WO2002012217A1 - Nouveaux derives de l'agarofurane, leur procede de preparation, composants pharmaceutiques les contenant et leurs applications sous forme de medicaments - Google Patents

Nouveaux derives de l'agarofurane, leur procede de preparation, composants pharmaceutiques les contenant et leurs applications sous forme de medicaments Download PDF

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WO2002012217A1
WO2002012217A1 PCT/CN2001/000738 CN0100738W WO0212217A1 WO 2002012217 A1 WO2002012217 A1 WO 2002012217A1 CN 0100738 W CN0100738 W CN 0100738W WO 0212217 A1 WO0212217 A1 WO 0212217A1
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hydrogen
trimethyl
oxatricyclo
group
formula
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PCT/CN2001/000738
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English (en)
Chinese (zh)
Inventor
Jiyu Guo
Weijun Wang
Wuyan Zhang
Dali Yin
Ruiwu Liu
Chun Li
Sujuan Sun
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Institute Of Materia Medica, Chinese Academy Of Medical Sciences
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Priority to AU2001287489A priority Critical patent/AU2001287489A1/en
Publication of WO2002012217A1 publication Critical patent/WO2002012217A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • 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
    • A61K31/343—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 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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

Definitions

  • the present invention relates to a new agarwood furan derivative, a method for preparing the same, a pharmaceutical composition containing the same, and its use as a medicament, especially as a medicament for treating or preventing cerebral degenerative diseases or symptoms.
  • Brain degenerative diseases or symptoms include, for example, Alzheimer's disease (senile dementia), multi-infarct dementia, Huntington's disease, Pick's disease, cerebral sclerosis, Parkinson's disease, alcohol or drug dementia, and the like.
  • the drugs used generally include: vasodilators, drugs that promote brain metabolism, neuropeptide drugs, drugs that affect neurotransmitters, neurotrophic factors, antioxidant stress, Anti-inflammatory or anti-excitatory drugs.
  • vasodilators drugs that promote brain metabolism, neuropeptide drugs, drugs that affect neurotransmitters, neurotrophic factors, antioxidant stress, Anti-inflammatory or anti-excitatory drugs.
  • the effects of these drugs are extremely limited. Therefore, it is necessary to develop new drugs for treating or preventing cerebral degenerative diseases or symptoms.
  • a moldy plant Aquila (Aquillaria agallocha Roxb) contains agarwood furan compounds. At present, the following 9 agarwood furan compounds from this agarwood plant have been reported in the text.
  • the object of the present invention is to develop medicines for treating or preventing cerebral degenerative diseases or symptoms.
  • the present inventors have discovered through extensive and in-depth research that a new agarwood of the following general formula I
  • the sulfan compound has the activity of enhancing learning and memory of animals, and has low toxicity, so it can be used as a medicine for treating or preventing brain degenerative diseases or symptoms.
  • a first aspect of the invention relates to a compound of general formula I or a stereoisomer thereof or a pharmaceutically acceptable
  • hydroxy D- H 6 substituted alkyl group, and a hydroxyl group in the hydroxy D- H 6 may be the following groups - is hydrogen, hydroxy (6 alkyl, C 2:
  • R 3 and R 4 is hydrogen, the other is absent,
  • R 5 is hydrogen, hydroxy, phenyl-d- 6 alkyl, C 2 - 6 alkyl, C 2 - 4 alkenyl group,
  • R 2 is hydrogen and R 2 is absent when it is 20,
  • R 4 is hydrogen, hydroxy 6 alkyl, ( 6 acyloxyalkyl,
  • a further aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the general formula I or a stereoisomer thereof or a pharmaceutically acceptable acid salt thereof, and a pharmaceutically acceptable carrier or excipient,
  • hydroxy D- H 6 substituted alkyl group, and a hydroxyl group in the hydroxy D- H 6 may be the following groups - is hydrogen, hydroxy (6 alkyl, C 2:
  • R 2 is absent
  • R 3 and R 4 is hydrogen, the other is absent,
  • R 5 is hydrogen, hydroxy, phenyl (6 alkyl, C 2 - 6 alkyl, C 2 - 4 alkenyl group,
  • R 5 and R 6 are different except that they are hydrogen
  • R 4 is hydrogen, hydroxy d- 6 alkyl, d- 6 alkoxyalkyl, acyloxy d- 6 alkyl,
  • R 5 and R 6 are both hydrogen.
