CN113880899A - Flavonoid glycoside-organic amine nerve agonist double salt compound and preparation method and application thereof - Google Patents

Flavonoid glycoside-organic amine nerve agonist double salt compound and preparation method and application thereof Download PDF

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CN113880899A
CN113880899A CN202111277510.XA CN202111277510A CN113880899A CN 113880899 A CN113880899 A CN 113880899A CN 202111277510 A CN202111277510 A CN 202111277510A CN 113880899 A CN113880899 A CN 113880899A
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double salt
salt compound
baicalin
double
scutellarin
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CN113880899B (en
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王化录
王鹿荧
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Hangzhou Lalin Intelligent Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/07—Benzo[b]pyran-4-ones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C225/18—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings the carbon skeleton containing also rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to a compound salt compound of flavonoid glycoside and organic amine nerve stimulant, wherein the flavonoid glycoside has the structure as shown in the specificationThe general structural formula shown in the formula (1), wherein R1～R9Each independently selected from-H, -OH, C1～C6Alkyl, alkoxy or substituted alkyl, and R1And R2At least one of them is selected from-OH. The invention also relates to a preparation method of the double salt compound. The invention further relates to pharmaceutical compositions containing a therapeutically effective amount and uses. The invention further relates to double-salt nano particles obtained by carrying out nano grinding on the double-salt compound and application thereof.

Description

Flavonoid glycoside-organic amine nerve agonist double salt compound and preparation method and application thereof
The present application claims priority of chinese patent application entitled "flavonoid glycoside-organic amine neuroagonist double salt, its preparation method and use" filed in chinese patent office under the name of 2020111909437 at 30/10/2020, which is incorporated herein by reference in its entirety.
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a flavonoid glycoside-organic amine nerve agonist double salt compound and a preparation method and application thereof.
Background
The neuroagonist comprises acetylcholinesterase inhibitor, NMDA receptor inhibitor, sphingosine phosphate receptor inhibitor, etc., and can be used for treating various neurodegenerative diseases caused by nerve injury, such as Alzheimer's disease, multiple sclerosis, Parkinson's syndrome, cerebral apoplexy sequelae, etc. Neurodegenerative diseases, which are characterized mainly by the massive loss of specific neurons, are a progressive complex disease that is disabling and severely lethal. Specifically, Alzheimer Disease (AD) is a neurodegenerative disease that causes gradual deterioration of brain function, mainly manifested as cognitive dysfunction, loss of daily living ability, and abnormal mental behaviors. Multiple Sclerosis (MS) is the most common central nerve demyelinating disease, is characterized by multiple lesions, remission and relapse courses, is better developed in optic nerves, spinal cords and brainstems, and can cause neuritis, retrobulbar neuritis, ophthalmoplegia, acroparalysis, cone beam syndrome and mental symptoms. Ataxia, tremor of limbs and nystagmus occur when the disease is localized in the cerebellum. Parkinsonism is also a degenerative disease of the central nervous system. The sequelae of cerebral apoplexy refers to a disease which is mainly manifested by hemiplegia, numbness, facial distortion and speech disorder after the acute cerebrovascular disease. At present, neuroagonist drugs are the main treatment means of neurodegenerative diseases, and are commonly used as donepezil, rivastigmine, amiloride, memantine, fingolimod, galantamine and the like.
Baicalin and scutellarin are flavonoid glycosides (flavonoid glycosides for short), and have rich pharmacological activities, such as improving oxidation resistance by resisting lipid peroxidation, scavenging free radicals and superoxide anions, improving blood circulation, increasing blood flow, resisting platelet aggregation, inhibiting virus infection, enhancing immunity, resisting cell anoxia, protecting nerve, inhibiting tumor cell growth, etc.
In addition, how to improve the solubility of the insoluble drugs, accelerate the dissolution speed and increase the blood concentration is also an urgent problem to be solved.
Disclosure of Invention
Based on the above, a flavonoid glycoside-organic amine nerve agonist double salt compound, a preparation method and an application thereof are needed. Compared with the organic amine nerve agonist, the flavonoid glycoside-organic amine nerve agonist double salt compound has higher inhibitory activity on nerve receptors.
In one aspect of the present invention, a double salt compound is a double salt of flavonoid glycoside and an organic amine neuroagonist, where the flavonoid glycoside has a general structural formula shown in formula (1) below:
Figure BDA0003329983570000021
wherein R is1～R9Each independently selected from-H, -OH, C1～C6Alkyl, alkoxy or substituted alkyl, and R1And R2At least one of them is selected from-OH.
In one embodiment, R1And R2Are all selected from-OH.
In one embodiment, the flavonoid glycoside is baicalin or scutellarin.
In one embodiment, the organic amine neuroagonist contains at least one amino group, each amino group being independently selected from-NH2-NR 'H or-NR'2And R' is an electron donating group.
In one embodiment, the organic amine neuroagonist is selected from any one of donepezil, rivastigmine, amiloride, memantine, fingolimod and galantamine.
In one aspect of the present invention, a preparation method of the double salt compound is further provided, which comprises the following steps:
mixing and dissolving the flavonoid glycoside, the organic amine nerve agonist and a polar aprotic organic solvent to obtain a mixed solution;
reacting the mixed solution to obtain a reaction solution; and
the reaction solution was freed of the solvent.
In one embodiment, the polar aprotic organic solvent is one or more of N, N-dimethylformamide, dimethylsulfoxide, or acetonitrile.
In another aspect of the present invention, there is further provided a pharmaceutical composition comprising a therapeutically effective amount of said double salt compound or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
In still another aspect of the present invention, there is provided a use of the double salt compound or the pharmaceutical composition for preparing a neural agonist drug.
In one embodiment, the neuroagonist drug is used for the treatment of a neurodegenerative disease, which is a cerebral apoplexy sequela, alzheimer's disease, multiple sclerosis or parkinson's syndrome.
In another aspect of the present invention, there is provided a double-salt nanoparticle, wherein the double-salt nanoparticle is obtained by nano-grinding the double-salt compound.
In a further aspect of the invention, the application of the double-salt nanoparticle in preparing a nerve agonist drug is provided.
In one embodiment, the anti-tumor drug is used for treating a tumor disease, and the neuroagonist drug is used for treating a neurodegenerative disease, wherein the neurodegenerative disease is cerebral apoplexy sequelae, Alzheimer's disease, multiple sclerosis or Parkinson's syndrome.
