CN1768732A - Application of aromatic nitro compound in preparation of medicine for treating tumor - Google Patents
Application of aromatic nitro compound in preparation of medicine for treating tumor Download PDFInfo
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- CN1768732A CN1768732A CN 200410067714 CN200410067714A CN1768732A CN 1768732 A CN1768732 A CN 1768732A CN 200410067714 CN200410067714 CN 200410067714 CN 200410067714 A CN200410067714 A CN 200410067714A CN 1768732 A CN1768732 A CN 1768732A
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- nitro compound
- aromatic nitro
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- tumor
- alkylating agent
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Abstract
The invention relates to the usage of aromatic nitro compound in the preparation of tumor curing medicine, especially for combining the anti-neoplastic of alkyl agent to cure tumor and malignancy. The aromatic nitro compound can be used lonely or combined with anti-neoplastic of alkyl agent to effectively restrain or kill the malignancy. The restrain ratio of selected aromatic nitro compound on the tumor cell can reach 35% or more. The invention has strong medicinal crop, with normal preparing method to attain the compound which be accepted by pharmacy.
Description
Technical field
The present invention relates to general oncotherapy field.More particularly, the present invention relates to the independent or application of merging alkylating agent series antineoplastic medicament in effective treatment tumor with aromatic nitro compound.
Background technology
The growth of malignant tumor is because the characteristic of their uniquenesses has formed serious challenge to modern medicine.These characteristics comprise: uncontrollable cell proliferation causes malignant tissue irregularly to be grown, and the ability of invasion part even remote organization lacks variation, lacks the symptom that detects.The more important thing is, lack effectively treatment and prevention method.
Cancer can take place in any tissue in any organ of any age bracket.The definition of the etiology of cancer is unclear, but mechanism such as, environmental factors irregular, viral such as gene susceptibility, chromosome breakage and immune disorder are all grown with malignant cell and made a variation relevant.
The chemical medicinal treatment of cancer is one of main means of treatment cancer.Antitumor drug can be divided into a lot of classifications: comprise alkylating agent, topoisomerase I inhibitor and tubulin enzyme inhibitor etc.
Alkylating agent makes cell protein and nucleic acid alkanisation to prevent cellular replication, puts into cellular metabolism, finally causes cell death.Typical alkylating agent has chlormethine, cyclophosphamide etc.That the toxicity relevant with alkylating agent treatment comprises is nauseating, the danger increase of vomiting, bald head, hemorrhagic cystitis, lung fibrosis and formation acute leukemia.
Purine, pyrimidine and antifol pair cell circulate and specificity are arranged, in order to promote antitumous effect, the DNA synthesis phase that they require cell to be in the cellular replication stage and to duplicate.
Folate antagonist is combined closely as methotrexate and desmoenzyme dihydrofolate reductase, finally causes cell death owing to pyrimidine can not synthesize.The toxicity of these chemical compounds comprises bald head, vomiting, feels sick, suppresses bone marrow, maincenter movement disorder and conventional symptom.
Plant alkaloid suppresses the protein synthesis of the synthetic and dependenc RNA of mitosis and DNA usually as vincristine etc.The toxicity of these medicines is similar to the toxicity of said medicine, comprises bone marrow depression, peripheral neuropathy, vomiting, feels sick and bald head etc.
Topoisomerase suppresses class, is the DNA synthetic inhibitor as hydroxycamptothecin, and experimentation shows that it mainly acts on DNA synthesis stage (being the S phase), to G
0The phase cell is effect not, to G
1, G
2With M phase cell slight lethality is arranged.Common adverse effect comprises bone marrow depression, peripheral neuropathy, vomiting, feel sick and bald head etc.
Therefore, people wish that pharmacy industry provides the chemotherapeutics of safety, low toxicity, these medicines can suppress effectively and/forbid the breeding and the growth of tumor cell, and be desirable to provide safety, effectively and the chemotherapy medication of taking convenience.
