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
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- nitro compound
- aromatic nitro
- application according
- tumor
- alkylating agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 44
- 239000003814 drug Substances 0.000 title claims abstract description 33
- -1 aromatic nitro compound Chemical class 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 230000000118 anti-neoplastic effect Effects 0.000 claims abstract description 13
- 201000011510 cancer Diseases 0.000 claims abstract description 10
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 25
- 229960004397 cyclophosphamide Drugs 0.000 claims description 22
- 229940100198 alkylating agent Drugs 0.000 claims description 19
- 239000002168 alkylating agent Substances 0.000 claims description 19
- MDOJTZQKHMAPBK-UHFFFAOYSA-N 4-iodo-3-nitrobenzamide Chemical compound NC(=O)C1=CC=C(I)C([N+]([O-])=O)=C1 MDOJTZQKHMAPBK-UHFFFAOYSA-N 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 230000004614 tumor growth Effects 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 5
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 229960005243 carmustine Drugs 0.000 claims description 4
- 229960000624 procarbazine Drugs 0.000 claims description 4
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 claims description 3
- 229960004961 mechlorethamine Drugs 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 claims description 2
- 241000219198 Brassica Species 0.000 claims description 2
- 235000003351 Brassica cretica Nutrition 0.000 claims description 2
- 235000003343 Brassica rupestris Nutrition 0.000 claims description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 2
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 claims description 2
- 206010039491 Sarcoma Diseases 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 229960000473 altretamine Drugs 0.000 claims description 2
- 238000013459 approach Methods 0.000 claims description 2
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 claims description 2
- 229960002092 busulfan Drugs 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229960003901 dacarbazine Drugs 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 2
- 229960001101 ifosfamide Drugs 0.000 claims description 2
- 229960002247 lomustine Drugs 0.000 claims description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 2
- 229960001924 melphalan Drugs 0.000 claims description 2
- 235000010460 mustard Nutrition 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229960003440 semustine Drugs 0.000 claims description 2
- 229940015849 thiophene Drugs 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- 229940034982 antineoplastic agent Drugs 0.000 abstract description 6
- 239000003795 chemical substances by application Substances 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 5
- 210000004881 tumor cell Anatomy 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 125000000217 alkyl group Chemical group 0.000 abstract 2
- 230000036210 malignancy Effects 0.000 abstract 2
- 230000000694 effects Effects 0.000 description 20
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 18
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 18
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 15
- 230000002401 inhibitory effect Effects 0.000 description 15
- 241000699670 Mus sp. Species 0.000 description 10
- 208000020816 lung neoplasm Diseases 0.000 description 9
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 8
- 201000005202 lung cancer Diseases 0.000 description 8
- 239000013642 negative control Substances 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 239000000890 drug combination Substances 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 241000220645 Leonotis nepetifolia Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 206010047700 Vomiting Diseases 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 230000003203 everyday effect Effects 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 230000008673 vomiting Effects 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000030833 cell death Effects 0.000 description 3
- 210000003811 finger Anatomy 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 102000009062 ADP Ribose Transferases Human genes 0.000 description 2
- 108010049290 ADP Ribose Transferases Proteins 0.000 description 2
- 206010065553 Bone marrow failure Diseases 0.000 description 2
- 230000005778 DNA damage Effects 0.000 description 2
- 231100000277 DNA damage Toxicity 0.000 description 2
- 230000006820 DNA synthesis Effects 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- 239000012661 PARP inhibitor Substances 0.000 description 2
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 230000003044 adaptive effect Effects 0.000 description 2
- 230000008827 biological function Effects 0.000 description 2
- 238000009395 breeding Methods 0.000 description 2