  • Another aspect of the present invention relates to a pharmaceutical composition for the prevention or treatment of a brain degenerative disease or condition, which comprises at least one compound of the general formula I or a stereoisomer thereof or a pharmaceutically acceptable acid salt thereof and a pharmaceutically acceptable carrier or excipient.
  • the present invention also relates to the use of a compound of general formula I or a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of a brain degenerative disease or symptom,
  • Is hydrogen, hydroxyalkyl, C 2 - 6 alkyl group, and a hydroxyl group in the hydroxy C M H may be substituted with the following groups:
  • R 3 and R 4 is hydrogen, the other is absent,
  • R 5 is hydrogen, hydroxy, phenyl-d_ 6 alkyl, C 2 - 6 alkyl, C 2 - 4 alkenyl group,
  • R 5 and R 6 are different except that they are hydrogen
  • R 4 is hydrogen, hydroxy d-6 alkyl, alkoxy d- 6 alkyl, d- 6 acyloxyalkyl,
  • RPR 6 is all hydrogen.
  • the present invention also relates to a method for preventing or treating a brain degenerative disease or condition, which comprises administering to a mammal including a human in need thereof a preventive or therapeutically effective amount of a compound of the general formula I or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • ⁇ Is hydrogen, hydroxy d- 6 alkyl, C 2 - 6 alkyl group, a hydroxyl group and a hydroxyl group H may be substituted with the following:
  • R 2 is absent
  • R 5 and R 6 are different except that they are hydrogen
  • Ri, R 3 , R 4 , R 5 , R 6 cannot be hydrogen at the same time
  • R 3 , R 4 , R 5 , and R 6 cannot be hydrogen at the same time; or a single bond
  • Is hydrogen, amino, benzoylamino, ( 6 -alkanoylamino, wherein the hydrogen on d- 6 alkyl in ( 6 -alkanoylamino) may be substituted by one or two substituents selected from 0, 0H or amino.
  • Oxymethylamino, N-0H, halogen, hydroxy C 6 alkyl, 6 alkoxy d- 6 alkyl, ( 6 acyloxyalkyl,
  • d- 6 alkyl refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl , Isobutyl, tert-butyl, pentyl, neopentyl, hexyl, etc.
  • C 2 - 6 alkyl refers containing 2 - straight-chain or branched-chain alkyl group having 6 carbon atoms such as ethyl, propyl, isopropyl, butyl, isobutyl, sec Butyl or tert-butyl, etc.
  • C 2--4 alkenyl means containing one double bond and 2 - 4 carbon atoms, a straight-chain or branched alkenyl groups such as vinyl, propenyl, allyl, isopropenyl, Butenyl, isobutylfluorenyl, tert-butenyl and the like.
  • Cw alkoxy means an alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy Group, isobutoxy or tert-butoxy, pentyloxy, hexyloxy.
  • V 6 alkanoylamino refers to an alkanoylamino group containing 1 to 6 carbon atoms, such as formamido, acetamido, propionamido, isopropylamido, butanoylamino, isobutanoyl Amino, etc.
  • d- 6 alkanoyloxy refers to an alkanoyloxy group containing 1 to 6 carbon atoms, such as formyloxy, acetoxy, propanoyloxy, isopropyloxy, butan Acyloxy, isobutyryloxy, etc.
  • brain degenerative disease or symptom is exemplified by: Alzheimer's disease (senile dementia), multi-infarct dementia, Huntington's disease, Pick's disease, cerebral sclerosis, Parkinson's disease, alcohol Or drug-induced dementia or learning, cognitive impairment, etc.
  • the present invention relates to an agarwood furan derivative of the general formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • Is hydrogen, hydroxy d- 6 alkyl, C 2 - 6 alkyl group, and a hydroxyl group in the hydroxy d- 6 H may be substituted with the following groups:
  • R 3 and R 4 is hydrogen, the other is absent,
  • R 5 is hydrogen, hydroxy, phenyl-d- 6 alkyl, C 2 - 6 alkyl, C 2 - 4 alkenyl group,
  • R 5 and R 6 are different except that they are hydrogen
  • R 4 is hydrogen, hydroxy d- 6 alkyl, d- 6 alkoxy ( 6- alkyl, acyloxy d- 6 ,
  • R 5 and 1 ⁇ are both hydrogen.
  • Is a double bond is a hydroxyl group ( 6 alkyl group, the hydrogen is substituted with a protected or unprotected galactosyl, lactosyl or glucosyl group, the protecting group is selected from acetyl, trifluoroacetyl, etc., or is substituted by picolinyl
  • R 2 is absent
  • R 3 is hydrogen
  • R 4 is absent
  • R 5 and R 6 are both hydrogen.
