WO2018153352A1 - 七元环小檗碱类似物及其药物组合物在制备治疗血液肿瘤的药物中的应用 - Google Patents

七元环小檗碱类似物及其药物组合物在制备治疗血液肿瘤的药物中的应用 Download PDF

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WO2018153352A1
WO2018153352A1 PCT/CN2018/077060 CN2018077060W WO2018153352A1 WO 2018153352 A1 WO2018153352 A1 WO 2018153352A1 CN 2018077060 W CN2018077060 W CN 2018077060W WO 2018153352 A1 WO2018153352 A1 WO 2018153352A1
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berberine
medicament
preparation
treating
group
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PCT/CN2018/077060
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English (en)
French (fr)
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朱维良
施菊妹
李波
陈格格
徐志建
张勇
胡亮凝
李钊
邹坤
蔡婷婷
陈凯先
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中国科学院上海药物研究所
上海市第十人民医院
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    • 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

Definitions

  • the invention relates to the technical field of medicines, in particular to a use of a seven-membered cyclic berberine analog and a pharmaceutical composition thereof for preparing a medicament for treating hematological tumors.
  • Malignant tumors greatly endanger human health and will become the first killer of human beings in the new century.
  • Malignant tumors are no longer just serious diseases in developed industrial countries, and developing countries face a greater burden of disease.
  • Malignant tumors include solid tumors (such as lung cancer, colorectal cancer, liver cancer, stomach cancer, etc.) and hematological tumors (such as myeloma, lymphoma, etc.), and the occurrence and treatment of the two diseases are significantly different, including myeloma and Lymphoma is a relatively common tumor of both blood systems.
  • MM multiple myeloma
  • MM multiple myeloma
  • the main method of traditional treatment of multiple myeloma is chemotherapy and hematopoietic stem cell transplantation, and its clinical efficacy is difficult to maintain.
  • new drugs such as the proteasome inhibitor bortezomib, the immunomodulators thalidomide and lenalidomide, the complete remission rate and overall survival rate of patients with multiple myeloma were significantly improved.
  • Lymphoma is one of the most common malignant tumors in the blood system, and it ranks 8th among the common malignant tumors in China, and its incidence is still increasing in recent years.
  • New treatment regimens such as chemotherapy, monoclonal antibodies, and cellular immunotherapy have significantly improved the survival of patients with lymphoma.
  • lymphoma Especially with the emergence of rituximab, the treatment of lymphoma has made a breakthrough, especially for CD20-positive B-cell lymphoma, which is more effective, longer remission time, and significantly improved prognosis.
  • CD20-positive B-cell lymphoma which is more effective, longer remission time, and significantly improved prognosis.
  • the proportion of patients with lymphoma who are relapsed or resistant is still high. Therefore, it is still necessary to further develop new drugs to improve the therapeutic effect and cure rate of lymphoma.
  • the inventors have unexpectedly discovered in the study that the seven-membered cyclic berberine analog represented by the general formula (I) obtained after the structural improvement of berberine has a good inhibitory effect on blood tumor cells, and is in the process of specification and science. After rigorous testing and pharmacological experiments, a seven-membered berberine analog and a pharmaceutical composition thereof are provided for use in the preparation of a medicament for treating hematological tumors.
  • a use of a seven-membered cyclic berberine analog for the preparation of a medicament for treating a hematological tumor the seven-membered cyclic berberine analog having the following general formula (I):
  • R1 is located 1 to 4 identical or different substituents
  • R2 is located 1 to 4 of the same or different substituents
  • R 5 is 1 to 3 identical or different substituents on the B ring
  • R 1 , R 2 and R 5 each independently represent hydrogen, hydroxy, amino, Mercapto, alkyl, aryl, alkoxy, alkylamino, alkylthio, aryl ether, arylamino, arylthio or halogen;
  • R 3 is hydrogen, oxygen, sulfur, hydroxy, amino, decyl, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylamino, alkylthio, aryl ether, arylamino, arylthio An aralkyl group, a C 1 -C 6 aldehyde group or a halogen;
  • R 4 is hydrogen, oxygen, sulfur, hydroxy, amino, decyl, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylamino, alkylthio, aryl ether, arylamino, arylthio An aralkyl group, a C 1 -C 6 aldehyde group or a halogen.
  • the middle For a single button As a double bond, R 3 is oxygen or sulfur.
  • the middle For a single button Is a single bond, and R 3 is hydrogen or an alkoxy group.
  • the ring on the B ring of formula (I) For double keys.
  • the seven-membered ring berberine analog is selected from one of the following structural formulae:
  • non-specific chemotherapeutic agent selected from at least melphalan, doxorubicin and cyclophosphamide One.
  • a targeted drug for preparing a medicament for treating a hematological tumor the targeted drug being selected from the group consisting of bortezomib, carfilzomib, thalidomide, At least one of lenalidomide and pomamide.
  • a pharmaceutical composition for treating a hematological tumor comprising the seven-membered cyclic berberine analog according to any one of the above, and a combination agent, which is a non-specific chemotherapeutic drug, a glucocorticoid or a targeted drug.
  • the results of pharmacological studies indicate that the seven-membered cyclic berberine analog represented by the general formula (I) obtained after the structural improvement of berberine has a good inhibitory effect on hematological tumor cells. Further, it was found that the seven-membered cyclic berberine analog represented by the general formula (I) inhibits blood tumor cell growth activity in vivo and in vitro by the activity test of various blood tumor cells and the evaluation of the in vivo efficacy of the animal, and Obvious toxic side effects indicate that the compounds have potential use in the treatment of hematological malignancies or cancer diseases and can be used to prepare drugs for treating hematological tumors.
  • Figure 1 is a statistical diagram showing the growth inhibitory activity of a seven-membered ring berberine analog on myeloma and lymphoma cells;
  • FIG 2 is a seven-membered ring analogues of berberine myeloma, chart lymphoma cells IC 50 values of inhibition;
  • Figure 3 is a graph showing the growth inhibitory activity of compound 2c against different types of multiple myeloma cells
  • Figure 4 is a statistical diagram of the activity of Compound 2c against multiple myeloma cells in animals
  • Figure 5 is a graph showing the growth inhibitory activity of Compound 2c against different types of lymphoma cells
  • Figure 6 is a statistical diagram of the activity of compounds 2c and 5k against colon cancer cells in animals
  • Figure 7 is a graph showing the inhibition of the growth of multiple myeloma cells in animals by the combination of compound 2c and bortezomib.
  • halogen may refer to F, Cl, Br or I. In some embodiments, the halogen atom is selected from one of F, Cl, and Br.
  • C 1 -C 6 alkyl may mean a straight or branched alkyl group comprising from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, tert-butyl, or the like.
  • alkoxy may refer to an alkoxy group having 1 to 10 carbon atoms, for example C 1 ⁇ C 6 alkoxy group.
  • C1-C6 alkoxy includes a straight or branched alkoxy group of 1 to 6 carbon atoms.
  • the following terms include unsubstituted forms as well as substituted forms: amino, mercapto, alkyl, aryl, alkoxy, alkylamino, alkylthio, aryl ether, arylamino, arylthio.
  • the alkyl group, the alkoxy group, the alkylamino group, and the alkylthio group have 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms. .
  • the aryl group, the aryl ether group, the arylamino group, and the arylthio group have 6 to 30, preferably 6 to 20, more preferably 6 carbon atoms. ⁇ 10.