- 230000001488 breeding effect Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 2
- 208000033808 peripheral neuropathy Diseases 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- GOLXNESZZPUPJE-UHFFFAOYSA-N spiromesifen Chemical compound CC1=CC(C)=CC(C)=C1C(C(O1)=O)=C(OC(=O)CC(C)(C)C)C11CCCC1 GOLXNESZZPUPJE-UHFFFAOYSA-N 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000002255 vaccination Methods 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 208000037088 Chromosome Breakage Diseases 0.000 description 1
- 206010011793 Cystitis haemorrhagic Diseases 0.000 description 1
- 125000000824 D-ribofuranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@]1([H])O[H] 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 229940123414 Folate antagonist Drugs 0.000 description 1
- PYAYDUBDRWOIHP-UHFFFAOYSA-N IC1=C(C=C(C(=O)N)C=C1)[N+](=O)[O-].IC1=C(C=C(C(=O)N)C=C1)[N+](=O)[O-] Chemical compound IC1=C(C=C(C(=O)N)C=C1)[N+](=O)[O-].IC1=C(C=C(C(=O)N)C=C1)[N+](=O)[O-] PYAYDUBDRWOIHP-UHFFFAOYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 208000016285 Movement disease Diseases 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 239000002295 alkylating antineoplastic agent Substances 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000005886 chromosome breakage Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 201000002802 hemorrhagic cystitis Diseases 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229960003552 other antineoplastic agent in atc Drugs 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 230000009919 sequestration Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000012622 synthetic inhibitor Substances 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410067714 CN1768732A (en) | 2004-11-02 | 2004-11-02 | Application of aromatic nitro compound in preparation of medicine for treating tumor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410067714 CN1768732A (en) | 2004-11-02 | 2004-11-02 | Application of aromatic nitro compound in preparation of medicine for treating tumor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1768732A true CN1768732A (en) | 2006-05-10 |
Family
ID=36750442
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410067714 Pending CN1768732A (en) | 2004-11-02 | 2004-11-02 | Application of aromatic nitro compound in preparation of medicine for treating tumor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1768732A (en) |
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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1222294C (en) | Combination preparations containing morpholine anthracycline derivatives and anticancer agents | |
| CN102438588A (en) | Methods of treating diseases using combination therapy | |
| CN1536995A (en) | Antitumor composition containing taxane derivative | |
| CN1429114A (en) | Combination chemotherapy | |
| CN1294516A (en) | Antitumor composition containing anthracycline derivatives and camptothecin derivatives with synergistic effect | |
| CN1897949A (en) | Combination therapy comprising the use of et-743 and paclitaxel for treating cancer | |
| CN1064407A (en) | Pharmaceutical composition | |
| CN118059108A (en) | Pharmaceutical composition and application thereof in preparation of antitumor drugs | |
| CN1768732A (en) | Application of aromatic nitro compound in preparation of medicine for treating tumor | |
| CN1787814A (en) | Method of increasing antitumor activity of anticancer agents | |
| CN1241573C (en) | Pharmaceutical compositions comprising acryloyl distamycin derivatives and topoisomerase I and II inhibitors | |
| CN1615136A (en) | Combinations comprising epothilones and anti-metabolites | |
| CN1224385C (en) | Drugs containing platinum complex compounds and uses thereof | |
| HK1054193A1 (en) | Use of substituted acryloyl distamycin derivatives in the treatment of tumors associated with high levels of glutathione | |
| CN100479824C (en) | Combined therapy against tumors comprising substituted acryloyl distamycin derivatives, taxanes and/or antimetabolites | |
| CN1343490A (en) | Sophoridine and its application in analgesic | |
| US20210315898A1 (en) | Combination therapy for treating cancer | |
| Einhorn | E21. Carboplatin versus cisplatin in lung cancer | |
| CN1817868A (en) | Group of ornidazole deriative for preventing anaerobe infection and production thereof | |
| CN101185628A (en) | Irinotecan sustained-release implant for treating solid tumor | |
| CN101181231B (en) | Sustained-release implantation agent of urotrotiken | |
| CN1780629A (en) | Medicinal compositions comprising n-(3-chloro-1h-indol-7-yl)-4-sulfamoylbenzenesulfonamide and further cytostatics | |
| HK40040825A (en) | Combination therapy for treating cancer | |
| EP1599210A1 (en) | A combined therapy comprising an indolopyrrolocarbazole derivative and another antitumor agent | |
| Weihrauch et al. | Topotecan in haematologic malignancies |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |