CN101463003A - Substituted tricyclodecane compound as anti-cancer compound - Google Patents
Substituted tricyclodecane compound as anti-cancer compound Download PDFInfo
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Abstract
The invention relates to a series of substituted tricyclic althea alkane compounds used as antitumor compounds and pharmaceutically acceptable salts, ester or prodrug thereof, composition of the new compounds and pharmaceutically acceptable carriers and the application of the new compounds. The compounds can inhabit the growth of malignant tumors correspondingly and treat patients with malignant tumors by means of veins, oral administration, subcutaneous tissue, administration in arteries or local administration.
Description
Technical field
The present invention relates to a series of substituted tricyclodecane compounds as anticancer compound, and pharmacy acceptable salt, ester or prodrug, the composition of new compound and pharmaceutically acceptable carrier and the application of new compound.The compounds of this invention can suppress malignant growth accordingly, and the mode by vein, oral, subcutaneous, intra-arterial administration or topical gives malignant tumor patient and treats, and has higher target, stability and lower toxicity.
Background technology
Cancer has become the most serious disease that threatens human life's health.Because the aging crowd is increasing all the time, estimate that the sickness rate of cancer can sustainable growth.The method of treatment cancer use has operation, radiation and chemotherapy at present.Type, position and the distribution situation of cancer depended in the selection of therapeutic modality.Chemotherapy is the important auxiliary section of having of operation and radiotherapy, can only be by means of chemotherapy for the cancer that can not perform the operation with radiotherapy.
Along with development to the fundamental biological knowledge research of tumour cell.The a plurality of steps in cell growth that relates to sexuality of knurl cell transformed and change and the oncogenesis that has write down several human tumors have been identified at present.Identified the oncogene of the cell growth that causes to regulate and it is characterized by genetic origin and function and has characterized in detail and regulated the specificity approach of cell replication cycle and cloned and characterized the protein that relates in this adjusting.In addition, sets forth in detail mediating apoptosis oppositely regulate the molecule of cell growth (Kerr etc., Cancer 1994,73:2013.Having confirmed at present to handle these cells regulates approach and can stop growth in the tumour cell and induce wherein apoptosis (Cohen, and Tohoku, Exp.Med., 1992,168:351; Fujiwara etc., J.Natl.Cancer Inst., 1994,86:458).Cell in the control tumour cell is grown and duplicated is important treatment target.
Studies show that three ring (5.2.1.0
2,6) certain herbaceous plants with big flowers alkane-8-alkene-3, the protein that the 5-dione compounds relates to during growth of tumour cell is regulated has affinity, have therapeutic and prophylactic action, it is the following mammalian diseases of feature that this compounds can effectively be treated with the abnormal cells increment: for example tumour, polyp, endometriosis, leukemia, autoimmune disorder, cancer etc.Walter has reported 10-oxa--4-azepine-three ring (5.2.1.0
2,6) certain herbaceous plants with big flowers alkane-8-alkene-3, the 5-diketone have better antitumor activity (Walter, W.G.J.Pharm.Sci.1989,78:66.).Report 4-azepine 4-(2-methyl-2-nitroso-group propylmercaptan)-three ring (5.2.1.0 are arranged in addition
2,6) certain herbaceous plants with big flowers alkane-8-alkene-3, the 5-diketone has illnesss (US7,238,814) such as treatment Raynaud ' s syndromes, inflammation, disorder of gastrointestinal tract and nervus centralis disorder.
The present invention has synthesized the N that does not appear in the newspapers on the basis of a large amount of experiments, and 1,7,8,9,10, the different three ring (5.2.1.0 that replace of 10-
2,6) certain herbaceous plants with big flowers alkane-8-alkene-3,5-diketone series compound studies show that this compounds has stronger anti-tumor activity, the verified tumour to some types of some compound has significant therapeutic action.
According to the present invention, this class new texture is to have the effect that the strong and lasting inhibition tumor growth of rendeing a service gets, and has reduced its side effect simultaneously.
Summary of the invention
Three ring (the 5.2.1.0 that the present invention relates to replace
2,6) certain herbaceous plants with big flowers alkane-8-alkene-3,5-dione compounds (I) and pharmacy acceptable salt or prodrug, the composition of new compound and pharmaceutically acceptable carrier and the application of new compound.The compounds of this invention has following general formula.
