WO2012000306A1 - 含二苯乙烯片段的苯基硝酮类化合物及其用途 - Google Patents
含二苯乙烯片段的苯基硝酮类化合物及其用途 Download PDFInfo
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- WO2012000306A1 WO2012000306A1 PCT/CN2011/001031 CN2011001031W WO2012000306A1 WO 2012000306 A1 WO2012000306 A1 WO 2012000306A1 CN 2011001031 W CN2011001031 W CN 2011001031W WO 2012000306 A1 WO2012000306 A1 WO 2012000306A1
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- phenyl
- nitrone
- group
- compound
- tert
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
- C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
Definitions
- the present invention relates to benzophenone-containing compounds and pharmaceutically acceptable salts thereof for use in the treatment of hyperproliferative diseases of mammalian cells, such as cancer, and as neuroprotective agents.
- the invention further relates to a process for the preparation of said compounds, to pharmaceutical compositions containing these compounds and to the use of these compounds in the preparation of antitumor drugs.
- Cancer resistance is one of the most difficult problems in current cancer treatment. To solve this problem, we must start with understanding the anti-drug mechanism of cancer cells, so as to develop a targeted new drug to solve the drug resistance problem of cancer cells.
- the tyrosine proteasome is one of the more intensive tumor targeting targets in recent years. The main functions of the proteasome play a key role in the proliferation of cancer cells, impede the apoptosis induced by chemotherapy drugs, and help cancer cells fight against chemotherapy drugs. Therefore, inhibition of protease activity can help solve the problem of drug resistance in cancer cells. Tyrosine proteasome inhibitors are also one of the current developments in anticancer drugs. Many other compounds have been identified, such as styrene derivatives, such as literature
- hypoxic cancer cells In cancer tissues, due to factors such as abnormal vascular structure and excessive growth of cancer cells, it is easy to cause local hypoxia. Hypoxic cells are commonly found in various cancer tissues, and their presence helps cancer cells resist chemotherapy and radiation therapy. Therefore, drug research targeting hypoxic cancer cells is one of the current research topics of anticancer drugs. Listed below are some of the compounds currently being developed in the world that target hypoxic cancer cells.
- AQ 4 N is currently being collaborated by Novacea Inc and KuDOS Pharmaceuticals for clinical research and is applicable to various cancers.
- quinoxaline l,4-di-N-oxide, reference Reporting by Bioorg Med Chem, 2001, 9.
- Tirapazamine is currently being developed by sanofi-aventis for clinical studies and is applicable to various cancers. Its mechanism of action may It is activated by various reductases in the body and produces free radicals in hypoxic cells, which induces single-strand and double-strand breaks in DNA, impaired base pairs, and ultimately cell death. Hypoxic cells are common in solid tumors. presence.
- Tirapazamine is only activated by hypoxic cells, so the drug has better targeting selectivity.
- Phenyl nitrone compounds can be found in Axlikon's newly developed anti-free radical drug NXY-059, which has a strong ability to capture free radicals. Once it combines with free radicals to form a stable new compound, this When free radicals lose their activity, they can no longer destroy cell tissue and participate in a series of biochemical changes.
- the present invention relates to a series of phenyl nitrone derivatives containing stilbene fragments having novel structural features, which are mainly represented by substituted stilbene fragments, substituted phenyl nitrones fragments, and substituted aromatic groups.
- the manner in which the chemical constituent fragments such as loop fragments are linked is different from the compounds reported in the above patent documents, and the inventors have surprisingly found that the novel compounds obtained by these differences have outstanding antitumor properties, and thus can be developed as antitumor drugs. Summary of the invention
- the present invention relates to a phenyl ketone compound of the following formula (I), and a pharmaceutically acceptable salt thereof and a prodrug thereof.
- an aspect of the present invention provides a compound of the following formula (I):
- p, q alone represent an integer from 0 to 4, with the condition that p ⁇ 4 q ⁇ 4; b represents a double bond which may or may not be present; when a double bond is present, the compound of formula (I) is in an E or Z configuration When the double bond is absent, the stereocenter of the compound of formula (I) has an R- or S-configuration;
- R and R' represent H alone; CC 2 o straight or branched alkyl; C 2 -C 20 straight or branched alkenyl; -C0 2 Z', where 2' is 11, sodium, potassium, or other A pharmaceutically acceptable counterion such as calcium, magnesium, ammonium, tromethamine, tetradecylammonium, etc.; -C0 2 R'"; -NH 2 ; -NHR'"; -NR 2 '"; -OH Halogen; substituted dC 2 .
