在式(III)中，R1～R4独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基，R1和R2可以连接并与其连接的苯环中的原子共同形成环，R3和R4可以连接并与其连接的苯环中的原子共同形成环，
R5、R6各自独立地为H、羟基、饱和或部分不饱和的C1-6烃基、饱和或部分不饱和的C1-6烃基-O-、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的C3-10环烃基-O-，优选为H。
在优选的实施方式中，R1～R4独立地选自H、甲基、乙基、丙基，R1和R2可以连接成为亚甲基、亚乙基，R3和R4可以连接成为亚甲基、亚乙基，
R5、R6各自独立地为H、羟基、甲氧基、乙氧基。
在优选的实施方式中，R1～R4中的三个以上为H。
在优选的实施方式中，所述化合物选自以下具体化合物，但是并非限于以下化合物：
本发明还提供式(I)所示的化合物在制备治疗帕金森疾病的药物中的应用，及式(I)所示的化合物具有抗帕金森活性，该活性可能与作为α-突触核蛋白聚集体形成抑制剂的活性直接相关，也可能基于其他独立的机理，式(I)所示的化合物具有抗帕金森活性不依赖于本发明中的机理推测的正确性。
式(I)所示的化合物在制备治疗帕金森疾病的药物中的应用及式(I)所示的化合物具有抗帕金森活性的优选实施方式与上述作为α-突触核蛋白聚集体形成抑制剂的优选实施方式也相同。
本发明还提供(I)所示的化合物本身，(I)所示的化合物的优选实施方式，也与上述相同。
本发明还提供一种，药物组合物，其包含预防或治疗有效量的上述本发明的化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，以及药学上可接受的载体，所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。
本发明的优选实施方式中，所述的药物组合物的剂型为口服剂型或注射剂，所述口服剂型包括片剂、胶囊剂、膜剂、颗粒剂。
本发明一种用于治疗神经退行性疾病的方法，包括给予需要此治疗的人有效量的本发明的化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药或者上述本发明的药物组合物。
本发明的化合物在结构上具有独创性，本发明的化合物(I)可以在制备与α-突触核蛋白聚集体形成相关疾病药物中应用，也可以在制备治疗帕金森和其他神经退行性疾病药物中应用，作为其他神经退行性疾病阿尔茨海默病(AD)、亨廷顿病(HD)、肌萎缩性侧索硬化(ALS)、不同类型脊髓小脑共济失调(SCA)、Pick病
以下对本发明的各要素进行更加详细的说明。
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
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。
如本文中所使用，术语“亚烷基”表示饱和二价烃基，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。
如本文中所使用，术语“烷基”定义为线性或支化饱和脂肪族烃。在一些实施方案中，烷基具有1至12个，例如1至6个碳原子。例如，如本文中所使用，术语“C 1-6烷基”指1至6个碳原子的线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基)，其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CH2F、CHF2、CF3、CCl3、C2F5、C2Cl5、CH2CF3、CH2Cl或-CH2CH2CF3等)。术语“C1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
如本文中所使用，术语“烯基”意指线性的或支化的单价烃基，其包含一个双键，且具有2-6个碳原子(“C2-6烯基”)。所述烯基为例如乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。
如本文中所使用，术语“炔基”表示包含一个或多个三键的单价烃基，其优选具有2、3、4、5或6个碳原子，例如乙炔基或丙炔基。
如本文中所使用，术语“环烷基”指饱和的单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等))，其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子。例如，术语“C 3-6环烷基”指3至6个成环碳原子的饱和的单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)，其任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。
如本文中所使用，术语“亚环烃基”、“环烃基”和“烃环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环碳原子的饱和(即，“亚环烷基”和“环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)单环或多环烃环，其包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环己烯基(环)等。
如本文中所使用，术语“杂环基”、“亚杂环基”和“杂环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环原子、其中至少一个环原子是选自N、O和S的杂原子且其余环原子是C的饱和(即，杂环烷基)或部分不饱和的(即在环内具有一个或多个双键和/或三键)环状基团。例如，“3-10元(亚)杂环(基)”是具有2-9个(如2、3、4、5、6、7、8或9个)环碳原子和独立地选自N、O和S的一个或多个(例如1个、2个、3个或4个)杂原子的饱和或部分不饱和(亚)杂环(基)。亚杂环基和杂环(基)的实例包括但不限于：(亚)环氧乙烷基、(亚)氮丙啶基、(亚)氮杂环丁基(azetidinyl)、(亚)氧杂环丁基(oxetanyl)、(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、(亚)四氢吡喃基、(亚)哌啶基、(亚)吗啉基、(亚)二噻烷基(dithianyl)、(亚)硫吗啉基、(亚)哌嗪基或(亚)三噻烷基(trithianyl)。所述基团也涵盖双环系统，包括螺环、稠合或桥连系统(诸如8-氮杂螺[4.5]癸烷、3，9-二氮杂螺[5.5]十一烷、2-氮杂双环[2.2.2]辛烷等)。亚杂环基和杂环(基)可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。
如本文中所使用，术语“(亚)芳基”和“芳环”指具有共轭π电子系统的全碳单环或稠合环多环芳族基团。例如，如本文中所使用，术语“C6-10(亚)芳基”和“C6-10芳环”意指含有6至10个碳原子的芳族基团，诸如(亚)苯基(苯环)或(亚)萘基(萘环)。(亚)芳基和芳环任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO2、C1-6烷基等)取代。
如本文中所使用，术语“(亚)杂芳基”和“杂芳环”指单环、双环或三环芳族环系，其具有5、6、8、9、10、11、12、13或14个环原子，特别是1或2或3或4或5或6或9或10个碳原子，且其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)，并且，另外在每一种情况下可为苯并稠合的。特别地，“(亚)杂芳基”或“杂芳环”选自(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)噁二唑基、(亚)三唑基、(亚)噻二唑基等，以及它们的苯并衍生物；或(亚)吡啶基、(亚)哒嗪基、(亚)嘧啶基、(亚)吡嗪基、(亚)三嗪基等，以及它们的苯并衍生物。
如本文中所使用，术语“芳烷基”优选表示芳基或杂芳基取代的烷基，其中所述芳基、杂芳基和烷基如本文中所定义。通常，所述芳基可具有6-14个碳原子，所述杂芳基可具有5-14个环原子，并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、苯基乙基、苯基丙基、苯基丁基。
作为更具体地术语解释如下：
“烷基”指饱和脂肪族烃基团，包括1-20个碳原子，或1-10个碳原子，或1-6个碳原子，或1-4个碳原子，或1-3个碳原子，或1-2个碳原子饱和直链或支链的单价烃基，其中烷基可以独立任选地被一个或多个本发明所描述地取代基所取代。烷基基团更近一步地实例包括，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是任选取代或未取代的。
“烯基”指2-12个碳原子，或2-8个碳原子，或2-6个碳原子，或2-4个碳原子直链或支链的一价烃基，其中至少一个C-C为sp2双键，其中烯基的基团可以独立任选地被1个或多个本发明所描述的取代基所取代，其中具体的实例包括，但并不限于乙烯基、烯丙基和烯丁基等等。烯基可以是任选取代或未取代的。
“环烷基”是指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包括3至20个碳原子，优选包括3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实施例包括，但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。环烷基可以是任选取代的或未取代的。
“螺环烷基”指5至18元，两个或两个以上环状结构，且单环之间彼此共用一个碳原子(称螺原子)的多环基团，环内含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺、双螺或多螺环烷基，优选为单螺和双螺环烷基，优选为4元/5元、4元/6元、5元/5元或5元/6元。“螺环烷基”的非限制性实施例包括但不限于：
“稠环烷基”指5至18元，含有两个或两个以上环状结构彼此公用一对碳原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，优选为6至12元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。“稠环烷基”的非限制性实施例包括但不限于：
所述环烷基环可以稠合于芳基、杂芳基或杂环基环上，其中与母体结构连接在一起的环为环烷基，非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。
“杂环基”、“杂环”或“杂环的”在本申请中可交换使用，本申请中可交换使用，都是指包含3-12个环原子的饱和或部分不饱和的单环、双环或三环的非芳香性杂环基，其中至少一个环原子原子是杂原子，如氧、氮、硫原子等。优选具有5至7元单环或7至10元双-或三环，其可以包含1，2或3个选自氮、氧和/或硫中的原子。“杂环基”的实例包括但不限于吗啉基，氧杂环丁烷基，硫代吗啉基，四氢吡喃基，1，1-二氧代-硫代吗啉基，哌啶基，2-氧代-哌啶基，吡咯烷基，2-氧代-吡咯烷基，哌嗪-2-酮，8-氧杂-3-氮杂-双环[3.2.1]辛基和哌嗪基。所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基。杂环基可以是任选取代的或未取代的。
“稠杂环基”指含有两个或两个以上环状结构彼此公用一对原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧、硫或S(O)m的杂原子，其余环原子为碳，m＝1或2。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。“稠杂环基”的非限制性实施例包括但不限于：
