CN108498518B - Application of seven-membered-ring berberine analogue and pharmaceutical composition thereof in preparation of medicines for treating multiple myeloma - Google Patents
Application of seven-membered-ring berberine analogue and pharmaceutical composition thereof in preparation of medicines for treating multiple myeloma Download PDFInfo
- Publication number
- CN108498518B CN108498518B CN201710104481.4A CN201710104481A CN108498518B CN 108498518 B CN108498518 B CN 108498518B CN 201710104481 A CN201710104481 A CN 201710104481A CN 108498518 B CN108498518 B CN 108498518B
- Authority
- CN
- China
- Prior art keywords
- membered ring
- analogue
- berberine analogue
- ring berberine
- multiple myeloma
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a seven-membered ring berberine analogue and application of a pharmaceutical composition thereof in preparing a medicament for treating hematological tumors, wherein the seven-membered ring berberine analogue has a general formula (I)
The seven-membered ring berberine analogue shown in the general formula (I) obtained after the structure of the berberine is improved has good inhibition effect on blood tumor cells, and can be used for preparing a medicament for treating blood tumors.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an application of a seven-membered ring berberine analogue and a pharmaceutical composition thereof in preparing a medicine for treating hematological tumors.
Background
Malignant tumors, one of the major public health problems worldwide, greatly endanger human health and will become the first killer of humans in the new century. Malignant tumors are no longer only serious diseases in developed industrial countries, and developing countries face a greater burden of diseases. Malignant tumors comprise solid tumors (such as lung cancer, colorectal cancer, liver cancer, gastric cancer and the like) and blood tumors (such as myeloma, lymphoma and the like), and the occurrence, development and treatment modes of the two diseases are obviously different, wherein the myeloma and the lymphoma are two common blood system tumors.
Among them, multiple Myeloma (MM) is a malignant disease in which clonal plasma cells abnormally proliferate, is the second most common malignant tumor of the blood system, accounts for about 10% of the malignant tumor of the blood system, is mostly found in middle-aged and elderly people, and cannot be cured at present, and the survival time of the middle-aged and elderly people is 5-6 years. The traditional main methods for treating multiple myeloma are chemotherapy and hematopoietic stem cell transplantation, and the clinical curative effect of the traditional methods is difficult to maintain. In the last 10 years, with the emergence of novel drugs such as proteasome inhibitor bortezomib, immunomodulators thalidomide and lenalidomide, the complete remission rate and the overall survival rate of multiple myeloma patients are obviously improved. But at the same time still has the following disadvantages: firstly, the effective rate of the medicines in a single medicine in patients who relapse and are difficult to treat is only 25 to 50 percent; second, despite prolonged disease-free survival, most patients will eventually relapse and develop significant drug resistance; thirdly, some serious side effects such as neuritis limit the application of the medicine. Therefore, the development and examination of new therapeutic drugs are still important problems required for the treatment of multiple myeloma at present. Lymphoma, one of the most common malignant tumors of the blood system, accounts for the 8 th position in the common malignant tumors in China, and the incidence rate of the lymphoma is still increasing in recent years. New treatment modalities such as chemotherapy regimens, monoclonal antibodies, cellular immunotherapy have significantly improved the survival of lymphoma patients. Particularly, the occurrence of rituximab, the treatment of lymphoma has breakthrough progress, and particularly for CD20 positive B cell lymphoma, the effective rate is higher, the remission time is longer, and the prognosis is obviously improved. However, the rate of recurrence or drug resistance in lymphoma patients remains high. Therefore, there is still a need to develop new drugs to improve the therapeutic effect and cure rate of lymphoma.
Although chemotherapy is one of the important means for treating tumors, great development and progress have been made in the last three decades, and a large number of clinical antitumor drugs with different action mechanisms are obtained. However, antineoplastic drugs also have many adverse reactions, such as alopecia, vomiting, rapid development of drug resistance, etc., which all result in failure of the chemical drugs to achieve the desired therapeutic effect. Therefore, research and development of new antitumor drugs are one of the hot and difficult problems in the pharmaceutical field at present.
Disclosure of Invention
The inventor unexpectedly finds that the seven-membered ring berberine analogue shown in the general formula (I) obtained after the structure of the berberine is improved has good inhibition effect on blood tumor cells, and provides the application of the seven-membered ring berberine analogue and the pharmaceutical composition thereof in preparing the medicine for treating the blood tumor after standard, scientific and rigorous tests and pharmacological experiments are carried out.
