CN102070463A - Medicine memantine with adamantane structure, and derivative and analog thereof, and application to new antineoplastic indication - Google Patents
Medicine memantine with adamantane structure, and derivative and analog thereof, and application to new antineoplastic indication Download PDFInfo
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Abstract
The invention discloses medicine memantine with an adamantane structure, and a derivative and an analog thereof with new antineoplastic activity and new indication and also relates to application of the compounds as medicine for resisting diseases such as tumors and the like. The medicine memantine comprises the following structures and the derivative and the analog generated by the structure. The medicine memantine comprises new structural compounds generated by using the structure as a structural matrix or a structural segment, and inorganic acid salt, organic acid salt, inorganic alkali salt, organic alkali salt or complex salt and prodrug of the derivative and the analog in the structure, wherein the antineoplastic pharmacological activities and the application as antineoplastic medicine are matched with those of other existing antineoplastic medicine to be used, and the application to the treatment on diseases relevant to tumors or other diseases with tumor diseases comprises the treatment on diseases caused by viruses, germs and epiphytes, nervous system diseases, endocrine system diseases, immune system diseases and the like, and the medicine memantine is used through being matched with other medicine.
Description
Technical field
The present invention relates to have the medicine Memantine hydrochloride of adamantane structure and derivative thereof and analogue and have new activity such as antitumor and new indication, the invention still further relates to this compounds as the antitumor application that waits disease medicament.
Background technology
Derivatives of Adamantane, Memantine hydrochloride (Memantine, chemical structure is seen chemical structure) are as antiviral drug, and treatment seat sore medicine is treated the pulmonary tuberculosis medicine and has been applied to for many years clinical.At home and abroad document and patent aspect; find through system's searching document; said medicine is except original indication; also have a large amount of research both at home and abroad and invent new indication and application thereof; these domestic and foreign literature reports and patented invention mainly concentrate on the application of anti-new virus, to neural activity and neuroprotective, skin diseases treatment; the respiratory tract infection treatment, tuberculosis treatment etc.Only find one piece of document at present, U.S. Pat 7250394, Memantine hydrochloride only limits to cancer such as neck glioma due to the anticol cell plastid hyperplasia treatment glial cells hyperplasia.In addition, domestic and international patent and article are retrieved by system, and the research of the extensive anti-tumor activity of said medicine and the indication of antineoplastic new are used and be yet there are no report.
Chemical structure
Memantine hydrochloride (Memantine), other English name and numbering: 1,3-Dimethyl-5-adamantanamine, 1-Amino-3,5-dimethyladamantane, Memantina, 3,5-Dimethyl-1-adamantylamine, 3, (3.3.1.1 (3 for 5-Dimethyltricyclo, 7) decan-1-amine, Memantinum, 3,5-Dimethyl-1-adamantanamine, (3.3.1.1 (3 for Tricyclo, 7) decan-1-amine, DMAA, HSDB 7327, chemistry registration number: 19982-08-2,51052-62-1,41100-52-1 (Hydrochloride), molecular formula C
12H
21N molecular weight: 179.3.The research report of other indication of Memantine hydrochloride, it is depressed to be used for refreshing smart systemic disease medicine treatment, psychiatric system disorders, schizophrenia, U.S. Pat 20060270742, US 20060035888, and US 20080282911, and US 20080249082, US 20060252788, US20050245460, US 20050288375, and US 7456224; Be used for the treatment of alzheimer's disease, US 20080044461, and US 60020042, and US 20060020042, and US 200600240007, and US 20050203191, and US 20040092427, Chinese neuropsychiatric disease magazine, 2008 the 34th volumes the 01st; Be used for the treatment of Parkinson disease, U.S. Pat 20070026054; Be used for the treatment of migraine, U.S. Pat 5939425, US 5891885; Be used for cancer such as neck glioma due to the anticol cell plastid hyperplasia treatment glial cells hyperplasia, U.S. Pat 7250394, US 20050192322; Be used for the treatment of the glaucoma disease, U.S. Pat 20070293558, US 7494983, and US 5922773, and US 20010047012.
