CN101254183A - Novel use of niclosamide and pharmaceutically acceptable salt thereof - Google Patents
Novel use of niclosamide and pharmaceutically acceptable salt thereof Download PDFInfo
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- CN101254183A CN101254183A CNA2008100268768A CN200810026876A CN101254183A CN 101254183 A CN101254183 A CN 101254183A CN A2008100268768 A CNA2008100268768 A CN A2008100268768A CN 200810026876 A CN200810026876 A CN 200810026876A CN 101254183 A CN101254183 A CN 101254183A
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Abstract
The invention discloses an application of niclosamide or pharmaceutically-acceptable salts thereof in preparing anti-tumor drugs, which provides a candidate drug for tumor patients and may further improve the therapeutic effect and the prognosis to patients. The effectiveness of niclosamide or pharmaceutically-acceptable salts thereof on various tumor cells indicates that the composition may be used for treating various cancers such as cerebroma, genitourinary tumor, lymphatic system, stomach cancer, cancer of larynx, nasopharyngeal cancer, skin cancer, bone cancer, leukaemia, leukaemia, breast cancer, histiocytic lymphoma, non-small-cell lung cancer, small-cell lung cancer, lung adenocarcinoma, epidermoid cancer, pancreatic cancer, prostatic cancer, liver cancer and epithelial cell cancer.
Description
Technical field
The present invention relates to the new application of chemical compound niclosamide or its pharmaceutically acceptable salt.
Technical background
Tumor is the No.1 killer of present human health and life, and its sickness rate is only second to cardiovascular disease.And along with the influence of environmental pollution or other factors, the sickness rate of malignant tumor is fast rise trend.According to the data that World Health Organization (WHO) 2003 announces, the total malignant tumor patient 1,000 ten thousand in the whole world in 2000, because of malignant tumor death person up to 6,200,000, account for 12%～25% of total death toll.Anticipate the year two thousand twenty, global annual new cases will reach 1,500 ten thousand.In recent years, though the exploitation listing of some novel targeting new drugs such as tyrosine protein inhibitor is arranged, but still can't satisfy growing clinical cancer patient's needs far away.The antitumor drug research and development also are still the important research direction of present medicament research and development circle.
In recent years, along with the fast rise of new drug development cost, and the progressively downslide of drug development success rate, most of drug patent expires, and under the situation that the reserve new drug is difficult to follow up, drugmaker is the new patent protection medicine of exploitation on existing medicine basis one after another." old medicine is newly used " become a focus of International Pharmaceutical research and development.
Carry out new drug development at existing medicine, the most directly method is new therapeutic effect (or further utilization of favourable side effect) to occur by observing old medicine in use or clinical research process, and then the therapeutic domain of increase or improvement medicine, this strategy is called " reorientating method (Reposition) ".As have more than 100 year historical medicine aspirin, and come into the market as the medicine of anti-inflammatory analgetic, find that in the process of using this medicine can reduce prostaglandin level in the body, stop platelet aggregation, thereby have prevention of stroke and cardiopathic function; Low dose of aspirin is used to prevent the elderly brain thrombosis; Aspirin can promote insulin secretion, and increases the utilization of tissue to glucose, thereby blood glucose is descended.Statins antilipemic drugs not only can suppress the synthetic of cholesterol, and can bone density improving, prevention of osteoporosis; Vitimin supplement A and zinc can strengthen the antituberculotics curative effect; Vitamin B12 can strengthen the anticarcinogen effect.The situation that one medicine is used more is very general, and every kind of medicine can be used for the clinical indication more than 3 kinds according to estimates, and multi-purpose discovery such as aspirin is the tip of the iceberg of " old medicine is newly used ", and old medicine is new for having bigger research and development space.
Compare with traditional new drug development, have following advantage by " old medicine is newly used " developing new drug:
1. the safety of medicine is reliable: nearly 10,000 kinds of medicine major parts of having gone on the market were carried out IV phase clinical experiment, listing is after millions of people use, their safety or the machine-processed more clearly of toxic and side effects occur, existing pharmaceutical preparation and delivery system also can directly apply to the new pharmaceutical uses of follow-up discovery.
2. saving reasearch funds: in case find the new pharmacological action of old medicine,, can directly enter II-III phase clinical experiment, it goes without doing the IV phase clinical experiment of most of medicine because character such as its medicine generation, toxicity and bioavailability are clearer and more definite.Therefore, development costs reduces greatly.
3. the intellectual property space is wide: the patent of most medicines is expired in the medicine of listing.Therefore, in case find the new purposes of old medicine, the medicine that can obtain independent intellectual property right comes into the market, and produces economic benefit widely.