Wherein, R
1For straight chain with 1-10 carbon atom or branched alkyl, alkoxyl group or aromatic heterocycle substituted radical, R
2For halogen (fluorine, chlorine, bromine, iodine) or have 1-10 carbon atom straight chain or branched alkyl substituent group, R
3For hydrogen atom or have 1-20 carbon atom, can have 1 or 2 two key or triple-linked straight chain or branched aliphatics or aromatic group.
Term as herein described " alkyl " is defined as comprising saturated monovalence hydrocarbon chain group; has straight chain; side chain or cyclic part or its combination; the non-annularity alkyl contains 1-20 carbon atom; preferred 1-6 carbon atom; cycloalkyl contains 3-8 carbon atom; also comprise such moieties; optionally replaced by 1 to 5 substituting group; substituting group is independently selected from by halogen; hydroxyl; sulfydryl; amino; nitro; cyano group; thiocyano; acyl derivative; sulfonyl-derivatives; the sulfinyl derivative; alkylamino; carboxyl; ester; ether; amido; azido-; sulfonic acid, sulfamyl; thio derivative; oxygen base ester; oxygen base amido; heterocycle; vinyl; C
1-5Alkoxyl group, C
6-10The group that aryloxy is formed.
Preferred alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl and 2, the 2-dimethyl propyl, replaced by at least one substituting group alternatively separately, substituting group is selected from the group of being made up of halogen, hydroxyl, sulfydryl, amino, nitro and cyano group.For example trifluoromethyl, trichloromethyl, 2,2,2-three chloroethyls, 1,1-dimethyl-2,2-two bromotrifluoromethanes, 1,1-dimethyl-2,2,2-three chloroethyls.
The alkoxyl group of herein mentioning, for containing 1-6 (preferably containing 1-4) carbon atom, hydrocarbon chain is side chain or straight chain.Preferred alkoxyl group comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, sec-butoxy and tert.-butoxy.
The alkenyl of herein mentioning that contains 2-7 carbon atom, for straight chain or branched, propenyl, butenyl, pentenyl, hexenyl or heptenyl for example vinyl, or straight chain or branched.Two keys can be in any position of alkenyl.
Mention herein contain 2-7 carbon atom alkynyl, for straight chain or branched, ethynyl for example, proyl, or straight chain or branched butynyl, pentynyl, hexin base or heptyne base.Triple bond can be in any position of alkynyl.
Term used herein " cycloalkyl " expression derives from the monovalence 3-20 carbon-based group of saturated cyclic or polynuclear hydrocarbon, it can be alternatively replaced by the group that is fit to arbitrarily, comprises being not limited to one or morely be selected from alkyl or as above about the part of described other group of alkyl.Limiting examples has cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, cyclopentenyl, cyclopentyl base, suberyl, ring octyl group etc.
Term used herein " aromatic group " is defined as comprising from formed and contained the aromatic hydrocarbyl of 6-30 carbon atom by 1-3 ring; for example phenyl and naphthyl; replaced by a plurality of substituting groups alternatively separately; substituting group is independently selected from halogen, hydroxyl, sulfydryl, amino, nitro, cyano group, thiocyano, acyl derivative, sulfonyl-derivatives, sulfinyl derivative, alkylamino, carboxyl, ester, ether, amido, azido-, sulfonic acid, sulfamyl, thio derivative, oxygen base ester, oxygen base amido, heterocycle, vinyl, C
1-5Alkoxyl group, C
6-10Aryloxy, C
1-10Alkyl, C
1-10Thiazolinyl, C
1-10Alkynyl, C
1-10Haloalkyl, its condition be 2 or more multi-substituent can constitute a ring that adheres to aromatic ring.
" heterocycle ", " heterocyclic radical " or " Heterocyclylalkyl ", " heterocyclic radical ", refer to have and have 1-10 carbon atom and 1-4 heteroatomic saturated or unsaturated group that is selected from nitrogen, sulphur or oxygen in a ring or a plurality of fused rings, the ring, in the fused rings system, if tie point is on heterocycle, one or more rings can be cycloalkyl, aryl or heteroaryl." heterocycle of replacement ", " Heterocyclylalkyl of replacement " or " heterocyclic radical of replacement " refer to use with the cycloalkyl that replaces in identical 1-3 the heterocyclic radical single, double or three substituting groups replace defining.