Summary of the invention
The purpose of this invention is to provide the medicine that a class has adamantane structure, Memantine hydrochloride (Memantine) and adamantane derivative and analogue, have new activity such as antitumor grade and new indication, the invention still further relates to this compounds as the antitumor application that waits disease medicament, and their pharmacologically active experimental technique and pharmacologically active are provided.
The object of the present invention is achieved like this, and its medicine Memantine hydrochloride molecular structure with adamantane structure is shown in chemical structure.
Described application with medicine Memantine hydrochloride and adamantane derivative and analogue of adamantane structure: it is active and as the application of antitumor drug to be included in the antitumor pharmacology of preparation, and activeconstituents is shown in the chemical structure.
Described and derivative and analog compounds are meant the Memantine hydrochloride structure are carried out the various derivatives that chemically modified obtained that these derivatives and Memantine hydrochloride have same or analogous structure parent nucleus; Be meant the Memantine hydrochloride structure is carried out chemically modified or directly synthetic preparation, described mother nucleus structure is simplified modified or increase further that to modify gained different with described Memantine hydrochloride structure parent nucleus or and at tool aspect the biological activity and Memantine hydrochloride homophylic classes of compounds is arranged.
Described and derivative and analog compounds, its separately or with known dosage antitumor and that immune drug is used be 0.001mg/kg-2.50g/kg (vein, abdominal cavity or oral administration); Wherein this tumour is from lung cancer, cancer of the stomach, colorectal carcinoma, small cell lung cancer, thyroid carcinoma, the esophageal carcinoma, carcinoma of the pancreas, carcinoma of endometrium, adrenocortical carcinoma, head and neck cancer, osteogenic sarcoma, mammary cancer, ovarian cancer, wilms' tumor, tumor of cervix, carcinoma of testis, the apparatus urogenitalis cancer, skin carcinoma, renal cell carcinoma, bladder cancer, primary brain cancer, prostate cancer, soft tissue sarcoma, neuroblastoma, rhabdosarcoma, Kaposi sarcoma, malignant melanoma, pernicious pancreas nesidioblastoma, non-Hodgkin lymphoma, malignant melanoma, multiple myeloma, neuroblastoma, the carcinoid malignant cancer, choriocarcinoma, acute and lymphocytic leukemia, primary macroglobulinaemia, chronic myelocytic leukemia, lymphocytic leukemia, acute myeloblastic leukemia, hairy cell leukemia, mycosis fungoides, malignant hypercalcemia, hyperplasia of cervix uteri or and Hodgkin's disease.
Wherein: it is active and be used as the known antitumor and immune drug of the application of antitumor drug and other to prepare antitumor pharmacology, also be selected from least with next group known cancer chemotherapeutics, a kind of in the pharmacologically acceptable salt of antiviral agent or this reagent and the prodrug or its combine to be used, comprise: endoxan, vincristine(VCR), busulfan, vinealeucoblastine(VLB), cis-platinum, carboplatin, ametycin, Zorubicin, colchicine, Etoposide, taxol, docetaxel, camptothecine, Hycamtin, white arsenic, the 5-ammonia cytidine of mixing, 5 FU 5 fluorouracil, methotrexate, 5-fluoro-2-deoxidation-uridine, hydroxyurea, Tioguanine, melphalan, Chlorambucil, ifosfamide, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium acetate, fludarabine, Sostatin, vitamin A acid, tamoxifen, Doxazosin, terazosin, tamsulosin, the fluorine pyridol, lovastatin, Simvastatin, Pravastatin, fluvastatin, atorvastatin, upright his spit of fland of cutting down of fourth, amprenavir, Abacavir, L 86-8275, ritonavir, Saquinavir, rofecoxib, alanosine, retinene, tretinointocoferil, 13-cis-vitamin A acid, 9-cis-vitamin A acid, alpha-difluoromethyl ornithine, fenretinide, N-4-carboxyl phenyl Viaminate, genistein, draw cloth in the plug, ara-C, CB-64D, CB-184, ILX23-7553, lactacystin, MG-132, PS-341, Glcevec, ZD1839 (IRessa), SH268, Herceptin, Rituxan, Gamcitabine, ABT-378, AG1776, BMS-232,632, CEP2563, SU6668, EMD121974, R115777, SCH66336, L-778,123, BAL9611, TAN-1813, UCN-01, Roscovitine, Olonoucine or and Valecoxib.