  • aralkyl refers to a group formed by the substitution of one or more H atoms of a C1 to C10 alkyl group by a C6-10 aryl group, and representative examples include a benzyl group.
  • alkyl includes a saturated or unsaturated, linear, branched, cyclic 1 to 10 carbon atom (C 1 - C 10 ) all-carbon alkyl group or 1 to 1 thereof.
  • aryl includes fused or non-fused aryl groups, usually containing from 6 to 30 carbon atoms, and representative aryl groups include phenyl, naphthyl, or oxygen, nitrogen, sulfur, etc. Aromatic group of atoms.
  • 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, with or without heteroatoms.
  • hetero atom may be, for example, N, O or S.
  • aryl group or the 5- to 6-membered heteroaryl group is independently represented.
  • R 1 is located 1 to 4 identical or different substituents
  • R 2 is located 1 to 4 of the same or different substituents
  • R 5 is 1 to 3 identical or different substituents on the B ring
  • R 1 , R 2 and R 5 each independently represent hydrogen, hydroxy, amino, Mercapto, alkyl, aryl, alkoxy, alkylamino, alkylthio, aryl ether, arylamino, arylthio or halogen.
  • R 3 is hydrogen, oxygen, sulfur, hydroxy, amino, decyl, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylamino, alkylthio, aryl ether, arylamino, arylthio An aralkyl group, a C 1 -C 6 aldehyde group or a halogen.
  • R 4 is hydrogen, oxygen, sulfur, hydroxy, amino, decyl, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylamino, alkylthio, aryl ether, arylamino, arylthio An aralkyl group, a C 1 -C 6 aldehyde group or a halogen.
  • A, B, C and D in the ring of the general formula (I) are for convenience of description only, and do not mean that atoms or groups are attached to the ring.
  • the aryl group or the 5- to 6-membered heteroaryl group is independently represented.
  • the hetero atom in the heteroaryl group can be, for example, an N or O or S hetero atom. Which with When it is a 6-membered heteroaryl ring, it may have 1 to 3 N or O or S in the ring, and when it is a 5-membered heteroaryl ring, it may have 1 to 3 N or O or S in the ring.
  • Ring and a ring and a connection to the R 1 and R 2 groups respectively attached thereto are exemplified, and the general formula (I) may be selected from one of the following structural formulas:
  • a representative R 3 or R 4 group can be a group having the R 3 group as an example, and the formula (I) can be selected from one of the following structural formulae:
  • O or S means that the position may be O or S; and R represents an alkyl group, an aryl group or the like.
  • R 3 is oxygen or sulfur.
  • seven-membered ring berberine analog may be selected from one of the following structural formulas:
  • the seven-membered ring berberine analogs of the above structure can be purchased or prepared by chemical synthesis.
  • the seven-membered ring berberine analog used in the study is synthesized by the Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
  • berberine may have the potential to develop anti-tumor drugs, but so far, there is no relevant anti-tumor drug listed. Careful comparison of the berberine antitumor activity data reported in the literature found that the effective dose of the in vivo activity test was too large and the oral bioavailability was low. For hematological tumors, the dose requirements for inhibiting the growth of blood tumor cells are higher due to the rapid transfer of tumor cells.
  • the inventors have unexpectedly discovered in the study that the seven-membered cyclic berberine analog represented by the general formula (I) obtained after the structural improvement of berberine has a good inhibitory effect on hematological tumor cells, and is standardized, scientific, and Rigorous experiments and pharmacological studies have shown that the above seven-membered berberine analogues have good inhibitory effects on a variety of myeloma and various lymphoma cells, with low IC50 values and can be inhibited both in vivo and in vitro. Blood tumor cell growth activity, no obvious toxic side effects. Therefore, the seven-membered ring berberine analog has a good application prospect in the preparation of a medicament for treating hematological tumors.
  • the above-described seven-membered cyclic berberine analog can be used, for example, in the preparation of a medicament for treating multiple myeloma, and the seven-membered cyclic berberine analog can also be used in the preparation of a medicament for treating lymphoma.
  • the term "compound of the invention” refers to a compound of formula (I), ie a seven-membered cyclic berberine analog.
  • the compound of formula (I) can be used in the manufacture of a medicament for the treatment of lymphoma in various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates.
  • one or more H may be deuterated, that is, the strontium isotope content of the hydrazine at the hydrazine substitution site is at least greater than the natural strontium isotope content (0.015%), for example More than 30%, or greater than 50%, or greater than 75%, or greater than 95%, or greater than 99%.
  • the "pharmaceutically acceptable salt” may, for example, be a salt of any one of the compounds represented by the formula (I) and an acid or a base which is suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • One type of salt is a salt of a compound of the invention formed with an acid.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Organic acids such as 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; Amino acids such as amino acid, phenylalanine, aspartic acid, and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid
  • formic acid
  • Another type of salt is a salt of a compound of the formula (I) with a base, such as an alkali metal salt (for example, a sodium salt or a potassium salt), an alkaline earth metal salt (such as a magnesium salt or a calcium salt), an ammonium salt (such as a lower grade).
  • a base such as an alkali metal salt (for example, a sodium salt or a potassium salt), an alkaline earth metal salt (such as a magnesium salt or a calcium salt), an ammonium salt (such as a lower grade).
  • Alkanol ammonium salts and other pharmaceutically acceptable amine salts such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine a salt, a tert-butylamine salt, an ethylenediamine salt, a hydroxyethylamine salt, a dihydroxyethylamine salt, a trishydroxyethylamine salt, and an amine salt formed of morpholine, piperazine, and lysine, respectively.
  • methylamine salt such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine a salt, a tert-butylamine salt, an ethylenediamine salt, a hydroxyethylamine salt, a dihydroxyethylamine salt, a trishydroxyethylamine salt, and an
  • Solvate means a complex in which a compound of the formula (I) is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • the compound of formula (I) can also be used as a "prodrug" in the manufacture of a medicament for the treatment of hematological malignancies.
  • a "prodrug” may be biologically active or inactive, a compound of formula (I), or a formula (eg, a compound of formula (I), which is metabolized or chemically reacted in the human body after administration by an appropriate method.
  • the prodrugs include, but are not limited to, carboxylic acid esters, carbonates, phosphates, nitrates, sulfates, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphorus In the form of an amide, a glucoside, an ether, an acetal or the like.
  • the compound represented by the formula (I) and various crystal forms thereof, a pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and a pharmaceutical composition containing the compound as an active ingredient can be used for the preparation.
  • a pharmaceutically acceptable inorganic or organic salt, hydrate or solvate and a pharmaceutical composition containing the compound as an active ingredient can be used for the preparation.
  • the pharmaceutical composition comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier, in a safe and effective amount.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions may generally contain from 1 mg to 2000 mg of a seven membered cyclic berberine analog per agent. For example, it contains 10 mg to 1000 mg of a seven-membered cyclic berberine analog/agent.
  • “one dose” is a capsule or a tablet.
  • “Pharmaceutically acceptable carrier” may mean one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity.
  • “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • vegetable oil such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyol such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifier such as Tween
  • a wetting agent such as sodium lauryl sulfate
  • a coloring agent such as a flavoring agent, a stabilizer, an antioxidant, a preservative
  • the administration manner of the above-mentioned seven-membered ring berberine analog or pharmaceutical composition is not particularly limited, and representative administration forms 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.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, 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 elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the above-described seven-membered cyclic berberine analog may be administered alone or in combination with other pharmaceutically acceptable other compounds such as an antitumor drug.