The example of heterocyclic radical and heteroaryl includes but not limited to: azetidine, the pyrroles, imidazoles, pyridine, pyrazoles, pyrimidine, pyrazine, pyridazine, middle nitrogen Yin, isoindole, indoles, indoline, indazole, purine, quinolizine, different quinolizine, quinoline, phthalazines, the naphthyl pyridine, quinoxaline, quinazoline, pteridine, carbazole, carboline, phenanthridines, phenanthroline, isothiazole, azophenlyene isoxazole, thiodiphenylamine phenoxazine, imidazolidine, tetrahydroglyoxaline, piperidines, piperazine, indoline, phthalic imidine, 1,2,3, the 4-tetrahydroisoquinoline, 4,5,6,7-tetrahydro benzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholinyl, thio-morpholinyl (being also referred to as sulphur Lin Ji), piperidyl, tetramethyleneimine, tetrahydrofuran base etc.
The compound pharmacy acceptable salt compounds of Chinese style of the present invention (I) representative can be fluorochemical, muriate, bromide, iodide, vitriol, nitrate, phosphoric acid salt, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, mesylate or tosilate.
The pharmaceutically acceptable ester compound of compound of Chinese style of the present invention (I) representative, finger is the ester of hydrolysis in vivo, being included in degrades in the human body discharges the ester of parent compound or its salt, suitable ester group for example comprises: derived from pharmaceutically acceptable aliphatic carboxylic acid or aliphatic family alcohol, especially paraffinic acid (alcohol), alkenoic acid (alcohol), naphthenic acid (alcohol) and alkane dicarboxylic acid's's (glycol) ester, wherein preferred each alkyl or alkenyl partly is less than 6 carbon atoms.
Compound described herein has affinity to the protein that relates in the long adjusting of tumour cell sound, have therapeutic and prophylactic action, it is the following mammalian diseases of feature that this compounds can effectively be treated with the abnormal cells increment: for example tumour, polyp, endometriosis, leukemia, autoimmune disorder, cancer etc.Be fit to preferably treat various malignant tumours with the disease specific that The compounds of this invention is treated, the neoplastic disease that medicine acted on is malignant tumour and the cancer that wide spectrum Mammals (comprising the people) health causes, wherein preferably act on Human Lung Cancer, human non-small cell lung cancer, mammary cancer, ovarian cancer and melanoma, especially solid tumor (for example, lung, ovarian cancer, mammary gland, stomach and intestine, colon, pancreas, bladder, kidney, prostate gland, brain) and various hemopoietic system cancer (for example, HodgkinShi disease, non-HodgkinShi lymphatic cancer, leukemia).Wherein said neoplastic disease is selected from leukemia and (comprises acute leukemia, the acute lymphoblastic leukemia, acute myelocytic leukemia, myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia, erythroleukemia, chronic leukemia, chronic granulocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma, Hodgkin, the non-hodgkin's disease, multiple myeloma, idiopathic macroglobulinemia disease, solid tumor, sarcoma and cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovioma, mesothelioma, ewing's tumor, leiomyosarcoma, rhabdosarcoma, colorectal carcinoma, carcinoma of the pancreas, mammary cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, rodent cancer, gland cancer, syringocarcinoma, sebaceous carcinoma, papillary carcinoma, adenocarcinoma of nipple, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, spermocytoma, embryonal carcinoma, wilms' tumor, cervical cancer, uterus carcinoma, tumor of testis, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, neurospongioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic tumor, oligodendroglioma, durosarcoma, melanoma, neuroblastoma and retinal neuronal cell knurl etc.
The methods of treatment of The compounds of this invention comprises and gives the patient with compound with pharmaceutically acceptable dosage form that its dosage is enough to effectively suppress described abnormal cells increment.Therefore, the invention provides the treatment patient various cancers method, described method comprise give cancer patients 1 μ g/kg to 500 μ g/kg, more preferably 1 μ g/kg is to the anti-increment compound of about 100 μ g/kg, wherein the further increment of cancer is suppressed, and preferred tumour shows partial reaction or complete reaction to treatment.