An application of a seven-membered ring berberine analogue in preparing a medicament for treating hematological tumors, wherein the seven-membered ring berberine analogue has the following general formula (I):
in the formula (I), the compound is shown in the specification,
represents a double bond or a single bond,
two of (1)
Is not a double bond at the same time,
two of (1)
Not simultaneously double bonds;
R 1 to be located at
1 to 4 identical or different substituents on, R 2 To be located at
1 to 4 identical or different substituents on, R 5 Is 1 to 3 identical or different substituents on the B ring, R 1 、 R 2 And R 5 Each independently represents hydrogen, hydroxyl, amino, mercapto, alkyl, aryl, alkoxy, alkylamino, alkylthio, aryl ether, arylamino, arylthio or halogen;
R 3 is hydrogen, oxygen, sulfur, hydroxyl, amino, sulfydryl, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylamino, alkylthio, aryl ether, arylamino, arylthio, aralkyl, C 1 ～C 6 Aldehyde group of (a) or halogen;
R 4 is hydrogen, oxygen, sulfur, hydroxyl, amino, sulfydryl, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylamino, alkylthio, aryl ether, arylamino, arylthio, aralkyl, C 1 ～C 6 Aldehyde group of (a) or halogen.
In one embodiment, the
In (1)
Is a single bond, and is a single bond,
is a double bond, R 3 Is oxygen or sulfur.
In one embodiment, the
In
Is a single bond, and is a single bond,
is a single bond, R 3 Is hydrogen or alkoxy.
In one embodiment, on ring B in formula (I)
Is a double bond.
In one embodiment, the seven-membered ring berberine analogue is selected from one of the following structural formulas:
the application of the seven-membered ring berberine analogue in preparing a medicine for treating multiple myeloma or the application of the seven-membered ring berberine analogue in preparing a medicine for treating lymphoma.
The application of the pharmaceutical composition formed by the seven-membered ring berberine analogue and the non-specific chemotherapeutic drug in preparing the drug for treating the hematological tumor, wherein the non-specific chemotherapeutic drug is at least one of majoram, adriamycin and cyclophosphamide.
The application of the pharmaceutical composition formed by the seven-membered ring berberine analogue and glucocorticoid in preparing a medicament for treating hematological tumors.
The seven-membered ring berberine analogue and a targeted drug form a pharmaceutical composition, and the targeted drug is selected from at least one of bortezomib, carfilzomib, thalidomide, lenalidomide and pomalidomide, and is applied to the preparation of a drug for treating hematological tumors.
A pharmaceutical composition for treating hematological tumors comprises any one of the seven-membered ring berberine analogues and a binding agent, wherein the binding agent is a non-specific chemotherapeutic drug, a glucocorticoid or a targeted drug.
The pharmacological research result shows that the seven-membered ring berberine analogue obtained by improving the structure of the berberine and shown in the general formula (I) has good inhibition effect on blood tumor cells. Further, activity tests on various blood tumor cells and in-vivo efficacy evaluation of animals discover that the seven-membered ring berberine analogues shown in the general formula (I) can inhibit the growth activity of the blood tumor cells in vivo and in vitro, have no obvious toxic or side effect, and indicate that the compounds have potential application in treating blood tumors or cancer diseases and can be used for preparing medicines for treating blood tumors.
Drawings
FIG. 1 is a statistical plot of the growth inhibitory activity of seven-membered ring berberine analogues on myeloma, lymphoma cells;
FIG. 2 shows the IC of seven-membered ring berberine analogue in inhibiting myeloma and lymphoma cells 50 A statistical map of values;
figure 3 is a graph of the growth inhibitory activity of compound 2c on different types of multiple myeloma cells;
figure 4 is a statistical plot of the anti-multiple myeloma cell activity of compound 2c in animals;
FIG. 5 is a graph of the growth inhibitory activity of Compound 2c on different types of lymphoma cells;
FIG. 6 is a statistical plot of the activity of compounds 2c and 5k against colon cancer cells in animals;
figure 7 is a statistical plot of the inhibition of multiple myeloma cell growth in animals using compound 2c in combination with bortezomib.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in detail below. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein, but rather should be construed as broadly as the present invention is capable of modification in various respects, all without departing from the spirit and scope of the present invention.
As used herein, "halogen" may refer to F, cl, br or I. In some embodiments, the halogen atom is selected from one of F, cl and Br.
As used herein, "C" is 1 ～C 6 The alkyl group "may mean a straight or branched alkyl group including 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, or the like.
As used herein, "alkoxy" may refer to an alkoxy group having 1 to 10 carbon atoms, e.g., C 1 ～C 6 An alkoxy group.
As used herein, "C1-C6 alkoxy" includes straight or branched chain alkoxy groups of 1 to 6 carbon atoms. Such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, or the like.
In the present invention, the following terms include unsubstituted forms as well as substituted forms: amino, mercapto, alkyl, aryl, alkoxy, alkylamino, alkylthio, aryl ether, arylamino, arylthio.
In a preferred embodiment of the present invention, the number of carbon atoms in the alkyl group, alkoxy group, alkylamino group, and alkylthio group is 1 to 10, preferably 1 to 6, and more preferably 1 to 3.
In a preferred embodiment of the present invention, the number of carbon atoms in the aryl group, the aryl ether group, the arylamino group and the arylthio group is 6 to 30, preferably 6 to 20, and more preferably 6 to 10.