  • a pharmaceutical composition for treating a hematological tumor includes the above-described seven-membered berberine analog and a combination agent, which is a non-specific chemotherapeutic drug, a glucocorticoid or a targeted drug.
  • a seven-membered cyclic berberine analog can be used in the manufacture of a medicament for treating a hematological tumor with a pharmaceutical composition formed from a non-specific chemotherapeutic drug.
  • the non-specific chemotherapeutic agent can be, for example, selected from at least one of melphalan, doxorubicin, and cyclophosphamide.
  • Previous studies have shown that a combination of a seven-membered ring berberine analogue and a non-specific chemotherapeutic drug maintains hematopoietic activity when a seven-membered berberine analog, melphalan, doxorubicin or cyclophosphamide acts alone. It can also reduce the drug resistance of tumors and play the role of synergistic treatment.
  • a pharmaceutical composition for treating a hematological tumor includes a seven-membered ring berberine analog, melphalan, doxorubicin, and cyclophosphamide, a seven-membered ring berberine analog, melphalan, doxorubicin, and cyclophosphamide.
  • the mass fraction ratio is 100 to 1:0 to 100:0 to 100:0 to 100.
  • a seven-membered cyclic berberine analog can also be used in the manufacture of a medicament for treating a hematological tumor with a pharmaceutical composition formed with a glucocorticosteroid.
  • the glucocorticoid may, for example, be selected from at least one of dexamethasone and prednisone.
  • Previous studies have shown that a combination of a seven-membered berberine analog and a glucocorticoid maintains a seven-membered berberine analog that inhibits blood tumor activity and glucocorticoid anti-inflammatory effects, and further protects the immune system. Reduce side effects and play synergistic treatments.
  • the pharmaceutical composition for treating a hematological tumor includes a mass fraction of a seven-membered ring berberine analog, dexamethasone and prednisone, a seven-membered ring berberine analog, dexamethasone and prednisone.
  • the ratio is 100 to 1:0 to 100:0 to 100.
  • the seven-membered cyclic berberine analog can also be used in the preparation of a medicament for treating a hematological tumor with a pharmaceutical composition formed by targeting a drug, for example, selected from the group consisting of bortezomib, carfilzomib, At least one of thalidomide, lenalidomide and pomamide.
  • a pharmaceutical composition of a seven-membered ring berberine analog with a targeted drug maintains the activity of a seven-membered berberine analog to inhibit hematological tumors and inhibits blood tumor activity when a targeted drug acts alone. It can further reduce the effective dose of the drug, reduce side effects, and play the role of synergistic treatment.
  • the pharmaceutical composition for treating a hematological tumor includes a seven-membered ring berberine analog and bortezomib, and the mass fraction of the seven-membered ring berberine analog to bortezomib is from 100 to 1:0.1. 100.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 mg to 2000 mg of a seven-membered cyclic berberine analog, for example, 50 mg to 1000 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the inventors unexpectedly found in the study that the seven-membered cyclic berberine analog represented by the general formula (I) obtained after the structural improvement of berberine has a good inhibitory effect on hematological tumor cells. Further, it was found that the seven-membered cyclic berberine analog represented by the general formula (I) inhibits blood tumor cell growth activity in vivo and in vitro by the activity test of various blood tumor cells and the evaluation of the in vivo efficacy of the animal, and Obvious toxic side effects indicate that the compounds have potential use in the treatment of hematological malignancies or cancer diseases and can be used to prepare drugs for treating hematological tumors.
  • the pharmaceutical composition formed by the seven-membered ring berberine analog with a non-specific chemotherapeutic drug, a glucocorticoid or a targeted drug can be used for the preparation of a medicament for treating hematological tumors, and can achieve synergistic therapeutic purposes.
  • Cell line Human multiple myeloma cells (ARP-1, H929, OCI-MY5, OPM2, RPMI-8226, U266) cells were purchased from ATCC, USA, and were preserved in this laboratory; H929R cells were obtained from Second Military Medical University. Professor Hou Jian), cultured in 1640 medium (containing 10% fetal bovine serum).
  • the cells were cultured in 1640 medium (containing 10% fetal bovine serum, pH 7.2), and the medium was added with 2 mmol/L glutamine, and cultured in a cell culture incubator at 37 ° C, 5% CO 2 .
  • 1640 medium containing 10% fetal bovine serum, pH 7.2
  • the medium was added with 2 mmol/L glutamine, and cultured in a cell culture incubator at 37 ° C, 5% CO 2 .
  • a single cell suspension of human myeloma cells (ARP-1, H929, OCI-MY5, OPM2, RPMI-8226, U266, cells) was taken, and the cell concentration was adjusted to 2 ⁇ 10 ⁇ 5 cells/mL after counting.
  • 95 ⁇ L of the above cell suspension was added to each well of a 96-well culture plate, and then 5 ⁇ L of the drug prepared with the medium was added at different concentrations, and the control medium was added with a corresponding volume of medium, and three parallel holes were set in each group.
  • the cells were cultured for 72 hours, 2 hours before the end of the culture, and 10 ⁇ L of CCK8 reagent was added to each well, and the culture was continued in a CO 2 incubator.
  • cell viability (%) (experiment OD mean / control well OD mean) x 100%.
  • Cell inhibition rate (%) 100% - cell viability (%).
  • the fitting function was used to determine the IC 50 concentration of the drug when the cell growth was inhibited by 50%. Each set of experiments was repeated three times.
  • the 1 ⁇ mol/L seven-membered ring berberine analogs inhibited the growth of myeloma H929 cells, myeloma H929R cells, and myeloma RPMI-8226 cells, respectively.
  • 2a to 2c, 3a to 3g, 4j, 5c to 5k, and 6d to 6j each represent a compound corresponding to the above specification.
  • the ability of the seven-membered berberine analog to inhibit the activity was significantly better than that of the control group (BB is berberine).
  • the results of the fitting experiments of different concentrations of drug experiments were found to determine the IC 50 concentration of the drug when the cell growth was inhibited by 50%.
  • the IC 50 value of the seven-membered ring berberine analog was also significantly lower than that of the control group (BB).
  • the experimental results indicate that the seven-membered ring berberine analog has the effect of inhibiting the growth of blood system tumor cells in vitro.
  • Cell line Human multiple myeloma cells (H929 cells) (American ATCC, subcultured in our laboratory), cultured in 1640 medium (containing 10% fetal bovine serum).
  • mice male BALB/C nude mice (6-8 weeks, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd.), placed in SPF-level environment for breeding (Shanghai Tenth People's Hospital Central Laboratory Animal House) ).
  • 1640 medium containing 2 ⁇ 10 ⁇ 6 H929 cells was injected subcutaneously into the left axilla of nude mice, and when the tumors grew and were measured, they were randomly assigned to the control group and the administration group.
  • the mice were sacrificed 15 days after administration and the tumors were taken.
  • Fig. 4 shows that the seven-membered ring berberine analog has the effect of inhibiting the growth of tumor cells in the blood system in animals, and has no obvious side effects.
  • Human lymphoma cells Hut78, Jurkat, NUDUL-1, OCI-LY8, SUDHL-4 cells
  • 1640 medium containing 10% fetal bovine serum
  • Compound 2c against different types of lymphoma cells (Hut78, Jurkat, NUDUL-1, OCI-LY8, SUDHL-4 cells) is shown in FIG. It is indicated that compound 2c has a good inhibitory effect on many different types of lymphoma cells.
