CN113880897B - Flavonoid glycoside-organic amine tyrosine kinase inhibitor double salt compound and preparation method and application thereof - Google Patents

Flavonoid glycoside-organic amine tyrosine kinase inhibitor double salt compound and preparation method and application thereof Download PDF

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CN113880897B
CN113880897B CN202111277499.7A CN202111277499A CN113880897B CN 113880897 B CN113880897 B CN 113880897B CN 202111277499 A CN202111277499 A CN 202111277499A CN 113880897 B CN113880897 B CN 113880897B
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baicalin
scutellarin
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CN113880897A (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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Abstract

The invention relates to a double salt compound of flavonoid glycoside and an organic amine tyrosine kinase inhibitor, wherein the flavonoid glycoside has a structural general formula shown in the following formula (1), and R is 1 ～R 9 Each independently selected from-H, -OH, C 1 ～C 6 Alkyl, alkoxy or substituted alkyl, and R 1 And R is 2 At 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 and uses comprising a therapeutically effective amount. The invention further relates to double salt nano particles obtained by double salt compound through nano grinding and application thereof.

Description

Flavonoid glycoside-organic amine tyrosine kinase inhibitor double salt compound and preparation method and application thereof
The present application claims priority from chinese patent application entitled "flavonoid glycoside-organic amine tyrosine kinase inhibitor double salt, method for preparing the same, and use thereof," filed in 30 months 10 in 2020, and filed in chinese patent office under application number 2020111958077, the entire contents of which are incorporated herein by reference.
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a flavonoid glycoside-organic amine tyrosine kinase inhibitor double salt compound and a preparation method and application thereof.
Background
Tyrosine kinase inhibitors are compounds capable of inhibiting the activity of tyrosine kinase, can be used as competitive inhibitors for combining Adenosine Triphosphate (ATP) with tyrosine kinase, can also be used as analogues of tyrosine, can block the activity of tyrosine kinase and inhibit cell proliferation, and have been developed into a plurality of antitumor drugs including gefitinib, erlotinib, pezopanib, octreotide, lapatinib and the like, and can be used for treating malignant tumors such as non-small cell lung cancer, renal cell carcinoma, soft Tissue Sarcoma (STS), ovarian cancer, breast cancer and the like. Baicalin and scutellarin are flavonoid glycosides (simply referred to as flavonoid glycoside) and have abundant pharmacological activities, such as improving antioxidant capacity through lipid peroxidation, scavenging free radicals and superoxide anions, improving blood circulation, increasing blood flow, resisting platelet aggregation, inhibiting virus infection, enhancing immunity, resisting cell hypoxia, neuroprotection, inhibiting tumor cell growth, etc.
The existing multi-target tyrosine kinase inhibitor for treating non-small cell lung cancer patients is inferior to other non-small cell lung cancer therapeutic drugs in terms of effective rate and survival data. Therefore, the research and development of the specific inhibitor with higher selectivity and stronger activity, increases the curative effect and limits the toxicity, and is hopeful to become a new means for treating various malignant tumors such as non-small cell lung cancer and the like.
In addition, how to improve the solubility, speed up the dissolution and increase the blood concentration of the poorly soluble drugs is also a problem to be solved urgently.
Disclosure of Invention
Based on the above, it is necessary to provide a flavonoid glycoside-organic amine tyrosine kinase inhibitor double salt compound, and a preparation method and application thereof. Compared with the organic amine tyrosine kinase inhibitor, the flavonoid glycoside-organic amine tyrosine kinase inhibitor double salt compound has higher inhibition activity on tyrosine kinase.
In one aspect of the invention, a double salt compound is provided, which is a double salt of flavonoid glycoside and an organic amine tyrosine kinase inhibitor, wherein the flavonoid glycoside has a structural general formula shown in the following formula (1):
Figure BDA0003329980780000021
wherein R is 1 ～R 9 Each independently selected from-H, -OH, C 1 ～C 6 Alkyl, alkoxy or substituted alkyl, and R 1 And R is 2 At least one of them is selected from-OH.
In one embodiment, R 1 And R is 2 Are all selected from-OH.
In one embodiment, the flavonoid glycoside is baicalin or scutellarin.
In one embodiment, the organic amine tyrosine kinase inhibitor contains at least one amino group, each of which is independently selected from the group consisting of-NH 2 -NR 'H or-NR' 2 And R' is an electron donor group.
In one embodiment, the organic amine tyrosine kinase inhibitor is selected from any one of gefitinib, erlotinib, pezopanib, octreotide and lapatinib.
In one aspect of the present invention, there is also provided a method for preparing the double salt compound, comprising the steps of:
mixing and dissolving the flavonoid glycoside, the organic amine tyrosine kinase inhibitor and a polar aprotic organic solvent to obtain a mixed solution;
reacting the mixed solution 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.
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, in association with a pharmaceutically acceptable carrier, excipient or diluent.
In a further aspect of the invention, there is provided the use of said double salt compound or said pharmaceutical composition in the manufacture of a medicament for use as a tyrosine kinase inhibitor.
In one embodiment, the tyrosine kinase inhibitor medicament is used for the treatment of malignant tumors including lung cancer, liver cancer, stomach cancer, esophageal cancer, cardiac cancer, colon cancer, rectal cancer, colorectal cancer, breast cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, laryngeal cancer, oropharyngeal cancer, brain tumor, brain glioma.
In yet another aspect of the present invention, there is provided a double salt nanoparticle obtained from the double salt compound by nano-milling.
In a further aspect, the invention provides application of the double salt nano-particles in preparation of tyrosine kinase inhibitor drugs.
In one embodiment, the tyrosine kinase inhibitor medicament is for the treatment of malignant tumors including lung cancer, liver cancer, stomach cancer, esophageal cancer, cardiac cancer, colon cancer, rectal cancer, colorectal cancer, breast cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, laryngeal cancer, oropharyngeal cancer, brain tumor, glioma or soft tissue sarcoma.
Compared with the prior art, the invention has the following beneficial effects:
the organic amine tyrosine kinase inhibitor is alkaline and can form salt with inorganic acid or small molecular organic acid to increase the stability and improve the physical properties, but the salt formed by the inorganic acid or small molecular organic acid and the organic amine tyrosine kinase inhibitor which are generally used for forming salt of medicines in the prior art cannot improve the biological activity of the medicines. The compound provided by the invention adopts flavonoid glycoside with a specific structure and an organic amine tyrosine kinase inhibitor to form double salts, the molecular structure of the flavonoid glycoside contains carboxyl and phenolic hydroxyl, and can be bonded with amino groups in the organic amine tyrosine kinase inhibitor, and the bonding effect between the flavonoid glycoside and the organic amine tyrosine kinase inhibitor is stronger than that of common drugs to form salts. Compared with the organic amine tyrosine kinase inhibitor, the double salt has higher inhibition activity on tyrosine kinase, and further has better effect on inhibiting tumor.
The flavonoid glycoside is a natural compound with poor water solubility, but because of carboxyl and phenolic hydroxyl in the molecular structure, the flavonoid glycoside is easy to dissolve in alkali and forms salt with small molecular organic alkali, so that the water solubility of the flavonoid glycoside is enhanced. Further, 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, the particle size of the material reaches the nano level, and the double salt compound has better water solubility.
