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WO2008083543A1 - Composés modifiés hétérocycliques contenant de l'azote et leurs utilisations - Google Patents

Composés modifiés hétérocycliques contenant de l'azote et leurs utilisations Download PDF

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Publication number
WO2008083543A1
WO2008083543A1 PCT/CN2007/002985 CN2007002985W WO2008083543A1 WO 2008083543 A1 WO2008083543 A1 WO 2008083543A1 CN 2007002985 W CN2007002985 W CN 2007002985W WO 2008083543 A1 WO2008083543 A1 WO 2008083543A1
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Prior art keywords
compound
salt
residue
disease
group
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English (en)
Chinese (zh)
Inventor
Yanmei Li
Weihui Wu
Peng Lei
Xiaoyang Su
Jia Hu
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Tsinghua University
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Tsinghua University
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Priority claimed from CNB2007100626299A external-priority patent/CN100551910C/zh
Priority claimed from CN2007100626284A external-priority patent/CN100999546B/zh
Priority claimed from CNB2007100626301A external-priority patent/CN100551911C/zh
Application filed by Tsinghua University filed Critical Tsinghua University
Publication of WO2008083543A1 publication Critical patent/WO2008083543A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to compounds and their use, and more particularly to compounds having nitrogen-containing heterocyclic modifications and their use in the manufacture of a medicament for the treatment and prevention of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and type 2 diabetes.
  • Nervous system degenerative diseases such as Alzheimer's disease and Parkinson's disease and type 2 diabetes are protein conformations.
  • AD Alzheimer's disease
  • a central nervous system degenerative disease clinical manifestations of cognitive impairment, memory loss, eventually loss of thinking ability, movement disorders, life Can't take care of themselves.
  • Pathological features are mainly senile plaque (SP), neurofibrillary tangles (NFT), and selective neuronal and synaptic loss.
  • the main drug for clinical treatment of this disease is cholinesterase inhibitor, which acts on the cholinergic nervous system and has a mitigating effect on the disease, but it cannot prevent the occurrence and development of the disease.
  • the pathogenesis of Alzheimer's disease is not very clear, but it is generally believed that the key cause of the disease is the accumulation of excess ⁇ -amyloid peptide ( ⁇ -amyloid peptide, ⁇ ).
  • the main component has a detrimental effect on cell membranes, synapses and axons, and leads to neurofibrillary tangles. Therefore, preventing the aggregation of ⁇ or degrading ⁇ can inhibit and eliminate the toxicity of ⁇ , thereby achieving the purpose of treating and preventing Alzheimer's disease.
  • An object of the present invention is to provide a compound having a nitrogen-containing heterocyclic ring modification which has an inhibitory effect on the aggregation of ⁇ , and which has a depolymerization effect on ⁇ aggregates and finally degrades ⁇ .
  • the nitrogen-containing heterocyclic modified compound provided by the present invention includes a polyphenol compound, a polypeptide compound, and a styryl compound.
  • Cyclen N-linked-1,4,7,10-tetraazacyclododecane
  • Trpn N-linked-indole, ⁇ '-bis(3-aminopropyl)propane-1,3- Diamine
  • ⁇ is preferably 1
  • 3 ⁇ 4 is preferably one of 20 natural amino acid residues or a corresponding amino acid residue having a modifying group (more preferably a methyl modified amino acid residue),
  • m is preferably 0 -3 (more preferably 1);
  • Yi is preferably curcumin (Cur), nordihydroguaiaretic acid (NDGA) or rosmarinic acid (RA).
  • the chemical structural formula of Cyclen is as shown in Formula IV: (Formula IV)
  • the chemical structural formula of the Tpn is as shown in Formula V
  • the polyphenol compound of the formula I is more preferably a glycine residue, a leucine residue, an isoleucine, an alanine residue, a proline residue, or a styrene-butene.
  • a tyrosine residue or a tyrosine residue particularly preferably a glycine residue, a leucine residue, an isoleucine, or an alanine residue.
  • the amino acid residue constituting the polyphenolic compound may be a D form (dextrorotatory), an L form (left-handed) conformation, preferably a D-type conformation.
  • the nitrogen-containing heterocyclic modified polypeptide compound provided by the present invention has the structural formula of the formula:
  • R 2 in the formula II is preferably Cyclen (N-linked-1,4,7,10-tetraazacyclotetradecene) or Trpn (3, 3- ', 3"-triaminotripropylamine); n is preferably 1; X 2 is preferably one of 20 natural amino acid residues or a corresponding amino modification (preferably methyl modified), m preferably 3 -5 (more preferably 5) The chemical structural formula of Cyclen is as shown in Formula IV; the chemical structural formula of the Trpii is as shown in Formula V.
  • X 2 is a lysine residue, a leucine residue, a proline residue, a phenylalanine residue, a tyrosine residue or an aspartic acid residue.
  • X 2 is particularly preferably a leucine residue, a proline residue, an aspartic acid residue or an amino acid residue constituting the polypeptide compound, which may be D-form (dextrorotatory), L-form (left-handed) conformation, It is preferably a D-type conformation.
  • the nitrogen-containing heterocyclic modified styrene compound provided by the present invention has the structural formula of the formula:
  • the R 3 is preferably Cyclen (N-linked-1,4,7,10-tetraazacyclododecane) or Trpn (N-linked-oxime, ⁇ '-bis(3-aminopropyl)propanoid-1 , 3-diamine); ⁇ is preferably 1; ⁇ 3 is preferably one of 20 natural amino acid residues or a corresponding amino acid residue having a modifying group (preferably methyl modified), m preferably 0- 3 (more preferably 1); Y 3 is preferably Congo red (CR) or Benzoic acid (3,3 '-[1 ,4-phenylenedi-(lE)-2,l -ethenediyl] bis [6-hydroxy-], BA).
  • the chemical structural formula of the Cyclen is as shown in Formula IV; the chemical structural formula of the Trpn is as shown in Formula V.
  • the structural formula of the BA is as (Formula XI)
  • X in the structural formula (Formula III) of the above styryl compound is more preferably a glycine residue, a leucine residue, an isoleucine, an alanine residue, a proline residue, or a benzene.
  • X is particularly preferably a glycine residue, a leucine residue, an isoleucine or an alanine residue.
  • the amino acid residue constituting the styryl compound may be D type (dextrorotatory), L type (left-handed) conformation, preferably L-shaped conformation.