“桥杂环基”指5至18元，含有两个或两个以上环状结构，彼此共用两个不直接相连接的原子的多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧、硫或S(O)m的杂原子，其余环原子为碳，m＝1或2。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。“桥杂环基”的非限制性实施例包括但不限于：
“芳基”是指含有一个或者两个环的碳环芳香系统，其中所述环可以以稠合的方式连接在一起。术语“芳基”包括比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C6-C10芳基，更优选芳基为苯基和萘基，最优选为苯基。芳基可以是取代或未取代的。所述“芳基”可与杂芳基、杂环基或环烷基稠合，其中与母体结构连接在一起的为芳基环，非限制性实施例包括但不限于：
“杂芳基”是指芳香族5至6元单环或9至10元双环，其可以包含1至4个选自氮、氧和/或硫中的原子。“杂芳基”的实施例包括但不限于呋喃基，吡啶基，2-氧代-1，2-二氢吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异噁唑基、噁唑基、噁二唑基、咪唑基、吡咯基、吡唑基、三唑基、四唑基、噻唑基、异噻唑基、1，2，3-噻二唑基、苯并间二氧杂环戊烯基、苯并咪唑基、吲哚基、异吲哚基、1，3-二氧代-异吲哚基、喹啉基、吲唑基、苯并异噻唑基、苯并噁唑基和苯并异噁唑基。 杂芳基可以是任选取代或未取代的。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包括但不限于：
“烷氧基”是指(烷基-O-)的基团。其中，烷基见本文有关定义。C1-C6的烷氧基为优先选择。其实例包括，但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“卤代烷基”指具有一个或者多个卤素取代基的烷基，其中烷基基团具有如本发明所述的含义。卤代烷基的实例包括，但并不限于氟甲基、二氟甲基、三氟甲基、全氟乙基、1,1-二氯乙基、1,2-二氯丙基等。
“羟基”指-OH基团。
“卤素”是指氟、氯、溴和碘，优选氟、氯和溴。
“氨基”指-NH2。
“氰基”指-CN。
“硝基”指-NO2。
“苄基”指-CH2-苯基。
“羧基”指-C(O)OH。
“乙酰基”指-C(O)CH3或Ac。
“羧酸酯基”指-C(O)O(烷基)或(环烷基)，其中烷基、环烷基的定义如上所述。
如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。
如本文中所使用，术语“含氮杂环”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子，其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C＝O、S、S＝O和S(＝O)2的环成员，其通过所述含氮杂环中的氮原子以及任一其余环原子与分子的其余部分连接，所述含氮杂环任选地为苯并稠合的，并且优选通过所述含氮杂环中的氮原子以及所稠合的苯环中的任一碳原子与分子的其余部分连接。
术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
如果取代基被描述为“任选地被取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。
如果取代基被描述为“独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘(2H)、氚(3H))；碳的同位素(例如11C、13C及14C)；氯的同位素(例如36Cl)；氟的同位素(例如18F)；碘的同位素(例如123I及125I)；氮的同位素(例如13N及15N)；氧的同位素(例如15O、17O及18O)；磷的同位素(例如32P)；及硫的同位素(例如35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即3H)及碳-14(即14C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如11C、18F、15O及13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，例如，D 2O、丙酮-d 6或DMSO-d 6。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1-3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本说明书所述的“取代”或“取代的”，如无特别指出，均是指基团可被一个或多个选自以下的基团取代：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、＝O、-C(O)Rb、-OC(O)Rb、-NRbRb、-C(O)NRbRb、-NRbC(O)Rb、-S(O)NRbRb或-S(O)2NRbRb，其中，Rb的定义如通式(I)中所述。
此处使用的“儿科病人”一词是指在诊断或治疗时未满16岁的病人。“儿童”一词还可分为以下几个亚类：新生儿(从出生到出生第一个月)；婴儿(1个月至两岁)；儿童(2岁至12岁)；青少年(12岁至21岁(直到但不包括22岁生日))。Berhman RE，Kliegman R，Arvin AM，Nelson we.尼尔森儿科教科书，第15版。费城：W.B.Saunders公司，1996年；Rudolph AM，等人。鲁道夫的儿科，第21版。纽约：McGrow-Hill，2002年；和Avery MD，第一LR。儿科医学，第二版。巴尔的摩：Williams&Wilkins；1994。
如本文所用，化合物的“有效量”是指足以负调节或激动Α-突触核蛋白聚集体形成的量。
如本文所用，化合物的“治疗有效剂量”是指足以改善或以某种方式减少症状、停止或逆转病情进展、或负调节或激动Α-突触核蛋白聚集体形成的量。这种剂量可以作为单一剂量使用，也可以按照一种方案服用，从而有效。
如此处所用，“治疗”是指以任何方式改善或以其他方式改变患者的病情、紊乱或疾病的症状或病理。
如本文所述，“通过使用某一特定化合物或药物组合物来改善某一特定疾病的症状”是指可归因于或与该组合物的使用有关的任何减少，不论是永久性的还是暂时性的、持久的或暂时性的。
本发明中立体化学的定义和惯例的使用通常参考以下文献：
S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-HillBook Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.本发明的化合物可以包含不对称中心或手性中心，因此存在不同的立体异构体。本发明的化合物所有的立体异构形式，包括但绝不限于，非对映体，对映异构体，阻转异构体，和它们的混合物，如外消旋混合物，组成了本发明的一部分。非对映异构体可以以其物理化学差异为基础，通过层析、结晶、蒸馏或升华等方法被分离为个别非对映异构体。对映异构体可以通过分离，使手性异构混合物转化为非对映异构混合物，其方式是与适当光学活性化合物(例如手性辅助剂，譬如手性醇或Mosher氏酰氯)的反应，分离非对映异构体，且使个别非对映异构体转化为相应的纯对映异构体。本发明的中间体与化合物也可以不同互变异构形式存在，且所有此种形式被包含在本发明的范围内。很多有机化合物都以光学活性形式存在，即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时，前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀d、l或(+)、(-)用来命名化合物平面偏振光旋转的符号，(-)或l是指化合物是左旋的，前缀(+)或d是指化合物是右旋的。这些立体异构体的原子或原子团互相连接次序相同，但是它们的立体结构不一样。特定的立体异构体可以是对映体，异构体的混合物通常称为对映异构体混合物。50：50的对映体混合物被称为外消旋混合物或外消旋体，这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物，缺乏光学活性。
“互变异构体”或“互变异构的形式”是指不同能量的结构的同分异构体可以通过低能垒互相转化。例如质子互变异构体(即质子移变的互变异构体)包括通过质子迁移的互变，如酮式-烯醇式和亚胺-烯胺的同分异构化作用。原子价(化合价)互变异构体包括重组成键电子的互变。除非其他方面表明，本发明所描述的结构式包括所有的同分异构形式(如对映异构，非对映异构，和几何异构)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本发明的化合物的单个立体化学异构体或其对映异构体，非对映异构体，或几何异构体的混合物都属于本发明的范围。
“药学上可接受的盐”指本发明化合物的盐，这类盐用于人或动物体内时具有安全性和有效性。化合物的盐可以通过在纯的溶液或合适的惰性溶解中用足量的碱或酸获得相应的加成盐。可药用的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐等，可药用的酸加成盐包括无机酸盐和有机酸盐，所述的无机酸和有机酸包括盐酸、氢溴酸、碳酸、碳酸氢根、磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸一氢根、乙酸、马来酸、丙二酸、琥珀酸、饭丁烯二酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸和甲磺酸等(参见Berge et al.,“Pharmaceutical Salts”,Journal of Pharmaceutical Science 66:1-19(1977))。
本文中可使用实线实楔形或虚楔形描绘本发明的化合物的化学键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。
本发明涵盖本发明的化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。
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、N-氧化物、代谢物、螯合物、络合物、包合物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐，包括但不限于含有氢键或配位键的盐。
适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、海苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐(naphthylate)、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐及昔萘酸盐(xinofoate)。