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FIGS. 1 to 4 are a nuclear magnetic resonance hydrogen spectrum, an infrared spectrum, a DSC test chart and an XRD chart of the double salt compound prepared in example 1 of the present invention;
FIGS. 5 to 8 are a nuclear magnetic resonance hydrogen spectrum, an infrared spectrum, a DSC test chart and an XRD chart of the double salt compound prepared in example 2 of the present invention;
FIGS. 9 to 12 are a nuclear magnetic resonance hydrogen spectrum, an infrared spectrum, a DSC test chart and an XRD chart of the double salt compound prepared in example 3 of the present invention;
FIGS. 13 to 16 are a nuclear magnetic resonance hydrogen spectrum, an infrared spectrum, a DSC test chart and an XRD chart of the double salt compound prepared in example 4 of the present invention;
FIGS. 17 to 20 are a nuclear magnetic resonance hydrogen spectrum, an infrared spectrum, a DSC test chart and an XRD chart of the double salt compound prepared in example 5 of the present invention;
FIGS. 21 to 24 are a nuclear magnetic resonance hydrogen spectrum, an infrared spectrum, a DSC test chart and an XRD chart of the double salt compound prepared in example 6 of the present invention;
FIGS. 25 to 28 are a nuclear magnetic resonance hydrogen spectrum, an infrared spectrum, a DSC test chart and an XRD chart of the double salt compound prepared in example 7 of the present invention;
FIGS. 29 to 32 are a nuclear magnetic resonance hydrogen spectrum, an infrared spectrum, a DSC test chart and an XRD chart of the double salt compound prepared in example 8 of the present invention;
fig. 33 to 36 are a nuclear magnetic resonance hydrogen spectrum, an infrared spectrum, a DSC test chart and an XRD chart of the double salt compound prepared in example 9 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 herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein 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 of skill in the chemical and biological arts. In particular, the following abbreviations may be used in the examples and throughout the specification.
DSC (differential scanning calorimetry) of DMF (N, N-dimethylformamide)
Terminology and definitions
Unless otherwise indicated or contradicted, terms or phrases used herein have the following meanings:
the term "alkyl" refers to a saturated hydrocarbon containing primary (positive) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof. Phrases containing this term, e.g., "C 1 ～C 6 Alkyl "means an alkyl group containing 1 to 6 carbon atoms, which at each occurrence may be, independently of one another, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl or C 6 An alkyl group. Suitable examples include, but are not limited to: methyl (Me, -CH) 3 ) Ethyl (Et, -CH) 2 CH 3 ) 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 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 (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 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, i.e. an alkyl group as defined above, attached to the parent core structure via an oxygen atom. Phrases containing this term, e.g., "C 1 ～C 6 Alkoxy "refers to an alkyl moietyEach containing 1 to 6 carbon atoms, and each occurrence may be, independently of the other, C 1 Alkoxy, C 2 Alkoxy, C 3 Alkoxy, C 4 Alkoxy, C 5 Alkoxy or C 6 An alkoxy group. Suitable examples include, but are not limited to: methoxy (-O-CH) 3 or-OMe), ethoxy (-O-CH 2 CH 3 or-OEt) and t-butoxy (-O-C (CH) 3 ) 3 or-OtBu).
"amino" refers to derivatives of ammonia, non-limiting types of amino groups include-NH 2 -N (alkyl) 2 -NH (alkyl), -N (cycloalkyl) 2 -NH (cycloalkyl), -N (heterocyclyl) 2 -NH (heterocyclyl), -N (aryl) 2 -NH (aryl), -N (alkyl) (heterocyclyl), -N (cycloalkyl) (heterocyclyl), -N (aryl) (heteroaryl), -N (alkyl) (heteroaryl), and the like.
By "pharmaceutically acceptable" is meant those ligands, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for administration to patients 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 compatible with pharmaceutical administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal 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 of the formulation and not deleterious 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 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.
"substitution" in reference to a group means that one or more hydrogen atoms attached to a member atom within the group are replaced by substituents selected from the defined or suitable substituents. It is to be understood that the term "substitution" includes the following implicit conditions: such substitution should be consistent with the permissible valences of the substituted atoms and substituents and the substitution results in stable compounds. When the Chen Shuji group may contain one or more substituents, one or more member atoms within the group may be substituted. In addition, individual member atoms within the group may be substituted with more than one substituent, so long as such substitution is consistent with the permissible valence of the atom. "Member atom" refers to an atom or atoms that form a chain or ring. In the case where there is more than one member atom in the chain and within the ring, each member atom is covalently bound 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 "IC 50 "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) 50 The smaller the value, the stronger the inhibitory activity of the compound for a given activity.
Compounds of formula (I)
In one aspect, the invention relates to a double salt compound which is a double salt of flavonoid glycoside and an organic amine tyrosine kinase inhibitor, wherein the flavonoid glycoside has a structural general formula shown in the following formula (1):
Figure BDA0003329980780000061
wherein R is 1 ～R 9 Each independently selected from-H, -OH, C 1 ～C 6 Alkyl, alkoxy or substituted alkyl, and R 1 And R is 2 At least one of them is selected from-OH.
The flavonoid glycoside has carboxyl hydrogen in gluconic acid unit and phenolic hydroxyl hydrogen (R) 1 Or R is 2 Hydrogen in (a), together forming a hydrogen ion rich region, which is a proton donor. The nitrogen atom of the organic amine in the organic amine tyrosine kinase inhibitor contains a lone pair electron and is a proton acceptor. The flavonoid glycoside-organic amine tyrosine kinase inhibitor double salt is formed by combining the flavonoid glycoside-organic amine tyrosine kinase inhibitor double salt. Due to steric hindrance, the carboxyhydrogens in the gluconic acid units and the phenolic hydroxyhydrogens in the flavone units in the flavone glycoside are located on both sides of the sugar ring respectively. When it is combined with an organic amine, the carboxyhydrogen and the phenolic hydroxyl hydrogen on both sides of the sugar ring are converted into the same side, as shown in formula (2), forming a microenvironment of proton nest (proton structure shown by a broken line frame of formula 2), carboxyl oxygen electron and nitrogen lone pair electron. From valence theory analysis, hydrogen protons and amines in proton pits can form very stable ammonium salts; from molecular orbit theoretical analysis, the empty orbit of hydrogen in a proton nest and the lone pair electron of amine can be perfectly combined; according to quantum chemistry and quantum entanglement theory analysis, the hydrogen electrons, carboxyl oxygen electrons and the lone electron pairs of nitrogen in organic amine in a proton nest are entangled in a salification area, and the biological activity of the flavonoid glycoside-organic amine tyrosine kinase inhibitor double salt is improved due to the fact that quantum entanglement exists after the organic acid and the organic base of the flavonoid glycoside-organic amine tyrosine kinase inhibitor double salt are dissociated from each other.
Figure BDA0003329980780000071
Preferably, said R 1 And R is 2 Are all selected from-OH.
In some embodiments, R 3 Selected from-Hor-OCH 3 。
In some embodiments, R 5 、R 6 、R 9 Are all selected from-H.
In some embodiments, R 7 、R 8 Each independently selected from-H or-OH.
In some embodiments, R 8 Selected from-H.
In some embodiments, R 7 Selected from-OH. In other embodiments, R 7 Selected from-H.
In some embodiments, the flavonoid glycoside may be any one of apigenin flavonoid glycoside, baicalin, scutellarin, chrysin flavonoid glycoside or wogonin glycoside, and preferably, the flavonoid glycoside is baicalin or scutellarin.