  • polyphenols, polypeptides and styrenated foods provided by the present invention can be synthesized by various conventional chemical synthesis methods, for example, by the method of ester formation or amide formation in the presence of a coupling agent or other methods for synthesizing Formula I and a compound of the formula III; a compound of the formula II can be synthesized by solid phase synthesis, including t-Boc chemistry and 9-fluorenylmethoxycarbonyl (Fmoc) chemistry, preferably 9 - ⁇ methoxycarbonyl Chemical law.
  • Another object of the present invention is to provide a medicament for the treatment and prevention of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and type 2 diabetes.
  • the active ingredient of the medicament provided by the present invention is a polyphenol, a polypeptide, a styrene compound, a complex of the above compound with a transition metal copper, cobalt, nickel, palladium, zinc or iron, and a salt of the above compound.
  • a polyphenol a polypeptide
  • a styrene compound a complex of the above compound with a transition metal copper, cobalt, nickel, palladium, zinc or iron, and a salt of the above compound.
  • a transition metal copper cobalt, nickel, palladium, zinc or iron
  • polyphenols, polypeptides and styrenic compounds may also be in the form of a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include those derived from organic or inorganic bases, organic or inorganic acids. Salts obtained from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts and zinc salts, etc., effects Preferred are ammonium salts, potassium salts, calcium salts, lithium salts, magnesium salts and sodium salts; pharmaceutically acceptable non-toxic organic base salts include primary, secondary and tertiary amine salts.
  • the acid to be reacted with the polyphenols, polypeptides and styrenic compounds provided by the present invention includes hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid and the like.
  • one or more pharmaceutically acceptable carriers may be added to the above-mentioned drugs, including conventional diluents, excipients, protective agents, absorption enhancers, fillers, binders, humectants in the pharmaceutical field. , disintegrants, surfactants, etc.
  • the excipient may be carboxymethyl starch, gelatin, cellulose, sodium hydrogencarbonate, sodium chloride or polyethylene glycol;
  • the protective agent may be EDTA or benzylammonium;
  • the absorption enhancer may be poly Sorbate-80, azone, carboxymethylcellulose or 9-dodecyl ether, and the like.
  • the medicament of the present invention can also be formulated into a plurality of pharmaceutical forms such as tablets, injections, solutions, granules and the like.
  • the above various dosage forms of the drug can be prepared according to a conventional method in the pharmaceutical field.
  • the oral dose of the drug is generally 0.05-50 mg/kg, which can be used one or more times for 1 to 6 months.
  • Figure 1 shows the experimental results of the inhibition of ⁇ aggregation by polyphenols by ThT fluorescence.
  • Figure 2 is the experimental results of the depolymerization of phenolic aggregates by polyphenols.
  • Figure 3 shows the results of inhibition of ⁇ aggregation by peptides detected by ThT fluorescence assay.
  • Figure 4 shows the results of the depolymerization of ⁇ aggregates by peptide compounds.
  • Figure 5 is an experimental result of the inhibition of ⁇ aggregation by styrene-based compounds by ThT fluorescence.
  • Figure 6 is the experimental result of depolymerization of stilbene-based compounds to ⁇ aggregates.
  • Figure 7 shows the results of electron microscopic observation on the inhibition of ⁇ aggregation by peptide compounds.
  • Figure 8 shows the results of electron microscopic observation of the depolymerization of peptides on ⁇ aggregates.
  • Figure 9 is an electron microscopic observation of the inhibitory effect of polyphenols on ⁇ aggregation.
  • Figure 10 is an electron microscopic observation of the inhibitory effect of styryl compounds on ⁇ aggregation.
  • Figure 11 shows the results of MALDI-TOF-MS analysis of the hydrolysis of ⁇ by polyphenols.
  • Figure 12 shows the results of MALDI-TOF-MS analysis of the cleavage of ⁇ by peptides.
  • 13 is a polyphenol compound produced results ⁇ 2 0 2 Inhibition of copper-mediated ⁇
  • FIG 14 is a peptide compounds produced inhibition results 3 ⁇ 40 2 of copper-mediated ⁇
  • Figure 15 is an analysis result of the inhibition effect of styrene-based compounds on copper-mediated ⁇ production
  • Figure 16 is the result of analysis of protective effects of polyphenols on rat hippocampal neurons by inhibiting ⁇ toxicity
  • Figure 17 is the analysis of the protective effect of peptide compounds on rat hippocampal neurons by inhibiting ⁇ toxicity.
  • Figure 18 shows the results of analysis of the protective effect of styryl compounds on rat hippocampal neurons by inhibiting ⁇ toxicity.
  • the synthesis of the polyphenolic compound of the formula XII of the present invention comprises the following steps:
  • Cyclen-containing monomer [4,7,10-tri-tert-butoxycarbonyl-1,4,7,10-tetraazacyclodene-1-yl]acetic acid: with Cyclen (purchased from Acros, USA) Company) as raw material, first reacted with Boc20 (di-tert-butyl dicarbonate, purchased from Shanghai Jill Biochemical Company) to obtain 1,4,7-tri-tert-butoxycarbonyl-1,4,7,10-tetraazacyclo Second House (3B 0C -Cyclen) (see Eiichi Kimura, Shin Aoki, Tohru Koike, and Motoo Shiro, A Tris(ZnII-1,4,7, 10-tetraazacyclododecane) Complex as a New Receptor for Phosphate Dianions in Aqueous Solution, Journal of American Chemical Society, 1997, Vol 119, 3068-3076), and reacting the product with ethyl bromoacetate (see Jo
  • step c After the reaction of the step b, the crude product was separated by a silica gel column (column separation conditions: ethyl acetate: petroleum ether (1: 4)), and the obtained product was removed with a cleavage reagent trifluoroacetic acid (TFA, purchased from Shanghai Jill Biochemical Co., Ltd.).
  • TFA cleavage reagent trifluoroacetic acid
  • the polyphenolic compound prepared by the above method has a correct structure, and its structural formula is as shown in Formula XII, and the purity is over 95%.
