Montelukast acid berberine quaternary ammonium salt compound, double salt composition, synthesis method and use thereof

Abstract

The present invention discloses a novel berberine quaternary ammonium salt, double salt or composition having anti-inflammatory, antibacterial and immunomodulatory effects, specifically a berberine quaternary ammonium salt, double salt or composition, solvate, hydrate, isotope-substituted product or isomer thereof having the structure represented by formula (I). #imgabs0#

Description

[0001] This application claims priority to a prior application, patent application number 202111358162.9, filed with the State Intellectual Property Office of China on November 16, 2021, entitled "Montelukastate berberine quaternary ammonium salt compounds, complex salt compositions, synthesis methods, and uses thereof." The entire text of that prior application is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry and specifically includes novel berberine montelukastate quaternary ammonium salt compounds and double salt compositions having the structure of formula (I), compositions containing such compounds, and the use of such compounds, compositions or double salts in the preparation of medicaments for preventing, alleviating and / or treating diseases related to allergies, inflammation, vascular malformations, infections, immunity, etc. (such as ulcerative colitis, rhinitis, asthma, vascular malformations / vasculitis, dry eyes, eye infections and inflammation, etc.). Background Art

[0003] Berberine is an isoquinoline alkaloid extracted from the root and bark of Coptis chinensis (Coptis chinensis), a plant of the genus Coptis chinensis (Ranunculaceae). Berberine, a major component of the traditional Chinese medicine Coptis chinensis, was previously considered poorly absorbed after oral administration. However, it is effective against intestinal infections caused by Escherichia coli and Staphylococcus aureus, conjunctivitis, and suppurative otitis media, and is clinically used primarily for the treatment of intestinal infections. In recent years, berberine has been shown to exhibit hypoglycemic and hypolipidemic, as well as anti-inflammatory effects. Studies have shown that in animal models of atherosclerosis, berberine treatment significantly reduces serum LDL-C and TC levels, inhibits secretion of the inflammatory cytokine IL-6, and reduces serum and tissue levels of ALP, BMP-2, OPG, OCN, RUNX2, and calcium, inhibiting vascular inflammatory infiltration and improving plaque stability. Berberine has also been shown to have some anti-angiogenic effects, primarily mediated by the inhibition of various pro-inflammatory and pro-angiogenic factors, including HIF, VEGF, COX-2, NO, NF-κB, and other pro-inflammatory cytokines. Berberine's anti-inflammatory mechanism can be summarized as affecting the balance between immune cells (Tregs) and Th17 cells by regulating pathways such as NF-κB, MAPK, and PPARγ signaling. This inhibits the secretion and expression of inflammatory factors such as IL-1β, IL-6, IL-8, IL-17, TNF-α, and ICAM-1, thereby hindering leukocyte adhesion and migration to the endothelium, reducing neutrophil infiltration, promoting cell apoptosis, and alleviating tissue damage. Current clinical studies have initially found that berberine plays a certain therapeutic role in inflammatory-related diseases such as metabolic and autoimmune diseases.

[0004] In the past, berberine was generally used in the form of its hydrochloride due to its poor water solubility and low oral bioavailability. However, the widely used berberine hydrochloride has poor water and fat solubility, leading to poor gastrointestinal absorption, resulting in low oral bioavailability and affecting its systemic therapeutic effects.

[0005] Montelukast acid or its sodium salt is a highly selective leukotriene receptor antagonist. Leukotrienes, metabolites of arachidonic acid 5-lipoxygenase, are potent inflammatory mediators that mediate a range of immune responses. Montelukast binds to leukotriene receptors with high selectivity, blocking the inflammatory effects of leukotrienes, thereby exerting anti-inflammatory and anti-allergic effects. It is widely used clinically to treat various respiratory allergic diseases. Recent animal and clinical studies have shown that montelukast also has significant antioxidant properties.

[0006]

[0007] Although berberine and montelukastic acid may have synergistic effects in anti-inflammatory, anti-infective, and immunomodulatory aspects, no relevant research has been reported previously. The applicant innovatively combined berberine and montelukastic acid to form the corresponding berberine montelukastic acid salt, which not only improves the solubility of both, increasing their solution stability and bioavailability, but also demonstrates a stronger anti-inflammatory effect, reduces side effects, and particularly avoids the potential risk of hyperchloremia associated with the hydrochloride, thereby improving safety.

[0008] Technical Effects

[0009] The present inventors unexpectedly discovered that some of the novel quaternary ammonium salt compounds of formula (I) or their complex salt compositions of the present invention not only improve the solubility of berberine / montelukast, but also improve the solubility of both, increase their solution stability and bioavailability, and also show stronger anti-inflammatory effects and reduce side effects. In particular, they avoid the potential risk of hyperchloremia of berberine hydrochloride, improve safety, and are more suitable for preparing drugs or various preparations for preventing, alleviating and / or treating diseases related to allergies, inflammation, vascular malformations, infections, and immunity (such as ulcerative colitis, rhinitis, asthma, vascular malformations / vasculitis, dry eyes, eye infections and inflammation, etc.). Summary of the Invention

[0010] The object of the present invention is to provide a quaternary ammonium salt conjugated compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, composition, enantiomer and isotope-substituted product or a complex salt thereof.