The molecular structural formula of the baicalin is shown as the following formula (1-1):
Figure BDA0003329980780000072
the molecular structural formula of the scutellarin is shown as the following formula (1-2):
Figure BDA0003329980780000081
the organic amine tyrosine kinase inhibitor contains at least one amino group, and each amino group is independently selected from-NH 2 -NR 'H or-NR' 2 The R' is an electron donating group
In some embodiments, R' is alkyl or alkoxy.
In some embodiments, the organic amine tyrosine kinase inhibitor is selected from any one of gefitinib, erlotinib, pezopanib, octreotide, and lapatinib.
Gefitinib is an oral epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitor, and inhibition of EGFR-TK can block growth, metastasis and angiogenesis of tumors and increase apoptosis of tumor cells. Clinically, the traditional Chinese medicine composition is used for treating non-small cell lung cancer. Gefitinib has the structural formula shown below:
Figure BDA0003329980780000082
Erlotinib is a targeted therapeutic drug, can specifically act on tumor cells, inhibit the formation and growth of tumors, and inhibit the signaling pathway of human Epidermal Growth Factor Receptor (EGFR). Erlotinib inhibits tumor growth by inhibiting the activity of tyrosine kinase, one of the important components in EGFR cells. Erlotinib can be tested for three-line treatment of locally advanced or metastatic non-small cell lung cancer with failure of two or more chemotherapy regimens. Erlotinib has the structural formula shown below:
Figure BDA0003329980780000091
pezopanib, also known as pazopanib, is a multi-tyrosine kinase inhibitor of Vascular Endothelial Growth Factor Receptor (VEGFR) -1, VEGFR-2, VEGFR-3, platelet Derived Growth Factor Receptor (PDGFR) and Fibroblast Growth Factor Receptor (FGFR) -1 and-3, cytokine receptor (Kit), interleukin-2 receptor inducible T cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). Pezopanib interferes with neoangiogenesis required for refractory tumor survival and growth, acts targeted to Vascular Endothelial Growth Factor Receptor (VEGFR), by inhibiting neoangiogenesis supplying blood to the tumor, and is useful in the treatment of advanced renal cell carcinoma (a type of renal carcinoma in which cancer cells are found in the renal tubules), soft Tissue Sarcoma (STS), epithelial ovarian cancer, and non-small cell lung cancer (NSCLC). The structural formula of pezopanib is shown as follows:
Figure BDA0003329980780000092
Ornitinib is a high-efficiency selectionSelective EGFR mutant inhibitors with IC50 s of 12.92nM,11.44nM and 493.8nM for exon 19 deleted EGFR, L858R/T790M EGFR and wild-type EGFR, respectively. Molecular weight is 499.61, molecular formula is C 28 H 33 N 7 O 2 . Ornitinib is a novel drug for treating advanced non-small cell lung cancer (NSCLC) patients by oral administration aiming at non-small cell advanced lung cancer. The structural formula of the octreotide is shown as follows:
Figure BDA0003329980780000093
lapatinib, an oral small molecule EGFR (EGFR: erbB-1, erbB-2) tyrosine kinase inhibitor, chemical name N- [ 3-chloro-4- [ (3-fluorophenyl) methoxy group]Phenyl group]-6- [5- [ (2-methylsulfonylethylamino) methyl ]]-2-furyl group]Quinazolin-4-amines of formula C 29 H 26 Cl F N 4 O 4 S, molecular weight is 581.05800. Lapatinib is an antitumor agent and is mainly used for treating ErbB-2 over-expression in combination with capecitabine clinically, and advanced or metastatic breast cancer including anthracycline, paclitaxel and trastuzumab (herceptin) treatment is accepted in the past. The structural formula of lapatinib is shown as follows:
Figure BDA0003329980780000101
in one aspect, the invention also relates to a method for preparing the double salt compound, which comprises the following steps:
s10, mixing and dissolving the flavonoid glycoside, the organic amine tyrosine kinase inhibitor and a polar aprotic organic solvent to obtain a mixed solution;
S20, reacting the mixed solution to obtain a reaction solution; and
s30, removing the solvent from the reaction solution.
The molar ratio of the flavonoid glycoside to the organic amine tyrosine kinase inhibitor can be any ratio between 1:3 and 3:1, for example, 1:2, 1:1.5, 1:1, 1.5:1, 2:1, preferably 1:1 can also be included.
The polar aprotic organic solvent may be one or more of N, N-dimethylformamide, dimethyl sulfoxide or acetonitrile.
In step S10, the method for obtaining the mixed solution by mixing and dissolving the flavonoid glycoside, the organic amine tyrosine kinase inhibitor and the polar aprotic organic solvent may be various. Preferably, the method can comprise the following steps
S11, dissolving the flavonoid glycoside in the polar aprotic organic solvent to obtain a first solution;
s12, dissolving the organic amine tyrosine kinase inhibitor in the polar aprotic organic solvent to obtain a second solution;
and 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 0.1mol/L to 1.0mol/L, preferably 0.33mol/L.
The concentration of the organic amine tyrosine kinase inhibitor in the second solution is 0.1mol/L to 1.0mol/L, preferably 0.33mol/L.
In the step of carrying out the reaction of the mixed solution, the reaction temperature may be 30 to 100 ℃, preferably 50 to 70 ℃, more preferably 70 ℃.
The solvent removal method may be reduced pressure concentration, and the temperature of the reduced pressure concentration may be 40 to 70 ℃, preferably 60 ℃.
Step S30 further includes a step of purification. The purification method may be beating. The solvent used for beating can be ethyl acetate. The dosage of the ethyl acetate is preferably 1:1 to 1:5, and most preferably 1:3 according to mol/L of acid (baicalin or scutellarin); the beating temperature may be 5-50 deg.c, preferably 20-30 deg.c, for 20-40 min.
The purification also comprises the steps of filtering the solution after pulping, 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 to 60 ℃, preferably 30 ℃, and the drying time may be 8 to 48 hours, preferably 24 hours. The freeze-drying temperature is less than 0 ℃, and the drying time can be 3 hours to 12 hours, preferably 6 hours.
In one aspect, the 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 use of said double salt compound in the preparation of a tyrosine kinase inhibitor medicament.
In some embodiments, tyrosine kinase inhibitor medicaments prepared according to the double salt compounds of the present invention are useful in the treatment of malignant tumors, including lung cancer, liver cancer, stomach cancer, esophageal cancer, cardiac cancer, colon cancer, rectal cancer, colorectal cancer, breast cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, laryngeal cancer, oropharyngeal cancer, brain tumor, glioma, soft tissue sarcoma, in particular for the treatment of non-small cell lung cancer.
In one aspect, the invention further relates to a method of treating a neurodegenerative disease, preferably comprising administering to a patient suffering from a neurodegenerative disease in need thereof a suitable amount of a composition comprising a double salt compound according to the invention as defined above.
In one aspect, the invention further relates to a double salt nanoparticle obtained from the double salt compound of any of the above embodiments by nanomilling.
In some embodiments, the double salt nanoparticles have an average particle size of 50nm to 500nm.
In one aspect, the invention also relates to a method of preparing the double salt nanoparticle comprising:
mixing the double salt compound, the suspending agent and the solvent, and grinding the mixture by a nano grinder.