As used herein, the term "aralkyl" refers to a group formed by substituting 1 or more H atoms in a C1-C10 alkyl group with a C6-10 aryl group, and representative examples include benzyl.
Further, in the present invention, the term "alkyl" includes saturated or unsaturated, straight-chain, branched-chain, cyclic 1 to 10 carbon atoms (C) 1 ～C 10 ) The whole carbon alkyl group or the alkyl group in which 1 to 3 carbon atoms are substituted with hetero atoms such as oxygen, nitrogen, sulfur and the like, and the aralkyl group bonded through 1 or more carbon atoms. Further, the alkyl group may be unsubstituted or substituted.
As used herein, the term "aryl" includes fused or non-fused aryl groups, typically containing from 6 to 30 carbon atoms, representative aryl groups including phenyl, naphthyl, or aromatic groups containing heteroatoms such as oxygen, nitrogen, sulfur, and the like.
As used herein, "5-to 6-membered ring" refers to a ring structure having 5 or 6 ring atoms (including C atoms and/or heteroatoms), which may be saturated or unsaturated, may be aromatic or non-aromatic, and may or may not contain heteroatoms. Such as "heteroatom" may be N, O or S, for example.
The application of the seven-membered ring berberine analogue in the preparation of the medicine for treating the hematological tumor is disclosed in the embodiment, wherein the seven-membered ring berberine analogue has the following general formula (I):
in the formula (I), the compound is shown in the specification,
represents a double bond or a single bond,
two of (1)An
Not simultaneously is a double bond,
two of (1)
Not simultaneously a double bond.
R 1 To be located at
1 to 4 identical or different substituents on, R 2 To be located at
1 to 4 identical or different substituents on, R 5 Is 1 to 3 identical or different substituents on the B ring, R 1 、 R 2 And R 5 Each independently represents hydrogen, hydroxyl, amino, mercapto, alkyl, aryl, alkoxy, alkylamino, alkylthio, aryl ether, arylamino, arylthio or halogen.
R 3 Is hydrogen, oxygen, sulfur, hydroxyl, amino, sulfydryl, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylamino, alkylthio, aryl ether, arylamino, arylthio, aralkyl, C 1 ～C 6 Aldehyde group of (a) or halogen.
R 4 Is hydrogen, oxygen, sulfur, hydroxyl, amino, sulfydryl, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylamino, alkylthio, aryl ether, arylamino, arylthio, aralkyl, C 1 ～C 6 Aldehyde of (2)A group or a halogen.
It should be noted that A, B, C and D in the ring of formula (I) are for descriptive convenience only and do not mean that an atom or group is attached in the ring.
In some embodiments of the present invention, the,
and
each independently represents an aryl group or a 5-to 6-membered heteroaryl group. The heteroatom in the heteroaryl group may be, for example, a N or O or S heteroatom. Wherein when
And
in the case of a 6-membered heteroaryl ring, 1 to 3N, O or S atoms may be present in the ring, and in the case of a 5-membered heteroaryl ring, 1 to 3N, O or S atoms may be present in the ring.
In some embodiments of the present invention, the,
ring and
ring and R respectively attached thereto 1 And R 2 The attachment of the radicals, to
Ring and R 1 For example, formula (I) may be selected from one of the following structural formulas:
in some embodiments, a representative R 3 Or R 4 The group may be as follows, with R 3 For example, the general formula (I) may be selected from the following formulaeOne of (1):
in the above formula, "O or S" means that the position may be O or S; r represents alkyl, aryl, etc.
In some embodiments, of formula (I)
In (1)
Is a single bond, and is a single bond,
is a double bond, R 3 Is oxygen or sulfur.
In other embodiments, of formula (I)
In (1)
Is a single bond, and is a single bond,
is a single bond, R 3 Is hydrogen or alkoxy.
In some embodiments, on ring B in formula (I)
Is a double bond.
Further, the seven-membered ring berberine analogue may be selected from one of the following structural formulas:
it should be noted that the seven-membered ring berberine analogues with the above structures can be purchased or prepared by chemical synthesis, and the seven-membered ring berberine analogues used in the research of the present invention are synthesized and provided by Shanghai pharmaceutical research institute of Chinese academy of sciences.
Some pharmacological studies show that berberine may have the potential to be developed into antitumor drugs, but so far, related antitumor new drugs are not available on the market. By carefully comparing berberine antitumor activity data reported in literatures, the effective dose of in vivo activity test is too large, and the oral bioavailability is low. For hematologic tumors, the dosage required to achieve inhibition of hematologic tumor cell growth is higher due to rapid tumor cell metastasis. The inventor unexpectedly finds that the seven-membered ring berberine analogue shown in the general formula (I) obtained after the structure of the berberine is improved has good inhibition effect on blood tumor cells, and standard, scientific and rigorous tests and pharmacological experimental researches show that the seven-membered ring berberine analogue has good inhibition effect on various myeloma cells, various lymphoma cells and the like, has low IC50 value, can inhibit the growth activity of the blood tumor cells in vivo and in vitro and has no obvious toxic or side effect. Therefore, the seven-membered ring berberine analogue has good application prospect in preparing the medicine for treating the hematological tumor. Specifically, the seven-membered ring berberine analogue can be applied to the preparation of a medicament for treating multiple myeloma and can also be applied to the preparation of a medicament for treating lymphoma.