  • the second line is a double bond
  • R 2 is absent, R 3 is hydroxymethyl, alkoxymethyl, C t - 6 alkanoyloxymethyl, R 4 is hydrogen, hydroxymethyl, d- 6 alkoxymethyl, (6 alkanoyloxymethyl, R 5, and 1? 6 are hydrogen.
  • the compound of formula I of the present invention is preferably the following specific compound or a stereoisomer thereof
  • the compound of formula I of the present invention can be prepared according to a method known in the art or a method in the literature or the following reaction scheme.
  • Reaction Scheme I Compound (1) and Compound (2) (for preparation, see New Synthesis of b-Agarofuran and of Dihydroagafuran, Greorge B ibhi and Hans W ttest. J. Org. Chem. Vol. 44. NO. 4 , 1979, p546) is subjected to condensation under basic conditions to form compound (3).
  • the base used may be an inorganic base, preferably potassium hydroxide.
  • the reaction solvent may be diethyl ether, isopropyl ether, ethanol or a mixture thereof or any other organic solvent which does not interfere with the reaction. The reaction is generally carried out in a water bath to room temperature.
  • Compound (3) is dehydrated under alkaline conditions to form compound (4), compound (4) and compound of formula XROP (where X is halogen; R is C 6 alkyl, P is hydroxyl protecting group, such as dihydropyranyl, C 2 - 6 Municipal chain alkyl group, etc.) in the presence of an alkaline medium
  • the organic solvent can be benzene, tert-butanol or any other organic solvent that does not interfere with the reaction.
  • the reaction temperature is not critical, the reaction is generally carried out at reflux temperature.
  • the basic medium is preferably an organic base, such as an alkali metal alcoholate such as sodium hydrogen or potassium tert-butoxide.
  • the compound (5) is reduced to form the compound (6).
  • the reducing agent used in the reaction may be a metal hydride, preferably sodium borohydride or potassium borohydride.
  • the reaction can be performed in an organic solvent such as ethanol, diethyl ether, tetrahydrofuran, or other solvents which do not interfere with the reaction.
  • the reaction is generally carried out at a temperature of 0 ° C to room temperature.
  • Compound (6) is cyclized to form compound (7) in an acidic medium, preferably an inorganic acid, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • the reaction is generally performed in a solvent that does not interfere with the reaction, such as water, methanol, ethanol, ether, and petroleum ether.
  • the reaction is generally carried out at a temperature of 0 to room temperature.
  • Compound (7) is further hydrolyzed under basic conditions to form compound (8) (wherein it is a hydroxyl d 6 alkyl group).
  • the base used may be an inorganic base, preferably potassium hydroxide.
  • the reaction solvent may be diethyl ether, isopropyl ether, ethanol or a mixture thereof or any other organic solvent which does not interfere with the reaction.
  • the reaction is generally carried out in a water bath to room temperature.
  • the compound of formula (8) and picolinic acid in the presence of a condensing agent, a catalyst and an acid binding agent generate a compound of formula (la) (wherein it is picolinyloxy-alkyl).
  • the solvent used may be toluene, benzene, methylene chloride, chloroform or any organic solvent which does not interfere with the reaction.
  • the condensing agent may be dicyclohexylcarbodiimide (DCC) and the like.
  • the catalyst may be p-dimethylaminopyridine (DMAP) and the like.
  • the acid-binding agent may be pyridine, triethylamine, or the like.
  • the reaction is usually carried out at room temperature.
  • the compound of formula la described above is reduced to form a compound of formula Id (where two is a single bond, and R is a picolinyloxy group) or a compound of formula 8 is first reduced and then esterified with picolinate to form a compound of formula Id (where two is a single Bond, picolinyloxy d- 6 alkyl).
  • a compound of formula (8) and a halogenated sugar with a protective group for example, the sugar may be galactose, lactose, or glucose), such as 1 ⁇ -bromotetraacetylglucose, to produce a compound of formula (la) in the presence of a catalyst and a desiccant (Two are the bonds, protecting the sugar group for the protecting group -0-alkyl).
  • the reaction can be carried out in dichloromethane, chloroform or any organic solvent which does not interfere with the reaction.
  • the catalyst may be an inorganic silver salt such as silver nitrate, silver carbonate, or silver chloride.
  • the desiccant may be 4A molecular sieve or the like. The reaction is generally carried out in the dark at room temperature.