Niclosamide (Niclosamide) has another name called niclosamide, Bayluscid, is synthesized successfully by German Shi Laofusi top grade people early than nineteen fifty-nine, carries out suitability for industrialized production by Bayer A.G.Originally be snail-killing medicine, has remarkable curative effect in schistosomicide treatment field, niclosamide can also be made Liniment with the prophylaxis of acute schistosomicide, kill oncomelania and schistosomulum, miracidium, have that sn ail control effect is good, toxic and side effects is little, to characteristics such as the toxicity of people and poultry are low, be the fresh combatants of treatment schistosomicide.
In addition, niclosamide also is the people and the domestic animal expelling tenia medicine of a kind of wide spectrum, efficient, low toxicity.By income Chinese Pharmacopoeia, British Pharmacopoeia, European Pharmacopoeia etc.
This medicine is high for human its other homeothermia animal and plant safety, basic nonhazardous effect, and the human oral safe dose is up to more than the 2 gram/skies, and is only harmful to Fish.Clinical toxic and side effects is slight dizzy, uncomfortable in chest, abdominal discomfort or stomachache, heating, Pruritus etc.
At present, this medicine of Shang Weiyou is used for the reported in literature of cancer clinical treatment.
The chemical constitution of niclosamide
Summary of the invention
One of technical issues that need to address of the present invention provide the new application of a kind of chemical compound niclosamide or its pharmaceutically acceptable salt.
Concrete technical scheme is as follows:
The application in the preparation antitumor drug of niclosamide or its pharmaceutically acceptable salt.
This patent relates to the application in the preparation antitumor drug of chemical compound niclosamide or its pharmaceutically acceptable salt, and its pharmaceutically acceptable salt comprises that niclosamide and inorganic base or organic base compounds react and the salt that obtains.The salt that derives from inorganic base is including, but not limited to aluminum salt, ammonium salt, calcium salt, mantoquita, iron salt, ferrous salt, lithium salts, magnesium salt, manganese salt, manganous salt, potassium salt, sodium salt, zinc salt etc.Preferred especially ammonium salt, calcium salt, magnesium salt, potassium salt and sodium salt.Derive from the salt of pharmaceutically acceptable organic nontoxic alkali, described alkali is including, but not limited to primary amine, the salt of secondary amine and tertiary amine, the amine that replaces comprises naturally occurring replacement amine, cyclic amine and deacidite be arginine for example, betanin, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2 one DEAE diethylaminoethanols, 2 one dimethylaminoethanols, ethylaminoethanol, ethanolamine, ethylenediamine, N one ethyl morpholine, N one ethyl piperidine, glucamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methyl glucoside amine, morpholine, piperazine, piperidines, the croak smack one's lips, the polyamines resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropyl amine (TPA), tromethane etc.
The valid density of described chemical compound niclosamide or its pharmaceutically acceptable salt is 1 * 10
-8～1 * 10
-5M.
This patent relates to the propagation that chemical compound niclosamide or its pharmaceutically acceptable salt can suppress kinds of tumor cells effectively, and the growth of tumour cell cycle is suppressed and cell death inducing.These tumor cells including, but not limited to cerebroma, urogenital system tumor, lymphsystem tumor, gastric cancer, laryngeal carcinoma, nasopharyngeal carcinoma, skin carcinoma, osteocarcinoma, leukemia, leukemia, breast carcinoma and histiocyte lymphatic cancer, nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, carcinoma of prostate, hepatocarcinoma, skin carcinoma, cell carcinoma, etc. tumor cell.Chemical compound niclosamide or its pharmaceutically acceptable salt are 1 * 10 to 50% inhibition concentration of these growth of tumour cell
-8～1 * 10
-5M.
Another technical issues that need to address of the present invention provide a kind of antitumor Pharmaceutical composition.
Concrete technical scheme is as follows:
A kind of antitumor Pharmaceutical composition includes niclosamide or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
Described compositions also includes to comprise and is selected from the following chemical compound one or more: the medicine and the cell death inducer at estrogenic agents, androgen receptor modifier, retinoid-like receptor modulators, cytotoxin/cytostatics, antiproliferative, protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV kinases inhibitor, reverse transcriptase inhibitors, angiogenesis inhibitor, cell proliferation and the agent of existence signal suppressing, the interference cell cycle outpost of the tax office.