  • Example 4 In vivo activity of compounds 2c, 5k against solid tumor animal models
  • Cell line Human colon cancer SW620 cell line (Shanghai Institute of Traditional Chinese Medicine, Chinese Academy of Sciences), inoculated subcutaneously in the right axilla of nude mice, the cell inoculation amount was 5 ⁇ 106/only, and the transplanted tumor was formed and used in the body for 2 generations.
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of nude mice under aseptic conditions.
  • the nude mice were subcutaneously transplanted with a vernier caliper to measure the diameter of the transplanted tumor. After the tumor was grown to an average volume of about 130 mm 3 , the animals were randomly divided into groups. Compound 2c 50 mg/kg and 10 mg/kg group, once daily for intraperitoneal administration for 21 days; compound 5k 50 mg/kg (100 mg/kg from day 11) and 10 mg/kg group, administered intraperitoneally daily Once, continuous administration for 21 days.
  • the positive control drug group CPT-1115 mg/kg was administered intravenously three times a week for 21 consecutive days.
  • the solvent control group was given the same amount of physiological saline.
  • the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed. The mice were sacrificed 21 days later and the tumors were taken.
  • the results of the activity test showed that the seven-membered berberine analogue has the effect of inhibiting the growth of tumor cells in the blood system in vitro and in vivo, and has no obvious side effects, indicating that the compound has potential treatment for hematological tumors or cancer diseases. use.
  • the experiment of Example 4 shows that the solid tumor is different from the medical treatment of hematological tumors, and the compounds with similar anti-tumor cell activity in vitro are shown in the solid tumor animal model (Fig. 6) and the hematological tumor animal model (Fig. 4).
  • the seven-membered ring berberine analog 2a is combined with melphalan, doxorubicin or cyclophosphamide to form a pharmaceutical composition for treating blood tumors in a mass ratio of 1:1.
  • the seven-membered ring berberine analog 2b is combined with dexamethasone or prednisone in a mass ratio of 10:1 to form a pharmaceutical composition for treating hematological tumors.
  • the seven-membered ring berberine analog 3a and bortezomib were combined to form a pharmaceutical composition for treating hematological tumors in a mass ratio of 50:1.
  • Example 2 The drug-administered components were two groups, one group was intraperitoneally injected with bortezomib 0.5 mg/kg per day, and the other group was administered with seven-membered berberine analog 2c in combination with bortezomib (40:1). 20.5 mg / kg.
  • Fig. 7 The experimental results are shown in Fig. 7.

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Abstract

本发明公开了一种七元环小檗碱类似物及其药物组合物在制备治疗血液肿瘤的药物中的应用，七元环小檗碱类似物具有如下通式（I）对小檗碱的结构改进后获得的如通式（I）所示的七元环小檗碱类似物对血液肿瘤细胞具有良好的抑制作用，可用于制备治疗血液肿瘤的药物。

Description

七元环小檗碱类似物及其药物组合物在制备治疗血液肿瘤的药物中的应用 技术领域
本发明涉及药物技术领域，尤其是涉及一种七元环小檗碱类似物及其药物组合物在制备治疗血液肿瘤的药物中的应用。
背景技术
恶性肿瘤作为全球较大的公共卫生问题之一，极大地危害人类的健康，并将成为新世纪人类的第一杀手。恶性肿瘤已不再只是发达工业国家的严重疾病，发展中国家面临着更大的疾病负担。恶性肿瘤包括实体瘤(如肺癌、结直肠癌、肝癌、胃癌等)和血液肿瘤(如骨髓瘤、淋巴瘤等)，两者疾病的发生发展和治疗方式有着较为显著的不同，其中骨髓瘤和淋巴瘤是较常见的两种血液系统肿瘤。
其中，多发性骨髓瘤(multiple myeloma,MM)是一种克隆性浆细胞异常增殖的恶性疾病，是血液系统第二位常见的恶性肿瘤，约占血液系统恶性肿瘤的10％，多发于中老年人群，目前仍无法治愈，其中位生存时间为5～6年。传统治疗多发性骨髓瘤的主要方法是化疗和造血干细胞移植，其临床疗效很难维持。近10年来，随着新型药物如蛋白酶体抑制剂硼替佐米、免疫调节剂沙利度胺及来那度胺等的出现，多发性骨髓瘤患者的完全缓解率及总体生存率明显提高。但同时仍存在以下不足：首先，以上这些药物在复发、难治患者中的单药有效率仅为25％～50％；其次，尽管无疾病生存时间得到延长，但多数患者终将复发，且出现显著的药物抵抗；第三，神经炎等某些严重的副作用限制了药物的应用。因而，研发、检验新的治疗药物仍然是目前多发性骨髓瘤治疗所需面临的重要难题。而淋巴瘤是血液系统最常见的恶性肿瘤之一，在我国常见恶性肿瘤中占第8位，并且近年来它的发病率仍在逐渐增加。新的化疗方案、单克隆抗体、细胞免疫治疗等治疗方式已经显著改善了淋巴瘤患者的生存。特别是利妥昔单抗的出现，淋巴瘤的治疗有了突破性的进展，尤其是对CD20阳性的B细胞淋巴瘤，有效率更高，缓解时间更长，显著改善预后。但是，淋巴瘤患者出现复发或耐药的比例仍然很高。因此仍需进一步研发新药，以提高淋巴瘤的治疗效果与治愈率。
虽然化学药物治疗作为治疗肿瘤的重要手段之一，在近三十年已经有了巨大的发展和进步，得到了一大批具有不同作用机制的临床抗肿瘤药物。但是抗肿瘤药也存在许多不良反应，比如脱发，呕吐，快速产生耐药性等等，这些都导致化学药物无法达到预期的治疗效果。因此，新的抗肿瘤药物的研究与开发是目前药学领域的热点和难点问题之一。
发明内容
发明人在研究中意外发现，对小檗碱的结构改进后获得的如通式(I)所示的七元环小檗碱类似物对血液肿瘤细胞具有良好的抑制作用，在进行规范、科学、严谨的试验与药理学实验后，提供一种七元环小檗碱类似物及其药物组合物在制备治疗血液肿瘤的药物中的应用。
一种七元环小檗碱类似物在制备治疗血液肿瘤的药物中的应用，所述七元环小檗碱类似物具有如下通式(I)：
Figure PCTCN2018077060-appb-000001
式中，
Figure PCTCN2018077060-appb-000002
代表双键或单键，
Figure PCTCN2018077060-appb-000003
中的两个
Figure PCTCN2018077060-appb-000004
不同时为双键，
Figure PCTCN2018077060-appb-000005
中的两个
Figure PCTCN2018077060-appb-000006
不同时为双键；
Figure PCTCN2018077060-appb-000007
和
Figure PCTCN2018077060-appb-000008
分别独立地表示芳基或5～6元杂芳基；
R1为位于
Figure PCTCN2018077060-appb-000009
上的1～4个相同或不同的取代基，R2为位于
Figure PCTCN2018077060-appb-000010
上的1～4个相同或不同的取代基，R 5为位于B环上的1～3个相同或不同的取代基，R 1、R 2和R 5分别独立地表示氢、羟基、氨基、巯基、烷基、芳基、烷氧基、烷氨基、烷硫基、芳醚基、芳氨基、芳硫基或卤素；
R 3为氢、氧、硫、羟基、氨基、巯基、烷基、链烯基、链炔基、芳基、烷氧基、烷氨基、烷硫基、芳醚基、芳氨基、芳硫基、芳烷基、C 1～C 6的醛基或卤素；
R 4为氢、氧、硫、羟基、氨基、巯基、烷基、链烯基、链炔基、芳基、烷氧基、烷氨基、烷硫基、芳醚基、芳氨基、芳硫基、芳烷基、C 1～C 6的醛基或卤素。
在一个实施方式中，所述
Figure PCTCN2018077060-appb-000011
中的
Figure PCTCN2018077060-appb-000012
为单键，
Figure PCTCN2018077060-appb-000013
为双键，R 3为氧或硫。
在一个实施方式中，所述
Figure PCTCN2018077060-appb-000014
中的
Figure PCTCN2018077060-appb-000015
为单键，
Figure PCTCN2018077060-appb-000016
为单键，R 3为氢或烷氧基。
在一个实施方式中，通式(I)中B环上的
Figure PCTCN2018077060-appb-000017
为双键。
在一个实施方式中，所述七元环小檗碱类似物选自如下结构式中的一种：
Figure PCTCN2018077060-appb-000018
Figure PCTCN2018077060-appb-000019
Figure PCTCN2018077060-appb-000020
上述七元环小檗碱类似物在制备治疗多发性骨髓瘤的药物中的应用或者上述七元环小檗碱类似物在制备治疗淋巴瘤的药物中的应用。
上述七元环小檗碱类似物与非特异性化疗药物形成的药物组合物在制备治疗血液肿瘤的药物中的应用，所述非特异性化疗药物选自马法兰、阿霉素和环磷酰胺中的至少一种。
上述七元环小檗碱类似物与糖皮质激素形成的药物组合物在制备治疗血液肿瘤的药物中的应用。
上述七元环小檗碱类似物与靶向药物形成的药物组合物在制备治疗血液肿瘤的药物中的应用，所述靶向药物选自硼替佐米、卡非佐米、沙利度胺、来那度胺和泊马度胺中的至少一种。
一种治疗血液肿瘤的药物组合物，包括上述任一项所述的七元环小檗碱类似物以及联合剂，所述联合剂为非特异性化疗药物、糖皮质激素或靶向药物。
药理学研究结果表明，对小檗碱的结构改进后获得的如通式(I)所示的七元环小檗碱类似物对血液肿瘤细胞具有良好的抑制作用。进一步通过对多种血液肿瘤细胞的活性测试以及动物体内药效评价发现如通式(I)所示的七元环小檗碱类似物在体内和体外均能抑制血液肿瘤细胞生长活性，且无明显的毒副作用，说明该类化合物具有潜在的治疗血液肿瘤或癌症疾病的用途，可用于制备治疗血液肿瘤的药物。
附图说明
图1为七元环小檗碱类似物对骨髓瘤、淋巴瘤细胞的生长抑制活性的统计图；
图2为七元环小檗碱类似物对骨髓瘤、淋巴瘤细胞抑制的IC 50值的统计图；
图3化合物2c对不同类型的多发性骨髓瘤细胞的生长抑制活性曲线图；
图4为化合物2c在动物体内抗多发性骨髓瘤细胞活性的统计图；
图5为化合物2c对不同类型的淋巴瘤细胞的生长抑制活性曲线图；
图6为化合物2c和5k在动物体内抗结肠癌细胞活性的统计图；
图7为化合物2c和硼替佐米联用抑制动物体内多发性骨髓瘤细胞生长的统计图。
具体实施方式
为使本发明的上述目的、特征和优点能够更加明显易懂，下面结合附图对本发明的具体实施方式做详细的说明。在下面的描述中阐述了很多具体细节以便于充分理解本发明。但是本发明能够以很多不同于在此描述的其它方式来实施，本领域技术人员可以在不违背本发明内涵的情况下做类似改进，因此本发明不受下面公开的具体实施的限制。
如本文所用，“卤素”可以指F、Cl、Br或I。在一些实施例中，卤原子选自F、Cl和Br中的一种。
如本文所用，“C 1～C 6烷基”可以是指包括1～6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、或类似基团。
如本文所用，“烷氧基”可以指具有1～10个碳原子的烷氧基，例如C 1～C 6烷氧基。
如本文所用，“C1～C6烷氧基”包括1～6个碳原子的直链或支链的烷氧基。例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、或类似基团。
在本发明中，以下术语包括未取代形式以及取代形式：氨基、巯基、烷基、芳基、烷 氧基、烷氨基、烷硫基、芳醚基、芳氨基、芳硫基。
在本发明的优选例中，烷基、烷氧基、烷氨基、和烷硫基中的碳原子数为1～10个，较佳地为1～6个，更佳地为1～3个。
在本发明的优选例中，所述的芳基、芳醚基、芳氨基、和芳硫基中的碳原子数为6～30个，较佳地为6～20个，更佳地为6～10个。
如本文所用，术语“芳烷基”指C1～C10烷基中的1个或多个H原子被C6～10芳基取代所形成的基团，代表性的例子包括苄基。
此外，在本发明中，术语“烷基”包括饱和或不饱和、直链、支链、环状的1～10个碳原子(C 1～C 10)的全碳烷基或其中的1～3个碳原子被氧、氮、硫等杂原子取代的烷基，以及通过1个或1个以上碳原子连接的芳烷基。此外，烷基可以是未取代的或取代的。
如本文所用，术语“芳基”包括稠合或非稠合的芳基，通常含有6～30个碳原子，代表性的芳基包括苯基、萘基，或含氧、氮、硫等杂原子的芳香基团。