[0011]

[0012] in,

[0013] R1 and R2 are each independently selected from hydrogen, deuterium, halogen, -CN, C1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocyclic groups, 6-10 membered aryl groups and 5-8 membered heteroaryl groups;

[0014] or any two adjacent R1 or any two adjacent R2 together with the carbon to which they are attached form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3;

[0015] R3 and R4 are each independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocyclic groups, 6-10 membered aryl groups and 5-8 membered heteroaryl groups;

[0016] or any two adjacent R3 or any two adjacent R4 together with the carbon to which they are attached form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3;

[0017] The heteroatoms in the heteroaryl and heterocyclic groups represent heteroatoms independently selected from O, N, S, P and their isotopes;

[0018] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0019] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0020] n is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0021] P is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0022] t is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

[0023] In one embodiment of the present invention, the quaternary ammonium salt conjugated compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution, composition or complex salt thereof has a structure of formula (IA),

[0024]

[0025] in,

[0026] R1 and R2 are each independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10saturated or partially saturated heterocyclic groups, 6-10 membered aryl groups and 5-8 membered heteroaryl groups;

[0027] or any two adjacent R1 or any two adjacent R2 together with the carbon to which they are attached form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3;

[0028] The heteroatoms in the heteroaryl and heterocyclic groups represent heteroatoms independently selected from O, N, S, P and their isotopes;

[0029] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0030] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0031] n is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0032] In one embodiment of the present invention, the quaternary ammonium salt conjugated compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution, composition or complex salt thereof has a structure of formula (IB),

[0033]

[0034] in,

[0035] R1 is independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocyclic groups, 6-10 membered aryl groups and 5-8 membered heteroaryl groups;

[0036] or any two adjacent R1 together with the carbon to which they are attached form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3;

[0037] The heteroatoms in the heteroaryl and heterocyclic groups represent heteroatoms independently selected from O, N, S, P and their isotopes;

[0038] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0039] m is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0040] In one embodiment of the present invention, the quaternary ammonium salt conjugated compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution, composition or complex salt thereof has a structure of formula (IC),

[0041]

[0042] in,

[0043] R2 are each independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocyclic groups, 6-10 membered aryl groups and 5-8 membered heteroaryl groups;

[0044] or any two adjacent R2 together with the carbon to which they are attached form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3;

[0045] The heteroatoms in the heteroaryl and heterocyclic groups represent heteroatoms independently selected from O, N, S, P and their isotopes;

[0046] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0047] n is an integer arbitrarily selected from 0, 1, 2, 3 and 4;

[0048] In one embodiment of the present invention, the quaternary ammonium salt conjugated compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution, composition or complex salt thereof has a structure of formula (ID),

[0049]

[0050] in,

[0051] R3 and R4 are each independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group; wherein the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, 6-10 membered aryl, 5-8 membered heteroaryl, 3-8 membered saturated or partially saturated cycloalkyl and 3-8 membered saturated or partially saturated heterocyclic group are optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, alkylamino, O=, CN, OH, C 3-10 Saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocyclic groups, 6-10 membered aryl groups and 5-8 membered heteroaryl groups;

[0052] or any two adjacent R3 or any two adjacent R4 together with the carbon to which they are attached form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3, OH, OCH3, or OCH2CH3;

[0053] The heteroatoms in the heteroaryl and heterocyclic groups represent heteroatoms independently selected from O, N, S, P and their isotopes;

[0054] The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

[0055] P is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

[0056] t is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

[0057] According to an embodiment of the present invention, each R1 is the same or different and is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy; or two R1 and the carbon atoms to which they are attached form a 3-8 membered heterocyclic ring;

[0058] According to an embodiment of the present invention, each R1 is the same or different and is independently selected from hydrogen, methyl or methoxy; or two R1 and their respective carbon atoms form

[0059] According to an embodiment of the present invention, each R2 is the same or different and is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy; or two R2 and the carbon atoms to which they are attached form a 3-8 membered heterocyclic ring;

[0060] According to an embodiment of the present invention, each R2 is the same or different and is independently selected from hydrogen, methyl or methoxy; or two R2 and their respective carbon atoms form

[0061] According to an embodiment of the present invention, each R3 is the same or different and is independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 alkoxy;

[0062] According to an embodiment of the present invention, each R3 is the same or different and is independently selected from fluorine, chlorine, bromine or iodine; preferably chlorine.

[0063] According to an embodiment of the present invention, each R4 is the same or different and is independently selected from hydrogen or hydroxyl C 1-6 alkyl;

[0064] According to an embodiment of the present invention, R4 is selected from hydrogen or

[0065] According to an embodiment of the present invention, m is selected from 0, 1, 2 or 3;

[0066] According to an embodiment of the present invention, n is selected from 0, 1, 2 or 3;

[0067] According to an embodiment of the present invention, t is selected from 0 or 1;

[0068] According to an embodiment of the present invention, p is selected from 0 or 1.