  • the synthesis of the polyphenolic compound of the formula XIII of the present invention comprises the following steps: a. glycine methyl ester (purchased from Shanghai Jill Biochemical Co., Ltd.) and Cyclen containing monomer [4,7,10-tri-tert-butoxycarbonyl-1, 4,7,10-tetraazacyclotetradecyl-1-yl]acetic acid coupling, the coupling condition is the coupling agent HBTU (purchased from Shanghai Yansheng Biochemical Company), HOBt (purchased from Shanghai Jill Biochemical Company), 1 times The amount of the Tpnn-containing monomer, 1 time amount of glycine methyl ester, 1 time amount of coupling agent HBTU and 1 time amount of HOBt were reacted at room temperature for 12 hours to obtain a coupling product.
  • HBTU purchased from Shanghai Yansheng Biochemical Company
  • HOBt purchased from Shanghai Jill Biochemical Company
  • step b After the reaction of the step a, the crude product is separated by a silica gel column (column separation conditions: ethyl acetate: petroleum ether (1: 4)) to obtain a glycine methyl ester containing a cyclen monomer, and then hydrolyzed with NaOH (see Joong Won).
  • a silica gel column column separation conditions: ethyl acetate: petroleum ether (1: 4)
  • step b The product obtained in step b is coupled with curcumin under the conditions of coupling agent EDC (purchased from Shanghai Yansheng Biochemical Co., Ltd.), HOBt (purchased from Shanghai Jill Biochemical Co., Ltd.) and catalyst DMAP (mixing ratio: 4 times the amount) Glycine containing Cyclen monomer, 1x amount of curcumin, 4 times the amount of coupling agent EDC and 4 times the amount of HOBt) were reacted at room temperature for 15 hours to obtain a coupled product.
  • EDC purchased from Shanghai Yansheng Biochemical Co., Ltd.
  • HOBt purchased from Shanghai Jill Biochemical Co., Ltd.
  • catalyst DMAP mixture: 4 times the amount Glycine containing Cyclen monomer, 1x amount of curcumin, 4 times the amount of coupling agent EDC and 4 times the amount of HOBt
  • step d After the reaction of the step c, the crude product was separated by a silica gel column (column separation conditions: ethyl acetate: petroleum ether (1: 4)), and the obtained product was subjected to a cleavage reagent, trifluoroacetic acid (TFA, purchased from Shanghai Jill Biochemical Co., Ltd.). The Boc protecting group is removed to give a crude polyphenolic compound.
  • the polyphenolic compound prepared by the above method has a correct structure, and its structural formula is as shown in Formula XIII, and the purity is over 95%.
  • Example 3 Preparation of polyphenolic compounds of the formula IX
  • the synthesis of the polyphenolic compound of the formula IX of the present invention comprises the following steps: a. Trpn-containing monomer [3(3',3"-di-tert-butoxycarbonyl-3',3"-diamino)aminopropyl.
  • the coupling condition is a coupling agent EDC (purchased from Shanghai Yansheng Biochemical Company), HOBt (purchased from Shanghai Jill Biochemical Co., Ltd.) and catalyst DMAP (mixing ratio: 4 times the amount of Tripn-containing monomer, 1 times the amount of curcumin, 4 times the amount of even The mixture EDC was reacted with 4 times the amount of HOBt) at room temperature for 15 hours to obtain the objective product.
  • EDC purchasedd from Shanghai Yansheng Biochemical Company
  • HOBt purchased from Shanghai Jill Biochemical Co., Ltd.
  • catalyst DMAP mixture
  • step c After the reaction of the step b, the crude product was separated by a silica gel column (column separation conditions: ethyl acetate: petroleum ether (1: 4)), and the obtained product was removed with a cleavage reagent trifluoroacetic acid (TFA, purchased from Shanghai Jill Biochemical Co., Ltd.). The protecting group is obtained to obtain a crude polyphenol compound.
  • the polyphenolic compound prepared by the above method has a correct structure, and its structural formula is as shown in Formula IX, and the purity is over 95%.
  • the synthesis of the polypeptide compound of the formula XV of the present invention comprises the following steps:
  • the amino acids (phenylalanine, phenylalanine, valine, leucine, lysine) were linked one by one according to the Fmoc solid phase synthesis strategy on Wang resin (purchased from Shanghai Jill Biochemical Co., Ltd.). It is said that the C terminal of the compound is a carboxyl group (a COOH), a Wang resin is used, and the C terminal is an amide (a CONH 2 ) ruthenium using a Rink resin).
  • Cyclen-containing monomer [4,7,10-tri-tert-butoxycarbonyl-1,4,7,10-tetraazacyclodene-1-yl]B
  • the acid is linked to the small peptide containing the Wang resin obtained in the step a by the method of linking the amino acids in the step a, and the coupling condition is the coupling agent HBTU (purchased from Shanghai Yansheng Biochemical Co., Ltd.) and HOBt (purchased from Shanghai Jill Biochemical Co., Ltd.) in the presence of Ratio: 4 times the amount of the Cyclen-containing monomer, 1 time of the small resin containing the Wang resin, 4 times the amount of the coupling agent HBTU and 4 times the amount of HOBt) were reacted at room temperature for 3 hours to obtain the objective product.
  • HBTU purchased from Shanghai Yansheng Biochemical Co., Ltd.
  • HOBt purchased from Shanghai Jill Biochemical Co., Ltd.
  • the polypeptide portion of the polypeptide-linked resin obtained by the reaction of the step c is cleaved off with the resin, and the protective group is removed, and filtered.
  • the TFA was removed to obtain a crude polypeptide compound.
  • the polypeptide compound prepared by the above method has the correct structure, and its structural formula is as shown in the formula XV, and the purity is over 95%.
  • the synthesis of the polypeptide compound of the formula XVI of the present invention comprises the following steps: a.
  • the amino acid phenylalanine, phenylalanine, valine, leucine, lysine
  • glycine are attached one by one to Wang resin.
  • the polypeptide moiety in the polypeptide-attached resin obtained by the reaction of the step b is cleaved from the resin by the cleavage reagent trifluoroacetic acid (TFA) used in the synthesis of the polypeptide, and the protective group is removed to obtain a crude polypeptide compound.
  • TFA cleavage reagent trifluoroacetic acid
  • polypeptide compound prepared by the above method has the correct structure, and its structural formula is as shown in Formula XVI, and the purity is over 95%.
  • the synthesis of the polypeptide compound of the formula XVII of the present invention comprises the following steps:
  • polypeptide moiety in the polypeptide-attached resin obtained by the reaction of the step b is separated from the resin by the cleavage reagent trifluoroacetic acid (TFA) used in the synthesis of the polypeptide, and the protective group is removed to obtain a crude polypeptide compound.