如本文所用，“5～6元环”指具有5或6个环原子(包括C原子和/或杂原子)的环结构，环结构可以是饱和的或不饱和的，可以是芳香的或非芳香的，可以含有或不含有杂原子。如“杂原子”例如可以是N、O或S。
一实施方式的七元环小檗碱类似物在制备治疗血液肿瘤的药物中的应用，其中，该七元环小檗碱类似物具有如下通式(I)：
Figure PCTCN2018077060-appb-000021
式中，
Figure PCTCN2018077060-appb-000022
代表双键或单键，
Figure PCTCN2018077060-appb-000023
中的两个
Figure PCTCN2018077060-appb-000024
不同时为双键，
Figure PCTCN2018077060-appb-000025
中的两个
Figure PCTCN2018077060-appb-000026
不同时为双键。
Figure PCTCN2018077060-appb-000027
和
Figure PCTCN2018077060-appb-000028
分别独立地表示芳基或5～6元杂芳基。
R 1为位于
Figure PCTCN2018077060-appb-000029
上的1～4个相同或不同的取代基，R 2为位于
Figure PCTCN2018077060-appb-000030
上的1～4个相同或不同的取代基，R 5为位于B环上的1～3个相同或不同的取代基，R 1、R 2和R 5分别独立地表示氢、羟基、氨基、巯基、烷基、芳基、烷氧基、烷氨基、烷硫基、芳醚基、芳氨基、芳硫基或卤素。
R 3为氢、氧、硫、羟基、氨基、巯基、烷基、链烯基、链炔基、芳基、烷氧基、烷氨基、烷硫基、芳醚基、芳氨基、芳硫基、芳烷基、C 1～C 6的醛基或卤素。
R 4为氢、氧、硫、羟基、氨基、巯基、烷基、链烯基、链炔基、芳基、烷氧基、烷氨基、烷硫基、芳醚基、芳氨基、芳硫基、芳烷基、C 1～C 6的醛基或卤素。
需要说明的是，通式(I)的环内的A、B、C和D仅是为了描述上的方便，并不是指环内连接有原子或基团。
在一些实施例中，
Figure PCTCN2018077060-appb-000031
和
Figure PCTCN2018077060-appb-000032
分别独立地表示芳基或5～6元杂芳基。杂芳基中的杂 原子例如可以是N或O或S杂原子。其中当
Figure PCTCN2018077060-appb-000033
和
Figure PCTCN2018077060-appb-000034
为6元杂芳基环时，环内可以具有1～3个N或O或S，为5元杂芳基环时，环内可以具有1～3个N或O或S。
在一些实施例中，
Figure PCTCN2018077060-appb-000035
环和
Figure PCTCN2018077060-appb-000036
环以及分别与其连接的R 1和R 2基团的连接方式，以
Figure PCTCN2018077060-appb-000037
环和R 1为例，通式(I)可以选自如下结构式中的一种：
Figure PCTCN2018077060-appb-000038
在一些实施例中，代表性的R 3或R 4基团可以为如下基团，以R 3基团为例，通式(I)可以选自如下结构式中的一种：
Figure PCTCN2018077060-appb-000039
上述结构式中，“O or S”表示该位置可以是O或S；R代表烷基、芳基等。
在一些实施例中，通式(I)中的
Figure PCTCN2018077060-appb-000040
中的
Figure PCTCN2018077060-appb-000041
为单键，
Figure PCTCN2018077060-appb-000042
为双键，R 3为氧或硫。
在另一些实施例中，通式(I)中的
Figure PCTCN2018077060-appb-000043
中的
Figure PCTCN2018077060-appb-000044
为单键，
Figure PCTCN2018077060-appb-000045
为单键，R 3为氢或烷氧基。
在一些实施例中，通式(I)中B环上的
Figure PCTCN2018077060-appb-000046
为双键。
进一步地，七元环小檗碱类似物可选自如下结构式中的一种：
Figure PCTCN2018077060-appb-000047
Figure PCTCN2018077060-appb-000048
需要说明的是，上述结构的七元环小檗碱类似物均可购买或通过化学合成的方法制备得到，本文中研究所用的七元环小檗碱类似物由中科院上海药物研究所合成提供。
有些药理研究表明，小檗碱可能具有开发成抗肿瘤药物的潜力，但迄今为止，尚缺乏相关的抗肿瘤新药上市。仔细比较文献报道的小檗碱抗肿瘤活性数据发现，其体内活性测试的有效剂量太大，口服生物利用度低。对于血液肿瘤来说，由于肿瘤细胞转移快，达到抑制血液肿瘤细胞生长的剂量需求更高。发明人在研究中意外发现，对小檗碱的结构改进后获得的如通式(I)所示的七元环小檗碱类似物对血液肿瘤细胞具有良好的抑制作用，进行规范、科学、严谨的试验与药理学实验研究表明，上述七元环小檗碱类似物对多种骨髓瘤以及多种淋巴瘤细胞等均具有良好的抑制作用，IC50值低，且在体内和体外均能抑制血液肿瘤细胞生长活性，无明显的毒副作用。因此，该七元环小檗碱类似物在制备治疗血液肿瘤的药物中具有良好的应用前景。具体的，上述七元环小檗碱类似物例如可应用于制备治疗多发性骨髓瘤的药物中，七元环小檗碱类似物还可应用于制备治疗淋巴瘤的药物中。
如本文所用，术语“本发明化合物”指通式(I)所示的化合物，即七元环小檗碱类似物。在一些实施方式中，通式(I)所示化合物可以以各种晶型形式、药学上可接受的盐、水合物或溶剂合物的形式应用于制备治疗淋巴瘤的药物中。通式(I)化合物或其药学上可接受的盐中，一个或多个H可以为氘代的，即氘在氘取代位置的氘同位素含量至少是大于天然氘同位素含量(0.015％)，例如大于30％，或大于50％，或大于75％，或大于95％，或大于99％。
“药学上可接受的盐”例如可以是通式(I)所示的任一化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类盐是本发明化合物与酸形成的 盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。
另一类盐是通式(I)所示的化合物与碱形成的盐，例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
“溶剂合物”指通式(I)所示的化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
在一些实施方式中，通式(I)所示的化合物还可作为“前药”应用于制备治疗血液肿瘤的药物中。“前药”可以是具有生物学活性的或非活性的，当用适当的方法服用后，化合物在人体内进行代谢或化学反应而转变成通式(I)的一类化合物，或通式(I)的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
具体地，通式(I)所示的化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有该化合物为活性成分的药物组合物可用于制备治疗、预防或缓解血液系统肿瘤的药物中。
在一些实施方式中，药物组合物中包含安全有效量范围内的通式(I)所示的化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。药物组合物通常可以含有1mg～2000mg七元环小檗碱类似物/剂。例如含有10mg～1000mg七元环小檗碱类似物/剂。其中，“一剂”为一个胶囊或药片。
“药学上可以接受的载体”可以指一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2018077060-appb-000049
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