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、苄星青霉素盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、乙醇胺盐、钾盐、钠盐、氨丁三醇盐及锌盐。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts：Properties，Selection，and Use”(Wiley-VCH，2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist，Comprehensive Organic Synthesis，vol.7，pp 748-750；A.R.Katritzky和A.J.Boulton，Eds.，Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry，vol.22，pp 390-392，A.R.Katritzky和A.J.Boulton，Eds.，Academic Press。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier，1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在T.W.Greene&P.G.M.Wuts，Protective Groups in Organic Synthesis，JohnWiley&Sons，1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。
本发明的优选化合物
已经记载本发明化合物的通式和优选范围。进一步优选地，作为α-突触核蛋白聚集体形成抑制剂的用途的本发明化合物的具体例子可以选自如下结构的任意一种，但是并不限于以下化合物：
本发明的典型化合物包括但不限于如上表格中的化合物，本发明中的化合物命名遵循系统命名，或者，使用ChemDraw软件进行命名。
本发明化合物获得的一般方法
本发明通式1所示的双四氢呋喃类化合物可以通过公知方法获得，例如通过公知的有机合成方法进行合成。以下给出了实例性的合成路线，但是本领域人员也可以通过公知的其他方法获得。
本发明中后述的实施例中的化合物D1(俗称连翘苷)和化合物D2(俗称芝麻素)为常见天然产物，在常用中药辛夷、厚朴、连翘、杜仲、芝麻中也提取分离到该类化合物。该类化合物的生物活性已被相继报道，包括抗肿瘤、肝保护、抗氧化、抗炎以及免疫抑制等，化合物D1和化合物D2可以获得市售品。以化合物D1和化合物D2为起始原料，基于本发明实施例中的合成方法，可以获得大量式(I)或式(II)或式(III)所示的化合物，具体方法参见后述的实施例，
药物组合物和治疗方法
本发明提供一种药物组合物，其包含有效量的本发明化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，以及药学上可接受的载体，所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。
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、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。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。
本发明的药物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(如静脉内、动脉内、皮下、腹膜内、肌内注射，包括滴注)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药物组合物。
所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂。
本发明所述的药物组合物可用于预防和/或治疗神经退行性疾病，在使用本发明药物制剂时，还可同时使用选自美多芭、泰舒达、森福罗、息宁、安坦、司来吉兰、雷沙吉兰、托卡朋中的药物。
本发明所述药物组合物，含有安全有效量的本发明化合物以及药学上可接受的载体或赋形剂。这类载体包括(但并不限于)：盐水、缓冲液、葡萄糖、水、甘油、乙醇、粉剂等中的一种或几种。药物制剂应与给药方式相匹配。
本发明的药物组合物可以被制成针剂形式，例如用生理盐水或含有葡萄糖和其他辅剂的水溶液通过常规方法进行制备。诸如片剂和胶囊之类的药物组合物，可通过常规方法进行制备。药物组合物如针剂、溶液、片剂和胶囊宜在无菌条件下制造。本发明的药物组合物也可以被制成粉剂用于雾化吸入。
活性成分的给药量是治疗有效量，例如每天约1微克/千克体重-约50毫克/千克体重；优选地，为约5微克/千克体重-约10毫克/千克体重；进一步优选地，为约10微克/千克体重-约5毫克/千克体重。此外，本发明化合物还可与其他治疗剂一起使用。
对于本发明的药物组合物，可通过常规的方式施用于所需的对象(如人和非人哺乳动物)。代表性的施用方式包括(但并不限于)：口服、注射、雾化吸入等。
使用药物组合物时，是将安全有效量的药物施用于哺乳动物，其中该安全有效量通常至少约10微克/千克体重，而且在大多数情况下不超过约50毫克/千克体重，较佳地，该剂量是约10微克/千克体重-约20毫克/千克体重。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
下面结合具体实施例，进一步阐述本发明。实施本发明的过程、条件、试剂、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。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，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
如本文中所使用的术语“有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。具体而言，如本文所用，化合物的“有效量”是指足以负调节或促进Α-突触核蛋白聚集体形成的量。如本文所用，化合物的“治疗有效剂量”是指足以改善或以某种方式减少症状、停止或逆转病情进展、或负调节或激动Α-突触核蛋白聚集体形成的量。这种剂量可以作为单一剂量使用，也可以按照一种方案服用，从而有效。
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
如此处所用，“治疗”是指以任何方式改善或以其他方式改变患者的病情、紊乱或疾病的症状或病理。如本文所述，“通过使用某一特定化合物或药物组合物来改善某一特定疾病的症状”是指可归因于或与该组合物的使用有关的任何减少，不论是永久性的还是暂时性的、持久的或暂时性的。
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。
附图说明
图1为细胞存活率检测结果及Gaussia荧光素酶活性检测结果的图；
图2为化合物03A10阻止α-synuclein蛋白聚集效果的图；
图3为化合物03A10改善α-synuclein蛋白聚集体对细胞的损伤作用的图；
图4为化合物03A10改善α-synuclein蛋白聚集体对细胞的ROS损伤作用的图；
图5为03A10缩短MPTP/p PD小鼠的下杆时间的图；
图6为03A10增加MPTP/p PD小鼠的转棒停留时间的图；
图7为03A10改善MPTP/p PD小鼠中脑黑质、纹状体多巴胺神经元的损伤的图。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例
提供这些实施例并非意在限制本发明的范围。
下面通过具体实施例对本发明的方法进行说明，以使本发明技术方案更易于理解、掌握，但本发明并不局限于此。
药物化学实验部分
下述实施例中1H NMR图谱是用Bruker仪器(400MHz)测定而得，化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。1H NMR的表示方法：s＝单峰，d＝双重峰，t＝三重峰，q＝四重峰，m＝多重峰，br＝变宽的，dd＝双重峰的双重峰，dt＝三重峰的双重峰。若提供偶合常数时，其单位为Hz。
质谱是用LC/MS仪测定得到，离子化方式为ESI。
高效液相色谱仪型号：安捷伦1260、赛默飞U3000；色谱柱型号：Waters xbrige C18(4.6*150mm,3.5μm)；流动相：A:ACN,B:Water(0.1％H3PO4)；流速：1.0mL/min；梯度：5％A for 1min,increase to 20％A within 4min,increase to 80％A within 8min,80％A for 2min,back to 5％A within 0.1min；波长：220nm；柱温箱：35℃。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.2mm-0.3mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
在下列实例中，除非另有指明，所有温度为摄氏温度，除非另有指明，各种起始原料和试剂来自市售或者是根据已知的方法合成，市售原料和试剂均不经进一步纯化直接使用，除非另有指明，市售厂家包括但不限于国药集团，百灵威科技有限公司，梯希爱(上海)化成工业发展有限公司，上海毕得医药科技有限公司和上海迈瑞尔化学科技有限公司等。
CD3OD：氘代甲醇
CDCl3：氘代氯仿
DMSO-d6：氘代二甲基亚砜
TLC：薄层色谱法
HPLC：高效液相色谱法
purity：纯度
&：和
氢气氛围是指反应瓶连接一个约1L容积的氢气气球。
实施例中无特殊说明，反应中的溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃-30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系或薄层色谱法的展开剂体系包括：A：石油醚和乙酸乙酯体系；B：二氯甲烷和甲醇体系；C：正己烷：乙酸乙酯；其中溶剂的体积比根据化合物的极性不同而不同，也可以加入少量的酸性或碱性试剂进行调节，如醋酸或三乙胺等。
实施例1化合物1(03A10)、化合物6(03A10-CH2)的合成
芝麻素(717mg,2.03mmol)于室温下溶解于无水苯(30ml)中，加入乙酸铅(IV)1.35g(3.04mmol,1.5eq.,)后，升温至80℃后过夜。反应液冷却至室温后加入75ml的乙酸乙酯稀释，稀释液用蒸馏水(50ml)洗涤3次后再用饱和食盐水(50ml)洗涤一次。有机相经无水硫酸镁干燥后减压蒸馏除去有机溶剂，剩余物溶解于5ml的THF/H2O(5:1)混合溶液中，加入过量的冰醋酸(10ml)后于室温下搅拌6h。反应液加入30ml饱和的NaHCO3淬灭后加蒸馏水稀释至100ml，稀释液用乙酸乙酯(50ml)萃取3次，有机相合并后分别用NaHCO3、蒸馏水和饱和食盐水洗涤3次，之后经无水硫酸镁干燥后减压蒸馏除去有机溶剂，剩余物经硅胶柱纯化(二氯甲烷：甲醇100:1～100:4)得化合物03A10(450mg,67％)和03A10-CH2(140mg,20％)。
03A10：白色固体，ESI-MS m/z 329.07[M-H]-,375.08[M+COOH]-,659.17[2M-H]-；1H NMR(500MHz,DMSO-d6)δ2.93(2H,m,H-1),3.68(2H,dd,J＝9.0,3.5Hz,H-9b and H-9’b),4.07(2H,dd,J＝9.0,7.1Hz,H-9a and H-9’a),4.53(2H,d,J＝4.3Hz,H-7 and H-7’),6.59(2H,dd,J＝8.1,1.9Hz,H-4 and H-4’),6.68(2H,d,J＝8.1Hz,H-5 and H-5’),6.73(2H,d,J＝1.9Hz,H-1 and H-1’)；13C NMR(125MHz,DMSO-d6)δ53.5(C-8 and C-8’),70.7(C-9 and C-9’),84.9(C-7 and C-7’),113.5(C-1 and C-1’),115.2(C-4 and C-4’),116.9(C-5 and C-5’),132.2(C-6 and C-6’),144.5(C-3 and C-3’),145.0(C-2 and C-2’).