Compound of the present invention also can be used as the adjuvant of conventional cancer therapy, with treatment apoptosis resistance tumor, and can be used for treating other disease, to overcome resistance.Compound of the present invention can with at least a conventional cancer therapy simultaneously or sequential giving.Conventional cancer therapy can be radiotherapy, chemotherapy and/or biotherapy.Preferred chemotherapy comprises antimetabolite, alkylating agent, vegeto-alkali and Hang Shengsu.U 42126 preferably, aclarubicin, the hydrochloric acid acodazole, acronine, U 73975, Dx, rIL-2, alitretinoin, epidermal growth factor, altretamine, Duazomycin C, the acetic acid ametantrone, aminoglutethimide, amsacrine, Anastrozole, anthramycin, Asparaginase, asperline, azacitidine, Azatepa, Azotomycin, Batimastat, benzodepa, bexarotene, bicalutamide, bisantrene hydrochloride, two methylsulfonic acid Bisnafides, bleomycin sulfate, brequinar sodium, Bropirimine, busulfan, Cabergoline, calusterone, caracemide, carubicin hydrochloride, celecoxib, Chlorambucil, U 12241, the methylsulfonic acid crisnatol, cyclic phosphoric acid amine, cytosine arabinoside, Dacarbazine, daunorubicin hydrochloride, Decitabine, Dezaguanine, diaziquone, docetaxel, droloxifene, dromostanolone propionate, duazomycin, edatrexate, Vaniqa, elsamitrucin, Ba Pu ammonia ester, Epipropidine, epirubicin hydrochloride, R 55104, esorubicin hydrochloride, estramustine, estramustine phosphate sodium, etanidazole, Ethyl ester of iodinated fatty acid of poppyseed oil I
131Etoposide, etoprine, Fadrozole Hydrochloride, fazarabine, fenretinide, fluorodeoxyuridine, fludarabine phosphate, Fluracil, flurocitabine, Fosquidone, Phosphotrienin sodium, gemcitabine, goserelin acetate, idarubicin hydrochloride, isoendoxan, Thio ALP, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprorelin acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol, maytenin, mustine hydrochlcride, Magace, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, Methoxsalen, U-197, U.S. appropriate in group, Mitindomide, mitogillin, Mitomalcin, mitomycin, mitosper, mitotane, hydrochloric acid rice holder anthracene is waken up, Mycophenolic Acid, R 17934, nogalamycin, oxisuran, taxol, the Pa Milin acid disodium, pegaspargase, peliomycin, neostigmine bromide, Peplomycin Sulfate, perfosfamide, group's pool bromine alkane, the pool Shu Fan of group etc.
Each compound of the present invention can be used as and composition by the antitumor drug that contains metal of platinum, titanium, vanadium, niobium, aluminium, rhenium or tin, and the antitumor drug that preferably contains metal is that cis-platinum, carboplatin, oxaliplatin, teraplatin, Platiniuln-DACH, ormaplatin, titanocene dichloride, dichloro cyclopentadiene vanadium, dichloro cyclopentadiene niobium, dichloro cyclopentadiene aluminium, dichloro cyclopentadiene rhenium, dihalo two organotins or other contain the antitumor drug of metal.
As the supplemental treatment regimens of other oncotherapy means, preferred radiotherapy comprises photodynamic therapy, radioactive nuleus thuja acid and radioimmunotherapy.Preferred biotherapy comprises the biological medicine of immunotherapy, differentiation agent and target cancer cell.More than general introduction has provided some feature of the present invention quite widely, so that understand detailed Description Of The Invention thereafter, also is convenient to understand better affiliated field of the present invention.According to following detailed Description Of The Invention, other purpose of the present invention and feature will be conspicuous.Yet, be appreciated that embodiment only is for illustrative purposes, not as restricted definition of the present invention, have only appended claims just the present invention to be limited.
Can be made into different modes of administration and formulation according to clinical needs, the administering mode of pharmaceutical preparation is whole body administration or topical, and formulation comprises that the mode of vein, oral, subcutaneous, intra-arterial administration or topical treats the patient.
Above-mentioned purpose of the present invention can realize by following synthetic route:
By 1,2,3,4, the maleic anhydride reaction that cyclopentadiene that 5-replaces and N-replace obtains target compound.
Concrete synthetic route is as shown below:
Embodiment
Specify the present invention with embodiment below, these embodiment should not be construed as the limitation of the present invention that goes up in all senses.
