WO2022089598A1 - Flavonoid glycoside-organic amine neuroagonist double salt compound, preparation method therefor, and application thereof - Google Patents

Abstract

A flavonoid glycoside and organic amine neuroagonist double salt compound, a preparation method therefor, and an application thereof, a pharmaceutical composition containing a therapeutically effective amount of the double salt compound and an application thereof, and a double salt nanoparticle obtained from the double salt compound by nanogrinding and an application thereof. Flavonoid glycoside has a structural general formula represented by formula (1) below, wherein R1-R9 are each independently selected from -H,-OH, C1-C6 alkyl, alkoxy or substituted alkyl, and at least one of R1 and R2 is selected from -OH.

Description

Flavone glycoside-organic amine nerve agonist double salt compound and preparation method and application thereof

Related applications

This application claims the priority of the Chinese patent application filed on October 30, 2020, with the application number of 2020111909437, and the invention name is "flavonoid glycoside-organic amine neural agonist double salt and its preparation method and application". The entire contents of this application are incorporated by reference.

technical field

The application relates to the technical field of medicinal chemistry, in particular to a flavonoid glycoside-organic amine neural agonist double salt compound and a preparation method and application thereof.

Background technique

Neural agonists include acetylcholinesterase inhibitors, NMDA receptor inhibitors, sphingosine phosphate receptor inhibitors, etc., which are used to treat Alzheimer's disease, multiple sclerosis, Parkinson's syndrome, and stroke sequelae. A neurodegenerative disease caused by nerve damage. Neurodegenerative diseases, characterized by massive loss of specific neurons, are a class of progressive and progressively disabling, severe and potentially fatal complex diseases. Specifically, Alzheimer's disease (AD) is a neurodegenerative disease that can cause the gradual decline of brain function, mainly manifested as cognitive dysfunction, loss of daily living ability and abnormal mental behavior. Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. It is characterized by multiple lesions, remission, and recurrence. It occurs in the optic nerve, spinal cord, and brain stem. Neuritis and retrobulbar optic neuritis may occur. , Ophthalmoplegia, limb paralysis, pyramidal tract signs and psychiatric symptoms. Ataxia, limb tremor, and nystagmus occur when the lesion is located in the cerebellum. Parkinson's syndrome is also a degenerative disease of the central nervous system. Stroke sequelae refers to a disease mainly manifested by hemiplegia, numbness, skewed mouth and eyes, and poor speech after the onset of acute cerebrovascular disease. At present, neuroagonist drugs are the main treatment methods for neurodegenerative diseases, such as donepezil, ristigmine, amiligin, memantine, fingolimod, and galantamine.

Baicalin and baicalin are both flavonoid glycosides (flavonoid glycosides for short), which have rich pharmacological activities, such as improving antioxidant capacity by resisting lipid peroxidation, scavenging free radicals and superoxide anions, improving blood circulation and increasing blood flow. , Anti-platelet aggregation, inhibit virus infection, enhance immunity, anti-cell hypoxia, neuroprotection, inhibit tumor cell growth, etc.

In addition, for poorly soluble drugs, how to improve their solubility, speed up the dissolution rate, and increase the blood drug concentration are also problems to be solved urgently.

SUMMARY OF THE INVENTION

Based on this, it is necessary to provide a flavonoid glycoside-organic amine nerve agonist double salt compound and its preparation method and application. Compared with the organic amine neural agonist itself, the flavonoid glycoside-organic amine neural agonist double salt compound has higher inhibitory activity on neural receptors.

In one aspect of the present application, a double salt compound is provided, which is a double salt of a flavone glycoside and an organic amine neural agonist, and the flavone glycoside has the general structural formula shown in the following formula (1):

Wherein, R ₁ to R ₉ are each independently selected from -H, -OH, C ₁ -C ₆ alkyl, alkoxy or substituted alkyl, and at least one of R ₁ and R ₂ is selected from -OH.

In one embodiment, R ₁ and R ₂ are both selected from -OH.

In one embodiment, the flavonoid glycoside is baicalin or baicalin.

In one embodiment, the organic amine neural agonist contains at least one amino group, each of the amino groups is independently selected from -NH ₂ , -NR'H or -NR' ₂ , and the R' is an electron donating group.

In one embodiment, the organic amine neuroagonist is selected from any one of donepezil, ristigmine, amiligin, memantine, fingolimod and galantamine.

On the one hand, this application also provides a kind of preparation method of described double salt compound, comprising the following steps:

Mixing and dissolving the flavonoid glycoside, the organic amine nerve agonist and the polar aprotic organic solvent to obtain a mixed solution;

The mixed solution is reacted to obtain a reaction solution; And

The solvent was removed from the reaction solution.

In one embodiment, the polar aprotic organic solvent is one or more of N,N-dimethylformamide, dimethylsulfoxide or acetonitrile.

Another aspect of the present application further provides a pharmaceutical composition, which contains a therapeutically effective amount of the double salt compound or its optical isomer, enantiomer, diastereomer, racemate or racemate mixture, and a pharmaceutically acceptable carrier, excipient or diluent.

In yet another aspect of the present application, there is provided the application of the double salt compound or the pharmaceutical composition in the preparation of a neural agonist drug.

In one of the embodiments, the neuroagonist drug is used for the treatment of neurodegenerative diseases, and the neurodegenerative diseases are stroke sequelae, Alzheimer's disease, multiple sclerosis or Parkinson's syndrome.

In another aspect of the present application, a double salt nanoparticle is provided, wherein the double salt nanoparticle is obtained by nano-grinding the double salt compound.

In another aspect of the present application, there is provided the application of the double salt nanoparticle in the preparation of a neural agonist drug.

In one embodiment, the antitumor drug is used for the treatment of tumor diseases, and the neural agonist drug is used for the treatment of neurodegenerative diseases, and the neurodegenerative diseases are stroke sequelae, Alzheimer's disease , multiple sclerosis, or Parkinson's disease.

Compared with the prior art, the present application has the following beneficial effects:

Organic amine neural agonists are alkaline and can form salts with inorganic acids or small-molecule organic acids to increase their stability and improve physical properties. Salts of acids with organic amine neuroagonists do not enhance the biological activity of these drugs. The double salt compound provided by the present application adopts a specific structure of flavonoid glycosides and an organic amine neuroagonist to form a double salt. The molecular structure of the flavonoid glycoside contains a carboxyl group and a phenolic hydroxyl group, which can interact with the amine in the organic amine neuroagonist. Base bonding, the binding effect between the two is stronger than the general drug salt formation. Compared with the organic amine neural agonist itself, the double salt exhibits higher inhibitory activity on nerve receptors, and shows better recovery of the animal's mobility after brain injury.