Compared with the prior art, the invention has the following beneficial effects:
the organic amine nerve agonist is alkaline and can be salified with inorganic acid or micromolecule organic acid to increase the stability and improve the physical property of the organic amine nerve agonist, but the salt formed by the inorganic acid or the micromolecule organic acid which is generally used for salifying the medicine and the organic amine nerve agonist in the prior art can not improve the biological activity of the medicine. The compound salt compound provided by the invention adopts flavonoid glycoside with a specific structure and organic amine neuroagonist to form compound salt, the molecular structure of the flavonoid glycoside contains carboxyl and phenolic hydroxyl, the flavonoid glycoside can be bonded with amino in the organic amine neuroagonist, and the bonding effect between the flavonoid glycoside and the amino is stronger than that of common medicine salt forming. Compared with the organic amine nerve agonist, the double salt shows higher inhibitory activity to nerve receptors and shows better recovery of animal mobility after brain injury.
The flavonoid glycoside is a natural compound with poor water solubility, but because the molecular structure has carboxyl and phenolic hydroxyl, the flavonoid glycoside is easy to dissolve in alkali and form salt with small molecular organic alkali, so that the water solubility of the flavonoid glycoside is enhanced. Furthermore, the double-salt compound provided by the invention is ground by a nano grinding technology, so that the particle size of the material is reduced to reach a nano level, and the double-salt compound has better water solubility.
Drawings
FIGS. 1 to 4 are a hydrogen nuclear magnetic resonance spectrum, an infrared spectrum, a DSC test chart and an XRD chart of a double salt compound prepared in example 1 of the present invention;
FIGS. 5 to 8 are a hydrogen nuclear magnetic resonance spectrum, an infrared spectrum, a DSC test chart and an XRD chart of a double salt compound prepared in example 2 of the present invention;
FIGS. 9 to 12 are a hydrogen nuclear magnetic resonance spectrum, an infrared spectrum, a DSC test chart and an XRD chart of a double salt compound prepared in example 3 of the present invention;
FIGS. 13 to 16 are a hydrogen nuclear magnetic resonance spectrum, an infrared spectrum, a DSC test chart and an XRD chart of a double salt compound prepared in example 4 of the present invention;
FIGS. 17 to 20 are a hydrogen nuclear magnetic resonance spectrum, an infrared spectrum, a DSC test chart and an XRD chart of a double salt compound prepared in example 5 of the present invention;
FIGS. 21 to 24 are a hydrogen nuclear magnetic resonance spectrum, an infrared spectrum, a DSC test chart and an XRD chart of a double salt compound prepared in example 6 of the present invention;
FIGS. 25 to 28 are a hydrogen nuclear magnetic resonance spectrum, an infrared spectrum, a DSC test chart and an XRD chart of a double salt compound prepared in example 7 of the present invention;
FIGS. 29 to 32 are a hydrogen nuclear magnetic resonance spectrum, an infrared spectrum, a DSC test chart and an XRD chart of a double salt compound prepared in example 8 of the present invention;
FIGS. 33 to 36 are a hydrogen nuclear magnetic resonance spectrum, an infrared spectrum, a DSC test chart and an XRD chart of a double salt compound prepared in example 9 of the present invention;
FIGS. 37 to 40 are a hydrogen nuclear magnetic resonance spectrum, an infrared spectrum, a DSC test chart and an XRD chart of a double salt compound prepared in example 10 of the present invention;
FIGS. 41 to 44 are a hydrogen nuclear magnetic resonance spectrum, an infrared spectrum, a DSC test chart and an XRD chart of a double salt compound prepared in example 11 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The 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 specification: DMF (N, N-dimethylformamide), DSC (differential scanning calorimetry).
Terms and definitions
Unless otherwise stated or contradicted, terms or phrases used herein have the following meanings:
the term "alkyl" refers to a saturated hydrocarbon containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof. Phrases containing the term, e.g., "C1～C6Alkyl "refers to an alkyl group containing 1 to 6 carbon atoms, which may be independently at each occurrence C1Alkyl radical, C2Alkyl radical, C3Alkyl radical, C4Alkyl radical, C5Alkyl or C6An alkyl group. Suitable examples include, but are not limited to: methyl (Me, -CH)3) Ethyl (Et-CH)2CH3) 1-propyl (n-Pr, n-propyl, -CH)2CH2CH3) 2-propyl (i-Pr, i-propyl, -CH (CH)3)2) 1-butyl (n-Bu, n-butyl, -CH)2CH2CH2CH3) 2-methyl-1-propyl (i-Bu, i-butyl, -CH)2CH(CH3)2) 2-butyl (s-Bu, s-butyl, -CH (CH)3)CH2CH3) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH)3)3) 1-pentyl (n-pentyl, -CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl-CH2CH(CH3)CH2CH3) 1-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) And 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3。
The term "alkoxy" refers to a group having an-O-alkyl group, i.e., an alkyl group as defined above attached to the parent core structure via an oxygen atom. Phrases containing the term, e.g., "C1～C6Alkoxy "means that the alkyl moiety contains 1 to 6 carbon atoms and, at each occurrence, may be independently C1Alkoxy radical, C2Alkoxy radical, C3Alkoxy radical, C4Alkoxy radical, C5Alkoxy or C6An alkoxy group. Suitable examples include, but are not limited to: methoxy (-O-CH)3or-OMe), ethoxy (-O-CH)2CH3or-OEt) and tert-butoxy (-O-C (CH)3)3or-OtBu).
"amino" refers to derivatives of ammonia, non-limiting types of amino groups include-NH2-N (alkyl)2NH (alkyl), -N (cycloalkyl)2NH (cycloalkyl), -N (heterocyclyl)2NH (heterocyclyl), -N (aryl)2NH (aryl), -N (alkyl) (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 which are, within the scope of sound medical judgment, suitable for administration to a patient 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, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Each carrier, excipient or diluent must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of 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-cyclodextrin; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, 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) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
Reference to "substitution" of a group means that one or more hydrogen atoms attached to the member atoms within the group is replaced by a substituent selected from the group of defined or suitable substituents. It is to be understood that the term "substituted" includes the following implied conditions: such substitution should be consistent with the permissible valences of the substituted atoms and substituents and the substitution results in stable compounds. When it is stated that a group may contain one or more substituents, one or more 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 such substitution is in accordance with the allowed valency of the atom. "Member atom" means 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 bonded to an adjacent member atom in the chain or ring. The atoms that make up the substituents on the 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, e.g., a neuroreceptor, including acetylcholinesterase, NMDA receptor, sphingosine phosphate receptor. IC (integrated circuit)50Smaller values indicate a stronger inhibitory activity of the compound for a given activity.
Compound (I)
In one aspect, the invention relates to a double salt compound, which is a double salt of flavonoid glycoside and organic amine nerve agonist, wherein the flavonoid glycoside has a general structural formula shown in the following formula (1):
Figure BDA0003329983570000061
wherein R is1～R9Each independently selected from-H, -OH, C1～C6Alkyl, alkoxy or substituted alkyl, and R1And R2At least one of them is selected from-OH.
