CN102038673B - Application of hydroxyl benzopyrone compound for preparing medicament for treating leukemia - Google Patents
Application of hydroxyl benzopyrone compound for preparing medicament for treating leukemia Download PDFInfo
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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Abstract
The invention relates to an application of a hydroxyl benzopyrone compound for preparing a medicament for treating leukemia, belonging to the field of chemical medicaments. A compound of formula (I) shown by an experiment), especially compound icaritin of formula II can restrain CML (Chronic Myeloid Leukemia) cell proliferation in a mode of concentration dependent and induce apoptosis of marrow cells of a CML patient in the mode of concentration dependent, can obviously reduce the number of leukocyte of peripheral blood and CD45+ leukemia cell proportion, can obviously lighten spleen weight of leukemic mice simultaneously, and also can restrain the expression ER alpha-36 receptor protein in K562 cells in the mode of the concentration dependent. Therefore, the compound of the formula (I) can treat chronic myeloid leukemia.
Description
Technical Field
The invention relates to application of hydroxybenzopyrone compounds. The compounds of the invention are suitable for the prophylaxis and treatment of chronic myelogenous leukemia. The invention also relates to pharmaceutical compositions comprising these compounds and to the use of said compounds, alone or in combination with other agents, for the treatment of chronic myelogenous leukemia.
Background
Estrogens are steroid hormones produced by the endocrine system in the body, and play important roles in the reproductive system, cardiovascular system, central nervous system, immune system, and skeletal system. Recent studies have shown that estrogens exert biological effects through two signal transduction pathways, the nuclear pathway and the cell membrane pathway; estrogens and their receptor signaling systems are widely involved in cell growth, differentiation and apoptosis processes in multiple systemic tissues in the body. Numerous studies have demonstrated that the estrogen receptor ER-alpha is present in leukemic cells of leukemic patients and that its receptor expression level correlates with the prognosis of clinical treatment; the ER- α mediated signal transduction pathway is likely involved in the process of leukemia formation and progression.
Current studies have demonstrated that estrogen receptors are divided into two subtypes, alpha and beta; wherein ER-alpha comprises three homologous isomers, ER-alpha 66, ER-alpha 46 and ER-alpha 36. The isoform ER- α 36 is transcribed from a promoter located in the first intron of the ER- α 66 gene, encoded by a partial exon of ER- α 66. Thus, ER- α 36 lacks two transcriptional domains, retaining the DNA binding domain and dimerization domain; more importantly, the hormone ligand binding region of ER-alpha 36 lacks part of the helical region, thereby completely changing the specificity and affinity of the hormone ligand binding region. ER-alpha 36 is distributed mainly in the cell membrane and cytoplasm, and is present in small amounts in the nucleus. ER- α 36 can regulate cell growth and apoptosis through the membrane signaling pathway of estrogen (1.ZY, Wang; XT, Zhang; P, Shen; BW, logie; YC, Chang; TF, Deuel. A variant of estrogenreceptor- α, hER- α 36: Transduction of estrogen-and antisense-dependent membrane-inert signaling. PNAS.2006, 103 (24): 9063-9068.2.LMJ, Lee; J, Cao; H, Deng; P, Chen; Z, Gatalman; ZY, Wang. ER- α 36, alpha. variant of ER- α, expressed ER-porous and-hydrophobic antibody. anticancer. 483. 479, 2008. 479, 479).
Disclosure of Invention
The compounds of the present invention are useful as estrogen receptor bioinformatic systems for the prevention and treatment of chronic myelogenous leukemia.
The invention relates to a compound of formula (I), the application of the pharmaceutically acceptable salt or the pharmaceutical composition thereof in preparing drugs for improving, preventing and treating leukemia,
wherein,
R1、R2and R3Independently of one another, from hydrogen, methyl, ethyl, propyl, isopropyl.
In a particularly preferred embodiment of the invention, the compound of formula (I) is: 3, 5, 7-Trihydroxyl-2- (4-methoxyphenyl) -8- (3-methyl-2-butene-) -4H-benzopyran-4-one (also known as Icaritin), i.e., the compound of formula (I) has the structure of formula (II):
in a particularly preferred embodiment of the invention, the compound of formula (I) is the demethylation product of a compound of formula (II), namely demethylicaritin of formula (III): 3, 5, 7-Trihydroxyl-2- (4-hydroxyphenyl) -8- (3-methyl-2-butene-) -4H-benzopyran-4-one.