Natural compounds such as flavonoid glycosides have poor water solubility, but because there are carboxyl groups and phenolic hydroxyl groups in the molecular structure, they are easily soluble in alkalis, and form salts with small molecular organic bases to enhance their water solubility. Further, the double salt compound provided by the present application is ground by nano-grinding technology to reduce the particle size of the material so that the particle size reaches the nanometer level, so that the double salt compound has better water solubility.

Description of drawings

Fig. 1～Fig. 4 is the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 1 of the application;

Fig. 5～Fig. 8 is the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 2 of the application;

Figures 9 to 12 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 3 of the application;

13 to 16 are the HNMR spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 4 of the application;

Figures 17 to 20 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 5 of the application;

Figures 21 to 24 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 6 of the application;

Figures 25 to 28 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 7 of the application;

Figures 29 to 32 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 8 of the application;

Figures 33 to 36 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 9 of the application;

37 to 40 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 10 of the application;

41 to 44 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 11 of the present application.

Detailed ways

The present application will be further described in detail below with reference to specific embodiments. The application may be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that a thorough and complete understanding of the present disclosure is provided.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this application belongs. The terms used herein in the specification of the application are for the purpose of describing specific embodiments only, and are not intended to limit the application. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

Abbreviations and symbols used herein are consistent with such abbreviations and symbols commonly used by those skilled in the chemical and biological arts. In particular, abbreviations may be used in the examples and throughout the description: DMF (N,N-dimethylformamide), DSC (differential scanning calorimetry).

Terms and Definitions

Unless otherwise stated or otherwise contradicted, terms or phrases used herein have the following meanings:

The term "alkyl" refers to a saturated hydrocarbon containing primary (normal) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof. Phrases containing this term, for example, "C ₁ -C ₆ alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, and each occurrence may independently be a C ₁ alkyl, C ₂ alkyl, C3 alkyl, _C4 alkyl, _C5 alkyl or _C6 alkyl _. Suitable examples include, but are not limited to: methyl (Me, _-CH3 ), ethyl (Et, -CH2CH3), ₁ -propyl (n-Pr, n _- propyl, _{-CH2CH2CH ) 3} ), 2-propyl (i-Pr, i-propyl, -CH(CH ₃ ) ₂ ), 1-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ) , 2-methyl-1-propyl (i-Bu, i-butyl, -CH ₂ CH(CH ₃ ) ₂ ), 2-butyl (s-Bu, s-butyl, -CH(CH _{3 )} )CH ₂ CH ₃ ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH ₃ ) ₃ ), 1-pentyl (n-pentyl, -CH ₂ CH _{2 )} CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2- Butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl ( -CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2- Methyl-2-pentyl (-C( _CH3 )2CH2CH2CH3), ₃ -methyl- ₂ -pentyl (-CH( _CH3 ) _CH ( _{CH3 ) CH2CH3 )} , 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ) , 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), and 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ .

The term "alkoxy" refers to a group having an -O-alkyl group, ie an alkyl group as defined above is attached to the core structure via an oxygen atom. Phrases containing this term, for example, "C ₁ -C ₆ alkoxy" means that the alkyl moiety contains 1 to 6 carbon atoms, and each occurrence may independently be C ₁ alkoxy, C ₂ alkoxy oxy, C ₃ alkoxy, C ₄ alkoxy, C ₅ alkoxy or C ₆ alkoxy. Suitable examples include, but are not limited to: methoxy (-O- _CH3 or -OMe), ethoxy (-O- _CH2CH3 or -OEt) and tert-butoxy (-OC( _{CH3 ) 3} or -OtBu).

"Amino" refers to a derivative of ammonia, non-limiting classes of amino groups include _-NH2 , -N(alkyl) ₂ , -NH(alkyl), -N(cycloalkyl) ₂ , -NH(cycloalkane) base), -N(heterocyclyl) ₂ , -NH(heterocyclyl), -N(aryl) ₂ , -NH(aryl), -N(alkyl)(aryl), -N(alkane (heterocyclyl), -N(cycloalkyl)(heterocyclyl), -N(aryl)(heteroaryl), -N(alkyl)(heteroaryl), and the like.

"Pharmaceutically acceptable" refers to those ligands, materials, compositions and/or dosage forms suitable for administration to a patient within the scope of sound medical judgment and commensurate with a reasonable benefit/risk ratio. "Pharmaceutically acceptable carrier, excipient, or diluent" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. As used herein, the language "pharmaceutically acceptable carrier, excipient or diluent" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents compatible with pharmaceutical administration agents, isotonic and absorption delaying agents and the like. Each carrier, excipient or diluent must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients in the formulation and not injurious to the patient. Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch, potato starch and substituted or unsubstituted beta-cyclodextrins; (3) cellulose and derivatives thereof, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; Formulations such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyvalent Alcohols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) Esters such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers such as magnesium hydroxide and hydrogen (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) pharmaceutical formulation other non-toxic compatible substances used in the product.

"Substituted" in reference to a group means that one or more hydrogen atoms attached to member atoms within the group are replaced with a substituent selected from defined or suitable substituents. The term "substitution" should be understood to include the implied condition that such substitution is consistent with the permissible valences of the substituted atoms and substituents and that the substitution results in a stable compound. When it is stated that a group may contain one or more substituents, one or more of the member atoms within the group may be substituted. In addition, a single member atom within the group may be substituted with more than one substituent, so long as the substitution is consistent with the permissible valence of the atom. A "member atom" refers to an atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. The atoms that make up a substituent on a chain or ring are not member atoms in the chain or ring.

The term " _IC50 " refers to the half-maximal inhibitory concentration of a compound relative to inhibition of a given activity, eg, neural receptors including acetylcholinesterase, NMDA receptors, sphingosine phosphate receptors. The smaller the _IC50 value, the stronger the inhibitory activity of the compound for a given activity.

compound

In one aspect, the application relates to a double salt compound, which is a double salt of a flavonoid glycoside and an organic amine neural agonist, and the flavonoid glycoside has the general structural formula shown in the following formula (1):

Wherein, R ₁ to R ₉ are each independently selected from -H, -OH, C ₁ -C ₆ alkyl, alkoxy or substituted alkyl, and at least one of R ₁ and R ₂ is selected from -OH.