The flavonoid glycoside has molecular structure including carboxyl hydrogen in gluconic acid unit and phenolic hydroxyl hydrogen (R) in flavone unit1Or R2Hydrogen in (c) together forming a hydrogen ion rich region, is a proton donor. The nitrogen atom of the organic amine in the organic amine nerve agonist contains lone pair electrons and is a proton acceptor. The two are combined to form the flavonoid glycoside-organic amine neuroagonist double salt. Due to steric hindrance, carboxyl hydrogen in a gluconic acid unit and phenolic hydroxyl hydrogen in a flavone unit in the flavonoid glycoside are respectively positioned at two sides of a sugar ring. When it is combined with an organic amine, the carboxyl hydrogen on both sides of the sugar ringAnd the phenolic hydroxyl hydrogen is converted into a microenvironment with the same side as that of the phenolic hydroxyl hydrogen, as shown in a formula (2), and a proton pit (a proton structure shown by a dotted line frame in the formula 2), a carboxyl oxygen electron and a nitrogen lone pair electron are formed. From the valence bond theory analysis, hydrogen protons and amine in the proton pit can form stable ammonium salt; from the theoretical analysis of molecular orbitals, the empty orbit of hydrogen in the proton nest can be perfectly combined with the lone pair of electrons of amine; from the analysis of quantum chemistry and quantum entanglement theory, the hydrogen electron, carboxyl oxygen electron in the proton pit and the lone electron pair of nitrogen in the organic amine realize entanglement in the salt forming area, because of the existence of quantum entanglement, after the organic acid and the organic base of the flavonoid glycoside-organic amine neuroagonist double salt are dissociated with each other, the quantum entanglement formed in the salt forming period continuously exists, and the biological activity of the flavonoid glycoside-organic amine neuroagonist double salt is improved.
Figure BDA0003329983570000062
Preferably, said R is1And R2Are all selected from-OH.
In some embodiments, R3Is selected from-H or-OCH3. In some embodiments, R5、R6、R9Are all selected from-H. In some embodiments, R7、R8Each independently selected from-H or-OH. In some embodiments, R8Is selected from-H. In some embodiments, R7Is selected from-OH. In other embodiments, R7Is selected from-H.
In some embodiments, the flavonoid glycoside may be any one of apigenin flavonoid glycoside, baicalin, scutellarin, chrysin flavonoid glycoside or wogonoside, preferably, the flavonoid glycoside is baicalin or scutellarin glycoside.
The molecular structural formula of the baicalin is shown as the following formula (1-1):
Figure BDA0003329983570000071
the molecular structural formula of the scutellarin is shown as the following formula (1-2):
Figure BDA0003329983570000072
the organic amine nerve agonist contains at least one amino group, and the amino groups are respectively and independently selected from-NH2-NR 'H or-NR'2And 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, rivastigmine, amiloride, memantine, fingolimod and galantamine.
Donepezil of formula C24H29NO3Can be used for treating Alzheimer's disease and apoplexy sequelae. The structural formula of donepezil is shown below:
Figure BDA0003329983570000073
rivastigmine with molecular formula C14H22N2O2The carbamic acid derivatives of physostigmine also belong to the second generation of AChE inhibitors. The structural formula of rivastigmine is shown below:
Figure BDA0003329983570000081
amiloride, also known as ipratropium, has the structural formula shown below:
Figure BDA0003329983570000082
memantine of formula C12H21N, belonging to the class of excitatory amino acid (NMDA) receptor inhibitors, for the treatment of dementia of the moderate to severe Alzheimer's type. The structural formula of memantine is shown below:
Figure BDA0003329983570000083
fingolimod, molecular formula C19H33NO2Fingolimod is a sphingosine phosphate receptor inhibitor and is mainly clinically used for treating relapsing and remitting multiple sclerosis. The structural formula of fingolimod is shown as follows:
Figure BDA0003329983570000084
galantamine having the molecular formula C17H22ClNO3Are inhibitors of sphingosine phosphate receptors and are useful in the treatment of multiple sclerosis. The structural formula of galanthamine is shown as follows:
Figure BDA0003329983570000085
in one aspect, the invention also relates to a preparation method of the double salt compound, which comprises the following steps:
s10, mixing and dissolving the flavonoid glycoside, the organic amine nerve agonist and a polar aprotic organic solvent to obtain a mixed solution;
s20, reacting the mixed solution to obtain a reaction solution; and
and S30, removing the solvent from the reaction solution.
The molar ratio of the flavonoid glycoside to the organic amine neuroagonist can be any ratio of 1: 3-3: 1, and can also include 1:2, 1:1.5, 1:1, 1.5:1, 2:1, and preferably 1:1. The polar aprotic organic solvent may be one or more of N, N-dimethylformamide, dimethyl sulfoxide or acetonitrile.
There are various methods for mixing and dissolving the flavonoid glycoside, the organic amine neuroagonist, and the polar aprotic organic solvent in step S10 to obtain a mixed solution. Preferably, the following steps can be included
S11, dissolving the flavonoid glycoside in the polar aprotic organic solvent to obtain a first solution;
s12, dissolving the organic amine nerve 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 glycoside in the first solution is 0.1 mol/L-1.0 mol/L, and preferably 0.33 mol/L.
The concentration of the organic amine nerve agonist in the second solution is 0.1-1.0 mol/L, and preferably 0.33 mol/L.
In the step of reacting the mixed solution, the reaction temperature may be 30 to 100 ℃, preferably 50 to 70 ℃, and more preferably 70 ℃.
The method for removing the solvent can be vacuum concentration, and the temperature of the vacuum concentration can be 40-70 ℃, and preferably 60 ℃.
Step S30 further includes a purification step. The purification method may be pulping. The solvent used for the pulping may be ethyl acetate. The amount of ethyl acetate is preferably 1:1 to 1:5, and most preferably 1:3, based on mol/L of acid (baicalin or scutellarin); the temperature of pulping is 5-50 ℃, preferably 20-30 ℃ and the time is 20-40 minutes.
And the purification also comprises filtering the solution after pulping, and further drying a filter cake after filtering. The drying method can be freeze drying or vacuum drying. The temperature of the vacuum drying can be 20-60 ℃, preferably 30 ℃, and the drying time can be 8-48 hours, preferably 24 hours. The temperature of the freeze drying is less than 0 ℃, and the drying time can be 3 to 12 hours, preferably 6 hours.
In one aspect, the present invention relates to a composition comprising a therapeutically effective amount of a double salt compound as described above, or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
In one aspect, the invention relates to the application of the double salt compound in preparing a nerve agonist medicament.