As used herein, the term "compound of the invention" refers to a compound of formula (I), i.e., a seven-membered ring berberine analogue. In some embodiments, the compound shown in the general formula (I) can be applied to the preparation of the drugs for treating lymphoma in the form of various crystal forms, pharmaceutically acceptable salts, hydrates or solvates. In the compounds of formula (I) or pharmaceutically acceptable salts thereof, one or more H may be deuterated, i.e. deuterium has a deuterium isotope content at the deuterium substitution position that is at least greater than the natural deuterium isotope content (0.015%), e.g. greater than 30%, or greater than 50%, or greater than 75%, or greater than 95%, or greater than 99%.
The "pharmaceutically acceptable salt" may be, for example, a salt of any of the compounds represented by the general formula (I) with an acid or a base, which is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One class of salts is that formed between the compounds of the present invention and an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and the like; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, etc.
Another class of salts are those formed with bases such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts) such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, triethanolamine salts, and amine salts formed with morpholine, piperazine, lysine, respectively.
"solvate" means a complex of a compound of formula (I) coordinated to solvent molecules in a specific ratio. "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.
In some embodiments, the compounds shown in the general formula (I) can also be used as a prodrug in the preparation of medicines for treating hematological tumors. A "prodrug" may be a biologically active or inactive compound that undergoes a metabolic or chemical reaction in the body to convert the compound to a class of compounds of formula (I) or to a salt or solution of a compound of formula (I) when administered by an appropriate method. Such prodrugs include, but are not limited to, carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amide, carbamate, azo, phosphoramide, glucoside, ether, acetal forms of the compounds.
Specifically, the compound shown in the general formula (I) and various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and a pharmaceutical composition containing the compound as an active ingredient can be used for preparing medicines for treating, preventing or relieving hematological tumors.
In some embodiments, the pharmaceutical composition comprises a safe and effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The pharmaceutical composition may generally contain 1mg to 2000mg of the seven-membered ring berberine analogue/dose. For example, containing 10mg to 1000mg of seven-membered ring berberine analogues/dose. Wherein, one dose is a capsule or a tablet.
"pharmaceutically acceptable carrier" can refer to one or more compatible solid or liquid fillers or gel materials that are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and between the compounds of the present invention without significantly diminishing the pharmaceutical effectiveness of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers
Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The administration mode of the seven-membered ring berberine analogue or the pharmaceutical composition is not particularly limited, and representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) Disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, in particular, cottonseed, groundnut, corn germ, olive, castor, and sesame oils or mixtures of these materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
In the preparation of the medicine for treating the hematological tumor, the seven-membered ring berberine analogue can be independently administered or can be administered together with other pharmaceutically acceptable compounds (such as antitumor medicines).
For example, the pharmaceutical composition for treating hematological tumors of one embodiment comprises the seven-membered ring berberine analogue and a combination agent, wherein the combination agent is a non-specific chemotherapeutic drug, glucocorticoid or targeted drug.
In some embodiments, the seven-membered ring berberine analogue can be used in the preparation of a medicament for treating hematological tumors in a pharmaceutical composition formed by a non-specific chemotherapeutic medicament. The non-specific chemotherapeutic agent may be selected from at least one of melphalan, doxorubicin, and cyclophosphamide, for example. The early-stage research shows that the pharmaceutical composition formed by the seven-membered ring berberine analogue and the non-specific chemotherapeutic drug can inhibit the activity of blood tumor when the seven-membered ring berberine analogue, majoram, adriamycin or cyclophosphamide act alone, and can also reduce the drug resistance of tumor and play the role of cooperative therapy.
The pharmaceutical composition for treating hematological tumors comprises a seven-membered ring berberine analogue, melphalan, adriamycin and cyclophosphamide, wherein the mass part ratio of the seven-membered ring berberine analogue to the melphalan to the adriamycin to the cyclophosphamide is 100-1:0-100.
In some embodiments, the seven-membered ring berberine analogue can also be applied to prepare a medicament for treating the hematological tumor by forming a medicinal composition with glucocorticoid. The glucocorticoid may be selected from at least one of dexamethasone and prednisone, for example. The previous research shows that the pharmaceutical composition formed by the seven-membered ring berberine analogue and the glucocorticoid keeps the activity of inhibiting blood tumors and the anti-inflammation effect of the glucocorticoid, and can further protect the immune system, reduce side effects and play the role of synergistic treatment.
The pharmaceutical composition for treating the hematological tumor comprises a seven-membered ring berberine analogue, dexamethasone and prednisone, wherein the mass part ratio of the seven-membered ring berberine analogue to the dexamethasone to the prednisone is 100-1:0-100.