In some embodiments, the suspending agent is one or more of tween, hypromellose, polyethylene glycol, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, fatty acid glyceride, polyol-type nonionic surfactant, polyoxyethylene-type nonionic surfactant, poloxamer, vitamin E polyethylene glycol succinate, phospholipid, gelatin, xanthan gum, sodium lauryl sulfate, and deoxycholate.
In some preferred embodiments, the suspending agent is a combination of tween, hypromellose, and polyethylene glycol.
In some embodiments, the mass ratio of the double salt compound to the suspending agent is 1000: (0.5-3).
In some embodiments, the rotational speed of the grinding is 2000rpm to 3000rpm and the time of the grinding is 30 minutes to 60 minutes. The diameter of the working cavity of the nano grinder used for grinding is 85mm. If the diameter of the working cavity of the nano grinder is changed, the rotating speed should be correspondingly adjusted.
In one aspect, the invention further relates to the use of the double salt nanoparticle in the preparation of a tyrosine kinase inhibitor drug.
In some embodiments, the tyrosine kinase inhibitor drug is used in the treatment of a malignancy including lung cancer, liver cancer, stomach cancer, esophageal cancer, cardiac cancer, colon cancer, rectal cancer, colorectal cancer, breast cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, laryngeal cancer, oropharyngeal cancer, brain tumor, glioma, or soft tissue sarcoma.
Administration and formulation
The production of medicaments containing the compounds according to 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 therapy according to the invention may be administered in the form of the original chemical compound, it is preferred that the active ingredient is incorporated in the pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents and/or other conventional pharmaceutical excipients. 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 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 present 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 administration by a slow release system. Suitable examples of slow 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 can therefore be placed into pharmaceutical and unit dosage forms thereof. Such forms include: solids, particularly in the form of tablets, filled capsules, powders and pills (pellets); and liquids, in particular aqueous or nonaqueous solutions, suspensions, emulsions, omnipotent drugs (elixir) and capsules filled therewith, all forms for oral administration, suppositories for rectal administration and sterile injectable solutions for parenteral use. These medicaments and unit dosage forms thereof may include conventional ingredients in conventional proportions, with or without other active compounds or components, and such unit dosage forms may contain any suitable effective amount of the active ingredient corresponding to the intended daily dosage range to be used.
The compounds useful according to the present invention may 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 one or more compounds useful according to the present invention as active ingredients.
For the preparation of a medicament from a compound useful according to the invention, the pharmaceutically acceptable carrier may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets (cachets), suppositories, and dispersible granules. The solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilising agents, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or an encapsulating material (encapsulating material).
In powders, the carrier is a finely divided solid which is admixed with the finely divided active component. In tablets, the active ingredient is mixed with a 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 an encapsulating material as a carrier, providing a capsule in which the active ingredient is surrounded by and thus bound to the carrier, with or without a carrier. Similarly, cachets and lozenges (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 component is uniformly dispersed therein, such as by stirring. The melted homogeneous mixture is then poured into a mold of moderate size, allowing it to cool and thereby solidify. Compositions suitable for vaginal administration may be presented as pessaries (pessaries), tampons (tampons), creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Liquid formulations include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. For example, parenteral injection liquid preparations may be formulated as aqueous polyethylene glycol solutions.
Thus, chemical compounds according to the invention may be formulated for parenteral administration (e.g., by injection, such as bolus injection or continuous infusion) and may be presented in unit dosage form in ampules with added preservative, pre-filled syringes, small volume infusions or in multi-dose containers. The composition may take such forms as a suspension, solution or emulsion in an oily or aqueous vehicle (vehicle) and may contain a formulation (formulation agent), such as a suspending, stabilizing and/or dispersing agent. Alternatively, the active ingredient may be in the form of a powder obtained by sterile separation of sterile solids or by lyophilization of a solution for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
Aqueous solutions suitable for oral use may be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the crushed active ingredient in water with a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
Also included are solid form formulations intended to be converted to liquid form formulations shortly before use for oral administration. Such liquid forms include solutions, suspensions and emulsions. These formulations may contain, in addition to the active ingredient, colorants, flavors, 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 (typically sucrose and acacia or tragacanth), pastilles comprising the active agent in an inert base (e.g. gelatin and glycerin or sucrose and acacia) and mouthwashes comprising the active agent in a suitable liquid carrier.
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 multiple dosage forms. 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 metering atomizing spray pump.
Administration to the respiratory tract may also be achieved by means of aerosols wherein the active ingredient is provided in a pressurized package 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 setting a metering valve.
Alternatively, the active ingredient may be provided in dry powder form, for example as a powder mixture of the compound in a suitable powder matrix such as lactose, starch derivatives such as hydroxypropyl methylcellulose, and polyvinylpyrrolidone (PVP). Conveniently, the powder carrier will form a gel within the nasal cavity. The powder composition may be presented in unit dosage form, for example, as a capsule or cartridge (cartridge) of gelatin, or as a blister pack (blister pack) from which the powder may be administered by an inhaler.
In compositions intended for administration to the respiratory tract, including intranasal compositions, the compounds typically 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.
Compositions suitable for sustained release of the active ingredient may be used, if desired.
The pharmaceutical formulation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged formulation containing discrete amounts of formulation, such as packaged tablets, capsules, and powders in vials or ampoules. Furthermore, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or it may be the packaging of any of a suitable number of these dosage forms. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
Additional details regarding techniques for formulation and administration can be found in the latest edition of "Remington's Pharmaceutical Sciences (Remington pharmaceutical science) (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 disclosed, for example, in "Arzneiformenlehre, paul Heinz List, einlehrbuchfurPharmazeuten, wissenschaftlicheVerlagsgesellschaft Stuttgart,4. Auflat, 1985" or "The theory and practice of industrial pharmacy", varghese Publishing House,1987 "or" Modern Pharmaceutics ", james Swarbrick editor, 2 nd edition," by Lachman et al.
The following are specific examples
The invention is further described below with reference to the following examples, which are intended to illustrate, but not limit the scope of the invention. Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods. The experimental methods without specific conditions noted in the examples were carried out according to conventional conditions, such as those described in the literature, books, or recommended by the manufacturer.
EXAMPLE 1 preparation of baicalin gefitinib salt
Gefitinib 4.47 g (0.01 mol) was suspended in 15ml DMF, baicalin 4.46 g (0.01 mol) was added to 30ml DMF, the above gefitinib 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 equally into two equal parts, the first part was suspended in 15ml of water, and the solvent was removed by freeze-drying for 6 hours to give a pale yellow solid product. The second cake was dried in vacuo at 30℃for 24 hours to give the product as a pale yellow solid. The first part of the product is obtained to obtain 3.74 g of baicalin gefitinib salt with the yield of 83.70 percent. The second part of the product is 3.78 g of baicalin gefitinib salt, and the yield is 84.66%.
The product is subjected to structural characterization test by nuclear magnetic resonance hydrogen spectrum, infrared spectrum, DSC and XRD, and the result is shown in figures 1-4, compared with the pure mixture of baicalin and gefitinib, the product is more soluble, the chemical shift of nuclear magnetic resonance hydrogen spectrum shows that the carboxyl hydrogen of the baicalin forms salt with gefitinib-N, the infrared spectrum also shows the characteristic, and the thermal weight loss shows that the product has a peak at 244 ℃ and 260 ℃. The physical properties, spectral characteristics and thermodynamic properties of the product are changed compared with those of baicalin and gefitinib, which indicates that the product is salified.
Example 2 preparation of scutellarin gefitinib salt
Gefitinib 4.47 g (0.01 mol) was suspended in 15ml DMF, scutellarin 4.62 g (0.01 mol) was added to 30ml DMF, the above gefitinib DMF solution was added to scutellarin DMF solution, 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 equally into two equal parts, the first part was suspended in 15ml of water, and the solvent was removed by freeze-drying for 6 hours to give a pale yellow solid product. The second cake was dried in vacuo at 30℃for 24 hours to give the product as a pale yellow solid. The first part is to obtain 3.98 g of scutellarin gefitinib salt with the yield of 87.46%, and the second part is to obtain 4.10 g of scutellarin gefitinib salt with the yield of 90.20%.
The product is subjected to structural characterization test by nuclear magnetic resonance hydrogen spectrum, infrared spectrum, DSC and XRD, and the result is shown in figures 5-8, compared with the pure mixture of scutellarin and gefitinib, the product is more soluble, the chemical shift of nuclear magnetic resonance hydrogen spectrum shows that the carboxyl hydrogen of scutellarin forms salt with gefitinib-N, the infrared spectrum also shows the characteristic, and the thermal weight loss shows that the product has a peak at 208 ℃. The physical properties, spectral characteristics and thermodynamic properties of the product are changed compared with those of scutellarin and gefitinib, which indicates that the product is salified.
EXAMPLE 3 preparation of baicalin erlotinib salt
The preparation was substantially the same as in example 1 except that gefitinib was replaced with erlotinib 3.93 g (0.01 mol).
The first part is to obtain 3.66 g of baicalin erlotinib salt with the yield of 87.17%, and the second part is to obtain 3.70 g of baicalin erlotinib salt with the yield of 88.20%.
The product is subjected to structural characterization test by nuclear magnetic resonance hydrogen spectrum, infrared spectrum, DSC and XRD, and the result is shown in figures 9-12, compared with a simple mixture of baicalin and erlotinib, the product is more soluble, the chemical shift of nuclear magnetic resonance hydrogen spectrum shows that the carboxyl hydrogen of the baicalin forms salt with erlotinib-NH, the infrared spectrum also shows the characteristic, and the thermal weight loss shows that the product has a peak at 105 ℃, 194 ℃ and 245 ℃. The physical properties, spectral characteristics and thermodynamic properties of the product are changed compared with those of baicalin and erlotinib, which indicates that the product is salified.
EXAMPLE 4 preparation of erigerotin salt
The preparation was substantially the same as in example 2 except that gefitinib was replaced with erlotinib 3.93 g (0.01 mol).
The first part is to obtain 3.47 g of scutellarin erlotinib salt with a yield of 81.07%, and the second part is to obtain 3.52 g of scutellarin erlotinib salt with a yield of 82.34%.
The product is subjected to structural characterization test by nuclear magnetic resonance hydrogen spectrum, infrared spectrum, DSC and XRD, and the result is shown in figures 13-16, compared with a simple mixture of scutellarin and erlotinib, the product is more soluble, the nuclear magnetic resonance hydrogen spectrum chemical shift shows that the carboxyl hydrogen of scutellarin forms salt with erlotinib-NH, the infrared spectrum also shows the characteristic, and the thermal weight loss shows that the product has a peak at the temperature of 168 ℃ and 203 ℃. XRD patterns showed the product to have characteristic diffraction peaks. The physical properties, spectral characteristics and thermodynamic properties of the product are changed compared with those of scutellarin and erlotinib, which indicates that the product is salified.
EXAMPLE 5 preparation of baicalin pezopanib salt
The preparation was substantially the same as in example 1 except that gefitinib was replaced with pezopanib 4.38 g (0.01 mol).
The first part is to obtain 3.49 g of baicalin pezopanib salt with the yield of 78.88%, and the second part is to obtain 3.52 g of baicalin pezopanib salt with the yield of 79.38%.
The product is subjected to structural characterization test by nuclear magnetic resonance hydrogen spectrum, infrared spectrum, DSC and XRD, and the result is shown in figures 17-20, compared with a simple mixture of baicalin and pezopanib, the product is more soluble, the chemical shift of nuclear magnetic resonance hydrogen spectrum shows that the carboxyl hydrogen of the baicalin forms salt with pezopanib-NH, the infrared spectrum also shows the characteristic, and the thermal weight loss shows that the product has a peak at 200 ℃ and 345 ℃. The physical properties, spectral characteristics and thermodynamic properties of the product are changed compared with those of baicalin and pezopanib, which indicates that the product is salified.
EXAMPLE 6 preparation of scutellarin Pexazopanib salt
The preparation was substantially the same as in example 2 except that gefitinib was replaced with pezopanib 4.38 g (0.01 mol).
The first part is 2.54 g of scutellarin pezopanib salt with the yield of 56.54%, and the second part is 2.60 g of scutellarin pezopanib salt with the yield of 57.78%.
The product is subjected to structural characterization test by nuclear magnetic resonance hydrogen spectrum, infrared spectrum, DSC and XRD, and the result is shown in figures 21-24, compared with a simple mixture of scutellarin and pezopanib, the product is more soluble, the nuclear magnetic resonance hydrogen spectrum chemical shift shows that the carboxyl hydrogen of the scutellarin and the pezopanib-NH form salt, the infrared spectrum also shows the characteristic, and the thermal weight loss shows that the product has a peak at the temperature of 198 ℃ and 320 ℃. The physical properties, spectral characteristics and thermodynamic properties of the product are changed compared with those of scutellarin and pezopanib, which indicates that the product is salified.
EXAMPLE 7 preparation of baicalin Ornitinib salt
The preparation was substantially the same as in example 1 except that gefitinib was replaced with 5.96 g (0.01 mol) of octreotide.
The first part is to obtain 4.30 g of baicalin octenib salt with the yield of 82.46%, and the second part is to obtain 4.35 g of baicalin octenib salt with the yield of 83.49%.
The product is subjected to structural characterization test by nuclear magnetic resonance hydrogen spectrum, infrared spectrum, DSC and XRD, and the result is shown in figures 25-28, compared with a simple mixture of baicalin and octreotide, the product is more soluble, the chemical shift of nuclear magnetic resonance hydrogen spectrum shows that the carboxyl hydrogen of the baicalin forms salt with the octreotide-N, the infrared spectrum also shows the characteristic, and the thermal weight loss shows that the product has wind at the temperature of 154 ℃, 210 ℃ and 337 ℃. The physical properties, spectral characteristics and thermodynamic properties of the product are changed compared with those of baicalin and octtinib, which indicates that the product is salified.
Example 8 preparation of erigeron breviscapus salt
The preparation was substantially the same as in example 1 except that gefitinib was replaced with 5.96 g (0.01 mol) of octreotide.
The first part is to obtain 4.18 g of scutellarin octreotide salt with the yield of 79.07%, and the second part is to obtain 4.22 g of scutellarin octreotide salt with the yield of 79.77%.
The results of structural characterization tests of the product by nuclear magnetic resonance hydrogen spectrum, infrared spectrum, DSC and XRD are shown in figures 29-32, compared with a simple mixture of baicalin and octreotide, the product is more soluble, the chemical shift of nuclear magnetic resonance hydrogen spectrum shows that the carboxyl hydrogen of the scutellarin forms salt with the octreotide-N, the infrared spectrum also shows the characteristic, and the thermal weight loss shows that the product has a peak at 154 ℃, 211 ℃ and 339 ℃. The physical properties, spectral characteristics and thermodynamic properties of the product are changed compared with those of baicalin and octtinib, which indicates that the product is salified.
EXAMPLE 9 preparation of scutellarin Lapatinib salt
The preparation was substantially the same as in example 2 except that gefitinib was replaced with lapatinib 5.81 g (0.01 mol).
The first part is 3.61 g of scutellarin lapatinib salt with the yield of 69.13 percent, and the second part is 3.64 g of scutellarin lapatinib salt with the yield of 69.80 percent.
The product is subjected to structural characterization test by nuclear magnetic resonance hydrogen spectrum, infrared spectrum, DSC and XRD, and the result is shown in figures 33-36, compared with a simple mixture of scutellarin and lapatinib, the product is more soluble, the nuclear magnetic resonance hydrogen spectrum chemical shift shows that the carboxyl hydrogen of scutellarin forms salt with lapatinib-NH, the infrared spectrum also shows the characteristic, and the thermal weight loss shows that the product has a peak at 210 ℃ and 266 ℃. The physical properties, spectral characteristics and thermodynamic properties of the product are changed compared with those of scutellarin and lapatinib, which indicates that the product is salified.
Example 10 Activity test
Tyrosine kinase inhibitor activity assay:
preparing each double salt compound into test products with different concentrations, measuring the inhibition of the test products on the tyrosine kinase activity by using a tyrosine kinase kit, and calculating the IC50.
The pharmaceutical activity of each double salt compound is shown in table 2:
TABLE 2
Active ingredient name Target spot IC50(nM)
Gefitinib Tyrosine kinase 27.6
Baicalin gefitinib Tyrosine kinase 18.4
Scutellarin gefitinib Tyrosine kinase 16.5
Erlotinib Tyrosine kinase 2.5
Baicalin erlotinib Tyrosine kinase 1.1
Scutellarin erlotinib Tyrosine kinase 0.9
Pezopanib Tyrosine kinase 10.4
Baicalin pezopanib Tyrosine kinase 4.5
Scutellarin pezopanib Tyrosine kinase 4.8
Oritinib Tyrosine kinase 15.0
baicalin-Ornitinib Tyrosine kinase 6.8
Scutellarin-octreotide Tyrosine kinase 7.5
Lapatinib Tyrosine kinase 9.8
Scutellarin lapatinib Tyrosine kinase 6.2
Baicalin Tyrosine kinase Greater than 100
Scutellarin (scutellarin) Tyrosine kinase Greater than 100
As can be seen from table 2, the inhibition activity of the baicalin gefitinib double salt compound and the scutellarin gefitinib double salt compound on tyrosine kinase is stronger than that of gefitinib;
the inhibition activity of the baicalin erlotinib double salt compound and the wild baicalin erlotinib double salt compound on tyrosine kinase is stronger than that of erlotinib on tyrosine kinase;
the inhibition activity of the baicalin pezopanib double salt compound and the scutellarin pezopanib double salt compound on tyrosine kinase is stronger than that of pezopanib on tyrosine kinase;
The inhibition activity of the baicalin-octreotide double salt compound and the wild baicalin-octreotide double salt compound on tyrosine kinase is stronger than that of the octreotide on tyrosine kinase;
the inhibition activity of the scutellarin lapatinib double salt compound on tyrosine kinase is stronger than that of lapatinib on tyrosine kinase.
Example 11 preparation of baicalin gefitinib double salt nanoparticles
1. 50 g of baicalin gefitinib double salt compound, 500 ml of water, 50 mg of suspending agent Tween-20 mg of hydroxypropyl methylcellulose, 50 mg of polyethylene glycol 6000 50 mg and grinding at 2500rpm for 40 minutes are added into a nano grinder to obtain the baicalin gefitinib double salt nano suspension.
2. The obtained baicalin gefitinib double salt nano suspension is dried in fluidized bed drying equipment, the drying inlet air temperature is 65 ℃, the drying is carried out until the moisture content is about 3%, and the baicalin gefitinib double salt nano particles with the particle size distribution within the range of 50 nm-500 nm are prepared.
Compared with the baicalin gefitinib double salt compound which is not subjected to nano grinding, the prepared baicalin gefitinib double salt nano particles have the advantage that the solubility of the baicalin gefitinib double salt compound is increased by 2.5 times at the temperature of 20 ℃ in 10 minutes.
Example 12 preparation of scutellarin gefitinib double salt nanoparticles
The preparation method is basically the same as that of example 11, except that the baicalin gefitinib double salt compound is replaced with the scutellarin gefitinib double salt compound. The particle size distribution of the nano particles of the gefitinib double salt of the scutellarin is in the range of 50 nm-500 nm.
Compared with the scutellarin gefitinib double salt compound which is not subjected to nano grinding, the solubility of the scutellarin gefitinib double salt nano particles is increased by 2.4 times in 10 minutes at 20 ℃.
EXAMPLE 13 preparation of baicalin erlotinib double salt nanoparticles
The preparation method is basically the same as that of example 11, except that the baicalin gefitinib double salt compound is replaced with a baicalin erlotinib double salt compound. The particle size distribution of the baicalin erlotinib double salt nano-particles is within the range of 50 nm-500 nm.
Compared with the baicalin erlotinib double salt compound which is not subjected to nano grinding, the prepared baicalin erlotinib double salt nano particles have the advantage that the solubility of the baicalin erlotinib double salt compound is increased by 1.8 times at 20 ℃ in 10 minutes.
EXAMPLE 14 preparation of erigerotin double salt nanoparticles
The preparation method was substantially the same as in example 13 except that the baicalin erlotinib double salt compound was replaced with a scutellarin erlotinib double salt compound. The particle size distribution of the nano particles of the erlotinib double salt of the scutellarin is within the range of 50 nm-500 nm.
Compared with the nano-ground compound of the erigeron breviscapus, the prepared nano-particles of the erigeron breviscapus double salt have the advantage that the solubility of the erigeron breviscapus double salt compound at the temperature of 20 ℃ for 10 minutes is increased by 2.0 times.
Example 15 preparation of baicalin pezopanib double salt nanoparticles
The preparation method is basically the same as that of example 11, except that the baicalin gefitinib double salt compound is replaced with the baicalin pezopanib double salt compound. The particle size distribution of the baicalin pezopanib double salt nano particles is within the range of 50 nm-500 nm.
Compared with the baicalin pezopanib double salt compound which is not subjected to nano grinding, the prepared baicalin pezopanib double salt nano particles have the advantage that the solubility of the baicalin pezopanib double salt compound is increased by 2.2 times at the temperature of 20 ℃ in 10 minutes.
EXAMPLE 16 preparation of Compound salt nanoparticles of scutellarin and pezopanib
The preparation method is basically the same as that of example 15, except that the baicalin pezopanib double salt compound is replaced with the scutellarin pezopanib double salt compound. The particle size distribution of the nano particles of the scutellarin pezopanib double salt is in the range of 50 nm-500 nm.
Compared with the scutellarin pezopanib double salt compound which is not subjected to nano grinding, the solubility of the prepared scutellarin pezopanib double salt nano particles is increased by 2.2 times in 10 minutes at 20 ℃.
Example 17 preparation of baicalin-Ornitinib double salt nanoparticles
The preparation method is basically the same as that of example 11, except that the baicalin gefitinib double salt compound is replaced with a baicalin octreotide double salt compound. The particle size distribution of the baicalin-octreotide double salt nano particles is in the range of 50 nm-500 nm.
Compared with the baicalin-octenib double salt compound which is not subjected to nano grinding, the prepared baicalin-octenib double salt nano particles have the advantage that the solubility of the baicalin-octenib double salt compound is increased by 2.4 times in 10 minutes at 20 ℃.
Example 18 preparation of Dilute baicalin Ornitinib double salt nanoparticles
The preparation method is basically the same as that of example 17, except that the baicalin-octreotide double salt compound is replaced with a scutellarin-octreotide double salt compound. The particle size distribution of the wild baicalin-octreotide double salt nano particles is in the range of 50 nm-500 nm.
Compared with the scutellarin-octreotide double salt compound which is not subjected to nano grinding, the solubility of the prepared scutellarin-octreotide double salt nano particles is increased by 2.2 times in 10 minutes at 20 ℃.
Example 19 preparation of double salt nanoparticles of scutellarin Lapatinib
The preparation method is basically the same as that of example 11, except that the baicalin gefitinib double salt compound is replaced with the scutellarin lapatinib double salt compound. The particle size distribution of the nano particles of the scutellarin lapatinib double salt is in the range of 50 nm-500 nm.
Compared with the scutellarin lapatinib double salt compound which is not subjected to nano grinding, the prepared scutellarin lapatinib double salt nano particles have the advantage that the solubility is increased by 2.5 times at 20 ℃ in 10 minutes.
Example 20 determination of in vivo anti-lung cancer tumor Activity in animals
A blank administration group, a baicalin group, a scutellarin group, a gefitinib group, an erlotinib group, a baicalin gefitinib double salt nanosuspension group (baicalin gefitinib double salt nanosuspension preparation method referred to example 11), a scutellarin gefitinib double salt nanosuspension group (scutellarin nilotinib nanosuspension preparation method referred to example 12), a baicalin erlotinib nanosuspension group (baicalin erlotinib nanosuspension preparation method referred to example 13), and a scutellarin erlotinib nanosuspension group (scutellarin nanosuspension preparation method referred to example 14) were respectively set.
1. Test cells and animals
Mice: balb/c nude mice, males, 6-8 weeks old. All mice were fed and drinking water freely and were kept at room temperature (23.+ -. 2 ℃ C.).
Tumor cells: HCC827 cell line, derived from NIH.
2. Test method
Lung cancer tumor mice were established and eligible mice were randomly grouped, 10 per group, with the following dosing regimen:
blank dosing group: only physiological saline was administered.
Baicalin group: baicalin was prepared into a solution for administration with sterile PBS, and administered at 38mg/kg, by intragastric administration once daily for 21 days.
Scutellarin group: the scutellarin is prepared into a dosing solution by using sterile PBS, and the dosing amount is 38mg/kg, the stomach is irrigated, and the dosing is carried out once a day for 21 days continuously.
Gefitinib group: gefitinib was formulated into a dosing solution with sterile PBS, and the dosing amount was 38mg/kg, and the dosing was performed once daily for 21 consecutive days.
Erlotinib group: erlotinib was formulated as a dosing solution with sterile PBS and dosed at 15mg/kg, intragastric, once daily for 21 consecutive days.
Baicalin gefitinib double salt nano suspension group: the baicalin gefitinib double salt nano suspension is taken as a dosing solution, and is subjected to gastric lavage according to the dosing amount of 75mg/kg once a day for 21 days.
Scutellarin gefitinib double salt nano suspension group: the scutellarin gefitinib double salt nano suspension is taken as a dosing solution, and is subjected to gastric lavage once a day according to the dosing amount of 75mg/kg for 21 days.
Baicalin erlotinib double salt nanosuspension group: the baicalin erlotinib double salt nano suspension is taken as a dosing solution, and is subjected to gastric lavage once a day according to the dosage of 35mg/kg, and is continuously dosed for 21 days.
Scutellarin erlotinib double salt nanosuspension group: the scutellarin erlotinib double salt nano suspension is taken as a dosing solution, and is subjected to gastric lavage once daily for 21 days according to the dosing amount of 35 mg/kg.
After the end of the dose, the tumor volume of the mice was measured, and the tumor inhibition rate (inhibition rate= (mean tumor volume in the blank dose group-mean tumor volume in the dose group)/mean tumor volume in the blank dose group 100%) was calculated as follows:
blank administration group inhibition ratio 0, baicalin group (38 mg/kg) inhibition ratio 24%, scutellarin group (38 mg/kg) inhibition ratio 28%, gefitinib group (38 mg/kg) inhibition ratio 66%, erlotinib group (15 mg/kg) 68%, baicalin gefitinib nano-suspension group (75 mg/kg) inhibition ratio 89%, scutellarin gefitinib nano-suspension group (75 mg/kg) inhibition ratio 87%, baicalin erlotinib nano-suspension group (35 mg/kg) inhibition ratio 89% and scutellarin erlotinib nano-suspension group (35 mg/kg) inhibition ratio 86%.
Example 21 determination of in vivo Activity of animals against renal cancer tumors
A blank administration group, a baicalin group, a scutellarin group, a pezopanib group and a scutellarin pezopanib double salt nano suspension group (the preparation method of the scutellarin pezopanib double salt nano suspension is referred to in example 15) and a scutellarin pezopanib double salt nano suspension group (the preparation method of the scutellarin pezopanib double salt nano suspension is referred to in example 16) are respectively arranged.
1. Test cells and animals
Mice: balb/c nude mice, males, 6-8 weeks old. All mice were fed and drinking water freely and were kept at room temperature (23.+ -. 2 ℃ C.).
Tumor cells: a498 cell line derived from NIH.
2. Test method
Renal carcinoma tumor mice were established, and qualified mice were randomly grouped into 10 groups each with the following dosing schedule:
blank dosing group: only physiological saline was administered.
Baicalin group: baicalin was prepared into a solution for administration with sterile PBS, and administered at a dose of 33mg/kg, by intragastric administration once daily for 21 days.
Scutellarin group: the scutellarin is prepared into a dosing solution by using sterile PBS, and the dosing amount is 33mg/kg, the stomach is irrigated, and the dosing is carried out once a day for 21 days continuously.
Pezopanib group: the pezopanib was formulated into a dosing solution with sterile PBS and dosed at 32mg/kg, and the stomach was irrigated once daily for 21 consecutive days.
Baicalin pezopanib double salt nanosuspension group: the baicalin pezopanib double salt nano suspension is taken as a dosing solution, and is subjected to gastric lavage according to the dosing amount of 65mg/kg once a day for 21 days.
Scutellarin pezopanib double salt nanosuspension group: the scutellarin pezopanib double salt nano suspension is taken as a dosing solution, and is subjected to gastric lavage according to the dosing amount of 75mg/kg once a day for 21 days.
After the end of the dose, the tumor volume of the mice was measured, and the tumor inhibition rate (inhibition rate= (mean tumor volume in the blank dose group-mean tumor volume in the dose group)/mean tumor volume in the blank dose group 100%) was calculated as follows:
blank administration group inhibition ratio 0, baicalin group (33 mg/kg) inhibition ratio 30%, scutellarin group (33 mg/kg) inhibition ratio 28%, pezopanib group (32 mg/kg) inhibition ratio 65%, baicalin pezopanib nano-suspension group (65 mg/kg) inhibition ratio 86%, scutellarin pezopanib nano-suspension group (65 mg/kg) inhibition ratio 91%.
Example 22 animal in vivo Activity assay
A blank administration group, a baicalin group, a scutellarin group, an octreotide group, and a baicalin-octreotide double salt nanosuspension group (for the preparation method of the baicalin-octreotide double salt nanosuspension, see example 17) and a scutellarin-octreotide double salt nanosuspension group (for the preparation method of the scutellarin-octreotide double salt nanosuspension, see example 18) were respectively set.
1. Test cells and animals
Mice: balb/c nude mice, males, 6-8 weeks old. All mice were fed and drinking water freely and were kept at room temperature (23.+ -. 2 ℃ C.).
Tumor cells: h1975 cell line, derived from NIH.
2. Test method
Lung cancer tumor mice were established, and qualified mice were randomly grouped into 10 groups each with the following dosing schedule:
blank dosing group: only physiological saline was administered.
Baicalin group: baicalin was prepared into a solution for administration with sterile PBS, and administered once daily for 21 days in an amount of 9 mg/kg.
Scutellarin group: the scutellarin is prepared into a dosing solution by using sterile PBS, and the dosing amount is 9mg/kg, the stomach is irrigated, and the dosing is carried out once a day for 21 days continuously.
Octenib group: ornitanib was formulated into a dosing solution with sterile PBS and dosed at 11mg/kg, and the dosing was performed once daily for 21 consecutive days.
Baicalin-octenib double salt nanosuspension group: the baicalin-octreotide double salt nano suspension is taken as a dosing solution, and is subjected to gastric lavage once a day according to the dosage of 20mg/kg for 21 days.
Scutellarin-octreotide double salt nanosuspension group: the nanometer suspension of the erigeron breviscapus double salt is taken as a dosing solution, and is subjected to gastric lavage once a day according to the dosage of 20mg/kg for 21 days.
After the end of the dose, the tumor volume of the mice was measured, and the tumor inhibition rate (inhibition rate= (mean tumor volume in the blank dose group-mean tumor volume in the dose group)/mean tumor volume in the blank dose group 100%) was calculated as follows:
the inhibition rate of the blank administration group is 0, the inhibition rate of the baicalin group (33 mg/kg) is 30, the inhibition rate of the scutellarin group (33 mg/kg) is 28, the inhibition rate of the octreotide group (32 mg/kg) is 65%, the inhibition rate of the baicalin octreotide nanosuspension group (65 mg/kg) is 86%, and the inhibition rate of the scutellarin octreotide nanosuspension group (65 mg/kg) is 91%.
Example 23 animal in vivo Activity assay
A blank administration group, a scutellarin group, a lapatinib group, and a scutellarin lapatinib double salt nanosuspension group were respectively set (the preparation method of the scutellarin lapatinib double salt nanosuspension is described in example 19).
1. Test cells and animals
Mice: balb/c nude mice, males, 6-8 weeks old. All mice were fed and drinking water freely and were kept at room temperature (23.+ -. 2 ℃ C.).
Tumor cells: BT474 cell line, derived from NIH.
2. Test method
Breast tumor mice were established and eligible mice were randomly grouped, 10 per group, with the following dosing regimen:
Blank dosing group: only physiological saline was administered.
Scutellarin group: the scutellarin is prepared into a dosing solution by using sterile PBS, and the dosing amount is 31mg/kg, the stomach is irrigated, and the dosing is carried out once a day for 21 days continuously.
Lapatinib group: lapatinib was formulated into a dosing solution with sterile PBS and dosed at 39mg/kg, and the stomach was irrigated once daily for 21 consecutive days.
Scutellarin lapatinib double salt nanosuspension group: the nanometer suspension of the scutellarin lapatinib double salt is taken as a dosing solution, and is subjected to gastric lavage once a day according to the dosing amount of 20mg/kg for 21 days.
After the end of the dose, the tumor volume of the mice was measured, and the tumor inhibition rate (inhibition rate= (mean tumor volume in the blank dose group-mean tumor volume in the dose group)/mean tumor volume in the blank dose group 100%) was calculated as follows:
the inhibition rate of the blank administration group is 0, the inhibition rate of the scutellarin group (31 mg/kg) is 25%, the inhibition rate of the lapatinib group (39 mg/kg) is 67%, and the inhibition rate of the scutellarin lapatinib nano suspension group (20 mg/kg) is 90%.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (9)

1. The double salt compound is characterized by being a double salt of flavonoid glycoside and an organic amine tyrosine kinase inhibitor, wherein the flavonoid glycoside is baicalin or scutellarin, and the organic amine tyrosine kinase inhibitor is any one of gefitinib, erlotinib, pezopanib, octreotide and lapatinib.
2. A process for the preparation of the double salt compound of claim 1, comprising the steps of:
mixing and dissolving the flavonoid glycoside, the organic amine tyrosine kinase inhibitor and a polar aprotic organic solvent to obtain a mixed solution;
reacting the mixed solution to obtain a reaction solution; and
the solvent was removed from the reaction solution.
3. The method for producing a double salt compound according to claim 2, wherein the polar aprotic organic solvent is one or more of N, N-dimethylformamide, dimethyl sulfoxide or acetonitrile.
4. A pharmaceutical composition comprising a therapeutically effective amount of the double salt compound of claim 1 in combination with a pharmaceutically acceptable carrier, excipient or diluent.
5. Use of a double salt compound according to claim 1 or a pharmaceutical composition according to claim 4 for the preparation of a tyrosine kinase inhibitor medicament.
6. The use according to claim 5, wherein the tyrosine kinase inhibitor medicament is for the treatment of malignant tumors, including lung cancer, liver cancer, stomach cancer, esophagus cancer, cardiac cancer, colon cancer, rectum cancer, large intestine cancer, breast cancer, cervical cancer, ovary cancer, pancreas cancer, prostate cancer, thyroid cancer, larynx cancer, oropharynx cancer, brain tumor, brain glioma or soft tissue sarcoma.
7. A double salt nanoparticle obtained by nano-milling the double salt compound of claim 1.
8. Use of the double salt nanoparticle of claim 7 in the preparation of a tyrosine kinase inhibitor drug.
9. The use according to claim 8, wherein the tyrosine kinase inhibitor medicament is for the treatment of malignant tumors including lung cancer, liver cancer, stomach cancer, esophagus cancer, cardiac cancer, colon cancer, rectum cancer, large intestine cancer, breast cancer, cervical cancer, ovary cancer, pancreas cancer, prostate cancer, thyroid cancer, larynx cancer, oropharynx cancer, brain tumor, brain glioma or soft tissue sarcoma.
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WO2011068403A2 (en) * 2009-12-02 2011-06-09 Ultimorphix Technologies B.V. Novel n-{3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamjne salts
CN101732417A (en) * 2010-02-09 2010-06-16 曾建国 Preparation method and application of ion pair mixture of macleaya cordata total alkaloid
CN106103429A (en) * 2014-04-24 2016-11-09 意大利合成制造有限公司 The eutectic of Lapatinib unitary hydrochlorate
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