In some embodiments, the neuroagonist drug prepared according to the double salt compound of the present invention is used for the treatment of neurodegenerative diseases, which are cerebral apoplexy sequelae, alzheimer's disease, multiple sclerosis or parkinson's syndrome.
In one aspect, the present invention further relates to a method of treating a neurodegenerative disease, preferably comprising administering to a patient in need thereof suffering from a neurodegenerative disease a suitable amount of a composition comprising a double salt compound according to the invention as defined above.
In one aspect, the present invention further relates to double-salt nanoparticles obtained by nano-milling the double-salt compound according to any one of the above embodiments.
In some embodiments, the double salt nanoparticles have an average particle size of 50nm to 500 nm.
In one aspect, the present invention also relates to a method for preparing the double salt nanoparticles, comprising:
the double salt compound, the suspending agent and the solvent are mixed and ground by a nano grinder to prepare the compound.
In some embodiments, the suspending agent is one or more of tween, hypromellose, polyethylene glycol, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, fatty acid glycerides, polyol-type nonionic surfactants, polyoxyethylene-type nonionic surfactants, poloxamers, vitamin E polyethylene glycol succinate, phospholipids, gelatin, xanthan gum, sodium lauryl sulfate, and sodium deoxycholate.
In some preferred embodiments, the suspending agent is a combination of tween, hydroxypropyl methyl fiber and polyethylene glycol.
In some embodiments, the mass ratio of the double salt compound to the suspending agent is 1000: (0.5 to 3).
In some embodiments, the milling is performed at a speed of 1000rpm to 3000rpm for a time period of 10 minutes to 60 minutes. The diameter of a working cavity of the nano grinder used for grinding is 85 mm. If the diameter of the working cavity of the nano grinder is changed, the rotating speed is adjusted correspondingly.
In one aspect, the invention further relates to application of the double-salt nanoparticle in preparing a nerve agonist drug.
In some embodiments, the neuroagonist drug is for the treatment of a neurodegenerative disease, which is a cerebral apoplexy sequela, alzheimer's disease, multiple sclerosis, or parkinson's syndrome.
Administration and formulation
The production of medicaments containing the compounds of the invention, their active metabolites or isomers and their use can be carried out according to well-known pharmaceutical methods.
Although the compounds of the invention useful in the treatment according to the invention may be administered as the original chemical compound, it is preferred to incorporate the active ingredient in the pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents and/or other conventional pharmaceutical adjuvants. Such salts of the compounds of the present invention may be anhydrous or solvated.
In a preferred embodiment, the present invention provides a medicament comprising a compound useful according to the present invention or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers therefor 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 deleterious to the recipient thereof.
The medicaments of the invention may be those suitable for oral, rectal, bronchial, nasal, topical, buccal, sublingual, transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration 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 compound of the invention, which matrices may be in the form of shaped articles, e.g. films, or microcapsules.
The compounds useful according to the invention, together with conventional adjuvants, carriers or diluents, may thus be placed in the form of medicaments and unit doses thereof. Such forms include: solids, in particular in the form of tablets, filled capsules, powders and pills (pellets); and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, universal drugs (elixir) and capsules filled therewith, all forms for oral administration, suppositories for rectal administration and sterile injection solutions for parenteral use. These medicaments and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without other active compounds or ingredients, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
The compounds useful according to the present invention 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 comprise one or more compounds useful according to the present invention as active ingredients.
For the preparation of medicaments from the compounds usable according to the invention, the pharmaceutically acceptable carriers may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets (cachets), suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or a coating material.
In powders, the carrier is a finely divided solid which is in admixture with the finely divided active component. In tablets, the active ingredient 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, and the like. The term "formulation" is intended to include active compound formulations having a coating material as a carrier, providing a capsule in which the active component is surrounded by, and thus associated with, a carrier, with or without a carrier. Similarly, cachets and lozenges (lozenge) 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 dispersed homogeneously therein, such as by stirring. The molten homogeneous mixture is then poured into a suitably sized mould, allowed to cool and thereby solidify. Compositions suitable for vaginal administration may be presented as pessaries (pessary), tampons (tampons), creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Liquid preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as aqueous polyethylene glycol solutions.
Thus, the chemical compounds according to the invention may be formulated for parenteral administration (e.g. by injection, e.g. bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules with an added preservative, in pre-filled syringes, in small volume infusions or in multi-dose containers. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles (vehicles), and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, for constitution before use, by sterile isolation of a sterile solid or by lyophilization from solution.
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 comminuted active ingredient in water with a viscous material such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. In addition to the active ingredient, these preparations may contain coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
In one embodiment of the invention, the drug is administered locally or systemically or by a combination of both routes.
For administration, in one embodiment, the compounds of the present invention may be administered in a formulation containing from 0.001% to 70% by weight of the compound, preferably from 0.01% to 70% by weight of the compound, even more preferably from 0.1% to 70% by weight of the compound. In one embodiment, a suitable amount of the compound administered is in the range of 0.01mg/kg body weight to 1g/kg body weight.
Compositions suitable for administration also include: lozenges comprising the active agent in a flavoured base (usually sucrose and acacia or tragacanth), pastilles comprising the active ingredient in an inert base (such as gelatin and glycerin or sucrose and acacia) (pastilles) and mouthwashes comprising the active ingredient in a suitable liquid carrier (mouthwash).
Solutions or suspensions are administered directly to the nasal cavity by conventional means, for example, with a dropper, pipette or nebulizer. The compositions may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering a suitable predetermined volume of solution or suspension. In the case of a nebulizer, this can be achieved, for example, by a metered atomizing spray pump.
Administration to the respiratory tract may also be accomplished by way of an aerosol formulation in which the active ingredient is provided in pressurized packs with a suitable propellant, such as a chlorofluorocarbon (CFC) (e.g., dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane), carbon dioxide or other suitable gas. The aerosol may also conveniently contain a surfactant, such as lecithin. The dosage of the medicament may be controlled by providing a metering valve.
Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently, the powder carrier will form a gel within the nasal cavity. The powder compositions may be presented in unit dosage form, for example, as capsules or cartridges of gelatin (cartridges), or as blister packs (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, for example about 5 microns or less. Such particle sizes may be obtained by means known in the art, for example by micronization.
If desired, compositions suitable for sustained release of the active ingredient may be used.
The pharmaceutical preparation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation, the package containing discrete quantities of the preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Moreover, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the packaged form of a suitable number of any of these dosage forms. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
Additional details regarding The art of formulation and administration can be found in The latest edition of "Remington's Pharmaceutical Sciences (Maack Publishing Co. Easton, Pa.) and Remington: The science and practice of medicine", Lippincott Williams and Wilkins.