Summary of the invention
The invention provides the application of aromatic nitro compound in preparation medicine for treating tumor thing, the feature of this application is the compositions that gives the pharmaceutically acceptable form of aromatic nitro compound separately, or merge administration with the alkylating agent series antineoplastic medicament, the dosage of aromatic nitro compound reaches to be enough to suppress effectively or the effect of regression tumor growth, and wherein aromatic nitro compound has following formula formula:
Or the compositions of its pharmaceutically acceptable form, wherein:
R
1, R
2And R
3Be selected from independently of one another: hydrogen base, hydroxyl, halogen, cyano group, nitro, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl, (C
3-C
7) cycloalkyl or phenyl.One of them particularly preferred chemical compound is a 4-iodo-3-nitrobenzamide.
Aromatic nitro compound, particularly 4-iodo-3-nitrobenzamide are the PARP inhibitor.PARP is called poly-(ADP-ribosyl) polymerase is called ADP-ribosyltransferase (ADPRT) again, is one to be positioned at the pigment desmoenzyme of most eukaryotic cells nuclears.This enzyme has three domains to participate in respectively in conjunction with DNA, the ribosylation of NAD and enzyme self.DNA has two zinc fingerses (ZnFn) in conjunction with the territory, by the CCHC in the zinc fingers (amino acid residue cys, cys, his, eys) sequestration zinc is being kept the stable of this structure.ADP-ribosyl polymerization in the PARP catalyzing N AD molecule produces energy and various nucleoprotein, comprises the covalently bound poly ADP-of PARP ribosyl itself.In normal cell, PARP has adaptive functions, participates in the normal transcription of DNA and duplicates.Yet at tumor cell, since the existence of unusual DNA (sudden change, cracking, over-replicate), the adaptive functions alienation of PARP.At this moment, PARP by its DNA in conjunction with the zinc fingers in territory exactly with the DNA combination, repel electric charge, cause PARP and DNA to dissociate, DNA repairs beginning, the cell division speedup, cell presents the malignant phenotype.Dissociate if suppress PARP and DNA, can duplicate by blocking dna, cell death inducing (body relies on this process to drive away damaging cells usually).Understanding to poly ADP-ribose polymerase (PARP) effect is to cause the key in application of developing drugs aromatic nitro compound in preparation medicine for treating tumor thing.At normal cell, PARP has the adaptability function to duplicating and transcribing of DNA.Yet do not have above-mentioned functions at tumor cell PARP, should be and have unusual DNA (as sudden change, fracture or unusual amplification).
4-iodo-3-nitrobenzamide has shown stronger cell growth inhibiting activity and cytotoxicity as the PARP inhibitor in list is tested with anti-tumor in vivo.
But, invent aromatic nitro compound safe and effective and easy to use and merge the scheme of other antineoplastic agents, can work in coordination with suppress and/forbid the breeding and the growth of tumor cell, be another object of the present invention thereby reach better antitumous effect.
In chemotherapeutics, the medicine with cancerous cell DNA damage function occupies significant proportion, as comprises antineoplastic alkylating agent cyclophosphamide etc.But one of limitation of this class medicine is drug-fast generation, this is because the cancerous cell DNA damage that medicine caused causes a large amount of activation of ribozyme PARP, the activation of PARP has promoted that then (PARP is a key factor in the DNA repairase system for the reparation of DNA, the dna single chain break causes the activation of PARP and then causes the reparation of DNA), thus the lethal effect of medicine weakened to cancerous cell.Just be based on the above biological function (biological function of PARP has multiformity) of PARP, so, aromatic nitro compound preferably drug combination to as if alkylating agent class antineoplastic agent.
The alkylating agent series antineoplastic medicament that can reach the synergistic antitumor purpose has chlormethine, cyclophosphamide, ifosfamide, thiophene for group, busulfan, formylmerphalan, the card mustard (nitrocaphanum) that disappears, carmustine (carmustine), Luo Mositing (lomustine), semustine (CH3-CCNU), procarbazine (procarbazine), dacarbazine (dacarbazinb), hexamethyl melamine, melphalan.All above alkylating agent class antineoplastic agents all are known, and application is arranged clinically.Among the present invention, cyclophosphamide is preferred alkylating agent class antineoplastic agent.
The present invention also is provided at and merges aromatic nitro compound and the administration of alkylating agent class antineoplastic agent in the oncotherapy, can use simultaneously, respectively or in order.
The further aspect of the present invention has provided the method for treatment mammal (comprising the mankind) tumor disease state, it comprises and gives aromatic nitro compound separately and merge the alkylating agent series antineoplastic medicament, wherein give the amount of aromatic nitro compound, reaching is enough to suppress effectively or the regression growth of tumor.