Embodiment 1 10,10-dimethoxy-1,7,8,9-tetrachloro-4-azepine-N-ethyl-three ring (5.2.1.0
2,6) certain herbaceous plants with big flowers alkane-8-alkene-3,5-diketone (1) synthetic
With 2.6g (10mmol) 3,3-dimethoxy-1,2,3, the 4-tetrachlorocycbpentadiene is dissolved in the 80mL ether, adds N-ethyl maleinamide 1.5g (12mmol), backflow stirring reaction 5 hours, steaming place solvent, column chromatography obtains white solid (1), 3.1g, yield 81%.Fusing point 124-126 ℃.Ultimate analysis: C
13H
13NO
4Cl
4: theoretical value %:C 40.13, and H 3.37, and N 3.60; Experimental value %:C 40.22, H 3.46, and N 3.63.
1H-NMR：δ(ppm，CD
3Cl)，3.65(s，3H)，3.61(s，2H)，3.59(s，3H)，3.49(m，2H)，1.09(m，3H)。
Embodiment 2 10,10-dimethoxy-1,7,8,9-tetrabromo-4-azepine-N-ethyl-three ring (5.2.1.0
2,6) certain herbaceous plants with big flowers alkane-8-alkene-3,5-diketone (2) synthetic
Synthetic method is with embodiment 1, by 3, and 3-dimethoxy-1,2,3,4-tetrabromo cyclopentadiene and the reaction of N-ethyl maleinamide.Get faint yellow solid (2), yield 73%, fusing point 105-109 ℃.Ultimate analysis C
13H
13NO
4Br
4, theoretical value %:C 47.73, and H 4.01, and N 4.28; Experimental value %:C 47.79 H 4.06, N 4.36.
1H-NMR：δ(ppm，CD
3Cl)，3.67(s，3H)，3.62(s，2H)，3.58(s，3H)，3.46(m，2H)，1.07(m，3H)。
Embodiment 3 10,10-dimethoxy-1,7,8,9-tetramethyl--4-azepine-N-ethyl-three ring (5.2.1.0
2,6) certain herbaceous plants with big flowers alkane-8-alkene-3,5-diketone (3) synthetic
Synthetic method is with embodiment 1, by 3, and 3-dimethoxy-1,2,3,4-tetramethyl-ring pentadiene and the reaction of N-ethyl maleinamide.Get white solid (3), yield 78%, fusing point 134-139 ℃.Ultimate analysis C
17H
25NO
4, theoretical value %:C 66.43, and H 8.20, and N 4.56; Experimental value %:C 66.49 H 8.26, N 4.66.
1H-NMR：δ(ppm，CD
3Cl)，3.67(s，3H)，3.62(s，2H)，3.58(s，3H)，3.46(m，2H)，2.34(m，6H)，1.34(m，6H)，1.07(m，3H)。
Embodiment 4 10,10-dimethoxy-1,7,8,9-tetrachloro-4-azepine-N-phenyl-three ring (5.2.1.0
2,6) certain herbaceous plants with big flowers alkane-8-alkene-3,5-diketone (4) synthetic
Synthetic method is with embodiment 1, by 3, and 3-dimethoxy-1,2,3,4-tetrachlorocycbpentadiene and the reaction of N-phenyl maleimide.Get faint yellow solid (4), yield 77%, fusing point 125-127 ℃.Ultimate analysis C
17H
13NO
4Cl
4, theoretical value %:C 46.71, and H 3.00, and N 3.20; Experimental value %:C 46.75 H 3.06, N 3.26.
1H-NMR：δ(ppm，CD
3Cl)，7.45(m，3H)，7.13(m，2H)，3.80(s，2H)，3.65(s，3H)，3.61(s，3H)。
Embodiment 5 10,10-dimethoxy-1,7,8,9-tetrabromo-4-azepine-N-phenyl-three ring (5.2.1.0
2,6) certain herbaceous plants with big flowers alkane-8-alkene-3,5-diketone (5) synthetic
Synthetic method is with embodiment 1, by 3, and 3-dimethoxy-1,2,3,4-tetrabromo cyclopentadiene and the reaction of N-phenyl maleimide.Get yellow solid (5), yield 68%, fusing point 106-109 ℃.Ultimate analysis C
17H
13NO
4Br
4, theoretical value %:C 54.42, and H 3.49, and N 3.73; Experimental value %:C 54.49 H 3.46, N 3.76.