The leukemia refers to Chronic Myelogenous Leukemia (CML).
The compound of the formula (I), and the pharmaceutically acceptable salt or the pharmaceutical composition thereof, in the preparation of the drugs for treating the related diseases regulated and controlled by estrogen receptor ER-alpha or ER-beta subtype,
wherein,
R1、R2and R3Independently of one another, from hydrogen, methyl, ethyl, propyl, isopropyl.
In a particularly preferred embodiment of the invention, the compound of formula (I) is: 3, 5, 7-Trihydroxyl-2- (4-methoxyphenyl) -8- (3-methyl-2-butene-) -4H-benzopyran-4-one (also known as Icaritin), i.e., the compound of formula (I) has the structure of formula (II):
in a particularly preferred embodiment of the invention, the compound of formula (I) is the demethylation product of a compound of formula (II), namely demethylicaritin of formula (III): 3, 5, 7-Trihydroxyl-2- (4-hydroxyphenyl) -8- (3-methyl-2-butene-) -4H-benzopyran-4-one.
The compound shown in the formula (I), (II) and (III), and pharmaceutically acceptable salts or pharmaceutical compositions thereof are applied to the preparation of medicines for treating related diseases regulated and controlled by estrogen receptor ER-alpha or ER-beta subtypes, wherein the ER-alpha subtypes comprise ER-alpha 36, ER-alpha 46 and ER-alpha 66.
The compounds of formula (I), (II), (III), and pharmaceutically acceptable salts or pharmaceutical compositions thereof are modulators of the estrogen receptors ER-alpha and ER-beta subtypes.
The term "compound of formula (I)" includes formula (I) as defined herein and all embodiments, preferred embodiments, more preferred embodiments and particularly preferred embodiments of this compound, including the specifically named or disclosed in the examples, each of which is a particularly preferred embodiment of the compound defined by the general formula. By "compound of the invention" is meant any compound of formula (I) as defined above.
The invention also relates to salts, polymorphs, solvates and hydrates of the compounds of the invention. The term "pharmaceutically acceptable salt" as used herein, unless otherwise indicated, includes salts that may be present in the compounds of the present invention.
The verb "treat" as used in the present invention, unless otherwise stated, refers to reversing, alleviating, inhibiting the course of a disease or disorder, or preventing such a disease or disorder. The term "treatment" as used herein refers to the act of treating, wherein the treatment is as defined above.
The invention also relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. For example, the pharmaceutical compositions may be administered orally in the form of tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions; the pharmaceutical compositions may also be administered parenterally in the form of sterile solutions, suspensions or emulsions; the pharmaceutical compositions may also be administered topically in the form of an ointment or cream; the pharmaceutical compositions may also be administered rectally in the form of suppositories. The pharmaceutical compositions may be presented in unit dosage form suitable for unitary administration of precise dosages. The pharmaceutical compositions comprise conventional pharmaceutical carriers or excipients and, as active ingredient, a compound of the invention. In addition, the pharmaceutical composition may include other medicinal or pharmaceutical agents, carriers, adjuvants, and the like.
Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical composition may contain other ingredients, such as flavoring agents, binders, excipients, and the like, if desired. Thus for oral administration, tablets may contain various excipients, for example citric acid and various disintegrants such as starch, alginic acid and certain complex silicates and binding agents such as sucrose, gelatin and acacia may be used. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often used in tablets. A similar type of solid composition may also be used with soft and hard filled capsules. Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols. When it is desired to administer the active compounds of the present invention orally, aqueous suspensions or elixirs may be combined with various sweetening or flavouring agents, colouring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin or combinations thereof.
Exemplary parenteral administration forms include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose. Such dosage forms may be suitably buffered if desired. The aqueous compositions of the present invention may include other pharmaceutically acceptable solutes, including additives and other drugs, as appropriate. Suitable additives are those well known in the art and include, but are not limited to, antioxidants, antibacterial agents, surfactants, chelating agents, sugars, and preservatives. The aqueous composition of the present invention can be administered by injection, wherein the injection can be intramuscular injection, intravenous injection or subcutaneous injection.