The flavonoid glycosides, the carboxyl hydrogen in the gluconic acid unit in the molecular structure, and the phenolic hydroxyl hydrogen (the hydrogen in R ₁ or R ₂ ) in the flavonoid unit together form a hydrogen ion-rich region and are proton donors. The nitrogen atom of the organic amine in the organic amine neural agonist contains a lone pair of electrons and is a proton acceptor. The two are combined to form the flavonoid glycoside-organic amine neural agonist double salt. Due to steric hindrance, the carboxyl hydrogen in the gluconic acid unit and the phenolic hydroxyl hydrogen in the flavonoid unit in the flavonoid glycosides are located on both sides of the sugar ring, respectively. When it is combined with an organic amine, the carboxyl hydrogen and the phenolic hydroxyl hydrogen on both sides of the sugar ring are converted to the same side, as shown in formula (2), to form a proton nest (proton shown in the dotted box in formula 2). structure), carboxyl oxygen electrons and nitrogen lone pair electrons. From the analysis of valence bond theory, the hydrogen proton and amine in the proton nest can form a very stable ammonium salt; from the analysis of molecular orbital theory, the empty orbital of hydrogen in the proton nest and the lone pair of electrons of amine can be perfectly combined; from quantum chemistry and quantum entanglement Theoretical analysis shows that hydrogen electrons in proton dens, carboxyl oxygen electrons and lone electron pairs of nitrogen in organic amines are entangled in the salt-forming region. Because of the existence of quantum entanglement, the organic acid and organic After the bases were dissociated from each other, the quantum entanglement formed during the salt formation continued to exist, which improved the biological activity of the flavonoid glycoside-organic amine neural agonist double salt.

Optionally, both R ₁ and R ₂ are selected from -OH.

In some embodiments, _R3 is selected from -H or _-OCH3 . In some embodiments, R ₅ , R ₆ , R ₉ are all selected from -H. In some embodiments, R ₇ , R ₈ are each independently selected from -H or -OH. In some embodiments, _R8 is selected from -H. In some embodiments, _R7 is selected from -OH. In other embodiments, _R7 is selected from -H.

In some embodiments, the flavone glycoside can be any one of apigenin flavone glycoside, baicalin, scutellarin, chrysin flavone glycoside or wogonin, optionally, the flavone glycoside is baicalin or Baicalin.

The molecular structural formula of the baicalin is shown in the following formula (1-1):

The molecular structural formula of the baicalin is shown in the following formula (1-2):

The organic amine neural agonist contains at least one amino group, each of the amino groups is independently selected from -NH ₂ , -NR'H or -NR' ₂ , and the R' is an electron donating group.

In some embodiments, R' is alkyl or alkoxy.

In some embodiments, the organic amine neuroagonist is selected from any one of donepezil, ristigmine, amiligin, memantine, fingolimod, and galantamine.

Donepezil, with molecular formula C ₂₄ H ₂₉ NO ₃ , is used for the treatment of Alzheimer's disease and stroke sequelae. The structural formula of donepezil is shown below:

Ristigmine, the molecular formula is C ₁₄ H ₂₂ N ₂ O ₂ , a carbamate derivative of physostigmine, also belongs to the second generation AChE inhibitor. The structural formula of Ristigmine is as follows:

Amiligen, also known as Epitacrine, has the following structural formula:

Memantine, with the molecular formula C ₁₂ H ₂₁ N, is an inhibitor of excitatory amino acid (NMDA) receptors for the treatment of moderate to severe Alzheimer's dementia. The structural formula of memantine is as follows:

Fingolimod, the molecular formula is C ₁₉ H ₃₃ NO ₂ , is a sphingosine phosphate receptor inhibitor, and is mainly used in the clinical treatment of relapsing-remitting multiple sclerosis. The structural formula of fingolimod is as follows:

Galantamine, the molecular formula is C ₁₇ H ₂₂ ClNO ₃ , is a sphingosine phosphate receptor inhibitor for the treatment of multiple sclerosis. The structural formula of galantamine is shown below:

In one aspect, the application also relates to a preparation method of a described double salt compound, comprising the following steps:

S10, mixing and dissolving the flavonoid glycoside, the organic amine neural agonist and the polar aprotic organic solvent to obtain a mixed solution;

S20, the mixed solution is reacted to obtain a reaction solution; And

S30, the solvent is removed from the reaction solution.

The molar ratio of the flavonoid glycosides to the organic amine neural agonist can be any ratio between 1:3 and 3:1, for example, it can also include 1:2, 1:1.5, 1:1, 1.5:1 , 2:1, optional 1:1. The polar aprotic organic solvent may be one or more of N,N-dimethylformamide, dimethylsulfoxide or acetonitrile.

In step S10, there are various methods for mixing and dissolving the flavonoid glycoside, the organic amine nerve agonist and the polar aprotic organic solvent to obtain a mixed solution. Optionally, the following steps can be included

S11, dissolving the flavonoid glycosides in the polar aprotic organic solvent to obtain a first solution;

S12, dissolving the organic amine neural agonist in the polar aprotic organic solvent to obtain a second solution;

S13, mixing the first solution and the second solution to obtain the mixed solution.

The concentration of the flavonoid glycosides in the first solution is 0.1 mol/L to 1.0 mol/L, optionally 0.33 mol/L.

The concentration of the organic amine neural agonist in the second solution is 0.1 mol/L to 1.0 mol/L, optionally 0.33 mol/L.

In the step of reacting the mixed solution, the reaction temperature may be 30°C to 100°C, optionally 50°C to 70°C, and more optionally 70°C.

The method for removing the solvent may be concentration under reduced pressure, and the temperature of the concentration under reduced pressure may be 40°C to 70°C, optionally 60°C.

Step S30 also includes a purification step. The method of purification can be beating. The solvent used in the beating can be ethyl acetate. The dosage of ethyl acetate should be 1:1 to 1:5 according to acid (baicalin or scutellarin) mol/L, and 1:3 is the best; the beating temperature can be 5°C to 50°C, or 20°C. ℃～30℃, time is 20 minutes～40 minutes.

The purification also includes filtering the solution after beating, and further drying the filter cake after filtering. The drying method can be freeze drying or vacuum drying. The temperature of the vacuum drying may be 20°C to 60°C, optionally 30°C, and the drying time may be 8 hours to 48 hours, optionally 24 hours. The temperature of the freeze-drying is less than 0°C, and the drying time can be 3 hours to 12 hours, optionally 6 hours.

In one aspect, the present application relates to a compound containing a therapeutically effective amount of the above-mentioned double salt compound or its optical isomer, enantiomer, diastereomer, racemate or racemic mixture, and a pharmaceutically acceptable carrier , excipient or diluent composition.

In one aspect, the present application relates to the application of the double salt compound in the preparation of a neural agonist drug.

In some embodiments, the neural agonist drug prepared according to the double salt compound of the present application is used for the treatment of neurodegenerative diseases, and the neurodegenerative diseases are stroke sequelae, Alzheimer's disease, multiple sclerosis or Parkinson's syndrome.

In one aspect, the application further relates to a method of treating a neurodegenerative disease, the method optionally comprising administering to a patient suffering from a neurodegenerative disease in need thereof an appropriate amount of a double salt as defined above, comprising a double salt according to the application composition of compounds.