1H-NMR：δ(ppm，CD
3Cl)，7.48(m，3H)，7.15(m，2H)，3.83(s，2H)，3.68(s，3H)，3.63(s，3H)。
Embodiment 6 10,10-dimethoxy-1,7,8,9-methyl-4-azepine-N-phenyl-three ring (5.2.1.0
2,6) certain herbaceous plants with big flowers alkane-8-alkene-3,5-diketone (6) synthetic
Synthetic method is with embodiment 1, by 13, and 3-dimethoxy-1,2,3,4-tetramethyl-ring pentadiene and the reaction of N-phenyl maleimide.Get yellow solid (6), yield 78%, fusing point 134-136 ℃.Ultimate analysis C
21H
25NO
4, theoretical value %:C 70.96, and H 7.09, and N 3.94; Experimental value %:C 70.90 H 7.06, N 3.96.
1H-NMR：δ(ppm，CD
3Cl)，7.46(m，3H)，7.13(m，2H)，3.82(s，2H)，3.64(s，3H)，3.60(s，3H)，2.34(m，6H)，1.34(m，6H)。
Embodiment 7 10,10-dimethoxy-1,7,8,9-tetrachloro-4-azepine-N-benzyl-three ring (5.2.1.0
2,6) certain herbaceous plants with big flowers alkane-8-alkene-3,5-diketone (7) synthetic
Synthetic method is with embodiment 1, by 3, and 3-dimethoxy-1,2,3,4-tetrachlorocycbpentadiene and the reaction of N-benzyl maleinamide.Get faint yellow solid (7), yield 72%, fusing point 113-116 ℃.Ultimate analysis C
18H
15NO
4Cl
4, theoretical value %:C 47.92, and H 3.35, and N 3.10; Experimental value %:C 47.95 H 3.26, N 3.16.
1H-NMR：δ(ppm，CD
3Cl)，7.37(m，2H)，7.26(m，3H)，455(s，2H)，3.62(s，6H)，3.55(s，3H)。
Embodiment 8 10,10-dimethoxy-1,7,8,9-tetrachloro-4-azepine-N-(2-chloro-phenyl-)-three ring (5.2.1.0
2,6) certain herbaceous plants with big flowers alkane-8-alkene-3,5-diketone (8) synthetic
Synthetic method is with embodiment 1, by 3, and 3-dimethoxy-1,2,3, the reaction of 4-tetrachlorocycbpentadiene and N-(2-chloro-phenyl-) maleinamide.Get faint yellow solid (8), yield 72%, fusing point 122-125 ℃.Ultimate analysis C
17H
12NO
4Cl
5, theoretical value %:C 43.30, and H 2.56, and N 2.97; Experimental value %:C 43.35 H 2.51, N 2.90.δ(ppm，CD
3Cl)，7.45(m，1H)，7.22(m，2H)，7.15(m，1H)，3.81(s，2H)，3.64(s，3H)，3.61(s，3H)。
Embodiment 9 10,10-dimethoxy-1,7,8,9-tetrachloro-4-azepine-N-(2-fluorophenyl)-three ring (5.2.1.0
2,6) certain herbaceous plants with big flowers alkane-8-alkene-3,5-diketone (9) synthetic
Synthetic method is with embodiment 1, by 3, and 3-dimethoxy-1,2,3, the reaction of 4-tetrachlorocycbpentadiene and N-(2-fluorophenyl) maleinamide.Get faint yellow solid (9), yield 72%, fusing point 118-122 ℃.Ultimate analysis C
17H
12NO
4Cl
4F, theoretical value %:C 44.87, and H 2.66, N3.08; Experimental value %:C 44.80 H 2.59, N 2.99.δ(ppm，CD
3Cl)，7.44(m，1H)，7.20(m，2H)，7.13(m，1H)，3.80(s，2H)，3.63(s，3H)，3.60(s，3H)。
Embodiment 10 10,10-dimethoxy-1,7,8,9-tetrachloro-4-azepine-N-(4-tolyl)-three ring (5.2.1.0
2,6) certain herbaceous plants with big flowers alkane-8-alkene-3,5-diketone (10) synthetic
Synthetic method is with embodiment 1, by 3, and 3-dimethoxy-1,2,3, the reaction of 4-tetrachlorocycbpentadiene and N-(4-tolyl) maleinamide.Get faint yellow solid (10), yield 72%, fusing point 101-104 ℃.Ultimate analysis C
18H
15NO
4Cl
4, theoretical value %:C 47.92, and H 3.35, and N 3.10; Experimental value %:C 44.80 H 3.39, N 3.02.δ(ppm，CD
3Cl)，7.42(m，3H)，7.11(m，2H)，3.82(s，2H)，3.64(s，3H)，3.61(s，3H)，2.35(s，3H)。
Embodiment 11 cytotoxicity pharmacological evaluation
Measure the inhibited proliferation of target compound with srb assay to 3 kinds of human cancer cells.People's cancer of the stomach SGC-7901 cell of taking the logarithm vegetative period, HeLa Cells, people early 5 kinds of human cancer cells such as young graininess leukemia HL-60 cell, human liver cancer cell Bet-7402 and human oral cavity epithelial cancer cells KB with 4 * 10
4Individual/mL cell inoculation is in 96 orifice plates.At 37 ℃, the CO of volume fraction 5%
2Cultivate 12h in the saturated humidity incubator, after the adding testing compound was handled 48h, the cell HL-60 that swims needed every hole to add the Tricholroacetic Acid of the volume fraction 80% of 4 ℃ of precoolings of 50 μ L, and making it finally reach volume fraction is 16%; The volume fraction that attached cell then needs every hole to add 4 ℃ of precoolings of 50 μ L is 50% Tricholroacetic Acid, and making it finally reach volume fraction is 10%.Behind 4 ℃ of refrigerator fixed cell 1h, it is 0.4% sulphonyl rhodamine B that every hole adds 50 μ L volume fractions, room temperature dyeing 30min.Last every hole adds 150 μ L 10mmolL
-1Tris alkali, the 15min that vibrates on micro oscillator all dissolves until dyestuff.Utilize microplate reader to survey absorbance (A value), the blank well absorbance of every hole solution at the 540nm place.Calculate as follows target compound to the inhibiting rate of tumour cell in-vitro multiplication (inhibition rate, IR):
IR％＝(1-A
sample/A
control)×100％
Half-inhibition concentration (IC with ICP1.0.0 computed in software medicine
50).And with positive control drug Luo Fei former times cloth and 5 FU 5 fluorouracil relatively.The result shows compound 2 (23.1), 3 (35.2), 5 (21.0), 7 (35.4) IC to people's cancer of the stomach SGC-7901 cell and HeLa Cells
50Value is lower than positive control drug (59.6); Compound 1 (13.1), 6 (18.1), 8 (25.1), 9 (28.1), 10 (29.1) IC to young graininess leukemia HL-60 cell people's morning
50Value is lower than positive control drug (53.1).Early young graininess leukemia HL-60 cell, human liver cancer cell Bet-7402 and human oral cavity epithelial cancer cells KB all have stronger inhibition activity to institute's test compounds to the people.
The experiment of embodiment 12 sample vitro culture antitumor actions
Adopt tetramethyl-azo azoles indigo plant (MTT) method to measure the retarding effect of institute's invention compound to growth of tumour cell.Method: will contain volume fraction is the murine sarcoma ascites strain (S of the RPMI-1640 nutrient solution preparation of 10% newborn calf serum
180), mouse ehrlich ascites tumor strain (EAC) and 3 kinds of tumour cell suspensions of rat liver cancer ascites strain (HeAP) are inoculated in 96 well culture plates respectively, (inoculum density is 5 * 105/mL) to every hole 180 μ L, add test-compound simultaneously and make every hole concentration be respectively 250,50,10,2,0.4 μ g/mL totally 5 concentration, each concentration is all done 3 multiple holes.It is 5%CO that culture plate is placed volume fraction
2, 37 ℃ of constant temperature, 100% relative humidity incubator in cultivate, every hole adds 50 μ L MTT (1mg/mL) respectively behind the 72h, continue to cultivate the 4h abandoning supernatant, every hole adds 150mL dimethyl sulfoxide (DMSO) (DMSO), concussion dissolving back adopts 3550 type microplate reader to survey absorbancy (D) value at wavelength 595nm place, calculates cell survival rate: p
Cell survival/ %=D
Experimental group/ D
Control group* 100%, the logarithm of cell survival rate and compound concentration is returned statistical treatment, calculation of half inhibitory concentration (p
IC50), and with the positive control drug cis-platinum relatively.The result shows: 2～8 pairs of 3 kinds of tumor cell lines of compound all demonstrate stronger restraining effect, act on equal significance and are higher than positive control drug cis-platinum (P＜0.01).