03A10-CH2：白色固体，ESI-MS m/z 341.03[M-H]-,683.11[2M-H]-；1H NMR(500MHz,DMSO-d6)δ2.96(2H,m,H-8,H-8’),3.71(1H,dd,J＝9.0,3.9Hz,H-9b),3.73(1H,dd,J＝9.0,3.7Hz,H-9’b),4.07(1H,dd,J＝9.0,6.9Hz,H-9a),4.11(1H,dd,J＝9.0,6.9Hz,H-9’a),4.54(1H,d,J＝4.3Hz,H-7),4.62(1H,d,J＝4.6Hz,H-7’),5.99(2H,s,O-CH2-O),6.59(1H,dd,J＝8.4,2.1Hz,H-4”),6.68(1H,d,J＝8.4Hz,H-5”),6.73(1H,d,J＝2.1Hz,H-2”),6.83(1H,dd,J＝8.2,1.6Hz,H-4’),6.86(1H,d,J＝8.2Hz,H-5’),6.92(1H,d,J＝1.6Hz,H-2’).13C NMR(125MHz,DMSO-d6)δ53.4(C-8),53.8(C-8’),70.6(C-9),70.97(C-9’),84.8(C-7),84.8(C-7’),100.8(O-CH2-O),106.4(C-1),107.9(C-4),113.5(C-1’),115.2(C-4’),116.9(C-5’),119.2(C-5),132.2(C-6’),135.4(C-6),144.5(C-3’),145.0(C-2’),146.4(C-3),147.3(C-2).
实施例2化合物5(03A10-Me)的合成
在氩气球的保护下，66mg的03A10(0.2mmol)和对甲苯磺酸甲酯(37.2mg,0.2mmol,1.0eq.,)溶解于无水四氢呋喃中置于冰浴锅中冷却至0℃，加入NaH(60％in mineral oil,40mg,1.0eq.,)后反应液升温至室温搅拌过夜。向反应液中滴加2ml的饱和NH4Cl溶液淬灭后加蒸馏水稀释至100ml，稀释液加乙酸乙酯(30ml)萃取三次，有机相合并后经饱和食盐水洗涤，再经无水硫酸镁干燥后减压蒸馏除去有机溶剂，剩余物经制备型TLC板纯化(二氯甲烷：甲醇100:4)后得03A10-Me(22mg,32％)。
03A10-Me：白色固体，ESI-MS m/z 343.03[M-H]-,687.11[2M-H]-；1H NMR(500MHz,MeOH-d4)δ2.96(2H,m,H-8,H-8’),3.77(1H,dd,J＝9.0,3.9Hz,H-9b),3.83(1H,dd,J＝9.0,3.7Hz,H-9’b),3.96(3H,s,-OCH3),3.3(2H,m,H-9a and H-9’a),4.35(1H,d,J＝7.0Hz,H-7),4.80(1H,d,J＝5.5Hz,H-7’),6.68(1H,dd,J＝8.4,1.6Hz,H-4),6.70(1H,dd,J＝8.2,1.6Hz,H-4’),6.76(1H,d,J＝8.4Hz,H-5),6.75(1H,d,J＝8.2Hz,H-5’),6.84 and 6.82(1H,d,J＝1.6Hz,H-2 and H-2’).
药理实验部分
药理实验中使用的化合物
实施例3：天然及合成的双四氢呋喃型木脂素阻止α-synuclein聚集活性的发现
本实验采用了萤光素酶蛋白片段互补分析方法，将萤光素酶的分泌序列去掉使萤光素酶只在细胞内表达，利用这种人工改造过的萤光素酶(Human Gaussiaprinceps Luciferase)作为报告蛋白，将其N端和C端分别融合到α-syn蛋白上，通过检测萤光素酶活性判断细胞内的α-syn聚集情况，α-syn聚集越多，检测出的萤光素酶活性越强，α-syn聚集越少，检测出的萤光素酶活性越弱，从而筛选出阻止α-synuclein聚集的候选化合物。
实验材料：
(1)实验细胞：SH-SY5Y人神经母细胞瘤细胞购自ATCC；
(2)实验试剂：MEM/F12培养基(GIBCO公司)，胰蛋白酶(SIGMA公司)，胎牛血清(BIOCHROM公司)，Fugene HD(Promega)，Renilla Luciferase Assay System(Promega公司)，MTT(SIGMA公司)
(3)实验仪器：酶标仪(NovoStar)，恒温二氧化碳培养箱(Thermo Fisher)
实验方法：
人神经母细胞瘤SH-SY5Y细胞(购自ATCC)培养于含有10％FBS的MEM/F-12培养基中，37℃、5％CO2恒温培养箱中孵育生长。
将SH-SY5Y细胞按1×105个/ml密度种于96孔板，置于37℃、5％CO2细胞培养箱中孵育24小时至细胞完全贴壁，换液进行质粒转染，转染步骤按照Fugene HD(Promega)说明书进行。培养箱孵育12小时后，每孔加入受试化合物10μM，继续给药培养24小时，再按照Renilla Luciferase Assay System(Promega)操作说明书，检测细胞内Gaussia萤光素酶的生物活性，结果归一化处理。
细胞活力测定采用四甲基偶氮唑盐(Thiazoly Blue,MTT)检测方法：细胞中加入MTT(终浓度为0.5mg/mL)，37℃继续培养4小时后吸去上清，加入二甲亚砜(DMSO)，置于摇床上，待结晶充分溶解后，NovoStar酶标仪595nm测定吸光度值。细胞活力以处理组细胞吸光度值相对于对照组细胞吸光度值的百分比进行数据处理统计。每种实验处理组做3个复孔，独立至少重复3次。
实验结果：
细胞毒实验结果显示，在10μM浓度下，所测化合物均对神经细胞的存活率无影响(图1a)，提示所述双四氢呋喃环型木脂素在10μM浓度下无明显的细胞毒性。酶活实验结果显示，在10μM浓度下，式(1)结构中邻二苯酚结构上至少保留一个羟基的化合物如化合物1(03A10)、化合物2、化合物3、化合物4以及化合物5(03A10-Me)、化合物6(3A10-CH2)可以促进α-synuclein聚集的降解，而邻二酚羟基全取代产物化合物(D1)和化合物(D2)则没有表现出促α-synuclein寡聚体解聚或者降解的作用。见图1(数据表示为mean±SEM,独立重复实验次数n＝3。*p<0.05,**p<0.01。)
实施例4：化合物03A10阻止大分子量聚集体蛋白增加，降低THT读值
硫磺素(thioflavin,ThT)于1959年首次报道，是一种常用来检测蛋白聚集体的荧光标记物，可以和蛋白聚集过程中出现的β-折叠结合，通过酶标仪中荧光值的数值大小反应蛋白的聚集程度，荧光染料的吸收和发射波长分别为450nm和485nm。通过ThT实验探究03A10是否能阻止α-synuclein蛋白的聚集。
实验材料：
(1)实验试剂：ThT购自sigma
(2)实验仪器：酶标仪(FlexStation3)
实验方法：
将α-synuclein蛋白溶液和10μM化合物03A10，在金属浴中共同孵育72小时后，吸取200μL蛋白加入终浓度为5μM的荧光染料thioflavin T,37℃孵育3分钟后转移至黑色不透光的96孔板内读取荧光值。
实验结果：
α-synuclein蛋白溶液随着聚合处理时间(37℃、1000rpm孵育)的增加，有助于形成纤维聚集体，结果显示化合物03A10在10μM浓度下可减少α-synuclein的聚集，ThT荧光读值与对照组相比具差异有显著意义(**p<0.01)(图2A，数据表示为mean±SEM,独立重复实验次数n＝3。**p<0.01-)。
实施例5：电镜结果显示化合物03A10阻止大分子量聚集体蛋白增加
透射电子显微镜以高能电子束为照明源，利用从样品下表面透出的电子束来成像，具有较高的分辨率，常用来观察蛋白样品、纳米材料等。
实验材料：
(1)实验试剂：乙酸铀和铜网购自中镜科仪集团
(2)实验仪器：120kv透射电子显微镜
实验方法：
将300目铜网辉光处理后进行电镜样品负染，将蛋白样品滴在铜网上固定后，用滤纸吸干，滴加10μL甲酸铀染液，边加边吸，随后加一滴甲酸铀染液，静置1min后用滤纸吸干，晒干铜网后小心将其放置于样品杆中，检查样品杆无毛絮、头发等可见杂质后，推入样品台，待系统抽真空完全后进行操作，观察蛋白样品。
实验结果：
120kv透射电子显微镜常用来检测负染的蛋白样品，观察蛋白形态，将α-synuclein蛋白溶液和10μM化合物03A10，在金属浴中共同孵育72h(37℃、1000rpm)后，取适量蛋白样品进行负染制样后，在透射电镜中观察，空白对照组蛋白呈现纤维聚集状，化合物03A10(10μM)共孵育组蛋白呈现非纤维聚集状(图2B)。