In addition, the application of described derivative and analogue: treating other disease with cancer and treatment of diseases and the application relevant with apoptosis, comprise application with the medicine of virus infection and nervous system disorders, and the application of acceptable salt and prodrug on the preparation pharmacology, with other known antiviral and anti-nervous system disorders compatibility of drugs use.
Wherein administering mode comprises: in oral, parenteral route, subcutaneous, intravenously, intramuscular, intraperitoneal, transdermal, cheek, the sheath, in the encephalic, nose or and local approach.
The present invention has following beneficial effect:
Because the medicine Memantine hydrochloride of adamantane structure and adamantane derivative thereof and the solubleness of analogue in water are very little, reduced bioavailability, directly influence its antitumour activity of knowing clearly, the present invention solves its low water solubility problem for this reason, promptly utilize contained amino and carboxyl to be prepared into corresponding salt, make injection liquid after water-soluble increasing it, the solution of injection preparation technology success of the present invention the intravenously administrable mode, well improve water-soluble and bioavailability, also improved anti-tumor activity simultaneously.
Description of drawings
Fig. 1 is that Memantine hydrochloride and positive control drug endoxan (CTX) suppress colorectal cancer cells (HT-29) growth in vitro effect (at embodiment 1,2,3,4,5,6 and 7).
Fig. 2 is that Memantine hydrochloride and positive control drug endoxan (CTX) suppress pancreatic cancer cell (Panc-1) growth in vitro effect (at embodiment 1,2,3,4,5,6 and 7).
Fig. 3 is that Memantine hydrochloride and positive control drug endoxan (CTX) suppress lung carcinoma cell (NCI-H460) growth in vitro effect (at embodiment 1,2,3,4,5,6 and 7).
Fig. 4 is that Memantine hydrochloride and positive control drug endoxan (CTX) suppress breast cancer cell (MCF7) growth in vitro effect (at embodiment 1,2,3,4,5,6 and 7).
Embodiment
1. being tried thing originates
Tried the thing Memantine hydrochloride and purchased rich U.S. medical company limited in Shenyang.
2. the test-compound structure is identified
Memantine hydrochloride (Memantine) is carried out structure identify, adopt infrared spectra, NMR (Nuclear Magnetic Resonance) spectrum, mass spectrum and purity check (the document 1:USP 3391142 that all conforms to literature value; Document 2:CP 200410013859.2; Document 3:CP1335299; Document 4:J.Med.Chem.6,760 (1963); Document 5: Chinese industrial medical magazine 2003,34 (5), see embodiment for details).
3. the salifiable preparation of test-compound
Get a certain amount of Memantine hydrochloride, quantitatively be dissolved in methyl alcohol, acetone, 4-hydrogen furans or 1,4 dioxane as dissolving is bad can heating makes it to become true solution keeping on the stable basis of compound suitably.The hydrogen chloride gas that slowly feeds dry in ice-water bath cooling, under stirring under this temperature after saturated fully, keeps feeding 5 minutes again.Be held in reactant salt 1-2 hour, and by the thin-layer chromatography detection reaction, until whole salifies.Boil off solvent under the decompression, be drying to obtain under the decompression.