[0069] In certain embodiments of the present invention, the quaternary ammonium salt conjugated compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution, composition or complex salt thereof is selected from the following structures:

[0070]

[0071]

[0072]

[0073]

[0074] Another object of the present invention is to provide a method for synthesizing the above-mentioned quaternary ammonium salt conjugated compound, solvate, enantiomer and isotope substitution product, and complex salt composition, which comprises the following steps:

[0075] 1) Preparation of various free berberine alkaloid acetone addition products: Weigh various acid radical berberine-type alkaloid quaternary ammonium salt compounds into a reaction flask, add an inorganic base (usually sodium hydroxide or KOH aqueous solution), then add acetone dropwise, and stir until the reaction is complete. The reaction mixture is filtered, and the filter cake is washed with water until neutral, and dried to obtain various free berberine alkaloid acetone addition products.

[0076] 2) Preparation of the quaternary ammonium salt conjugated compound, solvate or composition: Weigh montelukastic acid as needed into a reaction flask, add ethyl acetate, and after complete dissolution, add 8-acetonyldihydroberberine-type alkaloid compound under stirring to react until the raw materials react completely, and concentrate under reduced pressure or crystallize; or add an appropriate antisolvent to the reaction mixture to obtain a berberine montelukastic acid double salt composition;

[0077] Another object of the present invention is to provide the use of at least one of the compounds represented by formula (I) or pharmaceutically acceptable salts, solvates, compositions, enantiomers and isotope-substituted products thereof or complex salts thereof in the preparation of drugs for preventing, alleviating and / or treating diseases related to allergies, inflammation, vascular malformations, infections, immunity, etc. (such as ulcerative colitis, rhinitis, asthma, vascular malformations / vasculitis, dry eyes, eye infections, etc.).

[0078] According to an embodiment of the present invention, the disease includes but is not limited to overweight, obesity, diabetes (T1D and / or T2DM, including prediabetes), idiopathic T1D (type 1B), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney disease, tubular dysfunction, proinflammatory changes in the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity (including obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (such as osteoarthritis and urinary incontinence), eating disorders (including binge eating syndrome, bulimia nervosa and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain caused by the use of other medications (for example, steroids and antipsychotics), excessive sugar cravings, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, hyperinsulinemia), NAFLD (including steatosis, NASH, fibrosis, cirrhosis, hepatocellular carcinoma and other related diseases), cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (such as necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial hyperlipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, dry eye, glomerulosclerosis, chronic Renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, impaired glucose metabolism, impaired fasting blood glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, hyperlipoprotein B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, prevention or treatment of polycystic ovary syndrome and treatment of addiction (such as alcoholism and / or drug abuse).

[0079] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I) or at least one of its pharmaceutically acceptable salts, solvates, compositions, enantiomers and isotope substitutes or complex salts thereof, and a pharmaceutically acceptable carrier or excipient.

[0080] According to an embodiment of the present invention, the pharmaceutical composition is formulated for administration by a route selected from the group consisting of oral, parenteral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural.

[0081] According to an embodiment of the present invention, the pharmaceutical composition is preferably administered orally.

[0082] The oral dosage form is not particularly limited and can be any oral dosage form known in the art, preferably including tablets, capsules, suspensions, oral solutions, and the like. When used as an oral dosage form, the dosage standard used is, for example, 500-1500 mg / day, preferably 700-1200 mg / day, more preferably 800-1000 mg / day, and most preferably 1000 mg / day.

[0083] The duration of administration of the pharmaceutical composition according to the present invention may depend on the severity of the disease, and is preferably at least 1 month, for example, 1, 2, 3, 4, 5 or 6 months, and may be lifelong depending on the disease condition.

[0084] According to an embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable excipient selected from at least one of the following excipients, including but not limited to a filler, a disintegrant, a binder, a lubricant, a surfactant, a flavoring agent, a wetting agent, a pH adjuster, a solubilizer or cosolvent, and an osmotic pressure regulator. Those skilled in the art can easily determine how to select the corresponding excipients and their corresponding amounts based on the requirements of the specific dosage form.

[0085] According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0086] Another object of the present invention is to provide a berberine montelukastic acid double salt composition, wherein the berberine montelukastic acid double salt composition is prepared by adding berberine montelukastic acid double salt as an active ingredient to appropriate excipients and carriers to form a clinically acceptable pharmaceutical preparation.

[0087] The present invention also provides the compound represented by formula (I) or its pharmaceutically acceptable salt, solvate, composition, enantiomer and isotope-substituted product or complex salt, and the use of the pharmaceutical composition in preventing or treating diseases related to inflammation, immunity, infection, allergy, metabolism, etc. The diseases related to inflammation, immunity, infection, allergy, metabolism, etc. have the definitions described above.

[0088] The present invention also provides a method for preventing or treating diseases related to inflammation, immunity, infection, allergy, metabolism, etc., comprising administering to a patient a preventive or therapeutically effective amount of a compound represented by formula (I) or at least one of its pharmaceutically acceptable salts, solvates, compositions, enantiomers, isotopically substituted compounds, or complex salts thereof, or administering to a patient a preventive or therapeutically effective amount of the pharmaceutical composition described above. The diseases related to inflammation, immunity, infection, allergy, metabolism, etc. have the definitions described above.

[0089] In some embodiments, the patient is a mammal, preferably a human.