  • the compound of formula (la) obtained above generates another compound of formula la (wherein the two are double bonds, which is a glycosyl-0-d- 6 alkyl group) under hydrolysis conditions.
  • the reaction solvent may be methanol, ethanol or any organic solvent which does not interfere with the reaction.
  • the hydrolysis conditions can be ammonia, potassium hydroxide, sodium hydroxide, and the like.
  • the reaction can be carried out at room temperature or under heating.
  • the compound of formula la is reduced to form a compound of formula Id (wherein two is a single bond and is a glycosyl-0-d- 6 alkyl group).
  • the compound of formula (8) is first hydrogenated and then esterified or glycosylated and / or further hydrolyzed as described above to form a compound of formula Id (this route is not marked, the two are single bonds and are glycosyl-0-alkyl).
  • the reaction can be carried out in dichloromethane, diethyl ether or any organic solvent which does not interfere with the reaction.
  • the weak acid strong base salt is preferably sodium acetate.
  • the dehydrating agent is preferably a molecular sieve. This reaction is generally carried out at room temperature.
  • the formula Ie obtained above is subjected to a reduction reaction to form another compound of formula Ie (wherein R 3 is H 2 N).
  • the reduction conditions may be metal hydrides, preferably lithium aluminum hydride; in this case, the reaction may be performed in an organic solvent such as diethyl ether, tetrahydrofuran, dichloromethane, chloroform, benzene or other solvents that do not interfere with the reaction. Reduction conditions can also use catalytic hydrogenation.
  • the catalyst can be palladium / activated carbon, platinum dioxide, palladium hydroxide, and the like.
  • the compound of formula Ie (where R 3 is " ⁇ ") and d- 6 alkanoic anhydride form another compound of formula Ie (where R 3 is ( 6 -alkanoylamino)) under the action of a catalyst. This reaction can be carried out in an organic solvent.
  • Reaction Scheme 4 a compound of formula (14) (see Chinese Chemical Letters, 1997, 8167, 491-492) is reacted with d-e alkyl aldehyde in a basic aqueous solution or a basic 6 alcohol solution to form an Ig compound ( Where R 2 , R 5 , R 6 are like Ig In the definition, R 3 is hydroxymethyl, (-6 alkyl-0-methyl, R 4 is hydrogen, hydroxymethyl).
  • the reaction can be carried out in a d- 6 alkyl alcohol such as methanol or any organic solvent which does not interfere with the reaction.
  • the base is preferably an inorganic base such as potassium hydroxide, sodium hydroxide and the like. The reaction is generally carried out at room temperature.
  • a compound of formula (14) is subjected to a condensation reaction with paraformaldehyde in a basic aqueous solution to obtain a compound Ig (R 3 is a methylol group, and R 4 is a methylol group), and then the compound Ig and d- 6 alkanoic anhydride are mixed in a base. Under the action of an alkaline catalyst, another compound of the formula Ig is formed (wherein R 3 is hydroxymethyl, or ⁇ alkanoyloxymethyl, and 1 ⁇ is d- 6 alkanoyloxymethyl).
  • the reaction can be carried out in an organic solvent such as diethyl ether, tetrahydrofuran, methylene chloride, chloroform, benzene or other solvents which do not interfere with the reaction.
  • the catalyst may be p-dimethylaminopyridine.
  • the reaction is generally carried out at room temperature.
  • a compound of formula (iii) (see step D of Example 20) is subjected to an oxidation reaction to produce a compound of formula (iv).
  • the oxidizing agent may be chromic anhydride / pyridine, selenium dioxide, selenium dioxide / silica gel, preferably chromic anhydride / pyridine.
  • the reaction is generally carried out in an organic solvent such as dichloromethane, chloroform or any organic solvent which does not interfere with the reaction.
  • the reaction temperature is usually 0 ° C to room temperature.
  • Resulting formula (IV) with a compound of a metal organic compound of the reaction (LB) (where ⁇ is 0H, as ⁇ ⁇ alkyl, C 2 -! 4 alkenyl or benzyl, a metal organic reagent may be a Grignard, Organolithium compounds, etc.
  • the reaction can be performed in an organic solvent such as acetic acid, tetrahydrofuran or any other solvent that does not interfere with the reaction.
  • the application temperature is usually from water bath to room temperature.
  • the oxidizing agent lattice anhydride / pyridine, selenium dioxide, selenium dioxide / silica gel, and chromic anhydride / pyridine are preferred.
  • the reaction is generally carried out in an organic solvent such as methylene chloride, chloroform or any organic solvent which does not interfere with the reaction.