In some embodiments, the seven-membered ring berberine analogue can also be applied in the preparation of a medicament for treating hematological tumors in a pharmaceutical composition formed by the seven-membered ring berberine analogue and a targeted medicament, for example, at least one selected from the group consisting of bortezomib, carfilzomib, thalidomide, lenalidomide and pomalidomide. The early-stage research shows that the pharmaceutical composition formed by the seven-membered ring berberine analogue and the targeted drug maintains the activity of the seven-membered ring berberine analogue in inhibiting the hematological tumor and the activity of the targeted drug in inhibiting the hematological tumor under the single action, and can further reduce the effective dose of the drug, reduce the side effect and play the role of cooperative treatment.
The pharmaceutical composition for treating the hematological tumor of one embodiment comprises a seven-membered ring berberine analogue and bortezomib, wherein the mass part ratio of the seven-membered ring berberine analogue to the bortezomib is (100-1).
When using pharmaceutical compositions, a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment at a dosage that is pharmaceutically considered to be effective, typically 1mg to 2000mg of the seven-membered ring berberine analogue, e.g., 50mg to 1000mg, per day for a 60kg body weight human. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The inventor unexpectedly finds that the seven-membered ring berberine analogue shown in the general formula (I) obtained after the structure of the berberine is improved has good inhibition effect on blood tumor cells. Further, activity tests on various blood tumor cells and in-vivo efficacy evaluation of animals discover that the seven-membered ring berberine analogues shown in the general formula (I) can inhibit the growth activity of the blood tumor cells in vivo and in vitro, have no obvious toxic or side effect, and indicate that the compounds have potential application in treating blood tumors or cancer diseases and can be used for preparing medicines for treating blood tumors.
In addition, the pharmaceutical composition formed by the seven-membered ring berberine analogue and a non-specific chemotherapeutic drug, glucocorticoid or a targeted drug is applied to the preparation of the drug for treating the hematological tumor, and can play a role in synergistic treatment.
The following are specific examples
It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, molecular cloning is generally performed according to conventional conditions such as Sambrook et al: the conditions described in the Laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are by weight.
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. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Activity test Experimental example
Experimental example 1 Effect of seven-membered Ring Berberine analogs on the Activity of myeloma cells
1. Experimental materials:
(1) Cell lines: human multiple myeloma cells (ARP-1, H929, OCI-MY5, OPM2, RPMI-8226, U266) were purchased from ATCC in the United states and maintained for passage in this laboratory; H929R cells were supplied by professor Hou Jian, second military medical university) and cultured in 1640 medium (containing 10% fetal bovine serum).
(2) The main reagents are as follows: 1640 medium (Gibco, USA), fetal bovine serum (Gibco, USA), and Cell Counting Kit-8 Kit (CCK 8, cohn's chemical research institute, japan).
(3) The main apparatus is as follows: carbon dioxide incubator (Thermo Forma, usa), full automatic enzyme labeling apparatus (Bio-TEK, elx 800).
2. The experimental method comprises the following steps:
(1) Cell culture
Culturing the cells in 1640 medium (containing 10% fetal calf serum, pH 7.2), adding 2mmol/L glutamine to the medium, placing in a cell culture box, and making the cell culture at 37 deg.C and 5% CO 2 And (5) culturing under an environment.
(2) CCK8 kit for determining cytotoxicity of each drug
Collecting single cell suspension of human multiple myeloma cells (ARP-1, H929, OCI-MY5, OPM2, RPMI-8226, U266, cells), counting, and adjusting cell concentration to 2 × 10 ^5 One per mL. And (3) adding 95 mu L of the cell suspension into each well of a 96-well culture plate, then adding 5 mu L of the medicine prepared by the culture medium with different concentrations, adding the culture medium with corresponding volume into a control group, and arranging 3 parallel wells in each group. Continuously culturing for 72h, 2h before the culture is finished, adding 10 μ L of CCK8 reagent into each well, and adding into CO 2 And (5) continuously culturing in an incubator. And detecting the OD value of each hole of 450nm by an automatic microplate reader after 2 h. Calculating the survival rate and the inhibition rate of the cells: cell viability (%) = (experimental well OD mean/control well OD mean) × 100%. Cell inhibition (%) =100% -cell survival (%). The fitting function calculates the drug concentration IC when the growth of the inhibition cells reaches 50% 50 . Each set of experiments was repeated three times.
3. Results of the experiment
As shown in figure 1, 1 μmol/L seven-membered ring berberine analogue has growth inhibitory activity on myeloma H929 cell, myeloma H929R cell, and myeloma RPMI-8226 cell, respectively. 2a to 2c, 3a to 3g, 4j, 5c to 5k and 6d to 6j respectively represent compounds corresponding to the above description. The inhibitory activity of the seven-membered ring berberine analogue is obviously better than that of a control group (BB is berberine).