[0090] The present invention will now be further described by way of examples. The examples given below are for illustrative purposes only and are not intended to limit the scope of this invention. The compounds of the present invention can be prepared using many methods known in the art of organic synthesis. The examples of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry, or by methods modified therefrom. Preferred methods include, but are not limited to, the methods described below.

[0091] Compounds can be named manually or using Name it accordingly; if purchased commercially, you can also use the supplier's catalog name.

[0092] Figures in the specification

[0093] Figure 1 This is a comparison chart of the anti-inflammatory effects of the double salt compounds at different concentrations in Example 3.

[0094] Figure 2 This is a comparison chart of the anti-inflammatory effects of the double salt and its monomer in Example 4. DETAILED DESCRIPTION

[0095] In order to illustrate the present invention in more detail, the following examples are given, but the scope of the present invention is not limited thereto.

[0096] Example 1. Preparation of berberine montelukastate double salt (double salt 1):

[0097]

[0098] 1. Synthesis of 1-(9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxetine[4,5-g]isoquinolinyl[3,2-a]isoquinolin-8-yl)propan-2-one

[0099]

[0100] At room temperature, a 5M aqueous solution of sodium hydroxide (6 mL) was added dropwise to a 2 mL acetone solution of 9,10-dimethoxy-5,6-dihydro-[1,3]dioxetane[4,5-g]isoquinolyl[3,2-a]isoquinolin-7-ammonium chloride (1.00 g, 2.70 mmol). The mixture was allowed to react at room temperature for 4 hours. Upon completion of the reaction, the reaction solution was concentrated to obtain a crude product. The crude product was slurried with methanol (30 mL) for 30 minutes, then filtered. The filter cake was collected and dried to yield 1-(9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxetane[4,5-g]isoquinolyl[3,2-a]isoquinolin-8-yl)propan-2-one (830 mg, 2.11 mmol, yield: 78.1%) as a yellow solid.

[0101] Product NMR: 1 H NMR (400MHz, DMSO-d6) δ7.25(s,1H),6.86(d,J=8.4Hz,1H),6.76(s,1H),6.72(d,J=8.4Hz,1H),6.00(s,1H),5.99(s,2H),5.22-5.19(m, 1H),3.76(d,J=2.4Hz,6H),3.30-3.26(m,1H),3.20-3.19(m,1H),2.96-2.90(m,1H),2.78-2.76(m,2H),2.33-2.29(m,1H),2.03(s,3H).

[0102] 2. Synthesis of (R,E)-2-(1-(((1-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropyl-2-yl)phenyl)propyl)thio)methyl)cyclopropyl)acetic acid 9,10-dimethoxy-5,6-dihydro-[1,3]dioxacyclo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium couple

[0103]

[0104] Compound 1-(9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxacyclo[4,5-g]isoquinolinyl[3,2-a]isoquinolin-8-yl)propan-2-one (791 mg, 2.01 mmol) and compound (R,E)-2-(1-(((1-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropyl-2-yl)phenyl)propyl)thio)methyl)cyclopropyl)acetic acid (1.18 g, 2.01 mmol) were placed in a sealed tube containing methanol (8 mL) and water (0.1 mL). The reaction solution was heated to 80°C and reacted for 2 hours. After the reaction was completed, the solvent was removed from the reaction solution to obtain a yellow solid compound (11.90 g, 2.06 mmol, crude product). Then the crude compound (600 mg, 0.65 mmol) was added to a mixed solvent of chloroform (6.5 mL), methanol (3.5 mL) and water (0.1 mL), and the temperature was raised to 80°C until the crude product was completely dissolved. Stirring was continued at 80°C for 1 hour. After the reaction was completed, the reaction solution was naturally cooled to room temperature, and the reaction solution was directly concentrated to remove the solvent to obtain (R, E)-2-(1-(((1-(3-(2-(7-chloroquinoline-2- 9,10-dimethoxy-5,6-dihydro-[1,3]dioxacyclo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-ium couple (double salt 1, 600 mg, 0.65 mmol, yield: 100%) retention time: 1.271 min. LCMS: [M+H] + 336.1. Retention time: 1.853 min. LCMS: [M+H] + 586.3.

[0105] Product NMR: 1H NMR (400MHz, DMSO) δ9.89(s,1H),8.93(s,1H),8.40(d,J=8.8Hz,1H),8.20(d,J=9.2Hz,1H),8.03(d,J=2.4Hz,1H),8.01-7.94(m,3H) ,7.89(d,J=16.4Hz,1H),7.80(s,1H),7.73(s,1H),7.62-7.57(m,2H),7.51(d,J=16.4Hz,1H),7.40-7.33(m,3H),7.11-7.00(m,4H),6 .17(s,2H),4.94-4.91(m,2H),4.08(d,J=10.0Hz,6H),4.02(t,J=8.0Hz,1H),3.25-3.19(m,2H),3.13-3.06(m,1H),2.75-2.65(m,2H ),2.54(s,1H),2.29-2.20(m,1H),2.10-2.06(m,2H),1.95-1.91(m,1H),1.45(d,J=8.4Hz,6H),0.41-0.30(m,2H),0.25-0.14(m,2H).