This patent relate to chemical compound niclosamide or its pharmaceutically acceptable salt when treatment or prophylaxis of cancer can be selected from following chemical compound coupling: cytotoxic drug; the tyrosine protein inhibitor; the EGFR inhibitor; the VEGFR inhibitor; the serine/threonine protein inhibitor; the Bcr-Abl inhibitor; the c-Kit inhibitor; the Met inhibitor; the Raf inhibitor; mek inhibitor; the MMP inhibitor; topoisomerase enzyme inhibitor; the histidine deacetylase inhibitor; proteasome inhibitor; the CDK inhibitor; the Bcl-2 family protein inhibitor; the MDM2 family protein inhibitor; the IAP family protein inhibitor; the STAT family protein inhibitor; the PI3K inhibitor; the AKT inhibitor; the integrin blocker; interferon-' alpha '; il-1 2; cox 2 inhibitor; estrogenic agents; androgen receptor modifier; the retinoid-like receptor modulators; cytotoxin/cytostatics; antiproliferative; protein transferase inhibitor; the HMG-CoA reductase inhibitor; the HIV kinases inhibitor; reverse transcriptase inhibitors; angiogenesis inhibitor; cell proliferation and the agent of existence signal suppressing; the medicine and the cell death inducer at the interference cell cycle outpost of the tax office, p53; the p53 activator; VEGF antibody; EGF antibody etc.
The medicine that this patent relates to the preparation of chemical compound niclosamide or its pharmaceutically acceptable salt when treatment or prophylaxis of cancer can with the radiotherapy coupling.
The invention provides chemical compound niclosamide or its pharmaceutically acceptable salt new purposes,, might further improve curative effect, improve its prognosis the patient for tumor patient provides new treatment drug candidate at the preparation antitumor drug.The medicine of niclosamide or its pharmaceutically acceptable salt preparation is effective to kinds of tumor cells, indicate this chemical compound have can be used for comprising cerebroma, urogenital system tumor, lymphsystem tumor, gastric cancer, laryngeal carcinoma, nasopharyngeal carcinoma, skin carcinoma, osteocarcinoma, leukemia, leukemia, breast carcinoma and histiocyte lymphatic cancer, nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, carcinoma of prostate, hepatocarcinoma, skin carcinoma, cell carcinoma, etc. multiple treatment for cancer.
Description of drawings
Fig. 1 is the growth inhibited curve of niclosamide to lung carcinoma cell (adenocarcinoma of lung A549, lung squamous cancer L-78);
Fig. 2 is the growth inhibited curve of niclosamide to kidney cancer cell OS-RC-2;
Fig. 3 is the growth inhibited curve of niclosamide to oral squamous carcinoma cell KB;
Fig. 4 is the growth inhibited curve of niclosamide to prostate gland cancer cell Du145;
Fig. 5 is the growth inhibited curve of niclosamide to colon cancer cell HT-29;
Fig. 6 is the cell cycle figure of Du145 cell, and wherein 6a is not dosing group, and 6b is the medicine low concentration group, and 6c is a medicine higher concentration group;
The Annexin V expression figure that Fig. 7 is the Du145 cell after niclosamide is handled, the expression of the AnnexinV of cell after the 7a low concentration drug treating wherein, 7b is the expression that high concentration medicine is handled the AnnexinV of back cell;
Fig. 8 a is to the growth inhibited curve of Du145 cell behind niclosamide and the paclitaxel fixed dosage administering drug combinations; Fig. 8 b is to the growth inhibited curve of Du145 cell behind niclosamide and the paclitaxel fixed dosage administering drug combinations;
Concrete embodiment
Embodiment 1:
Chemical compound niclosamide (1 * 10 with variable concentrations
-8～1 * 10
-5M) handle A549 (adenocarcinoma of lung), L-78 (lung squamous cancer), Du145 (carcinoma of prostate), KB (mouth epithelial cells cancer), OS-RC-2 (renal carcinoma), six kinds of cells of colon cancer (HT-29) respectively, MTT after 72 hours, hatched again 4 hours, and measured its light absorption value with microplate reader then at 570nm.Found that niclosamide is handled can obviously reduce the absorption of various cells to MTT, illustrates that niclosamide can significantly suppress the propagation of these five kinds of cells, suppression ratio becomes positive correlation with drug level.According to the growth inhibited effect of niclosamide to these five kinds of cells, we calculate niclosamide is 1 * 10 to the half-inhibition concentration (IC50) of these five kinds of cells
-8～1 * 10
-5M.Referring to Fig. 1-Fig. 5.