In one aspect, the present application further relates to a double salt nanoparticle obtained by nano-milling the double salt compound of any of the above embodiments.

In some embodiments, the average particle size of the double salt nanoparticles ranges from 50 nm to 500 nm.

In one aspect, the application also relates to a method for preparing the double salt nanoparticles, comprising:

The compound salt compound, the suspending agent and the solvent are mixed and ground by a nano-grinder.

In some embodiments, the suspending agent is Tween, hypromellose, polyethylene glycol, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, fatty acid glycerides, polyol type nonionic Surfactant, polyoxyethylene type nonionic surface cleanser, poloxamer, vitamin E polyethylene glycol succinate, phospholipids, gelatin, xanthan gum, sodium lauryl sulfate and sodium deoxycholate one or more of them.

In some alternative embodiments, the suspending agent is a combination of Tween, hypromellose and polyethylene glycol.

In some embodiments, the mass ratio of the double salt compound and the suspending agent is 1000:(0.5-3).

In some embodiments, the rotation speed of the grinding is 1000 rpm to 3000 rpm, and the grinding time is 10 minutes to 60 minutes. The diameter of the working chamber of the nano-grinder used in the grinding is 85 mm. If the diameter of the working chamber of the nano-grinder changes, the speed should be adjusted accordingly.

In one aspect, further, the present application also relates to the application of the double salt nanoparticles in the preparation of neural agonist drugs.

In some embodiments, the neuroagonist drug is used for the treatment of neurodegenerative diseases, the neurodegenerative diseases are stroke sequelae, Alzheimer's disease, multiple sclerosis or Parkinson's syndrome.

Administration and Formulations

The production of medicaments containing the compounds of the present application, their active metabolites or isomers and their use can be carried out according to well known methods of pharmacy.

Although the compounds of the present application useful in therapy according to the present application may be administered in the form of the original chemical compound, optionally in combination with one or more adjuvants, excipients, carriers, buffers, diluents and/or The active ingredient is introduced into the pharmaceutical composition along with other conventional pharmaceutical excipients. Such salts of the compounds of the present application may be anhydrous or solvated.

In an alternative embodiment, the application provides a medicament comprising a compound usable according to the application or a pharmaceutically acceptable derivative thereof and one or more pharmaceutically acceptable carriers and optionally other Therapeutic and/or prophylactic ingredients. The carrier or carriers must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the recipient.

The medicament of the present application may be suitable for oral, rectal, bronchial, nasal, topical, buccal, sublingual, transdermal, vaginal or parenteral (including dermal, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral) , intraocular injection or infusion), or in a form suitable for administration by inhalation or insufflation (including powder and liquid aerosol administration) or by sustained release systems. Suitable examples of sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compounds of the present application, which matrices may be in the form of shaped articles such as films or microcapsules.

The compounds usable according to the present application can thus be placed in the form of medicaments and unit dosages thereof together with conventional auxiliaries, carriers or diluents. Such forms include: solids, in particular tablets, filled capsules, powders and pellets; and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs and fillings therewith capsules, all forms for oral administration, suppositories for rectal administration and sterile injectable solutions for parenteral use. These medicaments and unit dosage forms thereof may contain conventional ingredients in conventional proportions, with or without other active compounds or components, and such unit dosage forms may contain any suitable effective amount corresponding to the intended daily dosage range to be used. the active ingredient.

The compounds useful in accordance with the present application can be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may include as active ingredient one or more compounds useful in accordance with the present application.

For the preparation of medicaments from compounds useful in accordance with the present application, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material .

In powders, the carrier is a finely divided solid in admixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter Wait. The term "preparation" is intended to include the formulation of the active compound with a coating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by and thus in association with a carrier. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid forms suitable for oral administration.

To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is uniformly dispersed therein, eg, by stirring. The molten homogeneous mixture is then poured into appropriately sized molds, allowed to cool and thereby solidify. Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams containing in addition to the active ingredient suitable carriers known in the art agent or spray. Liquid preparations include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. For example, liquid preparations for parenteral injection can be formulated as aqueous polyethylene glycol solutions.

Thus, the chemical compounds according to the present application may be formulated for parenteral administration (eg, by injection, eg, bolus injection or continuous infusion), and may be presented in unit dosage form in ampoules, prefilled syringes with an added preservative , small volume infusion or in multi-dose containers. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickening agents as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water with viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations that are intended to be converted shortly before use to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These formulations can contain, in addition to the active ingredient, coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweetening agents, dispersing agents, thickening agents, solubilizers, and the like.

In one embodiment of the present application, the drug is administered locally or systemically or by a combination of both routes.

For administration, in one embodiment, 0.001% to 70% by weight of the compound, alternatively 0.01% to 70% by weight of the compound, even more alternatively The compounds of the present application are administered in formulations of the compounds. In one embodiment, a suitable amount of compound administered is in the range of 0.01 mg/kg body weight to 1 g/kg body weight.

Compositions suitable for administration also include: lozenges comprising the active agent in a flavoured base (usually sucrose and acacia or tragacanth), lozenges comprising the active agent in an inert base such as gelatin and glycerol or sucrose and acacia Pastilles of the ingredients and mouthwashes containing the active ingredient in a suitable liquid carrier.

Solutions or suspensions are administered directly to the nasal cavity by conventional means such as with a dropper, pipette or spray. Compositions may be presented in single or multiple dose form. In the latter case of a dropper or pipette, this can be accomplished by the patient administering a suitable predetermined volume of the solution or suspension. In the case of a nebulizer, this can be achieved, for example, by means of a metered atomizing spray pump.

Administration to the respiratory tract can also be accomplished by means of an aerosol with a suitable propellant such as a chlorofluorocarbon (CFC) (eg dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane), Carbon dioxide or other suitable gas provides the active ingredient in a pressurized pack. The aerosol may also conveniently contain a surfactant, such as lecithin. The dose of the drug can be controlled by setting the metering valve.

Alternatively, the active ingredient may be provided in dry powder form, eg, a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose, and polyvinylpyrrolidone (PVP). Conveniently, the powder carrier will form a gel in the nasal cavity. Powder compositions may be presented in unit dosage forms, eg, capsules or cartridges such as gelatin, or blister packs from which the powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract, including intranasal compositions, the compounds generally have a small particle size, eg, about 5 microns or less. Such particle sizes can be obtained by means known in the art, for example by micronization.

When desired, compositions suitable for sustained release of the active ingredient can be used.

The pharmaceutical formulations may optionally be presented in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are optional compositions.