The compounds of the present invention may be administered alone, but often together with suitable pharmaceutical excipients, diluents or carriers well known in the art, in connection with the intended route of administration and standard pharmaceutical practice. If appropriate, adjuvants may be added, including preservatives, antioxidants, flavouring agents, or colouring agents. The compounds of the invention may be formulated into suitable pharmaceutical compositions to provide direct, delayed, modified, sustained, pulsed or controlled release, depending on the particular route of administration and the specificity of the release profile, corresponding to the therapeutic need.
The compounds of the invention may be administered by routes such as, but not limited to, oral (including buccal, sublingual, etc.) forms well known in the art. In this context, "oral" means an oral administration mode in which the amount of oral use by the animal is plain, e.g., in food or drink, directly into the oral cavity, or is freely selected. In the present invention, the term "animal" refers to a warm-blooded animal of the animal kingdom that possesses adaptive functions, such as dogs and humans.
Typical oral solid forms may include tablets, powders, multiparticulate formulations (granules), capsules, chewables, lozenges, films, patches, and the like. Typical oral liquid (including semi-solid and colloidal) forms can include solutions, elixirs, gels, sprays, liquid-filled chews, and the like. Other oral administration forms may also be employed in which the active agent is suspended in a liquid or semi-solid carrier phase, e.g., a suspension.
The compounds of the present invention may also be administered parenterally. The term parenteral administration means that the route of administration does not pass through the oral cavity. Preferably for the compounds of the invention, parenteral administration may include topical and transdermal, rectal, vaginal, nasal, inhalation and injection administration (forms of administration requiring penetration of the skin barrier by needle and needle-free methods, including implants and reservoirs).
The compositions of the present invention include tablets. In a preferred embodiment, the tablet is prepared by a process selected from direct compression or wet, dry or melt granulation, melt congealing process and extrusion. In another embodiment, the tablet core portion of the composition of the present invention may be single-layered or multi-layered and coated with suitable coating materials known in the art.
Oral liquid forms of the compounds of the invention are preferably solutions or suspensions in which the active compound is fully or partially dissolved. In one embodiment, the solution comprises the active compound and a pharmaceutically-acceptable solvent suitable for oral administration. In a preferred embodiment, the solvent is one that exhibits good solubility for the compounds of the present invention. These solvents generally make up the major part of the formulation, i.e. more than 50% (by weight), preferably more than 80%, for example 95%. In a preferred embodiment, the solution further comprises adjuvants or additives. In a preferred embodiment thereof, the additive or adjuvant is a taste masking agent, a palatability agent, a flavoring agent, an antioxidant, a stabilizer, a texture modifier, a viscosity modifier, and a solubilizing agent.
Another embodiment is a process for preparing preferred oral liquid forms of the compounds of the present invention wherein the preferred components are mixed, optionally by mechanical or ultrasonic agitation, in a manner that favors the rate of dissolution, over a suitable temperature range.
The compound is prepared by extracting and separating the Chinese medicinal materials. The preparation of the compound of the invention refers to a method described in another invention patent 'preparation method of icaritin' (Mengkun, CN101302548A), and the compound of the invention is obtained by separating and extracting a chemical component icaritin from a traditional Chinese medicine epimedium herb.
Demethylicaritin was purchased from shanghai friend si biotechnology limited.
Biological experiments and tests
1. Inhibitory proliferation and apoptosis-inducing effects of compounds on CML cells:
MTT experiment is used for observing the proliferation inhibition rate of compounds with different concentrations on K562 cells and primary cells from CML patient bone marrow, the CML patient bone marrow cells are divided into an acute phase and a chronic phase, and normal human bone marrow cells are collected as a control; the percentage of apoptotic cells after different concentrations of the compound on primary cells in the bone marrow of CML patients was examined by flow cytometry.
2. Therapeutic effect of Compounds on NOD-SCID mice transplanted with K562 cell line:
adjusting the concentration of K562 cells to 1 × 10 with sterile physiological saline7Per ml, each NOD-SCID mouse was injected with 2X 10 cells of K562 cells via tail vein60.2 mL. Tumor-bearing mice were randomly divided into four groups; the blank control group was given equal amount of solvent; positive control group was given Imatinib (Glevec, Gleevec) 50. mu.g/g; the experimental groups were given two concentrations of compound, respectively. The tumor-bearing mice were administered with different drugs intraperitoneally once a day for 45 consecutive days. Weekly measurement of mouse peripheral blood leukocyte count and CD45+Leukemia cell number, pathological changes of mouse spleen observed by HE staining after mice die, and ER alpha-36 receptor expression of mouse spleen leukemia cells detected by immunohistochemistry.