  • TFA cleavage reagent trifluoroacetic acid
  • the synthesis of the polypeptide compound of the formula XVIII of the present invention comprises the following steps: a.
  • the amino acid phenylalanine, phenylalanine, valine, leucine, lysine
  • Trnpn-containing monomer [3 (3''3''-di-tert-butoxycarbonyl-3''3''-diamino)aminopropylamino]acetic acid and the small Wang resin-containing resin obtained in the step a Peptide-linked, in the presence of coupling agents HBTU and HOBt
  • the cleavage reagent trifluoroacetic acid (TFA) used in the synthesis of the polypeptide is cleaved from the resin in the polypeptide-attached resin obtained by the reaction of the step c, and the protective group is removed to obtain a crude polypeptide compound.
  • the crude polypeptide compound was isolated by HPLC method (isolation conditions were the same as in Example 4) to obtain a pure peptide compound.
  • the polypeptide compound prepared by the above method has a correct structure, and its structural formula is as shown in Formula XVIII, and the purity is over 95%.
  • the synthesis of the styryl compound of the formula XIX of the present invention comprises the following steps: a. Congo red (purchased from Sigma, USA) and containing. ( ⁇ 11 monomer [4,7,10-tri-tert-butoxycarbonyl-1,4,7,10-tetraazacyclotetradecyl]-acetic acid coupling, the coupling condition is the coupling agent EDC (purchased from Shanghai Prolonged biochemical company), HOBt (purchased from Shanghai Jill Biochemical Co., Ltd.) and catalytic amount DMAP (Acros, USA) in the presence of (mixing ratio: 4 times the amount of Cyclen-containing monomer, 1 times the amount of Congo red, 4 times the amount The coupling agent EDC, 4 times the amount of HOBt and a catalytic amount of DMAP) were reacted at room temperature for 15 hours to obtain the desired product.
  • EDC purchased from Shanghai Prolonged biochemical company
  • HOBt purchasedd from Shanghai Jill Biochemical Co., Ltd.
  • step b After the reaction of the step b, the crude product was separated by a silica gel column (column separation conditions: ethyl acetate: petroleum ether (1: 4)), and the obtained product was subjected to a cleavage reagent, trifluoroacetic acid (TFA, purchased from Shanghai Jill Biochemical Co., Ltd.). Removal of the protecting group gives a crude styrene-based compound.
  • TFA trifluoroacetic acid
  • the styrene-based compound prepared by the above method has a correct structure, and its structural formula is as shown in the formula XIX, and the purity is over 95%.
  • the synthesis of the styryl compound of the formula XX of the present invention comprises the following steps:
  • a. benzoic acid purchased from Sigma, USA
  • Cyclen-containing monomer [4,7,10-tri-tert-butoxycarbonyl-1,4,7,10-tetraazacyclotetradecyl]acetic acid Coupling
  • the connection condition is the coupling agent EDC (purchased from Shanghai Yan Long biochemical company), HOBt (purchased from Shanghai Jill Biochemical Company) and DMAP in the presence of (mixing ratio: 4 times the amount of Cyclen containing monomer, 1 times the amount of benzoic acid, 4 times the amount of coupling agent EDC and 4 times The amount of HOBt) was reacted at room temperature for 15 hours to obtain the objective product.
  • step b After the reaction of the step b, the crude product was separated by a silica gel column (column separation conditions: ethyl acetate: petroleum ether (1: 4)), and the obtained product was subjected to a cleavage reagent, trifluoroacetic acid (TFA, purchased from Shanghai Jill Biochemical Co., Ltd.). Removal of the protecting group gives a crude styrene-based compound.
  • TFA trifluoroacetic acid
  • the styrene-based compound prepared by the above method has the correct structure, and its structural formula is as shown in Formula XX, and the purity is over 95%.
  • the synthesis of the styryl compound of the formula XXI of the present invention comprises the following steps:
  • step b After the reaction of step b, the crude product is separated by a silica gel column (column separation conditions: ethyl acetate: petroleum ether)
  • the styrene-based compound prepared by the above method has a correct structure, and its structural formula is as shown in the formula XXI, and the purity is over 95%.
  • the synthesis of the harmless vinyl compound of the formula XXII of the present invention comprises the following steps : a. Glycine methyl ester (purchased from Shanghai Jill Biochemical Co., Ltd.) and Trpn-containing monomer [3(3''3''-di-tert-butoxycarbonyl-3''3''-diamino)aminopropylamino] Acetic acid (according to the embodiment 3a) coupling, the connection conditions are the coupling agent HBTU (purchased from Shanghai Yansheng Biochemical Company), HOBt (purchased from Shanghai Jill Biochemical Company), 1 times the amount of TRP-containing monomer, 1 time The amount of glycine methyl ester, 1 time amount of coupling agent HBTU and 1 time amount of HOBt were reacted at room temperature for 12 hours to obtain a coupled product.
  • HBTU purchased from Shanghai Yansheng Biochemical Company
  • HOBt purchased from Shanghai Jill Biochemical Company
  • the crude product is separated by a silica gel column (column separation conditions: ethyl acetate: petroleum ether (1: 4)) to obtain a glycine methyl ester containing a Trpn monomer and then hydrolyzed with NaOH (see Joong Won). Jeon,
  • step b Coupling the product obtained in step b with benzoic acid under the conditions of coupling agent EDC (purchased from Shanghai Yansheng Biochemical Co., Ltd.), HOBt (purchased from Shanghai Jill Biochemical Co., Ltd.) and catalyst DMAP (mixing ratio: 4 times the amount)
  • EDC purchased from Shanghai Yansheng Biochemical Co., Ltd.
  • HOBt purchased from Shanghai Jill Biochemical Co., Ltd.
  • catalyst DMAP mixture: 4 times the amount
  • the Tpn-containing monomer, 1 time amount of benzoic acid, 4 times the amount of coupling agent EDC and 4 times the amount of HOBt were reacted at room temperature for 15 hours to obtain a coupled product.
  • step c After the reaction of step c, the crude product is separated by a silica gel column (column separation conditions: ethyl acetate: petroleum ether)
  • the styrene-based compound prepared by the above method has the correct structure, and its structural formula is as shown in formula XXII, and the purity is over 95%.
  • ⁇ is aggregated into fibers under near physiological conditions in vitro.