The pharmacologically acceptable salt of The compounds of this invention also within the scope of the present invention, its acid can by and alkali reaction salify, for example yellow soda ash, sodium hydride, potassium hydroxide, ammonium hydroxide etc.Contain the nitrogen-atoms structure have alkalescence can by and acid-respons salify example hydrochloric acid, fumaric acid, toxilic acid, succsinic acid, acetate, citric acid, tartrate, carbonic acid, phosphoric acid, oxalic acid etc.
The prodrug of The compounds of this invention also within the scope of the present invention.Drug modification of the present invention can be become prodrug, increase its water-soluble and bioavailability, and can improve its activity and drug effect.
Medical compounds of the present invention can pass through any administration.In for example oral, parenteral route, subcutaneous, intravenously, intramuscular, intraperitoneal, transdermal, cheek, the sheath, in the encephalic, nose or local approach carry out administration.Dosage can decide according to the compatibility of weight in patients, age, the state of an illness, therapeutic modality and medicine, and wherein this effective dosage ranges is 0.001mg/kg-2.50g/kg (vein, abdominal cavity or an oral administration).
Below will the present invention will be further described by embodiment, but following embodiment only is the present invention's example wherein, does not limit the protection domain of claim of the present invention, and the protection domain of this claim is as the criterion with claims.
Embodiment
The test-compound structure is identified example
The structure of embodiment 1. Memantine hydrochlorides is identified
IR(KBr，cm
-1)3419，2943，2900，2861，2707，2613，2055，1615，1603，1513，1456，1364，1357，1344，1322；?
1H?NMR(DMSO-d6)δ8.24(b，2H)，2.15(m，1H)，1.65(m，2H)，1.45(m，4H)，1.29(m，4H)，1.06(m，2H)，0.85(s，6H)。
The anti-tumor agent example
Embodiment 2.
Anti-tumor agent 1: take by weighing 5.0g Memantine hydrochloride (referring to embodiment 1 described compound), add ethanol 600ml, stir and make dissolving, the dissolving back adds 600ml 1, and 2-propylene glycol and 100ml tween 80 mix, add the injection water to cumulative volume 5000ml, with 0.22 μ m membrane filtration, packing, 100 ℃ of pressure sterilizing 30min, leak detection, full inspection, packing, promptly get 5mg/5ml (ammonia bottle), totally 1000.
The anticancer experiment in vitro example
Embodiment 3.
(1) clone
Select human large intestine cancer clone HT-29, human pancreatic cancer cell Panc-1, human lung cancer cell line NCI-H460, MCF-7 MCF7 for use; Its substratum is DMEM (Gibco BRL), contains 10% foetal calf serum (Gibco BRL) and 2mM L-glutaminate (Gibco BRL).
(2) specimen: Memantine hydrochloride
Get above-mentioned sample dissolution in DMSO (U.S. Sigma company product), use the substratum doubling dilution then.The final concentration of DMSO in substratum is 0.5%, and this concentration has been proved no cytotoxicity.Positive control drug is endoxan (CTX, purity＞96%), uses the substratum doubling dilution.
(3) method
Cell is dispersed into individual cells behind tryptic digestion, and it is suspended in the above-mentioned substratum that contains penicillin (25U/ml) and Streptomycin sulphate (25 μ g/ml).Cell inoculation in 96 well culture plates (Corning Incorporated), at 37 ℃, is contained 5%C0
2Air, cultivate after 24 hours under relative humidity 100% condition, discard nutrient solution, add and contain the nutrient solution that a series of concentration are tried thing, each concentration is established parallel hole, cultivate after 48 hours, discard and contain the nutrient solution that is tried thing, replace and contain the thiophene indigo plant (MTT that gurgles, U.S. Sigma company product) nutrient solution, the MTT final concentration is 0.5g/L, continues incubation and adds acidifying Virahol lysate after 4 hours, purple crystal dissolves fully after 1 hour, detects the optical density(OD) (OD) of 570nm/630nm in SK601 type microplate reader (Seikagaku company of Japan product).Be calculated as follows cell survival rate:
(experimental group OD/ control group OD) * 100%;
Positive control drug CDDP and the above-mentioned thing that tried are handled synchronously equally.
To the colorectal cancer cells restraining effect: as shown in Figure 1, it is stronger to the antiproliferative effect of large bowel cancer HT-29 to be tried the thing Memantine hydrochloride.The antiproliferative effect IC of Memantine hydrochloride
50And 95% fiducial limit be respectively 18.81 (15.7-21.38) μ g/ml.This test does twice, and repeatability better.
Embodiment 4
To the pancreatic cancer cell restraining effect: as shown in Figure 2, tried the antiproliferative effect of thing Memantine hydrochloride to carcinoma of the pancreas Panc-1, Memantine hydrochloride is to the half-inhibition concentration (IC of Panc-1
50) and 95% fiducial limit be respectively 51.32 (48.95-55.51) μ g/ml.This test does twice, and repeatability better.
Embodiment 5
To the lung carcinoma cell restraining effect: as shown in Figure 3, tried the antiproliferative effect of thing Memantine hydrochloride, the IC of positive control drug CTX to lung cancer NCI-H460
50And 95% credible 4.30 (3.04-5.13) μ g/ml that is limited to.Memantine hydrochloride is to the IC of NCI-H460 cell
50And 95% fiducial limit is respectively 60.52 (58.66-62.14).The IC of Memantine hydrochloride
50(P＜0.05), this test does twice, and repeatability is better.
Embodiment 6
To the breast cancer cell restraining effect: as shown in Figure 4, tried the IC of thing Memantine hydrochloride to mammary cancer MCF7 cell
50And 95% credible 2.73 (1.21-4.02) that are limited to.The IC of positive control drug CTX
50And 95% credible 0.92 (0.03-2.02) μ g/ml that is limited to, this test does twice, and repeatability is better.
This test test-compound is a Memantine hydrochloride, and the screening cell strain is large bowel cancer HT-29, carcinoma of the pancreas Panc-1, lung cancer NCI-H460, mammary cancer MCF7.With the endoxan is that contrast is tested, and test-results shows that large bowel cancer, carcinoma of the pancreas, good to above-claimed cpd susceptibility with breast cancer cell also show certain activity to mammary cancer MCF7.
External anticancer cell result is referring to table 1.
The external anticancer cell result of table 1
The IC of compound 1
50(μ M) value
The anti-tumor in vivo experiment embodiment
Embodiment 7
(1) material
Specimen: memantine hydrochloride
Experimental animal: Kunming kind healthy mice, body weight 19～21g, male and female half and half grouping, is provided by Military Medical Science Institute institute of materia medica, Beijing animal center by 10 every group.
Knurl strain: murine sarcoma S
180For ascitic type goes down to posterity, derive from Military Medical Science Institute institute of materia medica, Beijing.
(2) method
The preparation of animal model for tumour: 7 days sarcoma S is given birth in aseptic absorption
180The mouse ascites that goes down to posterity, being diluted to density respectively with physiological saline is 4 * 10
7Cellml
-1The tumour cell suspension, it is subcutaneous that every mouse 0.2ml is inoculated in the right fore armpit, inoculates back 7 days, grows the more consistent tumour of size in the right oxter of modeling mouse, is the modeling success.For guaranteeing the vigor of inoculating cell, in the experimentation, cell suspension is placed the beaker that contains ice, whole modeling process is finished in 230min.
With the mouse random packet of inoculation back 24h, model control group, positive drug endoxan (CTX) control group 25mg/kg; Positive drug 5-fluor-uracil (5-FU) control group 15mg/kg; Memantine hydrochloride is 12.5mg/kg.
Each treated animal administration every day 1 time, successive administration 7 days, next day is put to death the knurl mouse in drug withdrawal, strips the knurl piece, and weighing mouse and knurl piece weight are calculated tumour inhibiting rate and body weight change situation.