实施例6：化合物03A10改善纤维聚集体导致的细胞损伤
为了在细胞水平探究03A10对α-synuclein的作用，首先探究α-synuclein纤维(pre-formed fibrils,PFF)对细胞的毒性作用，通过MTT实验探究03A10是否能缓解PFF的毒性作用。
实验材料：
(1)实验细胞：PC12细胞购自ATCC，构建过表达α-synuclein蛋白的PC12稳转细胞株后待用。
(2)实验仪器：酶标仪(NovoStar)。
实验方法：
噻唑蓝(MTT)是一种黄颜色粉末状化学试剂，常用来检测活细胞的存活，活细胞线粒体中的琥珀酸脱氢酶能使外源性MTT还原为水不溶性的蓝紫色结晶——甲臜，并沉积在细胞中。经处理后的96孔板细胞，每孔加入终浓度为0.5mg/ml的MTT，在细胞培养箱中继续培养4小时后，小心吸去上清，加入100ul DMSO，震荡混匀后，用PerkinElmer多孔板仪在490nm波长处测定吸光度值，计算细胞存活率。每种处理组3个复孔，实验重复3次。
实验结果：
在α-synuclein稳转株细胞中外源性加入0.4μMα-synuclein聚集体蛋白，MTT实验结果显示：随着聚集体蛋白处理时间的增加，细胞损伤增加(图2.3A)。当聚集体蛋白与化合物03A10的比例分别为：1:1、1：10和1：50加入到细胞中，共处理细胞48h，蛋白与03A10的比例1：50的组别，能够逆转细胞损伤(*p<0.05,**p<0.01)(图3)。
A.聚集体不同处理时间的MTT检测。B.化合物03A10与蛋白聚集体共处理后的MTT检测。数据表示为mean±SEM,独立重复实验次数n＝3。*p<0.05,**p<0.01。
实施例7：化合物03A10改善纤维聚集体导致的氧化应激进而导致的细胞损伤
通过流式细胞术探究PFF对细胞的ROS影响以及03A10的作用。
实验材料：
(1)实验细胞：PC12细胞购自ATCC，构建过表达α-synuclein蛋白的PC12稳转细胞株后待用。
(2)实验仪器：FACS Calibur流式细胞仪(BD)。
实验方法：
通过荧光探针DCFH-DA进行活性氧(Reactive oxygen assay,ROS)检测，具体操作按照荧光探针DCFH-DA(Thermo Fisher scientific)，简述如下：在待检测的细胞内加入DCFH-DA探针，培养箱中继续培养30min后，PBS洗细胞两次，消化后收集细胞，过滤后用FACS Calibur流式细胞仪检测，采集数据后用FlowJo软件进行分析。
实验结果：
分别在α-synuclein稳转株细胞中外源性加入0.4μMα-synuclein聚集体蛋白以及化合物不同比例的聚集体蛋白(聚集体蛋白：化合物03A10的比例，1:1、1：10和1：50)，处理细胞48h，用流式细胞仪检测氧化应激(ROS)信号，结果显示：α-synuclein聚集体蛋白能导致细胞ROS增加，蛋白与化合物03A10的比例1：50的组别，能够逆转细胞的ROS损伤(*p<0.05,**p<0.01)(图4，A.流式细胞仪的ROS检测。B.ROS荧光信号统计分析。数据表示为mean±SEM,独立重复实验次数n＝3。*p<0.05,**p<0.01。
实施例8：03A10改善PD动物行为学障碍，减轻中脑黑质多巴胺神经元的损伤。
MPTP可导致中脑多巴胺能神经元死亡，运动协调能力下降，是很好的模拟PD病人的造模剂。MPTP联用丙磺舒(MPTP/probenecid,MPTP/p)慢性PD模型，能够减缓MPTP体内代谢，表现出更多的病理特征，如神经炎症、α-synuclein沉积、细胞外谷氨酸异常升高等。该模型通过转棒实验、爬杆实验等探究小鼠的PD样症状。
实验材料：
(1)实验动物：MPTP/p诱导帕金森症的动物模型采用雄性C57/BL6J小鼠，购自上海斯莱克实验动物有限责任公司，小鼠体重25g左右。动物饲养条件如下：雄性小鼠最大饲养密度为6只每笼，每天交替12小时光照(7:00-19:00)，12小时黑夜(19:00-次日7:00)，饲养温度22±2℃，湿度35±5％，并给以充足的食料和洁净饮水。饲养大于7天后，用于实验。实验使用和操作均已经过中国科学院上海药物研究所实验动物福利与伦理委员会审批，并严格遵守其操作规范。
(2)实验试剂：MPTP购自Sigma-Aldrich公司；Probenecid购自MCE公司；
实验方法：
(1)MPTP/p亚急性PD小鼠模型
C57/BL6J小鼠购买于北京华阜康生物科技股份有限公司，将小鼠随机分笼分为5组，生理盐水对照组(control)、MPTP/probenecid(MPTP/p)模型组(model)、03A10 0.3mg/kg给药组，03A101mg/kg给药组，03A10 5mg/kg给药组。每3.5天造模一次，共造模10次(5周)。100mg/kg丙磺舒溶解于5％碳酸氢钠，模型组腹腔注射丙磺舒，对照组腹腔注射生理盐水；30分钟后模型组皮下注射MPTP，对照组皮下注射生理盐水。造模开始第一天，对照组和模型组灌胃给与生理盐水，给药组灌胃给与不同浓度的03A10。造模至5周进行爬杆实验、转棒实验行为学检测。
(2)转棒实验检测
转棒法(rotarod test)广泛用于运动协调和能力的评估。MPTP/p慢性小鼠模型，在造模第5周结束后进行行为学检测。将小鼠放置于转棒上，小鼠造模前每天以5-30rpm转速训练小鼠200s，训练三天，测试时以转速5-30rpm总时间200s记录小鼠棒上停留时间，超过200s按照200s记录。每只小鼠重复检测3次，每次间隔不少于0.5h。
(3)爬杆实验检测
爬杆法(pole test)用于检测PD中典型行为学症状——运动徐缓。在给药开始前每天训练小鼠爬杆，每天三次，训练三天。在造模第5周结束后进行行为学检测。将小鼠头向上轻柔的放在粗糙的杆顶(直径10mm，高55cm)。小鼠从头向上调整至头完全向下的时间记录为潜伏期(T-turn)，小鼠从向下运动至四肢全部到达杆底的时间记录为下杆时间(T-LA)，超过30s按照30s记录，每只小鼠重复检测3次。
(4)酪胺酸羟化酶(tyrosine hydroxylase,TH)免疫组化检测多巴胺能神经元和神经纤维丢失
实验终点到达后，小鼠用舒泰麻醉后，4％多聚甲醛灌流后取脑。脑组织由4％多聚甲醛后固定24h，再将样本转入30％的蔗糖溶液中脱水至样本沉底，在-20℃冰冻切片机中做冠状切片，小鼠脑切片厚度20μm。一抗为单克隆小鼠抗TH(1:1000,CHEMICON)，室温孵育2.5小时，TBST洗三遍后用HPR标记二抗，室温孵育1h。DAB显色，乙醇梯度脱水，二甲苯透明，中性树胶封片。
结果分析：用Image-pro plus软件对染色切片进行分析，以黑质区TH阳性总光密度作为黑质区多巴能阳性神经元数的参数，纹状体TH阳性染色平均光密度作为纹状体多巴能神经纤维数量的参数进行统计。
实验结果：
爬杆实验结果表明，与空白对照组(control)相比，MPTP/p模型对照组下杆时间明显增加，差异具有显著性(*p<0.05)；与MPTP/p模型对照组相比，灌胃给药03A10的MPTP/p PD小鼠下杆时间明显缩短(**p<0.01,***p<0.001)(图5)。
各组小鼠的爬杆下杆时间(T-LA)，数据表示为mean±SEM，control对照组小鼠只数n＝7，MPTP/p模型组小鼠只数n＝8，0.3mg/kg给药组小鼠只数n＝10，1mg/kg给药组小鼠只数n＝8，5mg/kg给药组小鼠只数n＝7。*p<0.05,**p<0.01，***p<0.001。
转棒实验结果表明，与空白对照组(control)相比，MPTP/p模型对照组在棒上停留时间明显缩短，两组相比差异有显著意义(**p<0.01)；与MPTP/p模型对照组相比，灌胃给药03A10的MPTP/p PD小鼠在棒上停留时间明显增加，两组相比差异有显著意义(*p<0.05，**p<0.01,***p<0.001)见图6，各组小鼠在转棒上的停留时间，数据表示为mean±SEM，control对照组小鼠只数n＝7，MPTP/p模型组小鼠只数n＝8，0.3mg/kg给药组小鼠只数n＝10，1mg/kg给药组小鼠只数n＝8，5mg/kg给药组小鼠只数n＝7。*p<0.05,**p<0.01，***p<0.001。