The result of drug experiments with different concentrations is fitted with a function to determine the drug concentration IC when the growth of the inhibited cells reaches 50% 50 As shown in fig. 2. IC of seven-membered ring berberine analogue 50 The value is also obviously lower than that of a control group (BB), and the experimental result shows that the seven-membered ring berberine analogue has the function of inhibiting the growth of tumor cells in a blood system in vitro.
The growth inhibitory activity of compound 2c against different types of multiple myeloma cells (ARP-1, H929, OCI-MY5, OPM2, RPMI-8226, U266) is shown in FIG. 3. The compound 2c has good inhibition effect on various different types of multiple myeloma cells.
Example 2 animal experiments for multiple myeloma
1. Experimental Material
(1) Cell lines: human multiple myeloma cells (H929 cells) (ATCC, usa, subcultured in this laboratory) were cultured in 1640 medium (containing 10% fetal bovine serum).
(2) Experimental animals: male BALB/C nude mice (6-8 weeks, purchased from Shanghai Sphere-BiKai laboratory animals Co., ltd.) were housed in SPF-grade environment (animal house, laboratory center of the tenth national Hospital, shanghai).
2. Experimental methods
(1) See example 1 for cell culture.
(2) Animal experiments
Will contain 2X 10 ^6 A1640 culture medium of H929 cells was injected subcutaneously into the left axilla of a nude mouse, and when the tumor grew and was measurable, it was randomly divided into a control group and an administration group. The administration group nude mice were intraperitoneally injected with 2c 15mg/kg every day, and the control group nude mice were injected with 2c 15mg/kg every dayThe same volume of solvent (200 μ L, solvent =15 μ L DMSO +185 μ L saline) was intraperitoneally injected daily. Measuring the size of the tumor every two days (measuring the length and width of the tumor, the tumor volume =4 pi/3 x (width/2) ^2 X (length/2)). Mice were sacrificed 15 days after dosing and tumors were photographed.
3. Results of the experiment
The experimental result is shown in figure 4, which shows that the seven-membered ring berberine analogue has the function of inhibiting the growth of tumor cells in a blood system in an animal body and has no obvious toxic or side effect.
Example 3 killing Activity against human lymphoma cells
1. Experimental Material
Human lymphoma cells (Hut 78, jurkat, NUDUL-1, OCI-LY8, SUDHL-4 cells) (ATCC in USA, subcultured in this laboratory) were cultured in 1640 medium (containing 10% fetal bovine serum). The rest was the same as in example 1.
2. See example 1 for experimental methods.
3. Results of the experiment
See again fig. 1 and 2 for experimental results. As can be seen in FIG. 1, the 1. Mu. Mol/L seven-membered ring berberine analogues were significantly superior to the control group (BB) in their growth inhibitory activities against lymphoma Jurkat cells, lymphoma NUDUL-1 and lymphoma OCI-LY8, respectively. IC of seven-membered ring berberine analogue 50 The value is also obviously lower than that of a control group (BB), and the experimental result shows that the seven-membered ring berberine analogue has the function of inhibiting the growth of tumor cells in a blood system in vitro.
Wherein the growth inhibitory activity of Compound 2c against different types of lymphoma cells (Hut 78, jurkat, NUDUL-1, OCI-LY8, SUDHL-4 cells) is shown in FIG. 5. The compound 2c is proved to have good inhibition effect on various types of lymphoma cells.
Example 4: in vivo Activity of Compounds 2c, 5k against solid tumor animal models
1. Experimental materials
(1) Cell line: the SW620 cell line of human colon cancer (Shanghai drug institute of Chinese academy of sciences) is inoculated subcutaneously into the right armpit of a nude mouse, the inoculation amount of the cells is 5X 106/mouse, and the cells are used after 2 generations in vivo after forming a transplantation tumor.
(2) Experimental animals: BALB/cA nude mouse, female, 4-5 weeks old, produced by Shanghai pharmaceutical research institute of Chinese academy of sciences, quality certification No.311613700000097, production license No: SCXK (Shanghai) 2013-0017. Shanghai drug use license number: SYXK (Shanghai) 2013-0049, number of animals per group: solvent control group 12, administration group 6.
2. Experimental method
Cutting tumor tissue in vigorous growth stage into 1.5mm 3 And left and right, under aseptic conditions, inoculated subcutaneously in the right axilla of nude mice. The diameter of the subcutaneous tumor graft of the nude mice was measured with a vernier caliper until the tumor growth reached an average volume of about 130mm 3 Animals were then randomized into groups. Compound 2c 50mg/kg and 10mg/kg, administered by intraperitoneal injection once a day for 21 consecutive days; the compound 5k 50mg/kg (100 mg/kg from day 11) and 10mg/kg were administered by intraperitoneal injection once a day for 21 consecutive days. The positive control drug CPT-11 15mg/kg group was administered intravenously three times a week for 21 consecutive days. The solvent control group was given an equal amount of physiological saline. Throughout the experiment, the diameter of the transplanted tumor was measured 2 times per week, while the body weight of the mice was weighed. Mice were sacrificed 21 days later and tumors were photographed.