  • the reduction reaction of the compound of formula (Ic) above yields another compound of formula Ic (where ⁇ is an alkyl group, R 2 is absent, R 3 is hydrogen, R 4 is absent, R 5 is H, and is 010.
  • the reducing agent used in the example may be a metal hydride, preferably sodium borohydride or potassium borohydride.
  • the reaction may be performed in an organic solvent such as methanol, ethanol, ethyl acetate, ether, dichloromethane or other solvents which do not interfere with the reaction.
  • the reaction is generally carried out at a temperature of 0 ° C to room temperature.
  • the base used may be an inorganic base, preferably potassium hydroxide.
  • the reaction solvent may be diethyl ether, isopropyl ether, ethanol or a mixture thereof or any other organic solvent which does not interfere with the reaction.
  • the reaction is generally carried out in a water bath to room temperature.
  • Compound (3) is dehydrated under alkaline conditions to form compound (4).
  • the base used may be an inorganic base, preferably sodium hydroxide or potassium hydroxide.
  • the reaction can be carried out in an organic solvent such as ethanol, ether, tetrahydrofuran, or without disturbing the reaction It is carried out in other solvents.
  • the reaction is generally carried out at a temperature of 0 ° C to room temperature.
  • the obtained compound of formula (10) is subjected to a cyclization reaction in an acidic medium, preferably an inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid to generate a compound of formula (i) (wherein R is an alkyl group, which is a double bond.)
  • the reaction is generally performed in a solvent that does not interfere with the reaction, such as water, methanol, ethanol, ether, petroleum ether, benzene, methylbenzene, and Methane, chloroform, ethyl acetate, tetrahydrofuran, or mixtures thereof, preferably petroleum ether - methanol - water, benzene - water reaction is usually carried out at room temperature to 0
  • the oxidant can be chromic anhydride / pyridine, selenium dioxide, selenium dioxide / silica gel, preferably chromic anhydride / pyridine.
  • the reaction is generally in an organic solvent such as methylene chloride, chloroform or The reaction is performed in any organic solvent that does not interfere with the reaction.
  • the reaction temperature is usually 0 ° C to room temperature.
  • the alkaline reagent may be an inorganic or organic base, preferably potassium hydroxide or sodium hydroxide.
  • Organic solvents such as methanol, ethanol, ethyl acetate, diethyl ether, dichloromethane or other solvents that do not interfere with the reaction.
  • the reaction is generally carried out at a temperature of 0 "C to room temperature.
  • metal-organic reagent may be a Grignard, organolithium Compounds, etc.
  • the reaction can be carried out in an organic solvent such as diethyl ether, tetrahydrofuran or any other solvent which does not interfere with the reaction.
  • the reaction temperature is generally 0 ° C to room temperature.
  • the compound of the formula (Ic) obtained by the above addition is hydrolyzed under alkaline reagent.
  • the alkaline reagent may be inorganic or organic
  • the base is preferably potassium hydroxide or sodium hydroxide.
  • the reaction can be performed in an organic solvent such as methanol, ethanol, or other solvents which do not interfere with the reaction.
  • the compounds of formula (I) may exist in stereoisomeric forms.
  • the asymmetric center present in the compound of the formula (I) may have an S configuration or an R configuration.
  • the invention includes all possible stereoisomers such as enantiomers or diastereomers, as well as mixtures of two or more stereoisomers, such as enantiomers and / or diastereomers in any desired proportion mixture.
  • the present invention relates to enantiomers, such as the left- and right-enantiomers in the enantiomerically pure form, and mixtures or racemates of the two enantiomers in different ratios. If cis / trans isomers are present, the invention relates to cis and trans forms and mixtures of these forms.
  • the preparation of a single stereoisomer may be carried out by resolving the mixture according to a conventional method, or by, for example, stereoselective synthesis. If a mobile hydrogen atom is present, the invention also relates to tautomeric forms of the compounds of formula (I).
  • the compound of formula (I) and its stereoisomers show excellent effects in animal learning and cognition models, and therefore can be used as drugs for preventing or treating brain degenerative diseases or symptoms in animals, preferably for breastfeeding. Animals, especially people.
  • the invention therefore also relates to an active ingredient containing at least one compound of formula (I) and / or a stereoisomer thereof and a conventional pharmaceutical excipient or feeding agent.
  • Pharmaceutical composition Generally, the pharmaceutical composition of the present invention contains 0.1 to 90% by weight of a compound of formula (I) and / or a physiologically acceptable salt thereof.