免疫组织化学检测黑质酪氨酸羟化酶的表达，结果显示与空白对照组(control)相比，MPTP/p模型组中脑酪氨酸羟化酶(tyrosine hydroxylase-positive，TH)阳性神经元表达量明显减少；与MPTP/p模型对照组相比，灌胃给药03A10后的MPTP/p PD小鼠的TH阳性神经元表达明显增加(图2.7A)。统计分析黑质致密部TH神经元的个数，与空白对照组(control)相比，MPTP/p模型组中脑TH阳性神经元表达量明显减少，差异具有显著意义(***p<0.001)；与MPTP/p模型对照组相比，灌胃给药03A10后的MPTP/p PD小鼠的TH阳性神经元表达明显增加，差异具有显著意义(*p<0.05)(图2.7B)。免疫组织化学检测纹状体TH阳性神经纤维的表达，结果显示灌胃给药03A10能明显改善MPTP/p PD小鼠纹状体多巴胺能神经纤维损伤(*p<0.05)(见图7)。
A.免疫组织化学实验检测小鼠中脑黑质区域TH阳性神经元，标尺＝200μm；B.黑质致密部TH阳性神经元的个数统计；C.免疫组织化学实验检测小鼠中脑纹状体区域TH阳性神经纤维，标尺＝200μm；D.纹状体TH阳性神经纤维光密度值统计分析。数据表示为mean±SEM，*p<0.05,**p<0.01，***p<0.001。
实施例3-7的实验结果表明，在蛋白水平，03A10可以有效减少α-synuclein的聚集；在细胞水平，03A10可以有效改善α-synuclein蛋白聚集体对神经细胞的损伤作用；在动物水平，03A10能改善PD小鼠的运动症状损伤，并阻止PD小鼠中脑黑质致密部多巴胺能神经元和纹状体多巴胺神经末梢的丢失。提示具有03A10结构特征的双四氢呋喃型木脂素是一类具有抗帕金森综合症作用、且具有应用前景的α-synuclein聚集的阻滞剂或抑制剂。
结果表明，化合物的结构(包括立体构型)与活性结果发现，C7，C8和C7’、C8’的手性对活性的影响不大，邻二酚羟基如果全取代则活性减弱或消失，增加羟基取代，则活性也较弱或消失。
申请人声明，本发明通过上述实施例来说明本发明的一种双四氢呋喃类化合物作为α-突触核蛋白聚集体形成抑制剂的用途、包含其的药物组合物、治疗帕金森和其他神经退行性疾病剂，但本发明并不局限于上述实施例，即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本发明的任何改进，对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本发明的保护范围和公开范围之内。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。

Claims (8)

  1. 式(I)所示的双四氢呋喃类化合物或者其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药作为α-突触核蛋白聚集体形成抑制剂的用途或者在制备用于减轻和/或消除帕金森症的药物中的用途，
    式(I)中，环A和环B分别独立地表示取代或未取代的C6-10芳香环、或者取代或未取代的C5-14杂芳香环，优选苯环、吡啶环、吡咯环；
    X1和X2分别独立地为NRC、O或S，优选为O或S，更优选为O，
    各RC独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基或者C6-12芳烷基，优选为H、C1-6烷基；
    Ra和Rb各自独立地为选自卤素、氨基、氰基、硝基、C1-6烷基、C1-6烷氧基、饱和或部分不饱和的C3-6环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、葡萄糖基、-C(＝O)Rd、-OC(＝O)Rd、-C(＝O)ORd、-ORd、-SRd、-S(＝O)Rd、-S(＝O)2Rd、-S(＝O)2N(Rd)2、-N(Rd)2、-C(＝O)N(Rd)2、-NRd-C(＝O)Rd、-NRd-C(＝O)ORd、-NRd-S(＝O)2-Rd、-NRd-C(＝O)-N(Rd)2、-C1-6亚烷基-N(Rd)2、-C1-6亚烷基-ORd、-C1-6亚烯基-OR8和-O-C1-6亚烷基-N(R8)2，m和n分别独立地为1～4的整数，优选为2～3的整数，进一步优选为2；条件是，Ra中至少2个为-ORd基团，Rb中至少2个为-ORd基团，
    各Rd独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、C5-14杂芳基或者C6-12芳烷基，多个Rd之间可以连接并与构成环A的原子共同形成环，条件是多个Rd中至少一个为H，
    Y和Z分别独立地表示选自H、卤素、NH2、OH、SH、C1-6烷基取代氨基、取代或未取代的C1-10的脂肪族烃基、取代或未取代的饱和或部分不饱和的C3-10的杂环基、取代或未取代的C6-10芳基、或者取代或未取代的C5-14的杂芳基、-C(＝O)RX、-OC(＝O)RX、-C(＝O)ORX、-ORX、-SRX、-S(＝O)RX、-S(＝O)2RX、-S(＝O)2N(RX)2、-N(RX)2、-C(＝O)N(RX)2、-NRX-C(＝O)RX、-NRX-C(＝O)ORX、-NRX-S(＝O)2-RX、C(＝O)-N(RX)2、-C1-6亚烷基-N(RX)2、-C1-6亚烷基-ORX、-C1-6亚烯基-ORX和-O-C1-6亚烷基-N(RX)2；其中，RX为H、胍基、C1～C6烷基、饱和或部分不饱和的C3-6环烃基、饱和或部分不饱和的3-10元杂环基或者C6-10芳基；Y和Z分别独立地优选为H、卤素、甲基、乙基、OH、甲氧基；
    此处“取代或未取代”中的“取代”是指任选地被1-3个卤素、C1-C3烷基、C1-C3烷氧基、C1-C6环烷基、C1-C6环烷氧基或C1-C3卤代烷基取代、氰基、硝基、羟基、氨基、氧膦基、磺酰基、磺酰胺基所取代，“—”划过的环结构的表达方式，表示连接位点于该环结构上任意能够成键的位置。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药作为α-突触核蛋白聚集体形成抑制剂的用途或者在制备用于减轻和/或消除帕金森症的药物中的用途，所述化合物具有下述式(II)的结构，
    在式II中，X1和X2表达的意思与权利要求1中相同，
    R1～R4独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、C5-14杂芳基或者C6-12芳烷基，优选为H、C1-6烷基，R1和R2可以连接并与其连接的苯环中的原子共同形成环，R3和R4可以连接并与其连接的苯环中的原子共同形成环，
    R5、R6各自独立地为H、羟基、饱和或部分不饱和的C1-6烃基、饱和或部分不饱和的C1-6烃基-O-、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的C3-10环烃基-O-、饱和或部分不饱和的C3-10环烃基-NH-、取代的饱和或部分不饱和的C1-6烃基、取代的饱和或部分不饱和的C3-10环烃基中的一种，优选为H、羟基，
    Y和Z分别独立地表示选自H、卤素、NH2、OH、SH、C1-6烷基取代氨基、取代或未取代的C1-10的脂肪族烃基、取代或未取代的饱和或部分不饱和的C3-10的杂环基、取代或未取代的C6-10芳基、或者取代或未取代的C5-14的杂芳基、-C(＝O)RX、-OC(＝O)RX、-C(＝O)ORX、-ORX、-SRX、-S(＝O)RX、-S(＝O)2RX、-S(＝O)2N(RX)2、-N(RX)2、-C(＝O)N(RX)2、-NRX-C(＝O)RX、-NRX-C(＝O)ORX、-NRX-S(＝O)2-RX、C(＝O)-N(RX)2、-C1-6亚烷基-N(RX)2、-C1-6亚烷基-ORX、-C1-6亚烯基-ORX和-O-C1-6亚烷基-N(RX)2；其中，RX为H、胍基、C1～C6烷基、饱和或部分不饱和的C3-6环烃基、饱和或部分不饱和的3-10元杂环基或者C6-10芳基；Y和Z分别独立地优选为H、卤素、甲基、乙基、OH、甲氧基；