- R' represents dC ⁇ straight or branched alkane a linear, branched or branched alkenyl or aralkyl-(CH 2 )x-Ar, wherein X is an integer from 1 to 6; -C0 2 R"", wherein R"" represents H, optionally substituted C20 Alkyl, optionally substituted CrC 2 () straight or branched alkyl, optionally substituted C 2 -C 2G alkenyl, or optionally substituted C 6 -C 10 aryl or morpholine, piperidine a cyclic moiety such as piperazine;
- A, A' represents a mono- or poly-substituted group, independently representing H, 0 ( 20 acylamino, CrC 20 Acyloxy, dC ⁇ alkanoyl, C!-Czoalkoxycarbonyl, d-Qw)alkoxy, d-Czoalkylamino, CC 2 o alkanoyl, aroyl, aralkanoyl, halogen, hydroxy, nitro Base; or
- A, A' represents a straight-chain or branched chain which may be optionally substituted ( ⁇ -(: 20 alkyl or C 2 -C 20 alkenyl; or an anthracene dioxy or ethylenedioxy group;
- p, q independently represent an integer from 0 to 4, with the condition ⁇ 4 and 9 ⁇ 4; b represents a double bond which may or may not exist; when a double bond is present, it may be an E or Z configuration, when When the bond is absent, the obtained stereocenter may have an R- or S-configuration;
- R and R' independently represent H; -C0 2 Z', wherein Z' _H, sodium, potassium, or other pharmaceutically acceptable counterions such as calcium, magnesium, ammonium, tromethamine, tetradecylammonium And -C0 2 R"", wherein R"" alone represents H, optionally substituted d-o alkyl, optionally substituted d-Czo straight or branched alkyl, preferably optionally substituted -C 6 Alkoxy (eg, decyloxy, ethoxy or propoxy), optionally substituted C 2 -C 2 Q alkenyl, or optionally substituted C 6 -C 1C aryl or morpholine, piperidine a cyclic moiety such as piperazine;
- A, A' represents a mono- or poly-substituted group, which may be H, d-Csoamido, d-Csoacyloxy, 0 ( 20 alkanoyl, C20 alkoxycarbonyl, d-o alkoxy, 0 ( 20 alkyl ⁇ , d-Czoalkanocarboxy, aroyl, aralkanoyl, silk, halogen, hydroxy, nitro; or
- A, A' may also represent an optionally substituted straight or branched d-Czo alkyl group or a C 2 -C 2Q alkenyl group; or an anthracene di L group or an ethylenedioxy group;
- Representative compounds of the invention include:
- the present invention further provides a process for producing a compound of the formula (I), which is exemplified below by using a representative compound 6 of the present invention as an example.
- the synthetic route 1 of the present invention is as follows:
- the invention further provides a pharmaceutical composition comprising a compound of formula (I), said composition comprising a therapeutically effective amount of a compound of formula (I) and a physiologically acceptable carrier.
- the therapeutically effective amount means that the amount of the compound of formula (I) contained in the pharmaceutical composition is sufficient to produce a clinically desirable therapeutic effect, e.g., the tumor size of the drug is reduced to a clinically acceptable range.
- the pharmaceutical composition of the present invention can be administered intravenously, intradermally, intramuscularly, subcutaneously, orally, and the pharmaceutical composition can be used as a gastrointestinal preparation such as a tablet, a capsule, a pill, etc. It may also be a parenteral preparation such as an injection or a topical preparation.
- the invention provides a method of treating an anti-tumor and related disease, the method comprising administering to a patient suffering from a cancer or a related condition a therapeutically effective amount of a compound of the formula (I).
- the melting point was measured on an RT-1 melting point apparatus (Tianjin Analytical Instrument Factory) and the temperature was corrected.
- 1H NMR spectra were recorded on a Bruker AV400 (400 MHz) spectrometer and described in a magnetic field of 4 parts per million (ppm) of TMS.