3. Effect of compounds on expression of ER α -36 receptor in K562 cells:
detecting the proportion of cells expressing ER alpha-36 receptor in K562 cells after no intervention and 8 mu M compound action by using a flow cytometer and an indirect immunofluorescence microscope, and detecting the expression quantity condition of ER alpha-36 receptor protein in K562 cells after the compound stem prognosis with different concentrations by using a Western blot method.
The experimental results show that the compound with the structure of the formula (I) is especiallyFormula (II) which inhibits CML cell proliferation in a concentration-dependent manner and induces apoptosis in bone marrow cells of a CML patient in a concentration-dependent manner; can significantly reduce the peripheral blood leukocyte count and CD45+The proportion of leukemia cells; meanwhile, the weight of the spleen of a leukemia mouse can be obviously reduced; can also inhibit the expression level of ER alpha-36 receptor protein in K562 cells in a concentration-dependent manner, thereby indicating that the compound with the structure of the formula (I) can treat chronic myelogenous leukemia.
Drawings
FIG. 1 MTT assay for proliferation inhibitory effect of Compound (II) on K562 cells.
FIG. 2 MTT test of the effect of compound (II) on the inhibition of proliferation of myeloid primary leukemia cells in 19 CML patients and myeloid mononuclear cells in 11 non-hematological tumor patients.
FIG. 3 Effect of Compound (II) on apoptosis Rate of CML patient myeloid Primary leukemia cells (compared to control group)*P＜0.05，**P＜0.01)。
FIG. 4 Effect of Compound (II) on mouse peripheral blood leukocyte counts as a function of time to live.
In the figure, IC 8 was 8. mu.g/g of Compound (II), IC 4 was 4. mu.g/g of Compound (II), Con was a blank control group, and Ima 50 was Imatinib 50. mu.g/g.
FIG. 5 Effect of Compound (II) on mouse peripheral blood human CD45 antigen expression as a function of survival time.
In the figure, IC 8 was 8. mu.g/g of Compound (II), IC 4 was 4. mu.g/g of Compound (II), Con was a blank control group, and Ima 50 was Imatinib 50. mu.g/g.
FIG. 6 Effect of Compound (II) on spleen size in tumor-bearing mice.
In the figure, Control is a blank Control group, IC 1628 is a group of compound (II) 8. mu.g/g, IC 1624 is a group of compound (II) 4. mu.g/g, and Ima 50 is an Imatinib 50. mu.g/g group.
FIG. 7 Effect of Compound (II) on mean spleen weight in tumor-bearing mice.
In the figure, Con is a blank control group, IC 8 is a group of compound (II) 8. mu.g/g, IC 4 is a group of compound (II) 4. mu.g/g, Ima 50 is an Imatinib 50. mu.g/g group (compared with the blank control group,*p is less than 0.05; compared with the positive control group, # P > 0.05; DELTA.P > 0.05) in comparison with the 4. mu.g/g group of Compound (II).
FIG. 8 Effect of Compound (II) on spleen ER α -36 receptor expression in tumor-bearing mice.
Wherein A, B, C and D are blank control group, Imatinib 50. mu.g/g group, compound (II) 4. mu.g/g group and compound (II) 8. mu.g/g group, respectively.
FIG. 9 Effect of Compound (II) on ER α -36 receptor expression in K562 cell membranes.
FIG. 10 Effect of Compound (II) on expression of ER α -36 receptor protein in K562 cells.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The following examples illustrate the preparation of the compounds and methods of the present invention. It is to be understood that the invention is not limited to the details provided below.
The following examples illustrate the preparation of compounds of formula (II).
3, 5, 7-Trihydroxyl-2- (4-methoxyphenyl) -8- (3-methyl-2-butenyl-) -4H-benzopyran-4-one (aka Icaritin, Icaritin; aka IC162 and IC in bioassay experiments)
The compound of the embodiment is prepared by separating and extracting a chemical monomer icaritin from a traditional Chinese medicine epimedium according to a method described in another invention patent 'preparation method of icaritin' (Mengkun, CN101302548A), namely the compound of the embodiment of the invention.
Biological experiments of the Compounds of the examples
The present invention has been described above in relation to the use of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the treatment of chronic myelogenous leukemia. Now, the compound (II) of the examples will be described in detail.