  • the fibers can be combined with Thioflavin T (ThT) to exhibit specific fluorescence at an excitation wavelength of 440 nm and an emission wavelength of 485 nm.
  • the intensity can quantitatively reflect the number of fibers, so that the quantitative determination of the degree of ⁇ aggregation can be achieved.
  • ThT fluorescence method is now used to detect the inhibition of ⁇ aggregation by the polyphenolic compounds provided by the present invention and the depolymerization of ⁇ aggregates.
  • the experimental methods are as follows:
  • ⁇ 42 stock solution preparation Add hexafluoroisopropanol (HFIP, Acros, USA) to ⁇ 42 (purchased from American Peptide Company), make the peptide concentration Img/mL, shake gently for 12 hours at room temperature, blow dry with nitrogen, add The 200 ⁇ & ⁇ solution was prepared into a ⁇ ⁇ 42 stock solution and stored in a -80 ° C refrigerator.
  • Preparation of polyphenolic compound stock solution The compounds synthesized in Examples 1, 2, and 3 were separately added to PBS with pH 7.4 (Na 2 HP0 4 -12H 2 0 3.73 g, KH 2 P0 4 0.43 g, NaCl 7.2 g). Prepare a 1.92 mM stock solution by adding water to 1000 mL) and store in a -80 °C freezer.
  • the above polyphenolic compound stock solution and copper chloride Take the 42 ⁇ 42 stock solution, the above polyphenolic compound stock solution and copper chloride to prepare a solution containing 20 ⁇ ⁇ 42, 0 to 160 ⁇ of the above polyphenolic compound and 0.4 to 128 ⁇ ⁇ ⁇ 2+ , adjusted to pH 7.4 at 37 ° C After 3 days of incubation, the ⁇ 42 stock solution incubated under the same conditions was used as a control.
  • the ThT measurement method was as follows: 20 ul of the incubation sample solution was placed in a 700 ul ⁇ ThT (pH 7.4) solution, and the mixture was uniformly mixed, and the fluorescence absorption at an excitation wavelength of 440 nm and an emission wavelength of 485 nm was measured.
  • the detection result is shown in FIG. 1 , and the degree of aggregation of the blank sample of ⁇ 42 is 100%, and is added to the embodiment of the present invention.
  • the ⁇ 42 stock solution was taken, diluted to a solution containing 20 ⁇ M ⁇ 42, adjusted to pH 7.4, and then incubated at 37 °C. Two days later, ThT fluorescence and electron microscopy (TEM) were performed on the incubation samples, and it was found that ⁇ 42 was aggregated, and then the polyphenol compound stock solution and copper chloride synthesized by the present invention were separately added to prepare 20, 40, 80 ⁇ m, respectively.
  • the phenolic compound and the solution of 16, 32, 64 ⁇ ⁇ ⁇ 2+ ( ⁇ 7.4) were further incubated at 37 ° C for 8 days, and the ThT fluorescence absorption of the ⁇ 42 solution was measured in the same manner as in the first step, and the continuous detection was carried out for 8 days. .
  • Example 13 ThT fluorescence detection of the inhibition of ⁇ aggregation by the polypeptide compounds of the present invention and the depolymerization of ⁇ aggregates
  • ⁇ will aggregate into fibers under near physiological conditions in vitro.
  • the fibers can be combined with thio yellow pigment TXThioflavin T, ThT).
  • TXThioflavin T ThT
  • emission wavelength (emission) 485nm specific fluorescence
  • fluorescence intensity can be Quantitatively reflects the number of fibers, so that the degree of aggregation of ⁇ can be quantitatively determined.
  • the ThT fluorescence method is now used to detect the inhibition of ⁇ aggregation by the polypeptide compounds of the present invention and the depolymerization of ⁇ aggregates.
  • the experimental method is as follows - formulating ⁇ 42 stock solution: adding hexafluoroiso to ⁇ 42 (purchased from American Peptide Company) Propanol (HFIP, purchased from Acros, USA), the peptide concentration was 1 mg/mL, shaken at room temperature for 12 hours, blown dry with nitrogen, and added to a solution of ⁇ ⁇ 42, which was placed in a -80 ⁇ refrigerator. save.
  • Formulating a stock solution of the polypeptide compound of the present invention dividing the polypeptide compound synthesized in Examples 4, 5, 6, and 7 2985 was mixed with pH 7.4 PBS (Na 2 HP0 4 -12H 2 0 3.73 g, KH 2 P0 4 0.43 g, NaCl 7.2 g, added water to 1000 mL, pH 7.4) to prepare a stock solution of 1.92 mM peptide compound. Store in a -80 ° C refrigerator.
  • the above-mentioned polypeptide compound stock solution and copper chloride were formulated into a solution containing 20 uM ⁇ 42, 0 to 160 uM of the above polypeptide compound and 0.4 to 128 ⁇ Cu 2+ , adjusted to pH 7.4, and incubated at 37 ° C.
  • the ⁇ 42 stock solution incubated under the same conditions was used as a control.
  • the ThT measurement method is as follows: 20 ul of the incubation sample solution is placed in a 700 ul lOuM ThT (pH 7.4) solution, and the mixture is homogenized to measure the fluorescence absorption at an excitation wavelength of 440 nm and an emission wavelength of 485 nm.
  • the degree of aggregation with the blank sample of ⁇ 42 was 100%, and the aggregation of ⁇ was significantly inhibited by the addition of the polypeptide compound of the present invention synthesized in Examples 4, 5, 6, and 7 (see the curve in Fig. 3).
  • I polypeptide compound prepared in Example 1
  • II polypeptide compound prepared in Example 5
  • III polypeptide compound prepared in Example 6
  • IV polypeptide compound prepared in Example 7
  • the compounds can significantly inhibit the aggregation of A ⁇ .
  • ⁇ 42 stock solution was taken, diluted to a solution containing 20 uM ⁇ 42, adjusted to pH 7.4, and then incubated at 37 °C. Two days later, ThT fluorescence and electron microscopy (TEM) were performed on the incubation samples, and it was found that ⁇ 42 was aggregated, and then the peptide compound compound solution and copper chloride synthesized by the present invention were separately added to prepare polypeptides containing 20, 40, and 80 ⁇ M, respectively.
  • TEM ThT fluorescence and electron microscopy
  • the compound and the solution of 16, 32, 64 ⁇ ⁇ ⁇ 2+ ( ⁇ 7.4) were further incubated at 37 ° C for 10 days, and the ThT fluorescence absorption of the ⁇ 42 solution was determined by the same method as in the first step, and the detection was continued until 10 day.
  • the detection results of the polypeptide compounds prepared in different concentrations in Example 4 are as shown in the curve II (20 ⁇ polypeptide compound), the curve III (40 ⁇ polypeptide compound), and the curve IV (80 ⁇ polypeptide compound) in FIG. 4, indicating The polypeptide compounds of the invention have a good depolymerization effect on the aggregated ⁇ 42 aggregates (curve I).
  • different concentrations of the polypeptide compounds synthesized in Examples 5, 6, and 7 also have a good depolymerization effect on the aggregated A ⁇ 42 aggregates, demonstrating that the polypeptide compounds of the present invention also have aggregated A ⁇ 42 aggregates. Very good depolymerization.
  • Example 14 ThT fluorescence method for the inhibition of ⁇ aggregation by the styryl compounds of the present invention and the depolymerization of ⁇ aggregates
  • ⁇ is aggregated into fibers under near physiological conditions in vitro.
  • the fibers can be combined with Thioflavin T (ThT) to exhibit specific fluorescence at an excitation wavelength of 440 nm and an emission wavelength of 485 nm.
  • the intensity can quantitatively reflect the number of fibers, so that the quantitative determination of the degree of ⁇ aggregation can be achieved.
  • ⁇ 42 stock solution preparation Add hexafluoroisopropanol (HFIP) to ⁇ 42 (purchased from American Peptide Company), make the peptide concentration lmg/mL, shake gently for 12 hours at room temperature, blow dry with nitrogen, add 200 ⁇ & ⁇ solution, prepare A 100 ⁇ ⁇ 42 stock solution was stored in a -80 ° C refrigerator.
  • HFIP hexafluoroisopropanol
  • Styrene-based compound stock preparation The styryl groups synthesized in Examples 8, 9, 10, and 11 were combined. Add PBS (Na 2 HP0 4 -12H 2 0 3.73 g, KH 2 P0 4 0.43 g, NaCl 7.2 g, add water to 1000 mL) of pH 7.4 to prepare a 1.92 mM stock solution, and place it in a refrigerator at -80 °C. Saved in. ⁇
  • the above styrene-based compound stock solution and copper chloride are formulated into a solution containing 20 ⁇ 42, 0 to 160 uM of the above styryl compound and 0.4 to 128 ⁇ Cu 2+ to adjust the pH to 7.4 at 37 ° C.
  • the cells were incubated for 3 days under the same conditions, and the ⁇ 42 stock solution incubated under the same conditions was used as a control.
  • the ThT measurement method is as follows: 20 ul of the incubation sample solution is placed in a 700 ul lOuM ThT (pH 7.4) solution, and the mixture is homogenized to measure the fluorescence absorption at an excitation wavelength of 440 nm and an emission wavelength of 485 nm.
  • the ⁇ 42 stock solution was taken, diluted to a solution containing 20 ⁇ M ⁇ 42, adjusted to pH 7.4, and then incubated at 37 °C. Two days later, ThT fluorescence and electron microscopy (TEM) were performed on the incubation samples, and it was found that ⁇ 42 was aggregated, and then the styrene-based compound storage solution and copper chloride synthesized by the present invention were separately added to prepare 20, 40, 80 ⁇ , respectively.
  • the styryl compound and the solution of 20, 32, 64 ⁇ Cu 2+ (pH 7.4) were further incubated at 37 ° C for 8 days, and the ThT fluorescence absorption of the ⁇ 42 solution was determined by the same method as in the first step, and the continuous detection was performed. 8 days.
  • Example 15 Electron microscopic observation of the inhibitory effect of compounds on ⁇ aggregation and depolymerization of ⁇ aggregates ⁇ aggregates can be observed under electron microscopy. The morphology of ⁇ 42 samples on copper network is observed directly by electron microscopy. To further detect the inhibitory effect of the polypeptide compound of the present invention on ⁇ aggregation and the depolymerization of ⁇ aggregates, the detection method is as follows:
  • Peptide compound stock solution The polypeptide compounds synthesized in Examples 4, 5, 6, and 7 were separately added to PBS pH 7.4 (Na 2 HP0 4 -12H 2 0 3.73 g, KH 2 P0 4 0.43 g, NaCl 7.2 g, Add 1.92 mM stock solution to water (100 mL) and store in a -80 ° C freezer.
  • the polypeptide compound significantly inhibited the aggregation of ⁇ .
  • the polypeptide compounds synthesized in Examples 5, 6, and 7 also significantly inhibited the aggregation of A ⁇ , indicating that the polypeptide compound of the present invention can significantly inhibit the aggregation of A ⁇ .
  • the above method can also be employed to observe the inhibitory effect of the compound on ⁇ aggregation.
  • the results of electron microscopic observation of the polyphenol compound synthesized in Example 1 are shown in Fig. 9; the results of electron microscopic observation of the styryl compound synthesized in Example 9 are shown in Fig. 10.
  • the polyphenols and styryl compounds synthesized by the present invention can significantly inhibit the aggregation of ⁇ .
  • the ⁇ 42 stock solution was taken, diluted to a solution containing 20 ⁇ M ⁇ 42, adjusted to 7.4, and then incubated at 37 °C. Two days later, ThT fluorescence and electron microscopy were performed on the incubation samples, and it was found that ⁇ 42 was aggregated, and then a solution of the polypeptide compound and copper chloride were separately added to prepare a solution containing 40 ⁇ of the polypeptide compound and 32 ⁇ of Cu 2+ (pH 7.4). Incubation was continued for 5 days at 37 ° C, and electron microscopic observation was carried out, and ⁇ 42 incubated under the same conditions was used as a control.
  • Example 16 MALDI-TOF-MS analysis of the hydrolysis of ⁇ by the compounds of the present invention
  • the ⁇ and its aggregates are hydrolyzed into small fragments by the action of the polyphenols or polypeptide compounds of the present invention, thereby achieving the action of removing ⁇ .
  • Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) is used to analyze the ⁇ hydrolysis and removal.
  • the polyphenols are used as an example. The specific methods are as follows:
  • polyphenolic compound stock solution The polyphenolic compounds synthesized in Examples 1, 2, and 3 were separately added to pH 7.4; PBS (Na 2 HP0 4 -123 ⁇ 40 3.73 g, KH 2 P0 4 0.43 g, NaCl 7.2 g, Add 1.92 mM stock solution to water (100 mL) and store in a -80 ° C freezer.
  • Example 12 Take ⁇ 42 stock solution (see Example 12 for formulation), prepare polyphenol compound stock solution and copper chloride to prepare a solution containing 20 ⁇ ⁇ 42, 160 ⁇ polyphenolic compound and 128 ⁇ Cu 2+ to adjust the pH to 7.4 at 37 °C. Incubate for 5 days as a sample solution. 20 ⁇ L of the sample solution was placed in a small centrifuge tube, and desalted by a Ziptip C18 purification column (Eppendorf), and then eluted with 80% acetonitrile, followed by MALDI-TOF-MS analysis.
  • ⁇ acts as a hydrolysis scavenging agent
  • ⁇ 42 without polyphenolic compounds in the control group has a distinct molecular ion front (see Figure ⁇ in Figure 11).
  • the polyphenol compounds synthesized in Examples 2 and 3 can also have a hydrolysis scavenging action on ⁇ , and it is proved that the polyphenol compound of the present invention has a hydrolysis scavenging effect on ⁇ .
  • the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to analyze the hydrolysis and scavenging effects of peptide compounds on ⁇ and its aggregates. The results are the same as above. Among them, the peptide compounds synthesized in Example 5 are used to remove ⁇ hydrolysis. The results of the MALDI-TOF-MS analysis of the effect are shown in the diagram of Fig. 12; indicating that the polyphenols and polypeptide compounds prepared by the present invention have a hydrolysis scavenging effect on both ⁇ and its aggregates.
  • Example 17 TCEP-DTNB method for detecting the inhibitory effect of the compound of the present invention on the production of hydrogen peroxide by ⁇ .
  • ⁇ can form hydrogen peroxide ( ⁇ 2 0 2 ) mediated by copper.
  • TCEP tris(2-carboxyethyl)phosphine hydrochloride
  • TCEP tris(2-carboxyethyl)phosphine hydrochloride
  • Unreacted TCEP can be combined with probe 5,5'-bisthio-(2-nitrobenzene).
  • DTNB 2,5,-dithiobis (2-nitrobenzoic acid, DTNB, purchased from Sigma, USA
  • NTB 2-nitro-5-thiobenzoate
  • the TCEP-DTNB method is used to detect the inhibition of hydrogen peroxide by ⁇ by the compound of the present invention. Taking polyphenols as an example, the experimental methods are as follows:
  • TCEP stock solution preparation TCEP was dissolved in PBS (Na 2 HP0 4 -12H 2 0 3.73 g, KH 2 P0 4 0.43 g, NaCl 7.2 g, added with water to 1000 mL) at pH 7.4 to obtain a jlO mM stock solution.
  • DTNB stock solution preparation DTNB was dissolved in PBS (Na 2 HP0 4 -12H 2 0 3.73 g, KH 2 P0 4 0.43 g, NaCl 7.2 g, added with water to 1000 mL) at pH 7.4 to obtain a 10 mM stock solution.
  • Gly-Cu stock solution configuration 10 mM CuCl 2 and 60 mMGly (purchased from Gil Biochemical) were dissolved in water and shaken at room temperature for 24 hours.
  • the test results are shown in Fig. 13 (the ordinate indicates the relative amount of hydrogen peroxide; the abscissa indicates different experimental groups, II is the polyphenol compound prepared in Example 1, 12 is the polyphenol compound prepared in Example 2, 13 is The polyphenol compound prepared in Example 3, the ⁇ group is a control group to which the polyphenol compound of the present invention is not added, and compared with the control group, the polyphenol compound of the present invention can significantly inhibit the catalytic generation of hydrogen peroxide by A ⁇ . Thereby weakening the toxic effect of A ⁇ .
  • Example 15 wherein II is the styryl compound prepared in Example 8, and 12 is the styrene group prepared in Example 9.
  • the compound, 13 is a styrene-based compound prepared in Example 10
  • 14 is a styrene-based compound prepared in Example 11
  • the ⁇ -group is a control group to which no styry-based compound of the present invention is added.
  • the polypeptides and styrene compounds prepared by the present invention can significantly inhibit the catalytic generation of hydrogen peroxide by A ⁇ , thereby weakening the toxic effect of A ⁇ .
  • Example 18 ⁇ (thiazole blue) method for detecting the protective effect of the compound of the present invention on nerve cells
  • the guanidine method is a tetramethylazozolium salt microenzyme reaction colorimetric method.
  • Rhodium is a thiazole salt, chemical name 3-(4,5-dimethyl-2-thiazole)-2,5-diphenyltetrazolium bromide, and the aqueous solution is yellow-orange.
  • Rat hippocampal neuron cells undergo proliferation and activation after ConA action, and their intracellular mitochondrial succinate dehydrogenase activity increases accordingly.
  • MTT acts as a substrate to participate in the reaction, forming blue formazan particles deposited on cells.
  • rat neurons refer to the literature (Isabella A. Graef, Paul G .
  • Example 12 Take the 42 ⁇ 42 stock solution (see Example 12 for formulation), prepare the polyphenolic compound stock solution and copper chloride of the present invention to prepare a solution containing 40 ⁇ 42, 40 ⁇ of the polyphenolic compound solution of the present invention and 32 ⁇ Cu 2+ to adjust the pH to 7.4. It was incubated at 37 ° C for 3 days as a sample solution. Then, the cells were diluted with the cell culture medium to a cultured neuron cell at a ratio of 1:4, and the neuron cells were further cultured at 37 ° C, 5% CO 2 for two days, and then purchased according to the MTT product specification (purchased from the United States). Sigma) Performs MTT experiments.
  • the test results are shown in Fig. 16 (the ordinate indicates the cell survival rate, and the abscissa indicates the different experimental groups, wherein II is the polyphenol compound prepared in Example 1, 12 is the polyphenol compound prepared in Example 2, and 13 is the preparation of Example 3.
  • the polyphenol compound, the ⁇ group is a control group in which the polyphenol compound of the present invention is not added
  • the blank group is a blank control group in which the polyphenol compound of the present invention and the ⁇ 42 stock solution are not added
  • the polyphenols of the present invention are not added.
  • the polyphenol compound synthesized by the present invention can significantly inhibit the cytotoxicity of A ⁇ .