[0106] Ster

[0107] Example 2, Preparation of Montelukast Acid Berberine Analog Double Salt (Double Salt 2-15):

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114] Example 3: Evaluation of the anti-inflammatory effects of test compounds using a hypertonic inflammatory cell model

[0115] 3.1 Cells and culture

[0116]

[0117] 3.2 Reagents, instruments and consumables

[0118]

[0119]

[0120] 3.3 Experimental methods and procedures

[0121] SV40 cell culture: SV40 cells were cultured in DMEM / F12 medium supplemented with 10% fetal bovine serum. Insulin and human epidermal growth factor were added to achieve a final insulin concentration of 5 μg / mL and a final human epidermal growth factor concentration of 10 ng / mL. Cells were routinely subcultured in a cell culture incubator at 37°C, 5% CO2, and 90% humidity. Cells were grown to 70% to 90% confluency for use in experiments.

[0122] Human primary cell culture: The remaining corneal limbus of the donor cornea used in surgery is processed with ophthalmic instruments to form a tissue block carrying corneal stem cells. The tissue block is attached to the bottom of a cell culture dish and cultured in SHEM medium in a cell culture incubator at 37°C, 5% CO2, and 90% humidity. After 3 to 5 days, human primary corneal epithelial cells can be seen crawling out of the corneal limbus stem cells. The cells are grown to a 70% to 90% confluence before use in experiments.

[0123] Solution Preparation: ① Hypertonic solution (500 mOsm): Prepare by adding 90 mmol / L NaCl solution to serum-free culture medium. ② Test drug solution: Dissolve 10 mg of the above-prepared product in 1 mL of 37°C DMSO to prepare a 104 μg / mL stock solution. Store in a -20°C refrigerator until needed. Dilute the stock solution with serum-free culture medium to a final concentration of 1 μmol / L. 10 μmol / L drug solution was used in the experiment.

[0124] Establishment of hypertonic inflammatory cell model and medication: discard the old culture medium, give hypertonic culture medium containing 500mOsm hypertonic solution and normal isotonic culture medium, culture the cells for four hours, then switch to drug solution for the drug group and switch to normal isotonic culture medium for the control group (including hypertonic model control and normal cell control), continue to culture for another four hours and then collect the samples.

[0125] Real-time fluorescence quantitative PCR (RT-PCR): RT-PCR was used to detect the mRNA expression of IL-6, IL-1β, IL-17A, IL-18, TNF-α and NLRP3 in different groups. SV40 and human corneal epithelial primary cells inoculated in 12-well plates were taken at different time points (after the hypertonic inflammatory cell model was established and four hours after drug administration), and the cells were collected for later use. The same experiment was repeated 3 times. The RNA of the cells was extracted according to the instructions of the RNA extraction kit, and the total RNA amount required for the synthesis of the cDNA template was calculated based on the measured concentration. The cDNA was synthesized using the M-MLV reverse transcription kit, and the reverse transcribed cDNA was stored at -20°C for subsequent PCR amplification. The gene primer sequences are as follows:

[0126]

[0127]

[0128] RT-PCR was performed using the SYBR Green fluorescent dye method. The relative expression of the target gene mRNA was calculated. Three replicate wells were set up in each group, and the final result was the average of the three replicates.

[0129] The t test was used to compare the two groups, and P < 0.05 was considered a significant difference.

[0130] 3.4 Results

[0131] The experimental results show that ( Figure 1 : NC: normal control, HS: hypertonic model, HS-1: hypertonic model plus 1μmol / L montelukast acid berberine double salt drug treatment group, HS-10: hypertonic model plus 10μmol / L montelukast acid berberine double salt drug treatment group). In the hypertonic model of human corneal epithelial primary cells and SV40 corneal epithelial cells, 1μmol / L and 10μmol / L montelukast acid berberine double salt drug treatment can significantly reduce the inflammation-related cytokines ( Figure 1 : AH, HS group vs. HS-1, HS-10 group, Ps < 0.01). This suggests that berberine montelukastate double salt has a good anti-inflammatory effect and has therapeutic potential for related diseases.

[0132] Example 4: Evaluation of the anti-inflammatory effects of the test compound and its monomer in a hypertonic inflammatory cell model

[0133] 4.1 Experimental methods and procedures

[0134] The reagents, instruments and consumables of this embodiment are the same as those of embodiment 3. The comparative drugs used are berberine base (Aladdin, B414323), montelukast (Aladdin, M421902)

[0135] Human primary cell culture: The remaining corneal limbus of the donor cornea used in surgery is processed with ophthalmic instruments to form a tissue block carrying corneal stem cells. The tissue block is attached to the bottom of a cell culture dish and cultured in SHEM medium in a cell culture incubator at 37°C, 5% CO2, and 90% humidity. After 3 to 5 days, human primary corneal epithelial cells can be seen crawling out of the corneal limbus stem cells. The cells are grown to a 70% to 90% confluence before use in experiments.

[0136] Solution preparation: ① Hypertonic solution (500 mOsm): Prepared by adding 90 mmol / L NaCl solution to serum-free culture medium. ② Test drug solution preparation: Dissolve 10 mg of the above-prepared product in 1 mL of 37°C DMSO solution to prepare a 104 μg / mL stock solution, which is stored in a -20°C refrigerator until further use; dilute the stock solution with serum-free culture medium to prepare a drug solution with a final concentration of 0.5 μmol / L for use in this experiment. ③ Berberine and montelukast drug solution preparation: Dissolve 10 mg of berberine or montelukast in 1 mL of 37°C DMSO solution to prepare a 104 μg / mL stock solution, which is stored in a -20°C refrigerator until further use; dilute the stock solution with serum-free culture medium to prepare a drug solution with a final concentration of 0.5 μmol / L for use in this experiment.

[0137] Real-time fluorescence quantitative PCR (RT-PCR): RT-PCR was used to detect the mRNA expression of IL-6, IL-1β, IL-17A, IL-18, TNF-α and NLRP3 in different groups. SV40 and human corneal epithelial primary cells inoculated in 12-well plates were taken at different time points (after the hypertonic inflammatory cell model was established and four hours after medication), and the cells were collected for later use. The same experiment was repeated 3 times. The RNA of the cells was extracted according to the instructions of the RNA extraction kit, and the total RNA amount required for the synthesis of the cDNA template was calculated based on the measured concentration. The cDNA was synthesized using the M-MLV reverse transcription kit, and the cDNA obtained by reverse transcription was stored at -20°C, and then amplified by PCR. The gene primer sequence is the same as that in Example 3.

[0138] The t test was used to compare the two groups, and P < 0.05 was considered a significant difference.

[0139] 4.2 Results

[0140] The experimental results show that ( Figure 2: UT: normal control, HS: hypertonic cell model, HS-0.5: hypertonic cell model plus 0.5μmol / L montelukast acid berberine complex salt drug treatment group, A: hypertonic cell model plus 0.5μmol / L montelukast, B: hypertonic cell model plus 0.5μmol / L berberine base). In the hypertonic model of primary human corneal epithelial cells, compared with the same concentration of berberine and montelukast alone, the obtained complex salt drug can produce a significantly stronger reduction effect on various inflammatory-related cytokines ( Figure 2 : AD, HS-0.5 groups were compared with A, B groups, respectively, Ps<0.01). This suggests that the anti-inflammatory effect of montelukastate berberine complex salt is superior to that of montelukast or berberine monomer.

[0141] Example 5. Comparison of the Stability of Montelukast Berberine Double Salt and Montelukast Berberine Base in a High Humidity Environment

[0142] 5.1 Experimental methods and procedures

[0143] In this example, a 1 / 10,000 electronic balance (Sartorius, Germany) was used, and the comparative drugs used were berberine base (Aladdin, B414323) and montelukast (Aladdin, M421902).

[0144] Take three portions of montelukastate berberine complex salt (complex salt 1), one gram each of montelukast and berberine, place them in flat dishes, and accurately weigh them. Place the test sample in a sealed container at a constant humidity level at 25°C and RH 90% ± 5% for 10 days. Accurately weigh the sample on the 5th and 10th days, and record the results. Calculate the moisture absorption weight gain ratio.

[0145] 5.2 Results

[0146] In high humidity environments, the hygroscopic weight gain ratio of montelukastate berberine double salt is lower than that of montelukast and berberine base, making it easier to store the compound.

[0147] Compound 5-day weight gain percentage (%) 10-day weight gain percentage (%) Berberine montelukastate double salt 3.3 4.9 Montelukast 4.5 6.3 Berberine base 4.2 6.7

[0148] Example 6. Comparison of the Solubility of Montelukast Berberine Double Salt and Montelukast Berberine Base in Solvents

[0149] 6.1 Experimental methods and procedures

[0150] Preparation of solvent: 1) Dissolution of carboxymethyl cellulose (CMC) (McLean: C889437): Take a 2L beaker and measure approximately 1500mL of 80℃ ultrapure water. Slowly add carboxymethyl cellulose (CMC) (3.75g, 0.25%) while stirring with an LED overhead stirrer. Stir for approximately 7 hours before adding other excipients. 2) Addition of hydroxypropyl-β-cyclodextrin (HPBCD) (Bismuth: BD44359): Slowly add hydroxypropyl-β-cyclodextrin (HPBCD) (82.5g, 5.5%) and stir until dissolved. Stir for approximately 1 hour. 3) pH adjustment: Measure the pH before adjustment, then add 1mol / L NaOH solution or 1mol / L HCl solution to adjust the pH to approximately 7.5-8.

[0151] Preparation of Reference Standards: 1) Montelukast Berberine Salt Reference Solution: Accurately weigh an appropriate amount of berberine salt into a volumetric flask, dissolve in methanol, and dilute to the mark. 2) Berberine Base Reference Solution: Accurately weigh an appropriate amount of berberine reference solution into a volumetric flask, dissolve in methanol, and dilute to the mark. 3) Montelukast Reference Solution: Accurately weigh an appropriate amount of berberine reference solution into a volumetric flask, dissolve in DMSO, and dilute to the mark. 4) Test Solution: Add berberine salt, berberine base, and montelukast to the solvent until supersaturated. Filter and adjust the pH to 7.5-8 with sodium hydroxide or hydrochloric acid solution.