The present invention's alleged " synergistic antitumor effect " is meant the inhibition growth of tumor, and it comprises that merging gives the aromatic nitro compound and the alkylating agent series antineoplastic medicament of mammal effective dose.
The present invention's alleged " administration " is meant oral or/and the parenteral administration mode." parenteral route " is meant vein, subcutaneous and intramuscular administration.In the present invention aromatic nitro compound can be separately or with the administration simultaneously of alkylating agent series antineoplastic medicament, perhaps also can give these chemical compounds successively in any order.More desirable way is according to following factor the method that adopted in the reality and the order of administration suitably to be changed, these factors comprise: the special formulation that can contain pharmaceutically acceptable carrier, solvent and the inert matter that can increase its dissolubility of applied aromatic nitro compound, the special formulation of applied alkylating agent series antineoplastic medicament, specific tumors model of being treated and the specific host of being treated.
Use the compositions of the pharmaceutically acceptable form of aromatic nitro compound.Said composition contains pharmaceutically acceptable carrier, solvent and the inert matter that can increase drug solubility.
In an application of the invention, wherein give the amount of aromatic nitro compound, reaching is enough to suppress effectively or the regression growth of tumor.For 4-iodo-3-nitrobenzamide, common consumption is about 5-200mg/kg, and preferred consumption is about 5-100mg/kg.
Antineoplaston is particularly suitable for treating cancer and the sarcoma of mammal (comprising the mankind) among the present invention.Preferably breast tumor, ovarian tumor, lung tumor, colon tumor etc.
Material of the present invention can adopt United States Patent (USP) 5464871 disclosed preparation methoies to obtain.
The specific embodiment
The following example has been enumerated feature of the present invention, and it will illustrate but not limit the present invention.
Embodiment 1: preparation
1. capsule
Per 1000 consumptions
Principal agent 150g
Lactose 80g
Pregelatinized Starch 65g
7%PVP or starch slurry or HPMC are an amount of
Low-substituted hydroxypropyl cellulose 18g
Micropowder silica gel 2.0g
With lactose, pregelatinized Starch mix homogeneously, add binder solution and make soft material after the principal agent porphyrize sieves, granulate wet grain drying.Add all the other component mixings in the prescription, encapsulated getting final product behind the granulate.
2. injection
Press following formulation injection (1000ml):
By 1000ml
Principal agent 10g
PEG400 400ml
Ethanol 100
Normal saline adds to 1000ml
By prescription preparation PEG400: alcohol solvent, principal agent add in this solvent, and heating makes dissolving, packing, after the sterilization promptly.
Embodiment 2:4-iodo-3-nitrobenzamide intravenously administrable list usefulness and merging cyclophosphamide are to the curative effect of Mice Bearing Lewis Lung Cancer (sc) model
Eugonic Mice Bearing Lewis tumor source is diluted to cancerous cell homogenate with normal saline under the aseptic condition, and subcutaneous vaccination was respectively inoculated after 24 hours, and two dosage groups are established in intravenous injection, and dosage is respectively 25mg/kg/d, 12.5mg/kg/d.Every day 1 time, continuous 7 days, 4-iodo-3-nitrobenzamide merging group was respectively prior to cyclophosphamide administration in 15 minutes.
Negative control gives test group high dose dilution factor identical equal-volume solution.Positive control cyclophosphamide 15mg/kg intraperitoneal administration, every day 1 time, continuous 7 days.
The taking-up tumor was weighed and is compared with negative control group when experiment finished, and was calculated as follows the tumour inhibiting rate of each group:
Tumour inhibiting rate %=[(matched group tumor weight-administration group tumor is heavy)/the matched group tumor is heavy] * 100
4-iodo-3-nitrobenzamide is with 25mg/kg/d, 12.5mg/kg/d dosage iv * 7qd, merges cyclophosphamide 15mg/kg ip * 7qd separately and respectively the tumour inhibiting rate of Mice Bearing Lewis Lung Cancer is respectively 41.43%, 35.93%, 82.43%, 76.50%.The individually dosed curative effect of cyclophosphamide 15mg/kg ip * 7qd is 42.14%, sees table 1 for details.