  • Pharmaceutical compositions can be prepared according to methods known in the art. For this purpose, if necessary, the compound of formula (I) / or stereoisomers can be combined with one or more solid rhenium liquid pharmaceutical excipients and / or adjuvants to be made into human or veterinary medicine. Appropriate application form or dosage form used.
  • the compound of formula (I) of the present invention or a pharmaceutical composition containing the same can be administered in unit dosage form, and the route of administration can be intestinal or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum or Rectum and so on.
  • Dosage forms such as tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powder injections, etc., can be ordinary preparations, sustained-release preparations, Controlled release formulations and various microparticle delivery systems. Seeds are formulated into unit dosage forms into tablets, and various carriers well known in the art can be widely used.
  • Examples of carriers are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, white ceramic, microcrystalline cellulose, silicic acid Aluminum, etc .; humectants and binders, such as water, glycerin, polyethylene glycol, ethanol, propanol, starch syrup, dextrin, syrup, honey, glucose solution, gum arabic, gelatin syrup, sodium carboxymethyl cellulose , Shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc .; disintegrants, such as dry starch, alginate, agar powder, alginate, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitan Sugar alcohol fatty acid esters, sodium dodecyl sulfonate, methyl cellulose, ethyl cellulose, etc .
  • the tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or layered tablets and multilayered tablets.
  • coated tablets such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or layered tablets and multilayered tablets.
  • various carriers known in the art can be widely used.
  • Examples of carriers are, for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, Kaolin, talc, etc .; binders, such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc .; disintegrants, such as agar powder, dried starch, alginate, twelve Sodium alkyl sulfonate, methyl cellulose, ethyl cellulose and the like.
  • various carriers known in the art can be widely used.
  • the carrier are, for example, polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like.
  • the active ingredient compound of formula (I) or a stereoisomer thereof is mixed with the above-mentioned various carriers, and the resulting mixture is placed in a hard gelatin capsule or a soft capsule .
  • the active ingredient of the compound of formula (I) or a stereoisomer thereof can also be made into a micro-elixir, suspended in an aqueous medium to form a suspension, and can also be filled into a hard gelatin tincture or used as an injection.
  • diluents commonly used in the art can be used, such as water, ethanol, polyethylene glycol, 1, 3 -Propylene glycol, ethoxylated isostearyl alcohol, polyoxidized isostearyl alcohol, polyoxyethylene sorbitol fatty acid ester, and the like.
  • an appropriate amount of sodium chloride, glucose, or glycerol may be added to the preparation for injection, and conventional co-solvents, buffers, pH adjusters, and the like may be added.
  • a colorant if necessary, a preservative, a flavor, a flavoring agent, a sweetener, or other materials may be added to the pharmaceutical preparation.
  • the dosage of the compound of formula (I) or its stereoisomers of the present invention depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight and individual response of the patient or animal, and the specifics used Compounds, routes of administration and number of administrations.
  • the above dosages may be administered in a single dosage form or divided into several, for example, two, three or four dosage forms.
  • Step A Dissolve pentaacetylglucose lg (2.564 mmol) in 10 ml of dichloromethane, and dropwise add 2.0 ml of 33% HBr / HAc. Keep dripping left and right. Then it was naturally warmed to room temperature and reacted for 1.5 hours. Post-treatment, dilute by adding 10ml of dichloromethane, pour 10ml of ice-cold saturated sodium bicarbonate solution, stir, separate the organic layer, wash with saturated sodium bicarbonate (5ml), saturated sodium chloride (5ml), dry (no Sodium sulphate), filtered and concentrated. The residue was recrystallized from ether / petroleum ether (3/1) to give white crystals. The yield was 53.3%. 1 ⁇ -bromotetraacetylglucose.
  • Step B (1R, 6S, 9R) 6, 10, 10, -trimethyl-2-hydroxymethyl-11-oxatricyclo [7.2.1.0 1 ' 6 ] dodec-2-ene Literature method (Chinese Chemical Letter, 1991, 2 (6), 425-42) Preparation] 30mg (0.127mmol), 1 ⁇ -bromotetraacetylglucose 104mg (0.253mmol), dissolved in 3ml of dichloromethane sequentially, add a small amount 4A molecular sieves. After stirring at room temperature for 1 hour, add 200 mg (0.724 mmol) of silver carbonate and stir in the dark at room temperature overnight. filter. The filtrate was concentrated, purified by column chromatography, and eluted with a gradient of petroleum ether / ether (3 / 1- 1/1) to obtain the expected product in a yield of 38.5%.