[0152] Chromatographic conditions: 1) Montelukast berberine salt chromatography conditions: An Agilent ZORBAX SB-C18 column (4.6 × 250 mm, 5 μm) was used; the mobile phase consisted of 0.01 mol / L ammonium dihydrogen phosphate solution (adjusted to pH 2.8 with phosphoric acid) and acetonitrile (75:25); the detection wavelength was 345 nm; the injection volume was 10 μL; the column temperature was 25°C; and the flow rate was 1.0 mL / min. Accurately measure the montelukast berberine salt test solution and the reference solution and inject them into the liquid chromatograph. 2) Montelukast Chromatographic Conditions: Column: Agilent Eclipse XDB-C18 (4.6×150 mm, 5 μm); Mobile Phase A: Dissolve 3.85 g of ammonium acetate in 1000 mL of water, add 1 mL of triethylamine, adjust the pH to 5.5 with glacial acetic acid, filter, and sonicate; Mobile Phase B: Methanol; Detection wavelength: 240 nm; Injection volume: 20 μL; Column temperature: 25°C; Flow rate: 1.0 mL / min. Assay: Accurately measure the Montelukast reference solution and inject it into the liquid chromatograph. Appropriately dilute the Montelukast test solution and inject it into the liquid chromatograph. 3) Berberine base chromatography conditions: The chromatographic column used was an Agilent ZORBAX SB-C18 (4.6 × 250 mm, 5 μm); the mobile phase was 0.01 mol / L ammonium dihydrogen phosphate solution (adjusted to pH 2.8 with phosphoric acid)-acetonitrile (75:25); the detection wavelength was 345 nm; the injection volume was 10 μL; the column temperature was 25°C; and the flow rate was 1.0 mL / min. The berberine base test solution and the reference solution were accurately measured and injected into the liquid chromatograph.

[0153] The t test was used to compare the two groups, and P < 0.05 was considered a significant difference.

[0154] 6.2 Results

[0155] Compound Concentration in solvent (μg / ml) Berberine montelukastate double salt 31.51 Montelukast Very small amount not detected Berberine base 24.45

[0156] The results showed that the solubility of berberine complex salt of montelukastate in the solvent was better than that of berberine base, and was significantly better than that of montelukast monomer (Ps<0.05).

[0157] Example 7 Comparison of the Stability of Montelukast Berberine Double Salt and Montelukast Berberine Base in Solvents

[0158] 7.1 Experimental methods and procedures

[0159] The reagents, instruments and consumables of this example are the same as those of Example 6. Since montelukast has extremely poor solubility in the solvent and cannot be detected, its sodium salt (Aladdin: M129586) and montelukastate berberine double salt are used to compare their stability in the solvent.

[0160] Preparation of solvent: 1) Dissolution of carboxymethyl cellulose (CMC) (McLean: C889437): Take a 2L beaker and measure approximately 1500mL of 80℃ ultrapure water. Slowly add carboxymethyl cellulose (CMC) (3.75g, 0.25%) while stirring with an LED overhead stirrer. Stir for approximately 7 hours before adding other excipients. 2) Addition of hydroxypropyl-β-cyclodextrin (HPBCD) (Bismuth: BD44359): Slowly add hydroxypropyl-β-cyclodextrin (HPBCD) (82.5g, 5.5%) and stir until dissolved. Stir for approximately 1 hour. 3) pH adjustment: Measure the pH before adjustment, then add 1mol / L NaOH solution or 1mol / L HCl solution to adjust the pH to approximately 7.5-8.

[0161] Preparation of Reference Standards: 1) Montelukast Berberine Salt Reference Solution: Accurately weigh an appropriate amount of berberine salt into a volumetric flask, dissolve in methanol, and dilute to the mark. 2) Berberine Base Reference Solution: Accurately weigh an appropriate amount of berberine reference solution into a volumetric flask, dissolve in methanol, and dilute to the mark. 3) Montelukast Sodium Reference Solution: Accurately weigh an appropriate amount of montelukast sodium reference solution into a volumetric flask, dissolve in DMSO, and dilute to the mark. 4) Test Solution: Add berberine salt, berberine base, and montelukast sodium to the solvent until supersaturated, filter, and adjust the pH to 7.5-8 with sodium hydroxide or hydrochloric acid solution.

[0162] Chromatographic conditions: 1) Montelukast berberine salt chromatography conditions: An Agilent ZORBAX SB-C18 column (4.6 × 250 mm, 5 μm) was used; the mobile phase consisted of 0.01 mol / L ammonium dihydrogen phosphate solution (adjusted to pH 2.8 with phosphoric acid) and acetonitrile (75:25); the detection wavelength was 345 nm; the injection volume was 10 μL; the column temperature was 25°C; and the flow rate was 1.0 mL / min. Accurately measure the montelukast berberine salt test solution and the reference solution and inject them into the liquid chromatograph. 2) Montelukast sodium chromatographic conditions: Column: Agilent Eclipse XDB-C18 (4.6×150 mm, 5 μm); Mobile phase A: Dissolve 3.85 g of ammonium acetate in 1000 mL of water, add 1 mL of triethylamine, adjust the pH to 5.5 with glacial acetic acid, filter, and sonicate; Mobile phase B: Methanol; Detection wavelength: 240 nm; Injection volume: 20 μL; Column temperature: 25°C; Flow rate: 1.0 mL / min. Assay: Accurately measure the montelukast sodium reference solution and inject it into the liquid chromatograph. Appropriately dilute the montelukast sodium test solution and inject it into the liquid chromatograph. 3) Berberine base chromatography conditions: The chromatographic column used was an Agilent ZORBAX SB-C18 (4.6 × 250 mm, 5 μm); the mobile phase was 0.01 mol / L ammonium dihydrogen phosphate solution (adjusted to pH 2.8 with phosphoric acid)-acetonitrile (75:25); the detection wavelength was 345 nm; the injection volume was 10 μL; the column temperature was 25°C; and the flow rate was 1.0 mL / min. The berberine base test solution and the reference solution were accurately measured and injected into the liquid chromatograph.