Suitable formulations and The manner of producing them are also disclosed, for example, in "Arzneiformenlehre, Paul Heinz List, EinlehrbuchufurPharmazeuten, Wissenschaftlichehergesellschaft Stuttgart,4. Aufiage, 1985" or "The term and practice of industrial pharmacy", Varghese Publishing House,1987 "or" model pharmaceuticals ", edited by James Swarrrick, 2 nd edition" written by Lachman et al.
The present invention is further described below with reference to the following examples, which are intended to illustrate and not limit the scope of the present invention. Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods. The experimental procedures, in which specific conditions are not indicated in the examples, were carried out according to conventional conditions, such as those described in the literature, in books, or as recommended by the manufacturer.
Example 1 preparation of baicalin donepezil salt
3.80 g (0.01mol) of donepezil is suspended in 15ml of DMF, 4.46 g (0.01mol) of baicalin is added into 30ml of DMF, the solution of donepezil is added into the solution of baicalin DMF, the mixture is stirred and reacted for 15 hours at 70 ℃, and the reaction solution is concentrated to dryness under reduced pressure at 60 ℃ to obtain a crude product. The crude product was slurried with 30ml of ethyl acetate at room temperature for 20 minutes, filtered, the filter cake was divided into two equal portions, the first portion was suspended in 15ml of water, and freeze-dried for 6 hours to remove the solvent to give a pale yellow solid product. The second filter cake was vacuum dried at 30 ℃ for 24 hours to give a pale yellow solid product. The first portion yielded 3.66 g of baicalin donepezil salt with a yield of 88.69%. The second portion yielded 3.64 g of baicalin donepezil salt with a yield of 88.41%.
The product is subjected to structural characterization test through nuclear magnetic hydrogen spectrum, infrared spectrum, DSC and XRD, the result is shown in figures 1-4, compared with a simple mixture of baicalin and donepezil, the product is easier to dissolve, the chemical shift of nuclear magnetic resonance hydrogen spectrum shows that carboxyl hydrogen of baicalin and donepezil-N are salified, the infrared spectrum also shows the characteristic, and the thermal weight loss shows that the product has peaks at 198 ℃ and 320 ℃. The physical properties, spectral characteristics and thermodynamic properties of the product are changed compared with those of baicalin and donepezil, which indicates that the product is salified.
EXAMPLE 2 preparation of Scutellarin donepezil salt
Donepezil 3.80 g (0.01mol) was suspended in 15ml DMF, scutellarin 4.62 g (0.01mol) was added to 30ml DMF, the above amantadine DMF solution was added to baicalin DMF solution, the reaction was stirred at 70 ℃ for 15 hours, and the reaction solution was concentrated to dryness under reduced pressure at 60 ℃ to give a crude product. The crude product was slurried with 30ml of ethyl acetate at room temperature for 20 minutes, filtered, the filter cake was divided into two equal portions, the first portion was suspended in 15ml of water, and freeze-dried for 6 hours to remove the solvent to give a pale yellow solid product. The second filter cake was vacuum dried at 30 ℃ for 24 hours to give a pale yellow solid product. The first portion obtained 3.58 g of scutellarin donepezil salt with yield of 85.13%, and the second portion obtained 3.60 g of scutellarin donepezil salt with yield of 85.44%.
The product is tested by nuclear magnetic hydrogen spectrum, infrared spectrum and DSC structure characterization, the result is shown in figures 5-8, compared with the pure mixture of scutellarin and donepezil, the product is easier to dissolve, the chemical shift of nuclear magnetic resonance hydrogen spectrum shows that the carboxyl hydrogen of the scutellarin forms salt with donepezil-N, the infrared spectrum also shows the characteristic, and the thermal weight loss shows that the product has peaks at 205 ℃ and 319 ℃. The physical property, spectral characteristic and thermodynamic property of the product are changed compared with scutellarin and donepezil, which indicates that the product is salified.
EXAMPLE 3 preparation of baicalin rivastigmine salts
The preparation process was substantially the same as in example 1, except that donepezil was replaced with rivastigmine 2.50 g (0.01 mol).
The first portion yielded baicalin rivastigmine salt in 2.84 g at 81.51% yield, and the second portion yielded baicalin rivastigmine salt in 2.83 g at 81.43% yield. The product is subjected to structure characterization test through nuclear magnetic hydrogen spectrum, infrared spectrum, DSC and XRD, the result is shown in figures 9-12, compared with a simple mixture of baicalin and rivastigmine, the product is easier to dissolve, chemical shift of nuclear magnetic resonance hydrogen spectrum shows that carboxyl hydrogen of the baicalin and rivastigmine-N form salt, the infrared spectrum also shows the characteristic, and the thermal weight loss shows that the product has peaks at 193 ℃ and 327 ℃. The physical property, spectral characteristic and thermodynamic property of the product are changed compared with baicalin and rivastigmine, which indicates that the product is salified.
EXAMPLE 4 preparation of scutellarin rivastigmine salt
The preparation process was substantially the same as in example 2, except that donepezil was replaced with rivastigmine 2.50 g (0.01 mol).
The first portion yielded 2.93 g of scutellarin rivastigmine salt with a yield of 84.34%, and the second portion yielded 2.94 g of scutellarin rivastigmine salt with a yield of 84.50%. The product is subjected to structure characterization test through nuclear magnetic hydrogen spectrum, infrared spectrum, DSC and XRD, the result is shown in figures 13-16, compared with a simple mixture of scutellarin and rivastigmine, the product is easier to dissolve, the chemical shift of the nuclear magnetic resonance hydrogen spectrum shows that carboxyl hydrogen of the scutellarin forms salt with rivastigmine-N, the infrared spectrum also shows the characteristic, and the thermal weight loss shows that the product has a peak at 200 ℃. The physical property, spectral characteristic and thermodynamic property of the product are changed compared with scutellarin and rivastigmine, which indicates that the product is salified.
Example 5 preparation of baicalin amiloride salt
The preparation process was substantially the same as in example 1, except that donepezil was replaced with amiloride 1.88 g (0.01 mol).
The first portion yielded 2.97 g of baicalin amiloride salt in 93.79% yield, and the second portion yielded 2.96 g of baicalin amiloride salt in 93.30% yield. The product is subjected to structure characterization test by nuclear magnetic hydrogen spectrum, infrared spectrum, DSC and XRD, and the results are shown in figures 17-20, compared with the simple mixture of baicalin and amiloride, the product is easier to dissolve, and the chemical shift of nuclear magnetic resonance hydrogen spectrum shows that carboxyl hydrogen of baicalin and amiloride-NH2Salification and infrared spectroscopy show the characteristics, and the thermal weight loss shows that the product has peaks at 94 ℃, 194 ℃ and 315 ℃. The XRD pattern showed that the product had characteristic diffraction peaks. The physical property, spectral characteristic and thermodynamic property of the product are changed compared with those of baicalin and amiloride, which indicates that the product is salified.