Additional details on techniques for formulation and administration can be found in the latest editions of "Remington's Pharmaceutical Sciences (Maack Publishing Co. Easton, Pa.) and Remington: The science and practice of pharmacy", Lippincott Williams and Wilkins.

Suitable formulations and ways of making them are also found in, for example, "Arzneiformenlehre, Paul Heinz List, Ein Lehrbuchfür Pharmazeuten, Wissenschaftliche Verlagsgesellschaft Stuttgart, 4. Auflage, 1985" or "The theory and practice of industrial pharmacy" by Lachman et al., Varghese Publishing House, 1987" or "Modern Pharmaceutics", edited by James Swarbrick, 2nd edition".

The following are specific examples, and the present application is further described below with reference to the following examples, which are intended to illustrate but not limit the scope of the present application. Unless otherwise stated, the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods. The experimental methods for which specific conditions are not indicated in the examples are realized according to conventional conditions, such as conditions described in literatures, books or methods recommended by manufacturers.

Example 1 Preparation of Baicalin Donepezil Salt

3.80 grams (0.01mol) of donepezil was suspended in 15ml DMF, 4.46 grams (0.01mol) of baicalin was added to 30ml DMF, the above-mentioned donepezil DMF solution was added to the baicalin DMF solution, and the reaction was stirred at 70°C for 15 hours, and the reaction solution was reduced at 60°C. Concentrate under pressure to dryness to give crude product. The crude product was slurried with 30 ml of ethyl acetate at room temperature for 20 minutes, filtered, and the filter cake was divided into two equal parts. The first part was suspended in 15 ml of water, and freeze-dried for 6 hours to remove the solvent to obtain a pale yellow solid product. The second filter cake was dried under vacuum at 30°C for 24 hours to obtain a pale yellow solid product. In the first portion, 3.66 g of baicalin donepezil salt was obtained, and the yield was 88.69%. In the second part, 3.64 g of baicalin donepezil salt was obtained, and the yield was 88.41%.

The product was characterized by 1H NMR, IR, DSC and XRD. The results are shown in Figures 1 to 4. Compared with the simple mixture of baicalin and donepezil, the product is more soluble, and the chemical shift of 1H NMR spectrum shows that baicalin The carboxyl hydrogen of the glycoside forms a salt with donepezil-N, and the infrared spectrum also shows this feature. The thermal weight loss shows that the product has peaks at 198°C and 320°C. Compared with baicalin and donepezil, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has formed a salt.

Example 2 Preparation of scutellarin donepezil salt

3.80 grams (0.01mol) of donepezil was suspended in 15ml DMF, 4.62 grams (0.01mol) of baicalin was added to 30ml DMF, the above-mentioned amantadine DMF solution was added to the baicalin DMF solution, and the reaction solution was stirred at 70°C for 15 hours. Concentrate to dryness under reduced pressure at 60°C to obtain crude product. The crude product was slurried with 30 ml of ethyl acetate at room temperature for 20 minutes, filtered, and the filter cake was divided into two equal parts. The first part was suspended in 15 ml of water, and freeze-dried for 6 hours to remove the solvent to obtain a pale yellow solid product. The second filter cake was dried under vacuum at 30°C for 24 hours to obtain a pale yellow solid product. The first part obtained 3.58 g of scutellarin donepezil salt with a yield of 85.13%, and the second part obtained 3.60 g of scutellarin donepezil salt with a yield of 85.44%.

The product was characterized by 1H NMR, IR and DSC structure characterization tests. The results are shown in Figures 5 to 8. Compared with the simple mixture of baicalin and donepezil, the product is more soluble, and the chemical shift of 1H NMR shows that baicalin The carboxyl hydrogen of the product forms a salt with donepezil-N, and the infrared spectrum also exhibits this feature. The thermal weight loss shows that the product has peaks at 205 °C and 319 °C. Compared with baicalin and donepezil, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has been formed into a salt.

Example 3 Preparation of Baicalin Ristigmine Salt

The preparation method was basically the same as that of Example 1, except that donepezil was replaced by 2.50 g (0.01 mol) of Ristigmine.

In the first part, 2.84 g of baicalin listigmine salt was obtained with a yield of 81.51%, and in the second part, 2.83 g of baicalin listigmine salt was obtained with a yield of 81.43%. The product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figures 9 to 12. Compared with the simple mixture of baicalin and ristigmine, the product is more soluble. The shift showed that the carboxyl hydrogen of baicalin was salted with Ristigmine-N, and the infrared spectrum also showed this feature. The thermal weight loss showed that the product had peaks at 193℃ and 327℃. Compared with baicalin and ristigmine, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.

Example 4 Preparation of scutellarin lisinate salt

The preparation method was basically the same as that of Example 2, except that donepezil was replaced with Ristigmine 2.50 g (0.01 mol).

The first part obtains 2.93 g of scutellarin lis' clear salt with a yield of 84.34%, and the second part obtains 2.94 g of scutellarin lis' clear salt with a yield of 84.50%. The product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 13 to Figure 16. Compared with the pure mixture of baicalin and ristigmine, the product is more soluble. The chemical shifts showed that the carboxyl hydrogen of baicalin was salted with Ristigmine-N, and the infrared spectrum also showed this feature. The thermal weight loss showed that the product had a peak at 200℃. The physical properties, spectral characteristics, and thermodynamic properties of the product were changed compared with those of baicalin and ristigmine, indicating that it has become a salt.

Example 5 Preparation of Baicalin Amiligen Salt

The preparation method was basically the same as that of Example 1, except that donepezil was replaced with 1.88 g (0.01 mol) of amiligin.

The first part obtains 2.97 g of baicalin amiligin salt with a yield of 93.79%, and the second part obtains 2.96 g of baicalin amiligin salt with a yield of 93.30%. The product was characterized by H NMR spectroscopy, infrared spectroscopy, DSC and XRD. The results are shown in Figure 17 to Figure 20. Compared with the pure mixture of baicalin and amiligin, the product is more soluble, and the chemical shift of H NMR spectrum is It shows that the carboxyl hydrogen of baicalin forms a salt with amiligin-NH ₂ , and the infrared spectrum also presents this feature. The thermal weight loss shows that the product has peaks at 94°C, 194°C, and 315°C. The XRD pattern shows that the product has characteristic diffraction peaks. Compared with baicalin and amiligin, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.

Example 6 Preparation of scutellarin amiligin salt

The preparation method was basically the same as that of Example 2, except that donepezil was replaced by 1.88 g (0.01 mol) of amiligin.