- Infrared spectra were recorded on a Nicolet Magna 550 FT-IR Fourier spectrophotometer.
- Mass spectra were recorded using a HP1100 Esquire 2000 liquid chromatography/mass spectrometer.
- UV spectra were recorded on a Shimadzu UV2410 UV spectrophotometer.
- a 10 mM compound was prepared in DMSO, diluted 1:5, and each compound was assayed at a final concentration of 50 ⁇ M.
- 0.5 ⁇ l was removed from the corresponding compound plate and added to the cell culture plate, and incubated in a 37 ° C incubator for 72 hours. The morphology of the cells was then observed under an inverted microscope, and 20 l5 mg/ml of MTT solution prepared from sterile PBS was added to each well. Incubate for 5 hours in a 37 ° C incubator, add ⁇ triple solution, and dissolve in a 37 °C biochemical incubator overnight. Absorbance values were measured using Flexstation3. Record the IC50 value obtained from the analysis. The inhibition rate of the above 12 compounds against cell growth is shown in Table 3.
- mice in logarithmic growth phase were collected and resuspended in serum-free medium to a final concentration of 5.0 ⁇ 10 7 cells/ml.
- 70 BALB / c mice trees (weeks 6-7 weeks old) were inoculated subcutaneously 0.2ml A549 cell suspension, seeding density of 1.0xl0 7 cells / mouse. Animals are monitored daily to observe daily performance.
- the tumor area (length X width) was measured three times per week using a vernier caliper, and the tumor volume was calculated by the formula (length X width 2 )/2. When the tumor volume reached an average of about 150 mm 3 , randomization was performed at a screening rate of 60% to 70%, and the remaining animals were euthanized.
- mice 48 animals were randomly divided into 6 groups for administration: 3 samples were administered, including 1 positive control drug, once a day, for 3 weeks, compound treatment: dissolved in DMSO to form 10 The mother liquor at the final concentration was diluted 1:9 in physiological saline before administration.
- the administration route of the test drug is intragastric administration, and the administration volume is O.lmVlOg.
- Body weight was measured before daily dosing and tumor volume was measured twice a week. Animals monitor their daily behavior. Health observations include animal mortality, appearance, spontaneous activity, posture, and food intake. Once any of the above mentioned side effects are found, it will be recorded. Once the animal has significant weight loss (relative weight change rate greater than 20%), cachexia or tumor oversize, which seriously affects animal vitality (feeding water, mobility), the animal will be euthanized; if the animal has severe ulcers, Or bloody tumors, will also be euthanized. At the end of the experiment, the tumors were stripped and weighed for sample collection for subsequent testing. The entire in vivo study process was 28 days.
- Tumor volume, tumor weight, tumor growth inhibition rate, and relative body weight change rate are shown in Table 4 below.
- the compound 15 high-dose group and the compound 6 low-dose group were statistically significant in inhibiting tumor growth of A549 tumor-bearing mice compared with the control group after 28 days of administration, while the compound 15 low-dose group was used. Not statistically significant, ie, did not significantly inhibit tumor growth.
- the compounds according to the invention may be combined with a physiologically acceptable carrier or vehicle to provide a pharmaceutical composition, such as a lyophilized powder in the form of a tablet or capsule containing various fillers and binders.
- a pharmaceutical composition such as a lyophilized powder in the form of a tablet or capsule containing various fillers and binders.
- the compounds can be co-administered with other agents, and co-administration should mean that at least two agents are used in the patient to provide the beneficial effects of the combination of the two agents.
- the dose can be applied simultaneously or sequentially within a certain period of time.
- the compounds of the invention may be used alone or in combination with one or more additional agents.
- Combination therapies contemplated by the present invention include, for example, the use of the compounds of the invention and additional agents in a single pharmaceutical formulation, as well as the use of the compounds of the invention and additional agents in separate pharmaceutical formulations.
- the compounds of the present invention can be administered to a dairy animal, preferably a human, alone or in combination with a pharmaceutically acceptable carrier or diluent, optionally together with known adjuvants such as microcrystalline cellulose, in a pharmaceutical composition according to standard pharmaceutical practice.
- the compounds can be administered orally or parenterally, including intravenous, intramuscular, internal, subcutaneous, rectal and topical routes of administration.