  • Example 2 The compound prepared in Example 2 was dissolved in methanol, ammonia water was added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and the residues were separately purified by column chromatography, eluting with dichloromethane / methanol (10/1), to obtain the expected product.
  • Step A (IS, 6R, 9R) 6, 10,10, -trimethyl-11-oxatricyclo [7.2.1.0 1 ' 6 ] dodecane-3-one Prepared according to literature methods (Chinese Chemical Letters, 2000, 11 (4): ⁇ 301-304 Step B: (IS, 6R, 9R) 6,10, 10, -trimethyl-11-oxatricyclo [7.2.1.0 1 ' 6 ] dodecane-3-oxime
  • the expected product was obtained with a yield of 4%.
  • Step A (1R, 3R, 6R, 9R) 6,10,10, -trimethyl-11-oxatricyclo [7. 2. 1. 0 1 ' 6 ] dodeca-2-one
  • the expected product was obtained, 0.14 g, in a yield of 6%.
  • Example 18 (1R, 3S, 6R, 9R) 6,10,10, -trimethyl-3-methyl ether methyl-11-oxatricyclo [7.2.1.0 1 ' 6 ] twelve-2- ketone 23 mg (1 mmol) of sodium metal was added to 10 ml of anhydrous methanol and stirred until the sodium completely disappeared. 55 mg (0.25 mmol) of the compound prepared in Step A of Example 13 was added to the above solution, and 7.5 mg (0.25 mmol) of paraformaldehyde was added under stirring at room temperature. After the disappearance, the same amount of paraformaldehyde was added. After five additional additions, the material disappeared. It was neutralized with 1N hydrochloric acid, and methanol was removed under reduced pressure. The residue was extracted with ethyl acetate and dried over anhydrous sodium sulfate. Column chromatography gave the expected product, 24 mg, yield 36.1%.
  • Step B (6R / S, 9R) 6-methyl-9 (1-methylepoxyethyl) -bicyclo [4. 4. 0] dec-butene-3 ketone
  • anhydrous ether solution of the compound prepared in step C was added dropwise under an ice bath, and the mixture was stirred in a water bath for half an hour After that, it was stirred at room temperature for another 3 hours, and then water was added dropwise. Saturated acetic acid and 2 ml of a 0% aqueous sodium hydroxide solution were used to remove the formed precipitate. The filtrate was dried and the solvent was distilled off to obtain the desired product.
  • Step D (1R, 6S, 9R) 6, 10, 10, -trimethyl-11-oxatricyclo
  • Step A (1R, 6R, 9R) 6-methyl-9-a-methyl-1-hydroxyethyl) -1-hydroxybicyclo [4.4.0] dec-3-one
  • Step B (6R, 9R) 6-methyl-9- (1-methyl-1-hydroxyethyl) -bicyclo [4. 4. 0] dec-1-ene-3 1.86 g (27.2 mmol) of potassium hydroxide was dissolved in 60 ml of water, 6.68 g (27.8 mmol) of the compound prepared in Step A was added, and the mixture was heated under reflux for 1 hour and then cooled to room temperature. Post-treatment, neutralization with concentrated hydrochloric acid, extraction with ethyl acetate (30 ml X 2), washing the organic phase with saturated sodium chloride (20 ml), and drying (anhydrous sodium sulfate).
  • Step C (6R, 9R) 6-methyl-2-butyl-9- (1-methyl-1-hydroxyethyl) -bicyclo [4. 4. 0] decadibene-3-one
  • Step D (3R / S, 6R, 9R) 6-methyl-2-butyl-9 (1-methyl-1-hydroxyethyl)-3-hydroxybicyclo [4. 4. 0] dec- 1-ene
  • Step E (1R, 6S, 9R) 6, 10, 10-trimethyl-2-butyl-11-oxatricyclo [7. 2. 1. 0 1 ' 6 ] dodec-2-ene.
  • the intermediate obtained in the above step D was not separated.
  • 200 ml of petroleum ether was added, and the mixture was stirred at room temperature for 5 hours and allowed to stand overnight.
  • the layers were separated, the water and methanol layers were concentrated to about 50 ml, and extracted with petroleum ether (20 ml).
  • the petroleum ether layers were combined, washed with saturated sodium chloride until neutral, and dried (anhydrous sodium sulfate). It was filtered, concentrated, and the crude product was purified by column chromatography, eluting with petroleum ether / ethyl acetate (70/1) to give 3.2 g of the desired compound. Yield: 81.1%.