    此处“取代或未取代”中的“取代”是指任选地被1-3个卤素、C1-C3烷基、C1-C3烷氧基、C1-C6环烷基、C1-C6环烷氧基或C1-C3卤代烷基取代、氰基、硝基、羟基、氨基、氧膦基、磺酰基、磺酰胺基所取代，“—”划过的环结构的表达方式，表示连接位点于该环结构上任意能够成键的位置。。
  3. 权利要求1所述的化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药作为α-突触核蛋白聚集体形成抑制剂的用途或者在制备用于减轻和/或消除帕金森症的药物中的用途，所述化合物具有下述式(III)所示的结构，
    在式(III)中，R1～R4独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基，R1和R2可以连接并与其连接的苯环中的原子共同形成环，R3和R4可以连接并与其连接的苯环中的原子共同形成环，
    R5、R6各自独立地为H、羟基、饱和或部分不饱和的C1-6烃基、饱和或部分不饱和的C1-6烃基-O-、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的C3-10环烃基-O-，优选为H，
    进一步优选的是R1～R4独立地选自H、甲基、乙基、丙基，R1和R2可以连接成为亚甲基、亚乙基，R3和R4可以连接成为亚甲基、亚乙基，
    R5、R6各自独立地为H、羟基、甲氧基、乙氧基，
    更进一步优选的是其中，R1～R4中的三个以上为H。
  4. [根据细则91更正 26.09.2023]
    权利要求1-3中任一项所述化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药作为α-突触核蛋白聚集体形成抑制剂的用途或者在制备用于减轻和/或消除帕金森症的药物中的用途，所述化合物选自以下具体化合物：
  5. [根据细则91更正 26.09.2023]
    式(I)所示的双四氢呋喃类化合物或者其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，
    式(I)中，环A和环B分别独立地表示取代或未取代的C6-10芳香环、或者取代或未取代的C5-14杂芳香环，优选苯环、吡啶环、吡咯环；
    X1和X2分别独立地为NRC、O或S，优选为O或S，更优选为O，
    各RC独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基或者C6-12芳烷基，优选为H、C1-6烷基；
    Ra和Rb各自独立地为选自卤素、氨基、氰基、硝基、C1-6烷基、C1-6烷氧基、饱和或部分不饱和的C3-6环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、葡萄糖基、-C(＝O)Rd、-OC(＝O)Rd、-C(＝O)ORd、-ORd、-SRd、-S(＝O)Rd、-S(＝O)2Rd、-S(＝O)2N(Rd)2、-N(Rd)2、-C(＝O)N(Rd)2、-NRd-C(＝O)Rd、-NRd-C(＝O)ORd、-NRd-S(＝O)2-Rd、-NRd-C(＝O)-N(Rd)2、-C1-6亚烷基-N(Rd)2、-C1-6亚烷基-ORd、-C1-6亚烯基-OR8和-O-C1-6亚烷基-N(R8)2，m和n分别独立地为1～4的整数，优选为2～3的整数，进一步优选为2；条件是，Ra中至少2个为-ORd基团，Rb中至少2个为-ORd基团，
    各Rd独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、C5-14杂芳基或者C6-12芳烷基，多个Rd之间可以连接并与构成环A的原子共同形成环，条件是多个Rd中至少一个为H，
    Y和Z分别独立地表示选自H、卤素、NH2、OH、SH、C1-6烷基取代氨基、取代或未取代的C1-10的脂肪族烃基、取代或未取代的饱和或部分不饱和的C3-10的杂环基、取代或未取代的C6-10芳基、或者取代或未取代的C5-14的杂芳基、-C(＝O)RX、-OC(＝O)RX、-C(＝O)ORX、-ORX、-SRX、-S(＝O)RX、-S(＝O)2RX、-S(＝O)2N(RX)2、-N(RX)2、-C(＝O)N(RX)2、-NRX-C(＝O)RX、-NRX-C(＝O)ORX、-NRX-S(＝O)2-RX、C(＝O)-N(RX)2、-C1-6亚烷基-N(RX)2、-C1-6亚烷基-ORX、-C1-6亚烯基-ORX和-O-C1-6亚烷基-N(RX)2；其中，RX为H、胍基、C1～C6烷基、饱和或部分不饱和的C3-6环烃基、饱和或部分不饱和的3-10元杂环基或者C6-10芳基；Y和Z分别独立地优选为H、卤素、甲基、乙基、OH、甲氧基；
    此处“取代或未取代”中的“取代”是指任选地被1-3个卤素、C1-C3烷基、C1-C3烷氧基、C1-C6环烷基、C1-C6环烷氧基或C1-C3卤代烷基取代、氰基、硝基、羟基、氨基、氧膦基、磺酰基、磺酰胺基所取代，“—”划过的环结构的表达方式，表示连接位点于该环结构上任意能够成键的位置，
    其中，式(I)所示的化合物不包括以下化合物
  6. [根据细则91更正 26.09.2023]
    根据权利要求5所述的化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，所述化合物具有下述式(II)的结构，
    在式II中，X1和X2表达的意思与权利要求1中相同，
    R1～R4独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、C5-14杂芳基或者C6-12芳烷基，优选为H、C1-6烷基，R1和R2可以连接并与其连接的苯环中的原子共同形成环，R3和R4可以连接并与其连接的苯环中的原子共同形成环，
    R5、R6各自独立地为H、羟基、饱和或部分不饱和的C1-6烃基、饱和或部分不饱和的C1-6烃基-O-、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的C3-10环烃基-O-、饱和或部分不饱和的C3-10环烃基-NH-、取代的饱和或部分不饱和的C1-6烃基、取代的饱和或部分不饱和的C3-10环烃基中的一种，优选为H、羟基，
    Y和Z分别独立地表示选自H、卤素、NH2、OH、SH、C1-6烷基取代氨基、取代或未取代的C1-10的脂肪族烃基、取代或未取代的饱和或部分不饱和的C3-10的杂环基、取代或未取代的C6-10芳基、或者取代或未取代的C5-14的杂芳基、-C(＝O)RX、-OC(＝O)RX、-C(＝O)ORX、-ORX、-SRX、-S(＝O)RX、-S(＝O)2RX、-S(＝O)2N(RX)2、-N(RX)2、-C(＝O)N(RX)2、-NRX-C(＝O)RX、-NRX-C(＝O)ORX、-NRX-S(＝O)2-RX、C(＝O)-N(RX)2、-C1-6亚烷基-N(RX)2、-C1-6亚烷基-ORX、-C1-6亚烯基-ORX和-O-C1-6亚烷基-N(RX)2；其中，RX为H、胍基、C1～C6烷基、饱和或部分不饱和的C3-6环烃基、饱和或部分不饱和的3-10元杂环基或者C6-10芳基；Y和Z分别独立地优选为H、卤素、甲基、乙基、OH、甲氧基；
    此处“取代或未取代”中的“取代”是指任选地被1-3个卤素、C1-C3烷基、C1-C3烷氧基、C1-C6环烷基、C1-C6环烷氧基或C1-C3卤代烷基取代、氰基、硝基、羟基、氨基、氧膦基、磺酰基、磺酰胺基所取代，“—”划过的环结构的表达方式，表示连接位点于该环结构上任意能够成键的位置。
  7. [根据细则91更正 26.09.2023]
    权利要求5所述的化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，所述化合物具有下述式(III)所示的结构，
    在式(III)中，R1～R4独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基，R1和R2可以连接并与其连接的苯环中的原子共同形成环，R3和R4可以连接并与其连接的苯环中的原子共同形成环，
    R5、R6各自独立地为H、羟基、饱和或部分不饱和的C1-6烃基、饱和或部分不饱和的C1-6烃基-O-、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的C3-10环烃基-O-，优选为H，