The first part obtained 2.17 g of scutellarin amiligin salt with a yield of 68.44%, and the second part obtained 2.22 g of scutellarin amiligin salt with a yield of 70.10%. The product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 21 to Figure 24. Compared with the pure mixture of baicalin and amiligin, the product is more soluble. The shift showed that the carboxyl hydrogen of baicalin formed a salt with amiligin-NH ₂ , and the infrared spectrum also showed this feature, and the thermal weight loss showed that the product had a peak at 202 °C. The XRD pattern shows that the product has characteristic diffraction peaks. Compared with baicalin and amiligin, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.

Example 7 Preparation of Baicalin Galantamine Salt

The preparation method was basically the same as that of Example 1, except that donepezil was replaced by 2.87 g (0.01 mol) of galantamine.

The first part obtained 3.22 g of baicalin-galantamine salt with a yield of 87.97%, and the second part obtained 3.24 g of baicalin-galantamine salt with a yield of 88.30%. The product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 25 to Figure 28. Compared with the simple mixture of baicalin and galantamine, the product is more soluble. The shift showed that the carboxyl hydrogen of baicalin was salted with galantamine-N, and the infrared spectrum also showed this feature. The thermal weight loss showed that the product had peaks at 198℃ and 279℃. Compared with baicalin and galantamine, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.

Example 8 Preparation of baicalin memantine salt

The preparation method is basically the same as that of Example 1, except that donepezil is replaced by 1.8 g (0.01 mol) of memantine.

The first part obtained 2.49 g of baicalin memantine salt with a yield of 79.67%, and the second part obtained 2.51 g of baicalin memantine salt with a yield of 80.30%. The product was characterized by H NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 29 to Figure 32. Compared with the simple mixture of baicalin and memantine, the product is more soluble, and the chemical shift of H NMR spectrum shows that baicalin The carboxyl hydrogen of the glycoside forms a salt with memantine-NH ₂ , and the infrared spectrum also shows this feature. The thermal weight loss shows that the product has peaks at 197°C and 361°C. The XRD pattern shows that the product has characteristic diffraction peaks. Compared with baicalin and memantine, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.

Example 9 Preparation of scutellarin memantine salt

The preparation method is basically the same as that of Example 2, except that donepezil is replaced by memantine 1.80 g (0.01 mol).

The first part obtained 2.75 g of scutellarin memantine salt with a yield of 87.91%, and the second part obtained 2.73 g of scutellarin memantine salt with a yield of 87.10%. The product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 33 to Figure 36. Compared with the pure mixture of baicalin and memantine, the product is more soluble, and the chemical shift of the hydrogen NMR spectrum shows that The carboxyl hydrogen of baicalin forms a salt with memantine-NH ₂ , and the infrared spectrum also shows this feature, and the thermal weight loss shows that the product has a peak at 204 °C. Compared with baicalin and memantine, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.

Example 10 Preparation of Baicalin Fingolimod Salt

The preparation method was basically the same as that of Example 1, except that donepezil was replaced by fingolimod 3.08 g (0.01 mol).

The first part obtained 3.11 g of baicalin fingolimod salt with a yield of 82.42%, and the second part obtained 3.14 g of baicalin fingolimod salt with a yield of 83.30%. The product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 37 to Figure 40. Compared with the simple mixture of baicalin and fingolimod, the product is more soluble. The shift showed that the carboxyl hydrogen of baicalin formed a salt with fingolimod-NH ₂ , and the infrared spectrum also showed this feature, and the thermal weight loss showed that the product had peaks at 190 °C and 326 °C. Compared with baicalin and fingolimod, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.

Example 11 Preparation of scutellarin fingolimod salt

The preparation method was basically the same as that of Example 2, except that donepezil was replaced by fingolimod 3.08 g (0.01 mol).

The first part obtained 3.07 g of scutellarin fingolimod salt with a yield of 81.35%, and the second part obtained 3.02 g of scutellarin fingolimod salt with a yield of 80.10%. The product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 41 to Figure 44. Compared with the pure mixture of baicalin and fingolimod, the product is more soluble. The chemical shift showed that the carboxyl hydrogen of baicalin formed a salt with fingolimod-NH ₂ , and the infrared spectrum also showed this feature, and the thermal weight loss showed that the product had a peak at 202 °C. Compared with baicalin and fingolimod, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has been formed into a salt.

Example 12 Activity test

1. Determination of acetylcholinesterase inhibitor activity: each compound salt compound was prepared into different concentrations of the test article, using acetylcholinesterase kit, acetylcholine as the substrate, the inhibition rate of the test article was determined, and IC50 was calculated.

2. Determination of the inhibitory activity of NMDA (N-methyl-D-aspartic acid): each compound salt compound was formulated into different concentrations of the test substance, using NMDA (N-methyl-D-aspartic acid) For receptor blockers, use patch clamp technique to determine the inhibition rate of the test article and calculate IC50.

3. Determination of Sphingosine Phosphate Receptor Inhibitor Activity: Each compound salt compound was formulated into different concentrations of the test article, the sphingosine phosphate receptor kit was used, and enzyme-linked immunosorbent assay was used to determine the inhibition rate of the test article. , calculate IC50.

The pharmaceutical activity of each double salt compound is shown in Table 2:

Table 2

Active ingredient name	target	IC50(nM)
donepezil	acetylcholinesterase	8.4
Baicalin Donepezil	acetylcholinesterase	5.2
baicalin donepezil	acetylcholinesterase	5.4
Ristigmine	acetylcholinesterase	5120
Baicalin Ristigmine	acetylcholinesterase	986
Baicalin Ristigmine	acetylcholinesterase	878
Amilkin	acetylcholinesterase	230
Baicalin Amiligen		acetylcholinesterase	95
scutellarin amiligin	acetylcholinesterase	110
Galantamine	acetylcholinesterase	4.8
Baicalin Galantamine	acetylcholinesterase	3.0
Baicalin	acetylcholinesterase	greater than 5000
Baicalin	acetylcholinesterase	greater than 5000
dollar steel	NMDA receptors	7100
Baicalin U.S. Steel	NMDA receptors	4020
Baicalin U.S. Steel	NMDA receptors	3980
Baicalin	NMDA receptors	greater than 10000
Baicalin	NMDA receptors	greater than 10000
fingolimod	sphingosine phosphate receptor	0.030
Baicalin Fingolimod	sphingosine phosphate receptor	0.015
baicalin fingolimod	sphingosine phosphate receptor	0.010
Baicalin	sphingosine phosphate receptor	greater than 100
Baicalin	sphingosine phosphate receptor	greater than 100

As can be seen from Table 2, the inhibitory activity of baicalin donepezil compound salt compound and baicalin donepezil compound salt compound to acetylcholinesterase is stronger than that of donepezil to acetylcholinesterase; The inhibitory activity of stigmine double salt compound on acetylcholinesterase is stronger than that of ristigmine on acetylcholinesterase; The inhibitory activity is stronger than that of amiligin on acetylcholinesterase; the inhibitory activity of baicalin-galantamine compound salt compound on acetylcholinesterase is stronger than that of galantamine on acetylcholinesterase; The inhibitory activity of salt compound, scutellarin and memantine double salt compound on NMDA receptor is stronger than that of memantine on NMDA receptor; The inhibitory activity on sphingosine phosphate receptors is stronger than that of fingolimod on sphingosine phosphate receptors.