(3) result: with the blank group relatively when p＜0.05 for significant difference is arranged, so Memantine hydrochloride has obvious anti-tumor activity.Test-results sees Table 2.
Table 2 couple sarcoma S
180The restraining effect of growth (
N=16)
* significant difference is compared with the Control group in p＜0.05; Significant differences is compared with the Control group in * p＜0.01
Experimental group is in mouse oxter inoculation S
180Tumour cell, administration was also observed 7 days, by the way of measurement mouse swelling of the axilla tumor weight, comparative sample group and positive controls (5-FU, endoxan) tumour inhibiting rate, the memantine hydrochloride tumour inhibiting rate is significantly better than positive controls endoxan and 5-FU.Test-results shows: memantine hydrochloride (12.5mg/kg) tumour inhibiting rate is all above 40%.
The present invention relates to described compound and have new activity such as antitumor grade and new indication, the invention still further relates to this compounds as the antitumor application that waits disease medicament.
Of the present invention have the medicine Memantine hydrochloride of adamantane structure and the application of adamantane derivative and analogue comprises: active and as the application of antitumor drug in the antitumor pharmacology of preparation, activeconstituents is the described Memantine hydrochloride of chemical structure and derivative and analog compounds, its separately or with known dosage antitumor and that immune drug is used be 0.001mg/kg-2.50g/kg (vein, abdominal cavity or oral administration); Wherein this tumour is from lung cancer, cancer of the stomach, colorectal carcinoma, small cell lung cancer, thyroid carcinoma, the esophageal carcinoma, carcinoma of the pancreas, carcinoma of endometrium, adrenocortical carcinoma, head and neck cancer, osteogenic sarcoma, mammary cancer, ovarian cancer, wilms' tumor, tumor of cervix, carcinoma of testis, the apparatus urogenitalis cancer, skin carcinoma, renal cell carcinoma, bladder cancer, primary brain cancer, prostate cancer, soft tissue sarcoma, neuroblastoma, rhabdosarcoma, Kaposi sarcoma, malignant melanoma, pernicious pancreas nesidioblastoma, non-Hodgkin lymphoma, malignant melanoma, multiple myeloma, neuroblastoma, the carcinoid malignant cancer, choriocarcinoma, acute and lymphocytic leukemia, primary macroglobulinaemia, chronic myelocytic leukemia, lymphocytic leukemia, acute myeloblastic leukemia, hairy cell leukemia, mycosis fungoides, malignant hypercalcemia, hyperplasia of cervix uteri or and Hodgkin's disease.
Its application can also be used with other known antitumor and immune drug, also be selected from least with next group known cancer chemotherapeutics, a kind of in the pharmacologically acceptable salt of antiviral agent or this reagent and the prodrug or its combine to be used, comprise: endoxan, vincristine(VCR), busulfan, vinealeucoblastine(VLB), cis-platinum, carboplatin, ametycin, Zorubicin, colchicine, Etoposide, taxol, docetaxel, camptothecine, Hycamtin, white arsenic, the 5-ammonia cytidine of mixing, 5 FU 5 fluorouracil, methotrexate, 5-fluoro-2-deoxidation-uridine, hydroxyurea, Tioguanine, melphalan, Chlorambucil, ifosfamide, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium acetate, fludarabine, Sostatin, vitamin A acid, tamoxifen, Doxazosin, terazosin, tamsulosin, the fluorine pyridol, lovastatin, Simvastatin, Pravastatin, fluvastatin, atorvastatin, upright his spit of fland of cutting down of fourth, amprenavir, Abacavir, L 86-8275, ritonavir, Saquinavir, rofecoxib, alanosine, retinene, tretinointocoferil, 13-cis-vitamin A acid, 9-cis-vitamin A acid, alpha-difluoromethyl ornithine, fenretinide, N-4-carboxyl phenyl Viaminate, genistein, draw cloth in the plug, ara-C, CB-64D, CB-184, ILX23-7553, lactacystin, MG-132, PS-341, Glcevec, ZD1839 (IRessa), SH268, Herceptin, Rituxan, Gamcitabine, ABT-378, AG1776, BMS-232,632, CEP2563, SU6668, EMD121974, R115777, SCH66336, L-778,123, BAL9611, TAN-1813, UCN-01, Roscovitine, Olonoucine or and Valecoxib.