Embodiment 2:
Niclosamide (1 * 10 with variable concentrations
-8～1 * 10
-5M) handle Du145 (carcinoma of prostate) cell, getting cell respectively after processing in 12,24,36,48 hours handles with PI (propidium iodide), detect with flow cytometer then, find that niclosamide can significantly prolong the G1 phase of Du145 cell, and the G1 phase is elongated along with the increase of drug level.Referring to Fig. 6.
Table 1
Embodiment 3:
Niclosamide (1 * 10 with variable concentrations
-8～1 * 10
-5M) handle Du145 (carcinoma of prostate) cell, getting cell respectively after processing in 12,24,36,48 hours handles with AnnexinV (annexin V)/7AAD (7-amino-actinomycin D), detect Annexin V positive cell with flow cytometer then, find that the niclosamide processing can make Du145 cell positive rate obviously increase, illustrate that niclosamide can induce the Du145 apoptosis, apoptotic cells takes place increase along with the increase of chlorine nitre thiamine concentration, the prolongation in processing time.Fig. 7 a is the expression of the AnnexinV of cell after the low concentration drug treating, and Fig. 7 b is the expression that high concentration medicine is handled the AnnexinV of back cell.Referring to Fig. 7.
Embodiment 4:
Use the Du145 cell, select chemical compound niclosamide (1 * 10-8～1 * 10-5M) and Taxol fixed concentration drug combination and the taxol of 6 variable concentrations and the niclosamide drug combination of fixed concentration of 6 variable concentrations for use, act on and measuring with mtt assay after 72 hours, and the growth inhibited effect of these five kinds of cells being calculated the half-inhibition concentration of drug combination according to niclosamide, the result can reduce concentration medicine after showing drug combination significantly.Referring to Fig. 8.
Claims (7)
1. niclosamide or its pharmaceutically acceptable salt application in the preparation antitumor drug.
2. application according to claim 1 is characterized in that: the valid density of described niclosamide or its pharmaceutically acceptable salt is 1 * 10
-8～1 * 10
-5M.
3. application according to claim 1 is characterized in that: described tumor is any in histiocyte lymphatic cancer, nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, breast carcinoma, carcinoma of prostate, hepatocarcinoma, skin carcinoma, cell carcinoma, carcinoma of prostate, nasopharyngeal carcinoma, the leukemia.
4. application according to claim 1 is characterized in that: described niclosamide or its pharmaceutically acceptable salt and estrogenic agents, androgen receptor modifier, retinoid-like receptor modulators, cytotoxin/cytostatics, antiproliferative, protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV kinases inhibitor, reverse transcriptase inhibitors, angiogenesis inhibitor, cell proliferation and the agent of existence signal suppressing, the medicine at the interference cell cycle outpost of the tax office and one or more couplings in the cell death inducer.
5. application according to claim 1; it is characterized in that: described niclosamide or its pharmaceutically acceptable salt and cytotoxic drug; the tyrosine protein inhibitor; the EGFR inhibitor; the VEGFR inhibitor; the serine/threonine protein inhibitor; the Bcr-Abl inhibitor; the c-Kit inhibitor; the Met inhibitor; the Raf inhibitor; mek inhibitor; the MMP inhibitor; topoisomerase enzyme inhibitor; the histidine deacetylase inhibitor; proteasome inhibitor; the CDK inhibitor; the Bcl-2 family protein inhibitor, the MDM2 family protein inhibitor; the IAP family protein inhibitor; the STAT family protein inhibitor; the PI3K inhibitor; the AKT inhibitor; the integrin blocker; interferon-' alpha '; il-1 2; cox 2 inhibitor; p53; the p53 activator; VEGF antibody; one or more couplings in the EGF antibody.