3. Results of the experiment
The experimental results are shown in fig. 6, and compounds 2c and 5k have no inhibitory effect on the growth of subcutaneous transplanted tumors in nude mice with human colon cancer SW 620. Specific data for fig. 6 are shown in tables 1 and 2 below:
TABLE 1.2 c, 5k Effect on tumor volume of human Colon cancer SW620 nude mice transplants
Note: pvaluevs solvent control
TABLE 2.2 c, 5k Effect on the body weight of human Colon cancer SW620 tumor-bearing mice
The results of activity test experiments show that the seven-membered ring berberine analogue has the function of inhibiting the growth of tumor cells in a blood system in vitro and in vivo without obvious toxic and side effects, and the compound has potential application in treating tumors or cancer diseases in the blood system. In addition, the experiment of example 4 shows that the drug treatment of solid tumors and hematological tumors are different, and that the compound with similar in vitro anti-tumor cell activity shows the opposite results in the solid tumor animal model (fig. 6) and the hematological tumor animal model (fig. 4), such as that the compound 2c inhibits the colon cancer SW620 cells in vitro with an IC50 value of 0.06uM, but has no inhibitory effect on the growth of subcutaneous transplantation tumor of human colon cancer SW620 nude mice; the IC50 value of inhibiting myeloma H929 cells in vitro is 0.65uM, but the compound has obvious inhibiting effect on the growth of subcutaneous transplantation tumor of myeloma H929 nude mice.
Example 5
The seven-membered ring berberine analogue 2a is taken to be matched with majoram, adriamycin or cyclophosphamide according to the mass part ratio of 1: 1 to form the pharmaceutical composition for treating the hematological tumor.
Example 6
The seven-membered ring berberine analogue 2b and dexamethasone or prednisone are matched to form the pharmaceutical composition for treating the blood tumor according to the mass part ratio of 10.
Example 7
The seven-membered ring berberine analogue 3a and the bortezomib are matched to form a pharmaceutical composition for treating the hematological tumor according to the mass part ratio of 50.
Example 8
Animal experiment of seven-membered ring berberine analogue 2c combined with bortezomib on multiple myeloma
1. Experimental materials: see example 2
2. The experimental method comprises the following steps: see example 2. The administration components are two groups, one group is intraperitoneally injected with 0.5mg/kg of bortezomib every day, the other group adopts the combination of the seven-membered ring berberine analogue 2c and the bortezomib (40.
3. Results of the experiment
The experimental results are shown in fig. 7, and the combination of the seven-membered ring berberine analogue 2c and bortezomib (40.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. The application of the seven-membered ring berberine analogue in the preparation of the medicine for treating multiple myeloma is characterized in that the seven-membered ring berberine analogue has the following general formula:
In the formula (I), the compound is shown in the specification,
represents a double or single bond;
R 2 is 1~4 identical or different substituents on the benzene ring D, R 2 Independently represent hydrogen or C 1-6 An alkoxy group;
R 4 is hydrogen or halogen;
R 5 is 1~3 identical or different substituents on ring B, R 5 Independently represent hydrogen or hydroxyl.
2. Use according to claim 1, wherein R is 2 Independently represent hydrogen or C 1-3 An alkoxy group; r 4 Is hydrogen, F, cl, br or I.
3. Use according to claim 1, characterized in that on ring B
Is a double bond.
4. The use according to claim 1, wherein the seven-membered ring berberine analogue is selected from one of the following structural formulae:
5. The use according to claim 4, wherein the seven-membered ring berberine analogue is selected from one of the following structural formulae:
6. The application of the seven-membered ring berberine analogue in the preparation of the medicine for treating multiple myeloma is characterized in that the seven-membered ring berberine analogue has the following structural formula:
7. The use of claim 6, wherein the seven-membered ring berberine analogue is selected from one of the following structural formulas:
8. The use of the seven-membered ring berberine analogue of any one of claims 1~7 and a non-specific chemotherapeutic selected from at least one of melphalan, doxorubicin, and cyclophosphamide, in the preparation of a medicament for the treatment of multiple myeloma.
9. The use of the seven-membered ring berberine analogue of any one of claims 1~7 in combination with a glucocorticoid for the preparation of a medicament for the treatment of multiple myeloma.