Merging effect calculates by following formula:
Q=[drug combination tumour inhibiting rate/(medication tumour inhibiting rate sum-the medication tumour inhibiting rate is long-pending separately separately)]
Merge the effect criterion: drug combination has synergism when Q>1.
Show 1.4-iodo-3-nitrobenzamide intravenously administrable list usefulness and merge the curative effect of cyclophosphamide Mice Bearing Lewis Lung Cancer (sc) model
Group | Dosage mg/kg/d | Dosage regimen | Number of animals (only) | The weight of animals (g) beginning/end | Heavy (g) X ± SD of tumor | Tumour inhibiting rate % | Merge effect Q |
Negative control 4-iodo-3-nitro-benzamide 4-iodo-3-nitro-benzamide 4-iodo-3-nitro-benzamide+endoxan | 25 12.5 25+ 15 | iv×7qd iv×7qd iv×7qd iv×7qd+ ip×7qd | 20 10 10 10 | 20.6/24.8 20.7/23.9 20.4/24.2 20.6/22.7 | 2.80±0.35 1.64±0.19 1.79±0.16 0.49±0.23 | 41.43 35.93 82.43 | 1.25 synergism is arranged |
4-iodo-3-nitro-Benzoylamide+cyclophosphamide cyclophosphamide | 12.5+ 15 15 | iv×7qd+ ip×7qd ip×7qd | 10 10 | 20.4/22.4 20.4/23.2 | 0.66±0.16 1.62±0.21 | 76.50 42.14 | 1.22 synergism is arranged |
The explanation of above result of the test, 4-iodo-3-nitrobenzamide intravenously administrable list with and the merging cyclophosphamide Mice Bearing Lewis Lung Cancer (sc) model is had significant curative effect.
Embodiment 3:4-iodo-3-nitrobenzamide gastric infusion list usefulness and merging cyclophosphamide are to the curative effect of Mice Bearing Lewis Lung Cancer (sc) model
Eugonic Mice Bearing Lewis tumor source is diluted to cancerous cell homogenate with normal saline under the aseptic condition, and subcutaneous vaccination was respectively inoculated after 24 hours, and gastric infusion, dosage are 40mg/kg/d.Every day 1 time, continuous 7 days, 4-iodo-3-nitrobenzamide was irritated the stomach approach prior to cyclophosphamide administration in 30 minutes.
Negative control adopts 0.5%CMC-Na solution, the same test group of dosage regimen.Positive control cyclophosphamide 15mg/kg intraperitoneal administration, every day 1 time, continuous 7 days.
The taking-up tumor was weighed and is compared with negative control group when experiment finished, and was calculated as follows the tumour inhibiting rate of each group:
Tumour inhibiting rate %=[(matched group tumor weight-administration group tumor is heavy)/the matched group tumor is heavy] * 100
4-iodo-3-nitrobenzamide is with suspensoid 40mg/kg/d dosage ig * 7qd, merges cyclophosphamide 15mg/kgip * 7qd separately and respectively the tumour inhibiting rate of Mice Bearing Lewis Lung Cancer is respectively 38.23%, 75.23%.The individually dosed curative effect of cyclophosphamide 15mg/kg ip * 7qd is 44.06%, sees table 2 for details.
Merging effect calculates by following formula:
Q=[drug combination tumour inhibiting rate/(medication tumour inhibiting rate sum-the medication tumour inhibiting rate is long-pending separately separately)]
Merge the effect criterion: drug combination has synergism when Q>1.
Show 2.4-iodo-3-nitrobenzamide gastric infusion list usefulness and merge the curative effect of cyclophosphamide Mice Bearing Lewis Lung Cancer (sc) model
Group | Dosage mg/kg/d | Dosage regimen | Animal (only) | Number the weight of animals (g) beginning/end | Heavy (g) X ± SD of tumor | Tumour inhibiting rate % | Merge effect Q |
Negative control 4-iodo-3-nitro-benzamide 4-iodo-3-nitro-benzamide+endoxan endoxan | 40 40+ 15 15 | ig×7qd ig×7qd ig×7qd+ ip×7qd ip×7qd | 20 10 10 10 | 20.8/26.3 20.6/25.6 20.5/23.7 20.4/24.4 | 2.86±0.34 1.77±0.12 0.71±0.15 1.60±0.14 | 38.23 75.23 44.06 | 1.15 synergism is arranged |
The explanation of above result of the test, 4-iodo-3-nitrobenzamide gastric infusion list with and the merging cyclophosphamide Mice Bearing Lewis Lung Cancer (sc) model is had significant curative effect.