Example 13 Preparation of Baicalin Donepezil Compound Salt Nanoparticles

1. Add 50 g of baicalin donepezil compound salt compound, 500 ml of water, 50 mg of Tween-20 as a suspending agent, 50 mg of hypromellose, 50 mg of polyethylene glycol 6000, and 50 mg of hypromellose into a nano-grinder, at 2000 rpm. Milling at a rotating speed for 40 minutes to obtain a nanosuspension of baicalin donepezil double salt.

2. The obtained baicalin donepezil compound salt nano-suspension was dried in a fluidized bed drying equipment, and the drying air inlet temperature was 65° C., and dried to a moisture content of about 3%, to prepare the baicalin donepezil compound salt nano-particles, with a particle size distribution in 50nm ~ 500nm range.

Compared with the baicalin donepezil compound salt compound without nano-grinding, the prepared baicalin donepezil compound salt nanoparticle doubles the solubility at 20° C. for 10 minutes.

Example 14 Preparation of scutellarin and donepezil double salt nanoparticles

The preparation method is basically the same as that of Example 13, except that the baicalin donepezil double salt compound is replaced by the baicalin donepezil double salt compound. The particle size distribution of quincetin donepezil compound salt nanoparticles is in the range of 50nm to 500nm.

The prepared scutellarin donepezil compound salt nanoparticles have a 1.2-fold increase in solubility at 20°C for 10 minutes compared to the scutellarin and donepezil compound salt compounds without nano-milling.

Example 15 Preparation of Baicalin Ristigmine Double Salt Nanoparticles

The preparation method of Example 13 is basically the same, except that the baicalin donepezil double salt compound is replaced by the baicalin listigmine double salt compound. The particle size distribution of baicalin listigmine double salt nanoparticles is in the range of 50nm to 500nm.

Compared with the baicalin-listigamine double-salt compound prepared without nano-grinding, the solubility of the prepared baicalin-listigamine double-salt compound at 20° C. for 10 minutes increased by 0.8 times.

Example 16 Preparation of scutellarin listigmine double salt nanoparticles

The preparation method is basically the same as that of Example 15, except that the baicalin listigmine double salt compound is replaced with the baicalin listigmine double salt compound. The particle size distribution of scutellarin listigmine double salt nanoparticles is in the range of 50nm to 500nm.

Compared with the non-nano-milled scutellarin-listigamine double-salt compound, the prepared scutellarin-listigamine double-salt nanoparticles have a 0.8-fold increase in solubility at 20° C. for 10 minutes.

Example 17 Preparation of baicalin-amiligin double salt nanoparticles

The preparation method is basically the same as that of Example 13, except that the baicalin donepezil double salt compound is replaced by the baicalin amiligin double salt compound. The particle size distribution of baicalin-amiligin double salt nanoparticles is in the range of 50nm to 500nm.

Compared with the baicalin-amiligin double-salt compound prepared without nano-milling, the solubility of the prepared baicalin-amiligin double-salt compound at 20° C. for 10 minutes increased by 1.0 times.

Example 18 Preparation of scutellarin-amiligin double salt nanoparticles

The preparation method is basically the same as that of Example 17, except that the baicalin-amiligin double-salt compound is replaced with the scutellarin-amiligin double-salt compound. The particle size distribution of scutellarin-amiligin double salt nanoparticles is in the range of 50nm to 500nm.

Compared with the scutellarin-amiligin double-salt compound prepared without nano-milling, the solubility of the prepared scutellarin-amiligin double-salt compound at 20° C. for 10 minutes increased by 1.0 times.

Example 19 Preparation of Baicalin Galantamine Double Salt Nanoparticles

The preparation method is basically the same as that of Example 13, except that the baicalin donepezil double salt compound is replaced by the baicalin galantamine double salt compound. The particle size distribution of baicalin-galantamine double salt nanoparticles is in the range of 50nm to 500nm.

Compared with the baicalin-galantamine double-salt compound without nano-milling, the prepared baicalin-galantamine double-salt nanoparticles have a 1.5-fold increase in solubility at 20°C for 10 minutes.

Example 20 Preparation of Baicalin-Memantine Double Salt Nanoparticles

The preparation method is basically the same as that of Example 13, except that the baicalin donepezil double salt compound is replaced by the baicalin memantine double salt compound. The particle size distribution of baicalin and memantine complex salt nanoparticles is in the range of 50nm to 500nm.

Compared with the baicalin-memantine double-salt compound without nano-grinding, the prepared baicalin-memantine double-salt nanoparticles have a 1.5-fold increase in solubility at 20° C. for 10 minutes.

Example 21 Preparation of scutellarin and memantine double salt nanoparticles

The preparation method is basically the same as that of Example 19, except that the baicalin-memantine double-salt compound is replaced with the baicalin-memantine double-salt compound. The particle size distribution of scutellarin and memantine complex salt nanoparticles is in the range of 50nm to 500nm.

The prepared scutellarin-memantine double-salt nanoparticles have a 1.5-fold increase in solubility at 20° C. for 10 minutes compared to the scutellarin-memantine double-salt compound without nano-milling.

Example 22 Preparation of baicalin fingolimod double salt nanoparticles

The preparation method is basically the same as that of Example 13, except that the baicalin donepezil double salt compound is replaced by the baicalin fingolimod double salt compound. The particle size distribution of baicalin fingolimod double salt nanoparticles is in the range of 50nm to 500nm.

The prepared baicalin fingolimod double salt nanoparticles have a 0.5-fold increase in solubility at 20°C for 10 minutes compared to the baicalin fingolimod double salt compound without nano-milling.

Example 23 Preparation of scutellarin fingolimod double salt nanoparticles

The preparation method is basically the same as that of Example 22, except that the baicalin fingolimod double salt compound is replaced with the baicalin fingolimod double salt compound. The particle size distribution of baicalin fingolimod double salt nanoparticles is in the range of 50nm to 500nm.

The prepared scutellarin fingolimod double salt nanoparticles have a 0.5-fold increase in solubility at 20°C for 10 minutes compared to the scutellarin fingolimod double salt compound without nano-milling.