In addition, the application of described compound Memantine hydrochloride and derivative thereof and analogue: treating other disease with cancer and treatment of diseases and the application relevant with apoptosis, comprise application with the medicine of virus infection and nervous system disorders, and the application of acceptable salt and prodrug on the preparation pharmacology, with other known antiviral and anti-nervous system disorders compatibility of drugs use.Wherein administering mode comprises: in oral, parenteral route, subcutaneous, intravenously, intramuscular, intraperitoneal, transdermal, cheek, the sheath, in the encephalic, nose or and local approach.
Claims (8)
1. have medicine Memantine hydrochloride and the derivative and the analogue of adamantane structure, it is characterized in that: molecular structure of chemistry as shown in the formula:
2. according to the described compound of claim 1 and derivative and analogue, it is characterized in that: have described Memantine hydrochloride structure and by derivative and analogue that described structure produced, comprise by described structure as the structure parent or as new structural compounds that structure fragment produced.
3. according to the described compound of claim 2 and derivative and analogue, it is characterized in that: described structure is carried out the various derivatives that chemically modified obtained, and these derivatives and Memantine hydrochloride have same or analogous structure parent nucleus; Described structure is carried out chemically modified or directly synthetic preparation, the mother nucleus structure of described compound simplified or increase modify gained, different with described compound Memantine hydrochloride mother nucleus structure or and the classes of compounds of similarity or dependency arranged at tool aspect the biological activity and Memantine hydrochloride.
4. according to described derivative of claim 3 and analogue, it is characterized in that: the derivative of described structure and the inorganic acid salt of analogue, organic acid salt, inorganic base salts, organic alkali salt or double salt and their prodrug.
5. one kind according to claim 1,2,3 and 4 described derivative and analogues, it is characterized in that: in application as antitumor drug, activeconstituents is compound 1 and described derivative and an analog compounds among chemical structure Fig. 1, its separately or with known dosage antitumor and that immune drug is used be 0.001mg/kg-2.50g/kg (vein, abdominal cavity or oral administration); Wherein this tumour is from lung cancer, cancer of the stomach, colorectal carcinoma, small cell lung cancer, thyroid carcinoma, the esophageal carcinoma, carcinoma of the pancreas, carcinoma of endometrium, adrenocortical carcinoma, head and neck cancer, osteogenic sarcoma, mammary cancer, ovarian cancer, wilms' tumor, tumor of cervix, carcinoma of testis, the apparatus urogenitalis cancer, skin carcinoma, renal cell carcinoma, bladder cancer, primary brain cancer, prostate cancer, soft tissue sarcoma, neuroblastoma, rhabdosarcoma, Kaposi sarcoma, malignant melanoma, pernicious pancreas nesidioblastoma, non-Hodgkin lymphoma, malignant melanoma, multiple myeloma, neuroblastoma, the carcinoid malignant cancer, choriocarcinoma, acute and lymphocytic leukemia, primary macroglobulinaemia, chronic myelocytic leukemia, lymphocytic leukemia, acute myeloblastic leukemia, hairy cell leukemia, mycosis fungoides, malignant hypercalcemia, hyperplasia of cervix uteri or and Hodgkin's disease.