- the selected compound can be administered, for example, in the form of a tablet or capsule or as an aqueous solution or suspension.
- usual carriers are usually added including lactose and corn starch, and lubricants such as magnesium stearate.
- diluents which may be employed include lactose and anhydrous corn starch, and when an aqueous suspension for oral use is required, the active ingredient is mixed with an emulsifier and a suspending agent. If necessary, add some sweeteners and/or flavoring agents.
- the total concentration of solutes should be controlled to make the formulation isotonic.
- Compound 6 80mg Microcrystalline cellulose 40mg Lactose 50mg Low-substituted hydroxypropyl cellulose 8mg Magnesium stearate 2mg
- the pharmaceutical composition of the above embodiment can also be prepared by the following method: Weighing compound 6, filler and disintegrant in a 50-fold prescription amount through 60, 80 mesh sieve, mixing uniformly, using 2 to 20% poly Venetian K30 50% ethanol solution soft material, 30 mesh sieve granulation, 60 ° C drying, particle moisture control within 3%, 20 mesh sieve granules, add appropriate amount of lubricant, mix evenly, tablet, ie Get the product.
- the compounds and compositions of the present invention have anti-tumor activity and have therapeutic effects in patients suffering from cancer or related conditions, and the present invention provides methods for their preparation and use.
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Description
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Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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AU2011274194A AU2011274194B2 (en) | 2010-07-01 | 2011-06-21 | Phenyl nitrone compounds containing stilbene segment and use thereof |
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CN201010216461.4 | 2010-07-01 | ||
CN201010216461.4A CN101898979B (zh) | 2010-07-01 | 2010-07-01 | 含二苯乙烯片段的苯基硝酮类化合物及其用途 |
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WO2012000306A1 true WO2012000306A1 (zh) | 2012-01-05 |
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CN (1) | CN101898979B (zh) |
AU (1) | AU2011274194B2 (zh) |
WO (1) | WO2012000306A1 (zh) |
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CN101898979B (zh) * | 2010-07-01 | 2014-03-05 | 深圳海王药业有限公司 | 含二苯乙烯片段的苯基硝酮类化合物及其用途 |
CN105175288B (zh) * | 2014-06-09 | 2017-07-07 | 深圳海王医药科技研究院有限公司 | 一种含二苯乙烯片段的苯基硝酮类化合物的制备方法 |
Citations (3)
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CN101070274A (zh) * | 2007-06-14 | 2007-11-14 | 复旦大学 | 一种具有抗肿瘤活性的二苯乙烯类化合物及其制备方法 |
CN101684114A (zh) * | 2008-09-27 | 2010-03-31 | 江苏正大天晴药业股份有限公司 | 新型二苯乙烯类化合物及其制备方法 |
CN101898979A (zh) * | 2010-07-01 | 2010-12-01 | 深圳海王药业有限公司 | 含二苯乙烯片段的苯基硝酮类化合物及其用途 |
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CN101638395A (zh) * | 2009-06-30 | 2010-02-03 | 深圳海王药业有限公司 | 二苯基乙烯化合物的杂环类似物及其应用 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101070274A (zh) * | 2007-06-14 | 2007-11-14 | 复旦大学 | 一种具有抗肿瘤活性的二苯乙烯类化合物及其制备方法 |
CN101684114A (zh) * | 2008-09-27 | 2010-03-31 | 江苏正大天晴药业股份有限公司 | 新型二苯乙烯类化合物及其制备方法 |
CN101898979A (zh) * | 2010-07-01 | 2010-12-01 | 深圳海王药业有限公司 | 含二苯乙烯片段的苯基硝酮类化合物及其用途 |
Non-Patent Citations (1)
Title |
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STEFAN HAUCK ET AL.: "p-Nitrostilbene-tert-Butyl-Nitrone: a Novel Fluorescent Spin Trap for the Detection of ROS with Subcellular Resolution", APPLIED MAGNETIC RESONANCE, vol. 36, no. 2-4, 2009, pages 133 - 147 * |
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AU2011274194A1 (en) | 2013-02-21 |
CN101898979B (zh) | 2014-03-05 |
AU2011274194B2 (en) | 2015-12-17 |
CN101898979A (zh) | 2010-12-01 |
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