Example 24 Determination of in vivo activity of animals

Set up blank control group, baicalin group, baicalin group, donepezil group, memantine group, galantamine group, baicalin donepezil compound salt nanosuspension group (baicalin donepezil compound salt nanosuspension preparation method) Referring to Example 13), the baicalin and donepezil double salt nanosuspension group (the preparation method of the scutellarin and donepezil compound nanosuspension nanosuspension group refers to Example 14), the baicalin and memantine double salt nanosuspension group (baicalin Refer to Example 21 for the preparation method of memantine double salt nanosuspension), scutellarin memantine double salt nanosuspension group (refer to Example 22 for the preparation method of scutellarin memantine double salt nanosuspension), baicalin Galantamine double salt nanosuspension group (refer to Example 19 for the preparation method of baicalin-galantamine double salt nanosuspension).

1. Experimental animals

Mice: C57BL/6J mice, male, body weight 20g, 6-8 weeks old. All mice had free access to food and water, and were kept at room temperature (23±2)°C.

2. Test method

Carotid artery embolization mice were established, and the qualified mice were randomly divided into groups of 6. The dosing regimen was as follows:

Blank control group: only normal saline was given.

Baicalin group: The baicalin was prepared into a dosing solution with sterile PBS, and the dose was 2.5 mg/kg, and the patients were administered orally.

Baicalin group: The scutellarin was formulated into a dosing solution with sterile PBS, and the dose was 2.5 mg/kg, and the patients were given intragastrically.

Donepezil group: Donepezil was prepared into a dosing solution with sterile PBS, and the dose was 2.5 mg/kg and administered by gavage.

Memantine group: memantine was prepared into a dosing solution with sterile PBS, and the dosage was 2.5 mg/kg, and then gavaged.

Galantamine group: Galantamine was prepared into a dosing solution with sterile PBS, and the dosage was 2.5 mg/kg, and then administered by gavage.

Baicalin Donepezil Compound Salt Nanosuspension Group: Baicalin Donepezil Compound Salt Nanosuspension was used as a dosing solution, and the dosage was 2.5 mg/kg by gavage.

Baicalin donepezil compound salt nanosuspension group: scutellarin donepezil compound salt nanosuspension was used as a dosing solution, and the dosage was 2.5 mg/kg by gavage.

Baicalin and memantine complex salt nanosuspension group: Baicalin and memantine complex salt nanosuspension was used as a dosing solution, and the dose was 2.5 mg/kg by gavage.

Scutellarin and memantine compound salt nanosuspension group: Scutellarin and memantine compound salt nanosuspension was used as a dosing solution, and the dosage was 2.5 mg/kg by gavage.

Baicalin-galantamine compound salt nanosuspension group: Baicalin-galantamine compound salt nanosuspension was used as a dosing solution, and the dosage was 2.5 mg/kg, administered by gavage.

Three hours after administration, the physical activity ability of each group of mice was evaluated and scored. The scoring standard was: 0-10 points. The higher the score, the stronger the physical activity ability. The results are as follows:

The blank control group scored 0 points, the baicalin group (dose 2.5 mg/kg) scored 2 points, the baicalin group (dose 2.5 mg/kg) scored 2 points, the donepezil group scored 3 points, and the memantine group scored 3 points, plus The lanthamine group scored 3 points, the baicalin donepezil compound salt nanoparticles group scored 8 points, the baicalin donepezil group scored 9 points, the baicalin-memantine compound salt nanoparticles group scored 8 points, and the scutellarin-memantine group scored 8 points The baicalin-galantamine compound salt nanoparticles group scored 8 points. Compared with the blank group, the natural product group and the small molecule group, the scores of each double salt nanosuspension group were significantly different, indicating that after the administration of each double salt nanosuspension, the recovery of the activity ability of mice after brain injury was improved. obvious.

The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity, all possible combinations of the technical features in the above-described embodiments are not described. However, as long as there is no contradiction between the combinations of these technical features, All should be regarded as the scope described in this specification.

The above-mentioned embodiments only represent several embodiments of the present application, and the descriptions thereof are relatively specific and detailed, but should not be construed as a limitation on the scope of the invention patent. It should be noted that, for those skilled in the art, without departing from the concept of the present application, several modifications and improvements can be made, which all belong to the protection scope of the present application. Therefore, the scope of protection of the patent of the present application shall be subject to the appended claims.

Claims (13)

1. A double salt compound is characterized in that it is a double salt of a flavone glycoside and an organic amine neural agonist, and the flavone glycoside has the general structural formula shown in the following formula (1):

   

   Wherein, R ₁ to R ₉ are each independently selected from -H, -OH, C ₁ -C ₆ alkyl, alkoxy or substituted alkyl, and at least one of R ₁ and R ₂ is selected from -OH.
2. The double salt compound according to claim 1, wherein R ₁ and R ₂ are both selected from -OH.
3. The double salt compound according to claim 1 or 2, wherein the flavonoid glycoside is baicalin or scutellarin.
4. The double salt compound according to claim 1, wherein the organic amine neural agonist contains at least one amino group, and the amino groups are each independently selected from -NH ₂ , -NR'H or -NR' ₂ , the R' is an electron donating group.
5. The double salt compound according to claim 1, wherein the organic amine neuroagonist is selected from the group consisting of donepezil, ristigmine, amiligin, memantine, fingolimod and galantamine any kind.
6. A method for preparing a double salt compound according to any one of claims 1 to 5, characterized in that, comprising the following steps:

   Mixing and dissolving the flavonoid glycoside, the organic amine nerve agonist and the polar aprotic organic solvent to obtain a mixed solution;

   The mixed solution is reacted to obtain a reaction solution; And

   The solvent was removed from the reaction solution.
7. The method for preparing a double salt compound according to claim 1, wherein the polar aprotic organic solvent is one or more of N,N-dimethylformamide, dimethyl sulfoxide or acetonitrile kind.
8. A pharmaceutical composition, which contains a therapeutically effective amount of the double salt compound according to any one of claims 1 to 5 or its optical isomer, enantiomer, diastereomer, racemate or racemate mixture, and a pharmaceutically acceptable carrier, excipient or diluent.
9. Application of the double salt compound according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 8 in the preparation of a neural agonist drug.
10. The use according to claim 9, characterized in that, the neural agonist drug is used for the treatment of neurodegenerative diseases, and the neurodegenerative diseases are stroke sequelae, Alzheimer's disease, multiple sclerosis or Parkinson's syndrome.
11. A double salt nanoparticle, characterized in that, it is obtained by nano-grinding the double salt compound according to any one of claims 1 to 5.
12. The application of the compound salt nanoparticle according to claim 11 in the preparation of a neural agonist drug.
13. The use according to claim 12, characterized in that, the neural agonist drug is used for the treatment of neurodegenerative diseases, and the neurodegenerative diseases are stroke sequelae, Alzheimer's disease, multiple sclerosis or Parkinson's syndrome.

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