    进一步优选的是，R1～R4独立地选自H、甲基、乙基、丙基，R1和R2可以连接成为亚甲基、亚乙基，R3和R4可以连接成为亚甲基、亚乙基，
    R5、R6各自独立地为H、羟基、甲氧基、乙氧基，
    更进一步优选的是，其中，R1～R4中的三个以上为H。
  8. [根据细则91更正 26.09.2023]
    权利要求5所述的化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药，所述化合物选自以下具体化合物：
PCT/CN2023/111505 2022-08-05 2023-08-07 双四氢呋喃类化合物作为α-突触核蛋白聚集体形成抑制剂的用途、包含其的药物组合物 WO2024027845A1 (zh)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006112686A1 (en) * 2005-04-21 2006-10-26 The Industry & Academic Cooperation In Chungnam National University Novel lignan compounds, their preparation methods and their uses
KR20100092094A (ko) * 2009-02-12 2010-08-20 숙명여자대학교산학협력단 신이로부터 분리된 리그난 성분과 그 용도
JP2017169547A (ja) * 2016-03-25 2017-09-28 国立大学法人 筑波大学 新規タンパク質及びその使用
CN108403683A (zh) * 2018-01-18 2018-08-17 山东大学 松脂醇在制备防治氧化应激诱发疾病的产品中的应用
KR20200121495A (ko) * 2019-04-16 2020-10-26 동아대학교 산학협력단 퇴행성 뇌질환의 예방 또는 치료용 약학적 조성물
CN112521396A (zh) * 2020-11-18 2021-03-19 右江民族医学院 连翘脂素衍生物及其制备方法和应用
CN114409667A (zh) * 2022-01-11 2022-04-29 西北农林科技大学 一种杜仲叶木脂素类化合物、制备方法及神经保护的应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006112686A1 (en) * 2005-04-21 2006-10-26 The Industry & Academic Cooperation In Chungnam National University Novel lignan compounds, their preparation methods and their uses
KR20100092094A (ko) * 2009-02-12 2010-08-20 숙명여자대학교산학협력단 신이로부터 분리된 리그난 성분과 그 용도
JP2017169547A (ja) * 2016-03-25 2017-09-28 国立大学法人 筑波大学 新規タンパク質及びその使用
CN108403683A (zh) * 2018-01-18 2018-08-17 山东大学 松脂醇在制备防治氧化应激诱发疾病的产品中的应用
KR20200121495A (ko) * 2019-04-16 2020-10-26 동아대학교 산학협력단 퇴행성 뇌질환의 예방 또는 치료용 약학적 조성물
CN112521396A (zh) * 2020-11-18 2021-03-19 右江民族医学院 连翘脂素衍生物及其制备方法和应用
CN114409667A (zh) * 2022-01-11 2022-04-29 西北农林科技大学 一种杜仲叶木脂素类化合物、制备方法及神经保护的应用

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
LIU W J; CHEN Y J; CHEN D N; WU Y P; GAO Y J; LI J; ZHONG W J; JIANG L: "A new pair of enantiomeric lignans from the fruits of Morinda citrifolia and their absolute configuration", NATURAL PRODUCT RESEARCH, TAYLOR & FRANCIS, LONDON, 1 January 2018 (2018-01-01), London , pages 933 - 938, XP018530715, ISSN: 1478-6427 *
NANAKO HAMADA; ARISA TANAKA; YASUNORI FUJITA; TOMOHIRO ITOH; YOSHIKO ONO; YOSHINORI KITAGAWA; NAMINO TOMIMORI; YOSHINOBU KISO; YUK: "Involvement of heme oxygenase-1 induction via Nrf2/ARE activation in protection against HO-induced PC12 cell death by a metabolite of sesamin contained in sesame seeds", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 19, no. 6, 28 January 2011 (2011-01-28), AMSTERDAM, NL, pages 1959 - 1965, XP028176798, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2011.01.059 *
TOURANDOKHT BALUCHNEJADMOJARAD, MONIREH MANSOURI, JAMILEH GHALAMI, ZAHRA MOKHTARI, MEHRDAD ROGHANI: "Sesamin imparts neuroprotection against intrastriatal 6-hydroxydopamine toxicity by inhibition of astroglial activation, apoptosis, and oxidative stress", BIOMEDICINE & PHARMACOTHERAPY, ELSEVIER, FR, vol. 88, 1 April 2017 (2017-04-01), FR , pages 754 - 761, XP055456470, ISSN: 0753-3322, DOI: 10.1016/j.biopha.2017.01.123 *
WANG QING, YAO SHENG, YANG ZE-XIAN, ZHOU CHEN, ZHANG YU, ZHANG YE, ZHANG LEI, LI JIN-TIAN, XU ZHI-JIAN, ZHU WEI-LIANG, ZHANG NAI-X: "Pharmacological characterization of the small molecule 03A10 as an inhibitor of α-synuclein aggregation for Parkinson’s disease treatment", ACTA PHARMACOLOGICA SINICA, NATURE PUBLISHING GROUP, GB, vol. 44, no. 6, 1 June 2023 (2023-06-01), GB , pages 1122 - 1134, XP093136243, ISSN: 1671-4083, DOI: 10.1038/s41401-022-01039-6 *

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