Claims (10)
1. the application of aromatic nitro compound in preparation medicine for treating tumor thing, wherein aromatic nitro compound has following formula formula:
Or the compositions of its pharmaceutically acceptable form, wherein:
R
1, R
2And R
3Be selected from independently of one another: hydrogen base, hydroxyl, halogen, cyano group, nitro, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl, (C
3-C
7) cycloalkyl or phenyl.
2. application according to claim 1, wherein said aromatic nitro compound are 4-iodo-3-nitrobenzamide.
3. application according to claim 1 and 2, the approach that wherein gives aromatic nitro compound is oral or/and the parenteral administration mode.
4. application according to claim 1 and 2, wherein the compositions of the pharmaceutically acceptable form of aromatic nitro compound is characterized in that containing pharmaceutically acceptable carrier, solvent or the inert matter that can increase drug solubility.
5. application according to claim 1 and 2 gives wherein that aromatic nitro compound can carry out separately or is giving the alkylating agent series antineoplastic medicament simultaneously, carry out respectively or in order.
6. application according to claim 1 and 2, wherein giving aromatic nitro compound is to give the alkylating agent series antineoplastic medicament while, carrying out respectively or in order.
7. application according to claim 5, wherein said alkylating agent series antineoplastic medicament are that chlormethine, cyclophosphamide, ifosfamide, thiophene are for group, busulfan, formylmerphalan, the card mustard (nitrocaphanum) that disappears, carmustine (carmustine), Luo Mositing (lomustine), semustine (CH3-CCNU), procarbazine (procarbazine), dacarbazine (dacarbazinb), hexamethyl melamine or melphalan.
8. application according to claim 7, wherein preferred alkylating agent series antineoplastic medicament is a cyclophosphamide.
9. application according to claim 1 and 2 wherein gives the amount of aromatic nitro compound, and reaching is enough to suppress effectively or the regression growth of tumor.
10. application according to claim 1 and 2, wherein malignant tumor is selected from cancer and sarcoma.
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CN 200410067714 CN1768732A (en) | 2004-11-02 | 2004-11-02 | Application of aromatic nitro compound in preparation of medicine for treating tumor |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7732491B2 (en) | 2007-11-12 | 2010-06-08 | Bipar Sciences, Inc. | Treatment of breast cancer with a PARP inhibitor alone or in combination with anti-tumor agents |
US7994222B2 (en) | 2006-09-05 | 2011-08-09 | Bipar Sciences, Inc. | Monitoring of the inhibition of fatty acid synthesis by iodo-nitrobenzamide compounds |
CN101190211B (en) * | 2006-11-23 | 2011-08-10 | 上海富海科申药业有限公司 | Application of aromatic nitro compound in preparing medicine for treating virus hepatitis |
US8143447B2 (en) | 2006-09-05 | 2012-03-27 | Bipar Sciences, Inc. | Treatment of cancer |
US8377985B2 (en) | 2005-07-18 | 2013-02-19 | Bipar Sciences, Inc. | Treatment of cancer |
-
2004
- 2004-11-02 CN CN 200410067714 patent/CN1768732A/en active Pending
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8377985B2 (en) | 2005-07-18 | 2013-02-19 | Bipar Sciences, Inc. | Treatment of cancer |
US7994222B2 (en) | 2006-09-05 | 2011-08-09 | Bipar Sciences, Inc. | Monitoring of the inhibition of fatty acid synthesis by iodo-nitrobenzamide compounds |
US8143447B2 (en) | 2006-09-05 | 2012-03-27 | Bipar Sciences, Inc. | Treatment of cancer |
CN101190211B (en) * | 2006-11-23 | 2011-08-10 | 上海富海科申药业有限公司 | Application of aromatic nitro compound in preparing medicine for treating virus hepatitis |
US7732491B2 (en) | 2007-11-12 | 2010-06-08 | Bipar Sciences, Inc. | Treatment of breast cancer with a PARP inhibitor alone or in combination with anti-tumor agents |
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