上述七元环小檗碱类似物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质 和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
在制备治疗血液肿瘤的药物中，上述七元环小檗碱类似物可以单独给药，或者与其他药学上可接受的其他化合物(如抗肿瘤药物)联合给药。
例如，一实施方式的治疗血液肿瘤的药物组合物，包括上述七元环小檗碱类似物以及联合剂，联合剂为非特异性化疗药物、糖皮质激素或靶向药物。
在一些实施方式中，七元环小檗碱类似物可以与非特异性化疗药物形成的药物组合物应用于制备治疗血液肿瘤的药物中。非特异性化疗药物例如可选自马法兰、阿霉素和环磷酰胺中的至少一种。前期的研究表明，七元环小檗碱类似物与非特异性化疗药物形成的药物组合物保持七元环小檗碱类似物、马法兰、阿霉素或环磷酰胺单独作用时抑制血液肿瘤的活性，还可降低肿瘤的耐药性，发挥协同治疗目的。
其中一实施例的治疗血液肿瘤的药物组合物包括七元环小檗碱类似物、马法兰、阿霉素和环磷酰胺，七元环小檗碱类似物、马法兰、阿霉素和环磷酰胺的质量份数比为100～1:0～100:0～100:0～100。
在一些实施方式中，七元环小檗碱类似物还可以与糖皮质激素形成的药物组合物应用于制备治疗血液肿瘤的药物中。糖皮质激素例如可选自地塞米松和强的松中的至少一种。前期的研究表明，七元环小檗碱类似物与糖皮质激素形成的药物组合物保持七元环小檗碱类似物抑制血液肿瘤的活性以及糖皮质激素消炎的作用，还可进一步保护免疫系统，减少副作用，发挥协同治疗目的。
其中一实施例的治疗血液肿瘤的药物组合物包括七元环小檗碱类似物、地塞米松和强的松，七元环小檗碱类似物、地塞米松和强的松的质量份数比为100～1:0～100:0～100。
在一些实施方式中，七元环小檗碱类似物还可以与靶向药物形成的药物组合物应用于制备治疗血液肿瘤的药物中，靶向药物例如选自硼替佐米、卡非佐米、沙利度胺、来那度胺和泊马度胺中的至少一种。前期的研究表明，七元环小檗碱类似物与靶向药物形成的药物组合物保持七元环小檗碱类似物抑制血液肿瘤的活性以及靶向药物单独作用时抑制血液肿瘤的活性，还可进一步降低药物有效剂量，减少副作用，发挥协同治疗目的。
其中一实施例的治疗血液肿瘤的药物组合物包括七元环小檗碱类似物和硼替佐米，七元环小檗碱类似物与硼替佐米的质量份数比为100～1:0.1～100。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1mg～2000mg的七元环小檗碱类似物，例如50mg～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
发明人在研究中意外发现，对小檗碱的结构改进后获得的如通式(I)所示的七元环小檗碱类似物对血液肿瘤细胞具有良好的抑制作用。进一步通过对多种血液肿瘤细胞的活性测试以及动物体内药效评价发现如通式(I)所示的七元环小檗碱类似物在体内和体外均能抑制血液肿瘤细胞生长活性，且无明显的毒副作用，说明该类化合物具有潜在的治疗血液肿瘤或癌症疾病的用途，可用于制备治疗血液肿瘤的药物。
此外，该七元环小檗碱类似物与非特异性化疗药、糖皮质激素或靶向药物形成的药物组合物应用于制备治疗血液肿瘤的药物中，能够发挥协同治疗目的。
以下为具体实施例部分
应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
活性测试实验实施例
实验例1七元环小檗碱类似物对骨髓瘤细胞的活性影响
1.实验材料：
(1)细胞株：人多发性骨髓瘤细胞(ARP-1,H929，OCI-MY5,OPM2，RPMI-8226,U266)细胞购自美国ATCC，本实验室传代保存；H929R细胞由第二军医大学侯健教授提供)，培养于1640培养基(含10％胎牛血清)。
(2)主要试剂：1640培养基(美国Gibco公司)，胎牛血清(美国Gibco公司)，Cell Counting Kit-8试剂盒(CCK8，日本株式会社同仁化学研究所)。
(3)主要仪器：二氧化碳培养箱(美国Thermo Forma公司)，全自动酶标仪(Bio-TEK，Elx800)。
2.实验方法：
(1)细胞培养
细胞培养于1640培养基(含10％胎牛血清，pH 7.2)，培养基加2mmol/L谷氨酰胺，置于细胞培养箱中在37℃、5％CO 2环境下培养。
(2)CCK8试剂盒测定各药物的细胞毒性
取人多发性骨髓瘤细胞(ARP-1,H929，OCI-MY5,OPM2，RPMI-8226,U266,细胞)的单细胞悬液，计数后调整细胞浓度至2×10 ^5个/mL。取96孔培养板每孔加入95μL上述细胞悬液，然后加不同浓度的用培养基配制的药物5μL，对照组加入相应体积的培养基，每组设置3个平行孔。连续培养72h，培养结束前2h，每孔加入CCK8试剂10μL，于CO 2孵箱中继续培养。2h后自动酶标仪检测450nm各孔OD值。计算细胞存活率与抑制率：细胞存活率(％)＝(实验孔OD均值/对照孔OD均值)×100％。细胞抑制率(％)＝100％-细胞存活率(％)。拟合函数求出抑制细胞生长达50％时药物浓度IC 50。每组实验重复三次。
3.实验结果
如图1所示，1μmol/L的七元环小檗碱类似物分别对骨髓瘤H929细胞、骨髓瘤H929R细胞、骨髓瘤RPMI-8226细胞生长抑制活性。2a～2c、3a～3g、4j、5c～5k以及6d～6j分别表示上述说明书对应的化合物。说明七元环小檗碱类似物抑制活性的能力明显优于对照组(BB为小檗碱)。
不同浓度的药物实验的结果拟合函数求出抑制细胞生长达50％时药物浓度IC 50如图2所示。七元环小檗碱类似物的IC 50值也明显低于对照组(BB)，实验结果说明七元环小檗碱类似物具有体外抑制血液系统肿瘤细胞生长的作用。
其中化合物2c对不同类型的多发性骨髓瘤细胞(ARP-1,H929，OCI-MY5,OPM2，RPMI-8226,U266)的生长抑制活性图如图3所示。说明化合物2c对多种不同类型的多发性骨髓瘤细胞均有良好的抑制作用。
实施例2针对多发性骨髓瘤的动物实验
1.实验材料
(1)细胞株：人多发性骨髓瘤细胞(H929细胞)(美国ATCC，本实验室传代保存)，培养于1640培养基(含10％胎牛血清)。
(2)实验动物：雄性BALB/C裸鼠(6-8周，购自上海西普尔-必凯实验动物有限公司)，置于SPF级环境中饲养(上海第十人民医院中心实验室动物房)。
2.实验方法
(1)细胞培养参见实施例1。
(2)动物实验
将含2×10 ^6个H929细胞的1640培养基注射到裸鼠左腋窝皮下，当瘤子长成并可测量时，随机分至对照组和给药组。给药组裸鼠每天腹腔注射2c 15mg/kg,对照组裸鼠每天腹腔注射相同体积的溶剂(200μL，溶剂＝15μL DMSO+185μL生理盐水)。每两天测量一次瘤子大小(测量瘤子的长和宽，瘤子体积＝4π/3×(宽/2) ^2×(长/2))。给药15天后处死老鼠并取瘤子拍照。
3.实验结果
实验结果见图4，说明七元环小檗碱类似物具有动物体内抑制血液系统肿瘤细胞生长的作用，且无明显的毒副作用。
实施例3:针对人淋巴瘤细胞的杀伤活性
1.实验材料
人淋巴瘤细胞(Hut78、Jurkat、NUDUL-1、OCI-LY8、SUDHL-4细胞)(美国ATCC，本实验室传代保存)，培养于1640培养基(含10％胎牛血清)。其他同实施例1。
2.实验方法参见实施例1。
3.实验结果
实验结果请再次参见图1和图2。图1中可以看出，1μmol/L的七元环小檗碱类似物分别对淋巴瘤Jurkat细胞、淋巴瘤NUDUL-1、淋巴瘤OCI-LY8生长抑制活性能力明显优于对照组(BB)。七元环小檗碱类似物的IC 50值也明显低于对照组(BB)，实验结果说明七元环小檗碱类似物具有体外抑制血液系统肿瘤细胞生长的作用。
其中化合物2c对不同类型的淋巴瘤细胞(Hut78、Jurkat、NUDUL-1、OCI-LY8、SUDHL-4细胞)的生长抑制活性图如图5所示。说明化合物2c对多种不同类型的淋巴瘤细胞均有良好的抑制作用。
实施例4：化合物2c、5k针对实体瘤动物模型的体内活性
1.实验材料
(1)细胞株：人结肠癌SW620细胞株(中科院上海药物所)，接种裸小鼠右侧腋窝皮下，细胞接种量为5×106/只，形成移植瘤后在体内传2代后使用。
(2)实验动物：BALB/cA裸小鼠，雌性，4-5周龄，中科院上海药物研究所生产，质量合格证编号No.311613700000097，生产许可证号：SCXK(沪)2013-0017。上海药物所使用许可证编号：SYXK(沪)2013-0049，每组动物数：溶剂对照组12只，给药组6只。2.实验方法
取生长旺盛期的瘤组织剪切成1.5mm 3左右，在无菌条件下，接种于裸小鼠右侧腋窝皮下。裸小鼠皮下移植瘤用游标卡尺测量移植瘤直径，待肿瘤生长至平均体积约为130mm 3后将动物随机分组。化合物2c 50mg/kg和10mg/kg组，每天腹腔注射给药一次，连续给药 21天；化合物5k 50mg/kg(第11天起为100mg/kg)和10mg/kg组，每天腹腔注射给药一次，连续给药21天。阳性对照药物CPT-1115mg/kg组，每周静脉给药三次，连续给药21天。溶剂对照组则给以等量生理盐水。整个实验过程中，每周2次测量移植瘤直径，同时称量小鼠体重。21天后处死老鼠并取瘤子拍照。
3.实验结果
实验结果如图6所示，化合物2c和5k对人结肠癌SW620裸小鼠皮下移植瘤的生长无抑制作用。图6的具体数据如下表1和表2所示：
表1. 2c、5k对人结肠癌SW620裸小鼠移植瘤相对肿瘤体积的影响
Figure PCTCN2018077060-appb-000050
注：Pvalue vs溶剂对照
表2. 2c、5k对人结肠癌SW620荷瘤鼠体重的影响
Figure PCTCN2018077060-appb-000051
综上活性测试实验结果说明，七元环小檗碱类似物具有体内外抑制血液系统肿瘤细胞生长的作用，且无明显的毒副作用，说明该类化合物具有潜在的治疗血液系统肿瘤或癌症疾病的用途。另外，实施例4的实验说明，实体瘤与血液肿瘤的药物治疗是不同的，体外抗肿瘤细胞活性相似的化合物在实体瘤动物模型(图6)和血液肿瘤动物模型(图4)上表现出截然相反的结果，如化合物2c在体外抑制结肠癌SW620细胞的IC50值达到0.06uM，但对人结肠癌SW620裸小鼠皮下移植瘤的生长无抑制作用；而其在体外抑制骨髓瘤H929细胞的IC50值为0.65uM，但对骨髓瘤H929裸小鼠皮下移植瘤的生长有明显的抑制作用。
实施例5
取七元环小檗碱类似物2a与马法兰、阿霉素或环磷酰胺，按质量份数比为1:1配合形成一种治疗血液肿瘤的药物组合物。
实施例6
取七元环小檗碱类似物2b与地塞米松或强的松，按质量份数比为10:1配合形成一种治 疗血液肿瘤的药物组合物。
实施例7
取七元环小檗碱类似物3a和硼替佐米，按质量份数比为50:1配合形成一种治疗血液肿瘤的药物组合物。
实施例8
七元环小檗碱类似物2c与硼替佐米联用对多发性骨髓瘤的动物实验
1.实验材料：参见实施例2
2.实验方法：参见实施例2。给药组分为两组，一组每天腹腔注射硼替佐米0.5mg/kg，另一组采用七元环小檗碱类似物2c与硼替佐米(40：1)联用，腹腔注射药物组合物20.5mg/kg。
3.实验结果
实验结果如图7所示，七元环小檗碱类似物2c与硼替佐米(40：1)联用，较之硼替佐米单用，能够更显著的抑制动物体内骨髓瘤细胞生长。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (10)

  1. 一种七元环小檗碱类似物在制备治疗血液肿瘤的药物中的应用，其特征在于，所述七元环小檗碱类似物具有如下通式(I)：
    Figure PCTCN2018077060-appb-100001
    式中，
    Figure PCTCN2018077060-appb-100002
    代表双键或单键，
    Figure PCTCN2018077060-appb-100003
    中的两个
    Figure PCTCN2018077060-appb-100004
    不同时为双键，
    Figure PCTCN2018077060-appb-100005
    中的两个
    Figure PCTCN2018077060-appb-100006
    不同时为双键；
    Figure PCTCN2018077060-appb-100007
    分别独立地表示芳基或5～6元杂芳基；
    R 1为位于
    Figure PCTCN2018077060-appb-100008
    上的1～4个相同或不同的取代基，R 2为位于
    Figure PCTCN2018077060-appb-100009
    上的1～4个相同或不同的取代基，R 5为位于B环上的1～3个相同或不同的取代基，R 1、R 2和R 5分别独立地表示氢、羟基、氨基、巯基、烷基、芳基、烷氧基、烷氨基、烷硫基、芳醚基、芳氨基、芳硫基或卤素；
    R 3为氢、氧、硫、羟基、氨基、巯基、烷基、链烯基、链炔基、芳基、烷氧基、烷氨基、烷硫基、芳醚基、芳氨基、芳硫基、芳烷基、C 1～C 6的醛基或卤素；
    R 4为氢、氧、硫、羟基、氨基、巯基、烷基、链烯基、链炔基、芳基、烷氧基、烷氨基、烷硫基、芳醚基、芳氨基、芳硫基、芳烷基、C 1～C 6的醛基或卤素。
  2. 根据权利要求1所述的七元环小檗碱类似物在制备治疗血液肿瘤的药物中的应用，其特征在于，所述
    Figure PCTCN2018077060-appb-100010
    中的
    Figure PCTCN2018077060-appb-100011
    为单键，
    Figure PCTCN2018077060-appb-100012
    为双键，R 3为氧或硫。
  3. 根据权利要求1所述的七元环小檗碱类似物在制备治疗血液肿瘤的药物中的应用，其特征在于，所述
    Figure PCTCN2018077060-appb-100013
    中的
    Figure PCTCN2018077060-appb-100014
    为单键，
    Figure PCTCN2018077060-appb-100015
    为单键，R 3为氢或烷氧基。
  4. 根据权利要求1所述的七元环小檗碱类似物在制备治疗血液肿瘤的药物中的应用，其特征在于，通式(I)中B环上的
    Figure PCTCN2018077060-appb-100016
    为双键。
  5. 根据权利要求1所述的七元环小檗碱类似物在制备治疗血液肿瘤的药物中的应用，其特征在于，所述七元环小檗碱类似物选自如下结构式中的一种：
    Figure PCTCN2018077060-appb-100017
    Figure PCTCN2018077060-appb-100018
    Figure PCTCN2018077060-appb-100019
    及
    Figure PCTCN2018077060-appb-100020
  6. 根据权利要求1所述的七元环小檗碱类似物在制备治疗血液肿瘤的药物中的应用，其特征在于，所述七元环小檗碱类似物在制备治疗多发性骨髓瘤的药物中的应用或者所述七元环小檗碱类似物在制备治疗淋巴瘤的药物中的应用。
  7. 如权利要求1～5任一项所述的七元环小檗碱类似物与非特异性化疗药物形成的药物组合物在制备治疗血液肿瘤的药物中的应用，所述非特异性化疗药物选自马法兰、阿霉素和环磷酰胺中的至少一种。
  8. 如权利要求1～5任一项所述的七元环小檗碱类似物与糖皮质激素形成的药物组合物在制备治疗血液肿瘤的药物中的应用。
  9. 如权利要求1～5任一项所述的七元环小檗碱类似物与靶向药物形成的药物组合物在制备治疗血液肿瘤的药物中的应用，所述靶向药物选自硼替佐米、卡非佐米、沙利度胺、来那度胺和泊马度胺中的至少一种。
  10. 一种治疗血液肿瘤的药物组合物，其特征在于，包括如权利要求1～5任一项所述的七元环小檗碱类似物以及联合剂，所述联合剂为非特异性化疗药物、糖皮质激素或靶向药物。
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