  • the results are the same as above.
  • the results of the detection of neuropeptide protection by the polypeptide compound are shown in FIG. 17, wherein the ruthenium group is the polypeptide compound prepared in Example 4, the 12 groups are the polypeptide compound prepared in Example 5, and the 13 groups are the embodiment 6.
  • the prepared polypeptide compound, 14 groups were the polypeptide compounds prepared in Example 7, the ⁇ group was the control group without the addition of the polypeptide compound of the present invention, and the blank group was the blank control of the polypeptide compound of the present invention and the ⁇ 42 stock solution. group).
  • the results of the detection of cytoprotective effects of styrene compounds are shown in Fig.
  • Example 18 wherein II is prepared in Example 8.
  • Styrene based compound 12 is the styryl compound prepared in Example 9
  • 13 is the styryl compound prepared in Example 10
  • 14 is the styryl compound prepared in Example 11, and the ⁇ group is not
  • the blank group was a blank control group in which the styryl compound and the ⁇ 42 stock solution of the present invention were not added.
  • the polypeptides and styrene compounds prepared by the present invention can significantly inhibit the cytotoxicity of A ⁇ , thereby protecting the nerve cells and making the cell survival rate higher. .
  • Cat and rat test models purchased from the Academy of Military Medical Sciences
  • cats 24, female, male and half, weighing 2.4-3.7 kg, divided into 4 groups, 6 in each group, with doses of 0.05, 50, respectively.
  • 120mg/kg test observe the effects of the peptide compounds prepared in Examples 4-7 on blood pressure, respiratory rate, heart rate, etc.; using mice (40, female, male and half, weighing 18-20g, divided into 4 groups, Each group of 10, with doses of 0.05, 30, 50 mg/kg, respectively, was tested to observe the effect of the polypeptide compounds prepared in Examples 4-7 on the spontaneous activity of rats.
  • the test results showed that the three doses of the polypeptide compound of the present invention had no significant effect on blood pressure, respiratory rate and amplitude, heart rate and heart rhythm of the cat, and had no significant effect on the number of spontaneous activities of the rats.
  • the above general toxicity test was carried out by using the polyphenols and styrene compounds synthesized by the present invention under the same experimental conditions as above, and the results were identical to those of the polypeptide compounds, indicating that the polyphenols and styrene compounds synthesized by the present invention exert blood pressure on the cats. There was no significant effect on respiratory rate and amplitude, heart rate, and heart rate, and there was no significant effect on the number of spontaneous activities of rats.
  • the polyphenol compound prepared in Example 1 of the present invention, the polypeptide compound prepared in Example 4, and the styryl compound prepared in Example 8 were tested for acute toxicity by the following method:
  • the experimental model purchased from the Academy of Military Medical Sciences
  • Kunming mice 40, divided into blank control group and the preparation group of the present invention, 20 in each group
  • the maximum oral administration rate 10.63 g/kg , equivalent to 2834 times the clinical dose (3.75mg/kg)
  • the test results are shown in Table 1:
  • the present invention provides a class of compounds having nitrogen-containing heterocyclic modifications, including polyphenolic compounds, polypeptide-based compounds, and styryl-based compounds. Studies have shown that this type of compound not only inhibits the aggregation of A ⁇ , but also depolymerizes the aggregated A ⁇ aggregates, and finally hydrolyzes and removes A ⁇ , inhibiting and eliminating the toxicity of A ⁇ .
  • a drug containing such a compound as an active ingredient can be used for the treatment and prevention of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and type 2 diabetes.

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Abstract

L'invention porte sur des composés modifiés hétérocycliques contenant de l'azote et sur leurs utilisations dans la préparation des médicaments pour prévenir et traiter la maladie d'Alzheimer, la maladie de Parkinson et autres maladies dégénératives du système nerveux ou du diabète de type deux. Des études montrent que les composés proposés peuvent inhiber l'agrégation de la Aβ, cause la dépolymérisation de la Aβ agrégée, éliminer finalement par hydrolyse la protéine Aβ, puis inhiber et éliminer la toxicité de la Aβ. Ces composés trouvent de larges applications dans le domaine de la médecine.
PCT/CN2007/002985 2007-01-11 2007-10-18 Composés modifiés hétérocycliques contenant de l'azote et leurs utilisations Ceased WO2008083543A1 (fr)

Applications Claiming Priority (6)

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CN200710062630.1 2007-01-11
CN200710062628.4 2007-01-11
CN200710062629.9 2007-01-11
CNB2007100626299A CN100551910C (zh) 2007-01-11 2007-01-11 具有含氮杂环修饰的苯乙烯基化合物及其应用
CN2007100626284A CN100999546B (zh) 2007-01-11 2007-01-11 具有含氮杂环修饰的多肽类化合物及其应用
CNB2007100626301A CN100551911C (zh) 2007-01-11 2007-01-11 具有含氮杂环修饰的多酚化合物及其应用

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006117077A1 (fr) * 2005-05-03 2006-11-09 Dsm Ip Assets B.V. Derives aryle de la curcumine, de la demethoxycurcumine, de la bisdemethoxycurcumine ou de la curcumine-isoxazolide et utilisation de ceux-ci comme additifs dans des aliments pour animaux
CN100999546A (zh) * 2007-01-11 2007-07-18 清华大学 具有含氮杂环修饰的多肽类化合物及其应用
CN100999495A (zh) * 2007-01-11 2007-07-18 清华大学 具有含氮杂环修饰的苯乙烯基化合物及其应用
CN100999496A (zh) * 2007-01-11 2007-07-18 清华大学 具有含氮杂环修饰的多酚化合物及其应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006117077A1 (fr) * 2005-05-03 2006-11-09 Dsm Ip Assets B.V. Derives aryle de la curcumine, de la demethoxycurcumine, de la bisdemethoxycurcumine ou de la curcumine-isoxazolide et utilisation de ceux-ci comme additifs dans des aliments pour animaux
CN100999546A (zh) * 2007-01-11 2007-07-18 清华大学 具有含氮杂环修饰的多肽类化合物及其应用
CN100999495A (zh) * 2007-01-11 2007-07-18 清华大学 具有含氮杂环修饰的苯乙烯基化合物及其应用
CN100999496A (zh) * 2007-01-11 2007-07-18 清华大学 具有含氮杂环修饰的多酚化合物及其应用

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