6. according to the application of described derivative of claim 5 and analogue, it is characterized in that: it is active and be used as the known antitumor and immune drug of the application of antitumor drug and other wherein to prepare antitumor pharmacology, also be selected from least with next group known cancer chemotherapeutics, a kind of in the pharmacologically acceptable salt of antiviral agent or this reagent and the prodrug or its combine to be used, comprise: endoxan, vincristine(VCR), busulfan, vinealeucoblastine(VLB), cis-platinum, carboplatin, ametycin, Zorubicin, colchicine, Etoposide, taxol, docetaxel, camptothecine, Hycamtin, white arsenic, the 5-ammonia cytidine of mixing, 5 FU 5 fluorouracil, methotrexate, 5-fluoro-2-deoxidation-uridine, hydroxyurea, Tioguanine, melphalan, Chlorambucil, ifosfamide, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium acetate, fludarabine, Sostatin, vitamin A acid, tamoxifen, Doxazosin, terazosin, tamsulosin, the fluorine pyridol, lovastatin, Simvastatin, Pravastatin, fluvastatin, atorvastatin, upright his spit of fland of cutting down of fourth, amprenavir, Abacavir, L 86-8275, ritonavir, Saquinavir, rofecoxib, alanosine, retinene, tretinointocoferil, 13-cis-vitamin A acid, 9-cis-vitamin A acid, alpha-difluoromethyl ornithine, fenretinide, N-4-carboxyl phenyl Viaminate, genistein, draw cloth in the plug, ara-C, CB-64D, CB-184, ILX23-7553, lactacystin, MG-132, PS-341, Glcevec, ZD1839 (IRessa), SH268, Herceptin, Rituxan, Gamcitabine, ABT-378, AG1776, BMS-232,632, CEP2563, SU6668, EMD121974, R115777, SCH66336, L-778,123, BAL9611, TAN-1813, UCN-01, Roscovitine, Olonoucine or and Valecoxib.
7. application according to claim 5 and 6 described derivatives and analogue, it is characterized in that: in of the application of treatment or other disease relevant with tumor disease with tumour, comprise the disease that virus causes and the treatment of hypoimmunity, broad-spectrum antimicrobial, antimycotic and the treatment by bacterium, fungus-caused disease, comprise application to the medicine of bacterial infective diseases and fungi infestation disease, and the application of acceptable salt and prodrug on the preparation pharmacology, with other known antibiotic or and the antifungal drug compatibility use.
8. according to the application of claim 5,6 and 7 described derivatives and analogue, it is characterized in that: administering mode comprises: in oral, parenteral route, subcutaneous, intravenously, intramuscular, intraperitoneal, transdermal, cheek, the sheath, in the encephalic, nose or and local approach.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
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| CN2010105611323A CN102070463A (en) | 2009-06-11 | 2009-06-11 | Medicine memantine with adamantane structure, and derivative and analog thereof, and application to new antineoplastic indication |
| PCT/CN2011/071503 WO2012065383A1 (en) | 2009-06-11 | 2011-03-04 | Application of drug memantine with adamantane structure, derivatives and analogues thereof for preventing tumor indication |
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| CN2010105611323A CN102070463A (en) | 2009-06-11 | 2009-06-11 | Medicine memantine with adamantane structure, and derivative and analog thereof, and application to new antineoplastic indication |
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| CNA2009101461413A Division CN101569617A (en) | 2009-06-11 | 2009-06-11 | Application of drug with adamantane structure, derivative and analogue thereof to preventing new tumor indication |
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Cited By (3)
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| CN108969478A (en) * | 2018-08-29 | 2018-12-11 | 江南大学 | A kind of Memantine difficulty soluble salt is slow-release injected and preparation method thereof |
| WO2020118096A1 (en) * | 2018-12-05 | 2020-06-11 | The Regents Of The University Of California | Anti-cancer activity of adamantane derivatives |
| CN115403497A (en) * | 2022-09-26 | 2022-11-29 | 长春工业大学 | Novel synthesis and antitumor activity research of Schiff base derivative containing adamantane skeleton |
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| WO2012065383A1 (en) | 2012-05-24 |
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