(1) Examples compound (II) inhibits proliferation and induces apoptotic effects on CML cells:
the experiment has the specific experimental method as aboveBiological experiments and testsIn part, experiment 1 (inhibition of proliferation and apoptosis-inducing effects of compounds on CML cells) describes. The compound (II) of the example was used in the other experiments at concentrations of 0. mu.M, 4. mu.M, 8. mu.M, 16. mu.M, 32. mu.M, 64. mu.M, except for the effect on the K562 cell cycle at a single concentration.
The experimental results show that compound (II) of the example can inhibit the proliferation of CML cells in a concentration-dependent manner and induce apoptosis of bone marrow cells of CML patients in a concentration-dependent manner. The results are shown in FIGS. 1-3.
(2) Example therapeutic effect of compound (II) on NOD-SCID mice transplanted with K562 cell line:
the specific experimental procedure of this experiment was as described in experiment 2 (therapeutic effect of compound on NOD-SCID mice transplanted with K562 cell line) in the previous biological experiments and test section. Example Compound (II) was used in two doses of 4. mu.g/g and 8. mu.g/g.
The experimental results show that the compound (II) in the example can obviously reduce the white blood cell count of peripheral blood and the proportion of CD45+ leukemia cells; example compound (II) significantly reduced spleen volume in leukemic mice while reducing spleen weight in leukemic mice. The experimental results also show that the spleen of the blank control group mice expresses much ER alpha-36 receptor, and the spleen of the mice treated by the compound (II) of the example shows no ER alpha-36 receptor expression. Specific results are shown in FIGS. 4-8, in which IC 8 and IC 1628 represent 8. mu.g/g of the example compound (II), IC 4 and IC 1624 represent 4. mu.g/g of the example compound (II), Con and Control represent blank Control, and Ima 50 represents Imatinib 50. mu.g/g.
(3) Examples effect of compound (II) on ER α -36 receptor expression in K562 cells:
the experiment has the specific experimental method as aboveBiological experiments and testsIn part, experiment 3 (effect of compounds on ER α -36 receptor expression in K562 cells). Example compound (II) was applied to K562 cells at a concentration of 8 μ M, and the proportion of cells expressing the era-36 receptor was measured by immunofluorescence and flow cytometry. Examples Compound (II) cells were treated with concentrations of 0. mu.M, 4. mu.M, 8. mu.M, 16. mu.M, 32. mu.M and 64. mu.M and examined for ER α -36 expression by Western blot.
The experimental result shows that the K562 cell membrane has the condition of strong expression of ER alpha-36 receptor, and the compound (II) in the embodiment can obviously reduce the expression of the ER alpha-36 receptor of the K562 cell membrane. Example Compound (II) also inhibited ER α -36 receptor protein expression in K562 cells in a concentration-dependent manner. The results are shown in FIGS. 9-10.
Claims (1)
1. The application of the compound of the formula (II) and the pharmaceutically acceptable salt thereof in preparing the medicines for improving, preventing and treating the chronic myelocytic leukemia,
wherein,
the chronic myelogenous leukemia is the chronic myelogenous leukemia with positive expression of an estrogen receptor ER-alpha 36.
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| CN2009101808791A CN102038673B (en) | 2009-10-20 | 2009-10-20 | Application of hydroxyl benzopyrone compound for preparing medicament for treating leukemia |
| PCT/CN2010/077334 WO2011047595A1 (en) | 2009-10-20 | 2010-09-26 | Use of hydroxy benzopyrone compounds in preparing medicine useful for treating leukemia |
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| CN103204838B (en) | 2012-01-13 | 2017-06-09 | 北京盛诺基医药科技有限公司 | The synthesis of polyhydroxy Benzofurantone compound and its antitumor action |
| WO2015024512A1 (en) * | 2013-08-23 | 2015-02-26 | 北京珅奥基医药科技有限公司 | Use of icaritin in preparation of drugs for treatment of diseases related to flt-3 |
| CN104230870A (en) * | 2014-09-16 | 2014-12-24 | 北京盛诺基医药科技有限公司 | Icaritin compound and application thereof |
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| CN101103973A (en) * | 2006-09-14 | 2008-01-16 | 殷正丰 | Anti-tumor medicine |
| CN101528038B (en) * | 2006-10-25 | 2011-05-11 | 盛诺基医药科技有限公司 | Compounds and methods for treating estrogen receptor-related diseases |
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