Claims (6)
1. formula (I) is a kind of three ring (5.2.1.0 that can be used for treating the replacement of tumour
2,6) certain herbaceous plants with big flowers alkane-8-alkene-3,5-dione compounds and pharmacy acceptable salt thereof or prodrug, and with the composition of pharmaceutically acceptable carrier:
Wherein, R
1For straight chain with 1-10 carbon atom or branched alkyl, alkoxyl group or aromatic substituents group, R
2For halogen (fluorine, chlorine, bromine, iodine) or have 1-10 carbon atom straight chain or branched alkyl substituent group, R
3For hydrogen atom or have 1-20 carbon atom, can have 1 or 2 two key or triple-linked straight chain or branched aliphatics or aromatic group.
2. the medicine of aforementioned claim can be that the pharmacologically acceptable salts compounds is fluorochemical, muriate, bromide, iodide, vitriol, nitrate, phosphoric acid salt, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, mesylate or tosilate.
3. the medicine of aforementioned claim, it can be pharmacy acceptable esters compound, finger is the ester of hydrolysis in vivo, being included in degrades in the human body discharges the ester of parent compound or its salt, suitable ester group for example comprises: derived from pharmaceutically acceptable aliphatic carboxylic acid or aliphatic family alcohol, especially paraffinic acid (alcohol), alkenoic acid (alcohol), naphthenic acid (alcohol) and alkane dicarboxylic acid's's (glycol) ester, wherein preferred each alkyl or alkenyl partly is less than 6 carbon atoms.
4. claim 1 each compound or pharmaceutical composition to the claim 3 can be used as composition with other antitumor drug, wherein make up with antitumor drug and be selected from the organic antibumor molecules of small molecules, biotechnological formulation or by platinum, titanium, vanadium, niobium, aluminium, the antitumor drug that contains metal of rhenium or tin, comprise inducer of apoptosis, polynucleotide (as ribozyme), polypeptide (as enzyme), medicine, the biosimulation thing, alkaloid, alkylating agent, antitumor antibiotic, antimetabolite, medicines such as new vessel generation inhibitor, the antitumor drug that preferably contains metal is a cis-platinum, carboplatin, oxaliplatin, teraplatin, Platiniuln-DACH, ormaplatin, titanocene dichloride, dichloro cyclopentadiene vanadium, dichloro cyclopentadiene niobium, dichloro cyclopentadiene aluminium, dichloro cyclopentadiene rhenium, dihalo two organotins or other contain the antitumor drug of metal.
5. claim 1 each neoplastic disease that compound or pharmaceutical composition acted on to the claim 3 is malignant tumour and the cancer that wide spectrum Mammals (comprising the people) health causes, wherein preferably act on Human Lung Cancer, human non-small cell lung cancer, mammary cancer, ovarian cancer and melanoma, especially solid tumor (for example, lung, ovarian cancer, mammary gland, stomach and intestine, colon, pancreas, bladder, kidney, prostate gland, brain) and various hemopoietic system cancer (for example, HodgkinShi disease, non-HodgkinShi lymphatic cancer, leukemia).
6. claim 1 each compound or pharmaceutical composition patient that can suffer from malignant tumour by the mode of vein, oral, subcutaneous, intra-arterial administration or topical to the claim 3.
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| CNA2008101474156A CN101463003A (en) | 2008-08-15 | 2008-08-15 | Substituted tricyclodecane compound as anti-cancer compound |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2687509A3 (en) * | 2012-07-16 | 2014-03-26 | Warszawski Uniwersytet Medyczny | Dicarboxyimides derivatives for use in the treatment of cancer |
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2008
- 2008-08-15 CN CNA2008101474156A patent/CN101463003A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2687509A3 (en) * | 2012-07-16 | 2014-03-26 | Warszawski Uniwersytet Medyczny | Dicarboxyimides derivatives for use in the treatment of cancer |
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