Example 6 preparation of scutellarin amiloride salt
The preparation process was substantially the same as in example 2, except that donepezil was replaced with amiloride 1.88 g (0.01 mol).
The first portion yielded 2.17 g of scutellarin amiloride gold salt with a yield of 68.44%, and the second portion yielded 2.22 g of scutellarin amiloride gold salt with a yield of 70.10%. The product is subjected to structure characterization test by nuclear magnetic hydrogen spectrum, infrared spectrum, DSC and XRD, and the results are shown in figures 21-24, compared with the simple mixture of scutellarin and amiloride, the product is easier to dissolve, and the chemical shift of nuclear magnetic resonance hydrogen spectrum shows that carboxyl hydrogen of scutellarin and amiloride-NH2Salification and infrared spectroscopy also show the characteristic, and the thermal weight loss shows that the product has a peak at 202 ℃. The XRD pattern showed that the product had characteristic diffraction peaks. The physical property, spectral characteristic and thermodynamic property of the product are changed compared with those of scutellarin and amiloride, which indicates that the product is salified.
Example 7 preparation of baicalin galanthamine salt
The preparation process was substantially the same as in example 1, except that donepezil was replaced with 2.87 g (0.01mol) of galantamine.
The first portion yielded 3.22 g of baicalin galanthamine salt with a yield of 87.97%, and the second portion yielded 3.24 g of baicalin galanthamine salt with a yield of 88.30%. The product is subjected to structure characterization test by nuclear magnetic hydrogen spectrum, infrared spectrum, DSC and XRD, the result is shown in figures 25-28, compared with a simple mixture of baicalin and galanthamine, the product is easier to dissolve, chemical shift of nuclear magnetic resonance hydrogen spectrum shows that carboxyl hydrogen of baicalin and galanthamine-N are salified, the infrared spectrum also shows the characteristic, and the thermal weight loss shows that the product has peaks at 198 ℃ and 279 ℃. The physical property, spectral characteristic and thermodynamic property of the product are changed compared with those of baicalin and galanthamine, which indicates that the product is salified.
EXAMPLE 8 preparation of baicalin memantine salt
The preparation process was substantially the same as in example 1, except that donepezil was replaced with memantine 1.8 g (0.01 mol).
The first portion yielded 2.49 g of baicalin memantine salt in 79.67% yield, and the second portion yielded 2.51 g of baicalin memantine salt in 80.30% yield. Product passingThe nuclear magnetic hydrogen spectrum, infrared spectrum, DSC and XRD are subjected to structure characterization tests, and the results are shown in figures 29-32, compared with a simple mixture of baicalin and memantine, the product is easier to dissolve, and the chemical shift of the nuclear magnetic resonance hydrogen spectrum shows that carboxyl hydrogen of baicalin and memantine-NH are mixed2Salification and infrared spectroscopy also show the characteristic, and the thermal weight loss shows that the product has peaks at 197 ℃ and 361 ℃. The XRD pattern showed that the product had characteristic diffraction peaks. The physical property, spectral characteristic and thermodynamic property of the product are changed compared with those of baicalin and memantine, and the salt is formed.
Example 9 preparation of scutellarin memantine salt
The preparation process was substantially the same as in example 2, except that donepezil was replaced with memantine 1.80 g (0.01 mol).
The first portion yielded 2.75 g of scutellarin memantine salt with a yield of 87.91%, and the second portion yielded 2.73 g of scutellarin memantine salt with a yield of 87.10%. The product is subjected to structure characterization test by nuclear magnetic hydrogen spectrum, infrared spectrum, DSC and XRD, and the results are shown in figures 33-36, compared with the simple mixture of scutellarin and memantine, the product is more soluble, and the chemical shift of nuclear magnetic resonance hydrogen spectrum shows that carboxyl hydrogen of scutellarin and memantine-NH2Salification and infrared spectroscopy also show the characteristic, and the thermal weight loss shows that the product has a peak at 204 ℃. The physical property, spectral characteristic and thermodynamic property of the product are changed compared with scutellarin and memantine, which indicates that the product is salified.
Example 10 preparation of baicalin fingolimod salt
The preparation method is basically the same as that of example 1, except that 3.08 g (0.01mol) of fingolimod is substituted for donepezil.
The first portion yielded baicalin fingolimod salt in 3.11 g with 82.42% yield, and the second portion yielded baicalin fingolimod salt in 3.14 g with 83.30% yield. The product is subjected to structure characterization test by nuclear magnetic hydrogen spectrum, infrared spectrum, DSC and XRD, and the result is shown in figures 37-40, compared with the simple mixture of baicalin and fingolimod, the product is easier to dissolve, and the chemical shift of nuclear magnetic resonance hydrogen spectrum shows that the baicalin and the fingolimod are pureCarboxy hydrogen of glycoside and fingolimod-NH2Salification and infrared spectroscopy also show the characteristic, and the thermal weight loss shows that the product has peaks at 190 ℃ and 326 ℃. The physical properties, spectral characteristics and thermodynamic properties of the product are changed compared with those of baicalin and fingolimod, which indicates that the product is salified.
Example 11 preparation of scutellarin fingolimod salt
The preparation method is basically the same as that of example 2, except that 3.08 g (0.01mol) of fingolimod is substituted for donepezil.
The first portion yielded 3.07 g of scutellarin fingolimod salt with a yield of 81.35%, and the second portion yielded 3.02 g of scutellarin fingolimod salt with a yield of 80.10%. The product is subjected to structure characterization test by nuclear magnetic hydrogen spectrum, infrared spectrum, DSC and XRD, and the result is shown in figures 41-44, compared with the pure mixture of scutellarin and fingolimod, the product is easier to dissolve, and the chemical shift of nuclear magnetic resonance hydrogen spectrum shows carboxyl hydrogen of the scutellarin and fingolimod-NH2Salification and infrared spectroscopy also show the characteristic, and the thermal weight loss shows that the product has a peak at 202 ℃. The physical property, spectral characteristic and thermodynamic property of the product are changed compared with those of the scutellarin and the fingolimod, which indicates that the product is salified.
Example 12 Activity assay
1. Determination of acetylcholinesterase inhibitor activity: preparing the compound into test samples with different concentrations, respectively, determining the inhibition rate of the test samples by adopting an acetylcholinesterase kit and acetylcholine as a substrate, and calculating the IC 50.
2. NMDA (N-methyl-D-aspartate) inhibitory activity assay: preparing the compound of each double salt into test samples with different concentrations, adopting NMDA (N-methyl-D-aspartic acid) receptor blocker, utilizing the patch clamp technology to measure the inhibition rate of the test samples, and calculating IC 50.
3. Sphingosine phosphate receptor inhibitor activity assay: preparing the compound into test samples with different concentrations, respectively, determining the inhibition rate of the test samples by using a sphingosine phosphate receptor kit and an enzyme-linked immunosorbent assay technology, and calculating IC 50.
The pharmaceutical activity of each double salt compound is shown in table 2:
TABLE 2
Figure BDA0003329983570000161
Figure BDA0003329983570000171
As is clear from table 2, the inhibitory activity of the baicalin donepezil double salt compound and the scutellarin donepezil double salt compound against acetylcholinesterase was higher than that of donepezil; the inhibitory activity of the baicalein rivastigmine double salt compound and the wild baicalein rivastigmine double salt compound on acetylcholinesterase is stronger than that of rivastigmine on acetylcholinesterase; the inhibitory activity of the baicalin amiloride double salt compound and the scutellarin amiloride double salt compound on acetylcholinesterase is stronger than that of amiloride on acetylcholinesterase; the inhibitory activity of the compound of baicalin galanthamine double salt to acetylcholinesterase is stronger than that of galanthamine to acetylcholinesterase; the inhibitory activity of the baicalin memantine double salt compound and the scutellarin memantine double salt compound on the NMDA receptor is stronger than that of memantine on the NMDA receptor; the inhibitory activity of baicalin fingolimod double salt compound and baicalin fingolimod rigid double salt compound on sphingosine phosphate receptor is stronger than that of fingolimod on sphingosine phosphate receptor.
Example 13 preparation of nanoparticles of baicalin donepezil double salt
1. Adding 50 g of the baicalin donepezil double salt compound, 500 ml of water, 50 mg of the suspending agent Tween-2050, 50 mg of hydroxypropyl methylcellulose and 600050 mg of polyethylene glycol into a nano grinder, and grinding at 2000rpm for 40 minutes to obtain the nano suspension of the baicalin donepezil double salt.
2. Drying the obtained baicalin donepezil double salt nano suspension in fluidized bed drying equipment at the drying air inlet temperature of 65 ℃ until the water content is about 3 percent, and preparing the baicalin donepezil double salt nano particles with the particle size distribution within the range of 50nm to 500 nm.
Compared with the baicalin donepezil double salt compound which is not nano-ground, the solubility of the prepared baicalin donepezil double salt nano-particles at 10 minutes and 20 ℃ is increased by 1 time.
Example 14 preparation of Scutellarin donepezil double salt nanoparticles
The procedure was substantially the same as in example 13, except that the baicalin donepezil double salt compound was replaced with the scutellarin donepezil double salt compound. The particle size distribution of the scutellarin donepezil double salt nano particles is within the range of 50nm to 500 nm.
Compared with the scutellarin donepezil double salt compound which is not nano-ground, the solubility of the prepared scutellarin donepezil double salt nano particles at 10 minutes and 20 ℃ is increased by 1.2 times.
Example 15 preparation of nanoparticles of baicalin rivastigmine double salt
Substantially the same as the production method in example 13, except that the baicalin donepezil double salt compound is replaced with the baicalin rivastigmine double salt compound. The particle size distribution of the baicalin rivastigmine double salt nano-particles is within the range of 50nm to 500 nm.
The prepared baicalin rivastigmine double salt nanoparticles have 0.8 times higher solubility at 10 min and 20 deg.C than that of the compound without nano grinding.
Example 16 preparation of scutellarin rivastigmine double salt nanoparticles
The procedure was substantially the same as in example 15, except that the scutelloside rivastigmine double salt compound was replaced with the scutelloside rivastigmine double salt compound. The particle size distribution of the scutellarin rivastigmine double salt nano particles is within the range of 50nm to 500 nm.
The solubility of the prepared scutellarin rivastigmine double salt nano particles at 10 minutes and 20 ℃ is increased by 0.8 times compared with the scutellarin rivastigmine double salt compound which is not nano-ground.
Example 17 preparation of baicalin amiri-gold double salt nanoparticles
Substantially the same as the production method in example 13 except that the baicalin donepezil double salt compound is replaced with the baicalin amiloride double salt compound. The particle size distribution of the baicalin amiloride double-salt nanoparticles is within the range of 50nm to 500 nm.
Compared with the baicalin amiloride double-salt compound which is not subjected to nano grinding, the prepared baicalin amiloride double-salt nano-particles have the solubility increased by 1.0 time at 10 minutes and 20 ℃.
Example 18 preparation of Scutellaria baicalensis glycoside Amimiri gold complex salt nanoparticles
The procedure was carried out in substantially the same manner as in example 17 except that the baicalin amiloride double salt compound was replaced with a scutellarin amiloride double salt compound. The particle size distribution of the scutellarin amiloride complex salt nanoparticles is within the range of 50 nm-500 nm.
Compared with the scutellarin amiloride double salt compound which is not ground in a nanometer way, the solubility of the prepared scutellarin amiloride double salt nano particles at 10 minutes and 20 ℃ is increased by 1.0 time.
Example 19 preparation of baicalin galanthamine double salt nanoparticles
Substantially the same as the production method in example 13 except that the baicalin donepezil complex salt compound is replaced with the baicalin galantamine complex salt compound. The particle size distribution of the baicalin galanthamine double salt nanoparticles is within the range of 50nm to 500 nm.
Compared with the baicalin galanthamine double salt compound which is not ground in a nanometer way, the solubility of the prepared baicalin galanthamine double salt nano-particles at 10 minutes and 20 ℃ is increased by 1.5 times.
Example 20 preparation of baicalin memantine double salt nanoparticles
Substantially the same as in example 13 except that the baicalin donepezil double salt compound is replaced with a baicalin memantine double salt compound. The particle size distribution of the baicalin memantine double salt nano particles is within the range of 50nm to 500 nm.
Compared with the baicalin memantine double salt compound which is not subjected to nano grinding, the solubility of the prepared baicalin memantine double salt nano-particles at 10 minutes and 20 ℃ is increased by 1.5 times.
Example 21 preparation of Scutellarin Memantine double salt nanoparticles
The preparation process was substantially the same as in example 19, except that the baicalin memantine double salt compound was replaced with a scutellarin memantine double salt compound. The particle size distribution of the scutellarin memantine double salt nano particles is within the range of 50 nm-500 nm.
Compared with the scutellarin memantine complex salt compound which is not nano-ground, the solubility of the prepared scutellarin memantine complex salt nano-particles at 10 minutes and 20 ℃ is increased by 1.5 times.