6. an antitumor Pharmaceutical composition is characterized in that: include niclosamide or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
7. antitumor Pharmaceutical composition according to claim 6 is characterized in that: also include and be selected from the following chemical compound one or more: the medicine and the cell death inducer at estrogenic agents, androgen receptor modifier, retinoid-like receptor modulators, cytotoxin/cytostatics, antiproliferative, protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV kinases inhibitor, reverse transcriptase inhibitors, angiogenesis inhibitor, cell proliferation and the agent of existence signal suppressing, the interference cell cycle outpost of the tax office.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100268768A CN101254183A (en) | 2008-03-19 | 2008-03-19 | Novel use of niclosamide and pharmaceutically acceptable salt thereof |
| CN200810145234A CN101537001A (en) | 2008-03-19 | 2008-07-28 | Application of compound as JAK-STAT3 signal passage inhibitor |
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| CNA2008100268768A CN101254183A (en) | 2008-03-19 | 2008-03-19 | Novel use of niclosamide and pharmaceutically acceptable salt thereof |
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| CN200810145234A Pending CN101537001A (en) | 2008-03-19 | 2008-07-28 | Application of compound as JAK-STAT3 signal passage inhibitor |
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| CN101775032A (en) * | 2009-01-08 | 2010-07-14 | 中国科学院广州生物医药与健康研究院 | Niclosamide phosphate ester and pharmaceutically acceptable salt and application thereof |
| CN102432493A (en) * | 2011-11-15 | 2012-05-02 | 安徽东盛制药有限公司 | Method for preparing niclosamide piperazine salt |
| WO2012079232A1 (en) * | 2010-12-15 | 2012-06-21 | Lai Hung-Cheng | Compounds used for treating cancer and the use thereof |
| CN102697760A (en) * | 2012-05-21 | 2012-10-03 | 南京大学 | Application of niclosamide and salts of niclosamide in preparation of drugs for preventing and treating pulmonary fibrosis |
| CN105566147A (en) * | 2015-12-07 | 2016-05-11 | 北京信德润兴科技有限公司 | Compound, preparation method and application thereof and corresponding targeted drug delivery system and chemotherapy drugs |
| CN106589346A (en) * | 2016-10-20 | 2017-04-26 | 哈尔滨医科大学 | Water-soluble pegylated niclosamide, preparation method thereof and application in anti-tumor therapy |
| CN111233695A (en) * | 2020-03-13 | 2020-06-05 | 中国科学院成都有机化学有限公司 | Niclosamide cyclopropyl derivative, preparation method and application thereof |
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| CN109053480A (en) * | 2018-08-15 | 2018-12-21 | 河南省锐达医药科技有限公司 | The preparation method of a kind of novel niclosamide derivative and the application in oncotherapy |
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- 2008-03-19 CN CNA2008100268768A patent/CN101254183A/en active Pending
- 2008-07-28 CN CN200810145234A patent/CN101537001A/en active Pending
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| CN101775032A (en) * | 2009-01-08 | 2010-07-14 | 中国科学院广州生物医药与健康研究院 | Niclosamide phosphate ester and pharmaceutically acceptable salt and application thereof |
| WO2012079232A1 (en) * | 2010-12-15 | 2012-06-21 | Lai Hung-Cheng | Compounds used for treating cancer and the use thereof |
| CN103429235A (en) * | 2010-12-15 | 2013-12-04 | 赖鸿政 | Compounds used for treating cancer and use thereof |
| CN102432493A (en) * | 2011-11-15 | 2012-05-02 | 安徽东盛制药有限公司 | Method for preparing niclosamide piperazine salt |
| CN102432493B (en) * | 2011-11-15 | 2013-08-21 | 安徽东盛制药有限公司 | Method for preparing niclosamide piperazine salt |
| CN102697760A (en) * | 2012-05-21 | 2012-10-03 | 南京大学 | Application of niclosamide and salts of niclosamide in preparation of drugs for preventing and treating pulmonary fibrosis |
| US10905665B2 (en) | 2015-06-24 | 2021-02-02 | Duke University | Chemical modulators of signaling pathways and therapeutic use |
| CN105566147A (en) * | 2015-12-07 | 2016-05-11 | 北京信德润兴科技有限公司 | Compound, preparation method and application thereof and corresponding targeted drug delivery system and chemotherapy drugs |
| US10464885B2 (en) | 2015-12-07 | 2019-11-05 | Beijing Xinde Runxing Technology Co., Ltd. | Compound, preparation method therefor, applications thereof, corresponding targeted drug delivery system, chemotherapy drugs, and treatment method |
| CN106589346A (en) * | 2016-10-20 | 2017-04-26 | 哈尔滨医科大学 | Water-soluble pegylated niclosamide, preparation method thereof and application in anti-tumor therapy |
| CN111233695A (en) * | 2020-03-13 | 2020-06-05 | 中国科学院成都有机化学有限公司 | Niclosamide cyclopropyl derivative, preparation method and application thereof |
| CN111233695B (en) * | 2020-03-13 | 2024-01-26 | 中国科学院成都有机化学有限公司 | Chlor Liu Anhuan propyl derivative, preparation method and application thereof |
| WO2022033459A1 (en) * | 2020-08-10 | 2022-02-17 | 萧乃文 | Use of double non-oncology drug in preparation of pharmaceutical composition for treating cancers |
| WO2023020539A1 (en) * | 2021-08-19 | 2023-02-23 | 南京施江医药科技有限公司 | Application of benzanilide compound in tumor treatment |
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| Publication number | Publication date |
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| CN101537001A (en) | 2009-09-23 |
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