[0163] Experimental Procedure: 1) Photostability Test: Take a 0-hour test solution of montelukast acid berberine salt, a 0-hour test solution of berberine base, and a 0-hour test solution of montelukast sodium, expose these solutions to light, and take samples after 8 hours, 5 days, and 10 days, respectively. The test solutions of each substance under each condition are compared with the standard solution. 2) Thermal Stability Test: Take a 0-hour test solution of montelukast acid berberine salt, a 0-hour test solution of berberine base, and a 0-hour test solution of montelukast sodium, expose these solutions to 40°C (protected from light) and 60°C (protected from light), and take samples after 8 hours, 5 days, and 10 days, respectively. The test solutions of each substance under each condition are compared with the standard solution.

[0164] The t test was used to compare the two groups, and P < 0.05 was considered a significant difference.

[0165] 7.2 Results

[0166]

[0167]

[0168] The results showed that the overall photothermal stability of montelukastate berberine complex salt in the commonly used solvent of the eye drops was better than that of montelukast (Ps<0.05) at three time points: 8 hours, 5 days, and 10 days, and the photothermal stability was equivalent to that of berberine base (Ps>0.05).

[0169] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A double salt represented by formula (I); （I） in, R1 is selected from C 1-10 alkoxy; Two R2 and their respective carbon atoms form ; R3 is selected from hydrogen, halogen, C 1-10 Alkyl, C 1-10 alkoxy; R4 is selected from OH substituted C 1-10 alkyl; m is an integer arbitrarily selected from 1, 2, 3 and 4; n is 2; p is an integer arbitrarily selected from 1, 2, 3, 4 and 5; t is an integer arbitrarily selected from 1, 2, 3 and 4.

2. The double salt according to claim 1, having the structure of formula (IA), Formula (IA) in, R1, R2, m and n have the meanings as defined in claim 1.

3. The double salt according to claim 1, having the structure of formula (IB), Formula (IB) in, R1 and m have the meanings as defined in claim 1.

4. The double salt according to claim 1, having a structure of formula (IC), Formula (IC) in, R2 and n have the meanings as defined in claim 1.

5. The double salt according to claim 1, having the structure of formula (ID), Formula (ID) in, R3, R4, p and t have the meanings as defined in claim 1.

6. The double salt according to claim 1, characterized in that Each R1 is the same or different and is independently selected from C 1-6 Alkoxy.

7. The double salt according to claim 1, characterized in that Each R1 is the same or different and is independently selected from methoxy.

8. The double salt according to claim 1, characterized in that Each R3 is the same or different and is independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy.

9. The double salt according to claim 1, characterized in that Each R3 is the same or different and is independently selected from fluorine, chlorine, bromine or iodine.

10. The double salt according to claim 1, characterized in that Each R4 is the same or different and is independently selected from a hydroxy-substituted C 1-6 alkyl.

11. The double salt according to claim 1, characterized in that R4 is selected from .

12. The double salt according to claim 1, characterized in that m is selected from 1, 2 or 3; n is 2; t is selected from 1; p is selected from 1.

13. A double salt selected from the following structural compounds or corresponding isomers or combinations thereof: Compound 1 Compound 2 Compound 6 Compound 8 Compound 14.

14. A method for synthesizing the double salt according to any one of claims 1 to 13, comprising the steps of: 1) Preparation of various free berberine alkaloid acetone addition products: Weigh various acid radical berberine-type alkaloid quaternary ammonium salt compounds into a reaction flask, add an inorganic base, and then add acetone dropwise, stirring until the raw materials react completely; filter the reaction mixture, wash the filter cake with water until neutral, and dry to obtain various free berberine alkaloid acetone addition products; 2) Preparation of the double salt: Montelukast acid is weighed as needed into a reaction flask, ethyl acetate is added, and after complete dissolution, the free berberine alkaloid acetone addition product is added with stirring to react until the raw materials are completely reacted, and then concentrated under reduced pressure or crystallized; or an appropriate antisolvent is added to the reaction mixture to obtain the double salt.

15. The synthesis method according to claim 14, characterized in that The inorganic base is sodium hydroxide or KOH aqueous solution.

16. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a therapeutically effective amount of at least one of the double salts according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

17. A berberine-montelukast acid double salt composition, characterized in that: The berberine-montelukast acid double salt composition is prepared into a clinically acceptable pharmaceutical preparation by adding the double salt according to any one of claims 1 to 13 as an active ingredient to appropriate excipients and carriers.

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