Example 22 preparation of baicalin fingolimod double salt nanoparticles
Substantially the same as in example 13 except that the baicalin donepezil double salt compound is replaced with a baicalin fingolimod double salt compound. The particle size distribution of the baicalin fingolimod double salt nano particles is within the range of 50nm to 500 nm.
Compared with the baicalin fingolimod double salt compound which is not subjected to nano grinding, the solubility of the prepared baicalin fingolimod double salt nano particles at 10 minutes and 20 ℃ is increased by 0.5 times.
Example 23 preparation of Scutellarin Fingolimod double salt nanoparticles
Substantially the same as in example 22 except that the baicalin fingolimod double salt compound is replaced with a scutellarin fingolimod double salt compound. The particle size distribution of the scutellarin fingolimod complex salt nano particles is within the range of 50 nm-500 nm.
Compared with the scutellarin fingolimod compound salt compound which is not nano-ground, the solubility of the prepared scutellarin fingolimod compound salt nano-particles at 10 minutes and 20 ℃ is increased by 0.5 times.
EXAMPLE 24 in vivo Activity assay in animals
A blank control group, a baicalin group, a scutellarin group, a donepezil group, a memantine group, a galantamine group, a baicalin donepezil double salt nanosuspension group (the baicalin donepezil double salt nanosuspension preparation method refers to example 13), a scutellarin donepezil double salt nanosuspension group (the scutellarin donepezil double salt nanosuspension preparation method refers to example 14), a baicalin memantine salt nanosuspension group (the baicalin memantine nanosuspension preparation method refers to example 21), a scutellarin memantine double salt nanosuspension group (the scutellarin memantine nanosuspension preparation method refers to example 22), and a baicalin galantamine double salt nanosuspension group (the baicalin galantamine double salt nanosuspension preparation method refers to example 19) were set, respectively.
1. Test animal
Mice: c57BL/6J mice, male, weighing 20g,6-8 weeks old. All mice were fed food and water ad libitum and were kept at room temperature (23 + -2) ° c.
2. Test method
Carotid embolized mice were established and eligible mice were randomly grouped into 6 mice each, and the dosing regimen was as follows:
blank control group: only saline was given.
Baicalin group: preparing baicalin into administration solution with sterile PBS, and performing intragastric administration according to administration amount of 2.5 mg/kg.
Scutellarin group: the scutellarin is prepared into a dosing solution by sterile PBS, and the solution is perfused into the stomach according to the dosing amount of 2.5 mg/kg.
Donepezil group: donepezil is prepared into a dosing solution by sterile PBS, and the administration amount is 2.5mg/kg for intragastric administration.
Memantine group: memantine was formulated into a dosing solution with sterile PBS and gavaged at 2.5 mg/kg.
Galantamine group: preparing galanthamine into a dosing solution by using sterile PBS, and performing intragastric administration according to the dosing amount of 2.5 mg/kg.
Baicalin donepezil double salt nanosuspension group: the baicalin donepezil double salt nanometer suspension is used as a drug delivery solution, and the drug delivery amount is 2.5mg/kg for intragastric administration.
Scutellarin donepezil double salt nanometer suspension group: the scutellarin donepezil double salt nanometer suspension is used as a drug administration solution, and the drug administration amount is 2.5mg/kg for intragastric administration.
Baicalin memantine double salt nanosuspension group: the baicalin memantine double-salt nanometer suspension is used as a drug delivery solution, and the drug delivery amount is 2.5mg/kg for intragastric administration.
Scutellarin memantine double salt nanometer suspension group: the scutellarin memantine double salt nanometer suspension is used as a drug administration solution, and the drug administration amount is 2.5 mg/kg.
Baicalin galanthamine double salt nanometer suspension group: the baicalin galanthamine double salt nano suspension is used as a drug delivery solution and is perfused into the stomach according to the drug delivery of 2.5 mg/kg.
Three hours after dosing, each group of mice was evaluated for physical activity and scored for: scoring according to 0-10, wherein the higher the score is, the stronger the physical activity is, and the result is as follows:
a blank control group with a score of 0, a baicalin group (dose of 2.5mg/kg) with a score of 2, a scutellarin group (dose of 2.5mg/kg) with a score of 2, a donepezil group with a score of 3, a memantine group with a score of 3, a galantamine group with a score of 3, a baicalin donepezil double salt nanoparticle group with a score of 8, a scutellarin donepezil group with a score of 9, a baicalin memantine double salt nanoparticle group with a score of 8, a scutellarin memantine group with a score of 8, and a baicalin galantamine double salt nanoparticle group with a score of 8. Compared with a blank group, a natural product group and a small molecule group, the scores of the double-salt nanometer suspension groups are obviously different, which shows that the recovery effect of the activity ability of the mice after brain injury is obviously improved by the administration of the double-salt nanometer suspensions.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (13)

1. A double salt compound is characterized in that the compound is a double salt of flavonoid glycoside and organic amine nerve agonist, wherein the flavonoid glycoside has a general structural formula shown as the following formula (1):
Figure FDA0003329983560000011
wherein R is1～R9Each independently selected from-H, -OH, C1～C6Alkyl, alkoxy or substituted alkyl, and R1And R2At least one of them is selected from-OH.
2. The double salt compound according to claim 1, wherein R is1And R2Are all 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 neuroagonist comprises at least one amino group, and each amino group is independently selected from-NH2-NR 'H or-NR'2And R' is an electron donating group.
5. The double salt compound according to claim 1, wherein the organic amine neuroagonist is selected from any one of donepezil, rivastigmine, amiloride, memantine, fingolimod and galantamine.
6. A method for preparing a double salt compound according to any one of claims 1 to 5, comprising the steps of:
mixing and dissolving the flavonoid glycoside, the organic amine nerve agonist and a polar aprotic organic solvent to obtain a mixed solution;
reacting the mixed solution to obtain a reaction solution; and
the reaction solution was freed of the solvent.
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, dimethylsulfoxide, or acetonitrile.
8. A pharmaceutical composition comprising a therapeutically effective amount of a double salt compound according to any one of claims 1 to 5, or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
9. The use of the double salt compound of any one of claims 1 to 5 or the pharmaceutical composition of claim 8 in the preparation of a neuroagonist medicament.
10. The use according to claim 9, wherein the neuroagonist medicament is for the treatment of a neurodegenerative disease, which is a sequela of stroke, alzheimer's disease, multiple sclerosis or parkinson's syndrome.
11. A double-salt nanoparticle, which is obtained by nano-grinding the double-salt compound according to any one of claims 1 to 5.
12. Use of double salt nanoparticles according to claim 11 for the preparation of a neuroagonist medicament.
13. The use according to claim 12, wherein the neuroagonist medicament is for the treatment of a neurodegenerative disease, which is a sequela of stroke, alzheimer's disease, multiple sclerosis or parkinson's syndrome.
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