  • Step E 500 mg of the compound obtained in Step E was dissolved in 2 ml of dichloromethane, 150 mg of selenium dioxide, 0.66 ml of tert-butanol peroxide were added, and the mixture was stirred at 25 ° C for 10 days. 5 ml of 10% sodium bisulfite was added and stirred for 2 hours. The organic layer was separated, washed with saturated sodium chloride, dried, and the solvent was evaporated. 5% ⁇ Purified by column chromatography to obtain the expected product 140mg, yield 26.5%.
  • reaction solution was sequentially washed with 1N hydrochloric acid (10ml), IN sodium hydroxide (10ml), saturated sodium chloride (10ml), dried (anhydrous sodium sulfate), filtered, and concentrated to obtain white crystals, which were acetylated (, 68 , 91 6,10,10, -trimethyl-2-hydroxymethyl-11-oxatricyclo [7. 2. 1. 0 1 ' 6 ] dodec-2-ene, yield 95%.
  • Step B Dissolve 232 mg (0.898 mmol) of freshly prepared chromic anhydride / pyridine in 2 ml of dichloromethane, add 25 mg (0.0898 mmol) of the product obtained in step A, and stir at room temperature for one day. Chromic anhydride / pyridine 232 mg (0.898 mmol) was added thereto, followed by stirring at room temperature for one day. On the third day, additional 232 mg (0. 898 mmol) of chromic anhydride / pyridine was added, followed by stirring at room temperature for 6 hours. Work up, filter, and concentrate the filtrate to obtain a crude product, which is purified by column chromatography and eluted with petroleum ether / ethyl acetate (48) to obtain the desired product.
  • Example 27 (1R, 6R, 9R) 6, 10, 10, -trimethyl-2-hydroxymethyl-11-oxatricyclo [7. 2. 1. 0 1 ' 6 ] twelve-2 -Ene-4-ketone 150 mg (0.514 mmol) of the compound prepared in Example 26 was dissolved in 5 ml of methanol, and 1.23 ml of a 1 mol / L potassium carbonate aqueous solution was added.
  • the expected product was 110 mg, yield 57.4%,
  • bromobutane was used instead of bromopropane to obtain the desired product in a yield of 57.3%.
  • mice were randomly divided into groups of 10 mice.
  • the administration group was administered the compound of Example 21 (ip.), And the vehicle blank control group (ip,). 5 minutes after the administration, the mice were placed in the dark room with their backs to the dark room, and the mice were exposed to the soles of the feet when they entered the dark room. Copper grid 36v electric shock And pile out, no longer enter the dark room. Observation time: 5 minutes. After 24 hours, the mice were put into the bright room again, and the incidence of re-entry into the dark room within 5 minutes (memory affected memory) and changes in the latency period were observed, and compared with the blank control group (2% lecithin).
  • Example 21 Compared with the corresponding control group, P ⁇ 0.05 (two-tailed method). Conclusion: In the mouse light and dark box acquired memory experiment, the compound of Example 21 has significant memory for mice at 1.25m g / kg (ip). Enhancement.

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Abstract

L'invention concerne de nouveaux dérivés de l'agarofurane, leur procédé de préparation, les composants pharmaceutiques les contenant et les médicaments associés. L'invention concerne plus particulièrement les applications desdits médicaments dans le traitement et la prévention de la maladie d'Alzheimer ou des symptômes apparentés à cette maladie.
PCT/CN2001/000738 2000-05-12 2001-05-11 Nouveaux derives de l'agarofurane, leur procede de preparation, composants pharmaceutiques les contenant et leurs applications sous forme de medicaments WO2002012217A1 (fr)

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CN114190578A (zh) * 2021-12-03 2022-03-18 天津港保税区有维生物科技有限公司 一种具有镇静安神作用的烟油及其制备方法
CN114560833A (zh) * 2021-03-23 2022-05-31 北京承颐医药科技有限公司 一种沉香呋喃类化合物及其制备方法和应用

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CN108813614B (zh) * 2018-06-13 2022-02-01 中国医学科学院药用植物研究所海南分所 一种沉香有效部位提取物抗焦虑抗抑郁的应用及其制备方法
TWI778243B (zh) * 2019-03-14 2022-09-21 三顧股份有限公司 沉香萃取物之用途

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114560833A (zh) * 2021-03-23 2022-05-31 北京承颐医药科技有限公司 一种沉香呋喃类化合物及其制备方法和应用
CN114190578A (zh) * 2021-12-03 2022-03-18 天津港保税区有维生物科技有限公司 一种具有镇静安神作用的烟油及其制备方法

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