10. The use of the seven-membered ring berberine analogue of any one of claims 1~7 and a targeted drug selected from at least one of bortezomib, carfilzomib, thalidomide, lenalidomide and pomalidomide in the preparation of a medicament for the treatment of multiple myeloma.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710104481.4A CN108498518B (en) | 2017-02-24 | 2017-02-24 | Application of seven-membered-ring berberine analogue and pharmaceutical composition thereof in preparation of medicines for treating multiple myeloma |
| PCT/CN2018/077060 WO2018153352A1 (en) | 2017-02-24 | 2018-02-23 | Applications of heptatomic-ring berberine analogue and pharmaceutical composition thereof in preparation of drugs for treating hematological malignancies |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710104481.4A CN108498518B (en) | 2017-02-24 | 2017-02-24 | Application of seven-membered-ring berberine analogue and pharmaceutical composition thereof in preparation of medicines for treating multiple myeloma |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108498518A CN108498518A (en) | 2018-09-07 |
| CN108498518B true CN108498518B (en) | 2022-10-21 |
Family
ID=63254154
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710104481.4A Active CN108498518B (en) | 2017-02-24 | 2017-02-24 | Application of seven-membered-ring berberine analogue and pharmaceutical composition thereof in preparation of medicines for treating multiple myeloma |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN108498518B (en) |
| WO (1) | WO2018153352A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116731009A (en) * | 2023-05-06 | 2023-09-12 | 珠海市人民医院 | Monoethyl succinate substituted berberine derivative, preparation method thereof and application thereof in preparation of medicines for treating osteosarcoma |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102464615B (en) * | 2010-11-09 | 2015-08-19 | 中国科学院上海药物研究所 | Aryl isoquinoline derivative and pharmaceutical composition, preparation method and purposes |
| CN104906088B (en) * | 2015-02-16 | 2018-04-10 | 上海交通大学医学院附属瑞金医院 | Application of the berberine in the medicine for preparing treatment t cell lymphoma |
| CN105985349B (en) * | 2015-03-04 | 2020-01-14 | 中国科学院上海药物研究所 | Seven-membered ring berberine analogue, and pharmaceutical composition, preparation method and application thereof |
| CN104739831B (en) * | 2015-04-10 | 2018-04-17 | 上海交通大学医学院附属瑞金医院 | Application of the berberine in the medicine for preparing treatment B cell lymphoma |
| CN105030770B (en) * | 2015-07-13 | 2017-11-17 | 长沙市中心医院 | Application of the berberine in the medicine for preparing treatment acute myeloid leukemia |
-
2017
- 2017-02-24 CN CN201710104481.4A patent/CN108498518B/en active Active
-
2018
- 2018-02-23 WO PCT/CN2018/077060 patent/WO2018153352A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2018153352A1 (en) | 2018-08-30 |
| CN108498518A (en) | 2018-09-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101848131B1 (en) | Low-dose antitumor agent including irinotecan hydrochloride hydrate | |
| CA3163095A1 (en) | Combination therapy involving diaryl macrocyclic compounds | |
| WO2017198194A1 (en) | Boronic acid and borate ester compound and applications thereof | |
| TW201914592A (en) | Use of combination of apatinib and c-met inhibitor in the preparation of medicament for treating tumor | |
| CN108498518B (en) | Application of seven-membered-ring berberine analogue and pharmaceutical composition thereof in preparation of medicines for treating multiple myeloma | |
| CN114450278B (en) | Maleic acid salt of nicotinyl alcohol ether derivative, and crystal form and application thereof | |
| TWI615145B (en) | Antitumor agent containing irinotecan hydrochloride hydrate | |
| EP2902028A1 (en) | Drug composition for treating tumors and application thereof | |
| WO2017177515A1 (en) | Application of 4-hydroxy salicylanilide in preparation of anti-myeloma or anti-lymphoma drugs | |
| JP7311177B2 (en) | Combined use of A-NOR-5α androstane drugs with anticancer drugs | |
| CN110698491B (en) | 2- (camptothecin-10-oxyl) acetamide compound and application thereof | |
| KR20140032586A (en) | A pharmaceutical composition for radiation therapy of egfr-tki-resistant lung cancer caused by pten function deficiency | |
| KR20170106478A (en) | Sunitinib prodrug and pharmaceutical composition | |
| AU2008248188A1 (en) | Dihydropyridine derivative for treating cancer or a pre-cancerous condition and other conditions | |
| CN112442062B (en) | Salinamide phenol organic silicon compound and anti-tumor application thereof | |
| CN109320553A (en) | For antiviral novel nucleoside reverse transcriptase inhibitor | |
| EP4331614A1 (en) | Use of medicament in treatment of tumor disease | |
| CA2438001A1 (en) | Use of the disorazoles and their derivatives for the treatment of benign and malignant oncoses | |
| EP2902027A1 (en) | Drug composition for treating tumors and application thereof | |
| CN108135894B (en) | Therapeutic agent for tumor | |
| CN117700419A (en) | Nitric oxide donor carbazole derivatives and their use in the treatment of neoplastic diseases | |
| CN113993515A (en) | Methods of treating solid tumors using crocetin | |
| KR20120105739A (en) | 3,4-dihydroquinazoline dihydrochloride and anti-cancer agent including the same | |
| NZ740252B2 (en) | Antitumor agent including low-dose irinotecan hydrochloride hydrate | |
| NZ740252A (en) | Antitumor agent including low-dose irinotecan hydrochloride hydrate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |