CN104447598A - Macrocyclic polyamine derivatives of CA-4 and anti-tumor characteristic of macrocyclic polyamine derivatives - Google Patents

Macrocyclic polyamine derivatives of CA-4 and anti-tumor characteristic of macrocyclic polyamine derivatives Download PDF

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CN104447598A
CN104447598A CN201310428519.5A CN201310428519A CN104447598A CN 104447598 A CN104447598 A CN 104447598A CN 201310428519 A CN201310428519 A CN 201310428519A CN 104447598 A CN104447598 A CN 104447598A
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replacement
independently selected
aryl
alkyl
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CN104447598B (en
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王建平
王建国
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Zhejiang Dade Pharmaceutical Group Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
    • C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6524—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having four or more nitrogen atoms as the only ring hetero atoms

Abstract

The invention discloses macrocyclic polyamine derivatives (represented by formula I) of CA-4 as well as a pharmaceutically acceptable salt or configurational isomers of the macrocyclic polyamine derivatives. The compounds can be used for inhibiting a tumor from genesis or growth. Substituent groups R1 and R2, ring A, and a linking group L are defined in the description. The invention further discloses a preparation method of the compounds shown as formula I, a medicament composition, and application of the compounds in treating tumor diseases.

Description

The cyclen derivatives of CA-4 and antitumor properties thereof
Technical field
The present invention relates to medical art, be specifically related to Macrocyclic polyamine analog derivative and the metal complexes thereof of CA-4, or this compounds pharmacy acceptable salt, combine separately or optionally to one or more other pharmaceutically active compounds and be used for the treatment of the relevant disease of tumour.
Background technology
Macrocyclic polyamine is the important ligand molecular of a class, with the sterie configuration of its mutability and electronic structure, result in a series of special property.Because the nitrogen-atoms introduced has special coordination affinity to transition metal ion, heavy metal ion, the macrocyclic complex formed is significant in host-guest chemistry, chemical simulation, molecular magnet, molecular recognition and information transmission, but also metal ion match that some has ad hoc structure can be utilized as Model Molecule, for research life active procedure provides possibility widely.
Structurally, Macrocyclic polyamine title complex and the interior macrocyclic complex existed of organism, as the title complex of porphyrin and corrin, there is similarity, compared with general crown compound, Macrocyclic polyamine has two key characters: Macrocyclic polyamine and many metal ions can form stable title complex, and ring member nitrogen atoms has strong basicity, therefore energy and H +form ammonium ion; Ring more easily imports carboxyl, hydroxyl, phosphonate group and other hydrophilic radical or functional group, multiple water miscible part can be obtained.The very important purposes of of Macrocyclic polyamine metal complexes is applied in enzyme simulation research, as the research of the catalytic hydrolysis for carboxylicesters, phosphoric acid ester and nucleic acid.Macrocyclic polyamine molecular energy and many metal ions form stable title complex, and ring member nitrogen atoms has strong basicity, energy and H +form ammonium salt, more easily import carboxyl, hydroxyl, phosphonate group and other hydrophilic radicals or functional group, a series of water soluble ligand can be obtained.In this year, the research of Macrocyclic polyamine and metal complexes thereof gets more and more, and in succession reports synthesis and the character of all kinds of cyclen derivatives and metal complexes thereof both at home and abroad.The macrocyclic polyamine compound that current application prospect is larger mainly contains: Isosorbide-5-Nitrae, 7-7-triazacyclononane (1), Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand (cyclen, 2), Isosorbide-5-Nitrae, 8,11-tetraazacyclododecane tetradecane (cyclam, 3).
Macrocyclic tetraaza part is similar to elementary cells such as the vitamin B12 in organism, chlorophyll, many steps of vital process all can think the redox processes using metal ion match as reactive center, wherein the stand-in of the interior enzymatic structure unit of macrocyclic tetraaza title complex Chang Zuowei organism, therefore study macrocyclic tetraaza title complex significant.Studying often in Macrocyclic polyamine metal complexes to be take Cyclen as the title complex of parent.
Macrocyclic polyamine part has the performance of DNA cutting, has certain anti-cancer function.Comparatively early super coiled DNA (pBR322) can be cut into the type of incising and linear DNA by the Cyclen title complex of research under aerobic conditions, pharmacological evaluation shows, this title complex has antitumour activity to P388 and BEL-7404 clone in vivo, and has interference effect to K562 cancerous cell line in the G0-G1 stage.After this, the nitrogen-atoms of researchist on ring connects various different functional group, make the research of Cyclen title complex more deep.The title complex formed after four nitrogen-atoms of Cyclen all connect new group, at H 2o 2when existing, strand and double-strand scissors can be served as, super coiled DNA is cut into the type of incising and linear DNA.Be that the electron paramagnetic resonance result of trapping bait proves with DMPO, cutting mechanism may be free radical mechanism.
In addition, Macrocyclic polyamine title complex also has the function of Supramolecular Recognition, can identify Nucleotide and DNA, RNA.Macrocyclic tetraamines as l, 4,7, lO-tetraazacyclododecanand (Cyclen) and derivative and Zn 2+the title complex formed, not only shows very unique activity in hydrolyse phosphate esters, and is also highly effective at the identification aspect such as Nucleotide and DNA, RNA.Zn (II) one Cyclen title complex with side arm aromatic ring can pass through Zn 2+the formation of-imido grpup negative ion key, T or U is combined in simple helix and duplex DNA or RNA selectively, plays the part of the function of molecule zipper lock in the A-T chain of DNA breakage.Title complex with the macrocyclic tetraamines compound of one or two arylmethyl group can selectivity connect, in conjunction with occurring in A_T rich region with natural duplex DNA (containing 150 base pairs).This selectivity and binding ability are fixed against ability and the number of aromatic rings of aromatic ring π-π stacking
And its structure of drug of compete A-4 4(is as shown in Equation 4) be two phenyl ring connected by ethylenic linkage, there is powerful pi-pi accumulation ability.It also has anti-tumor activity simultaneously, can directly act on endotheliocyte, the endothelial cell apoptosis of proliferative induction, thus the generation of Tumor suppression new vessel.
Therefore, this invention exploits a kind of new antitumor drug, Macrocyclic polyamine title complex and CA-4 are organically combined by chemical bond.We wish that the DNA of Macrocyclic polyamine title complex in this compound identifies and cutting action combines with the microtubulin-resisting Synthesis of CA-4, make it have good anti-tumor activity.
Summary of the invention
The invention discloses a kind of compound of representing containing logical formula I below or pharmacy acceptable salt or its prodrug
Wherein
A ring represents the macrocyclic polyamine compound that can be optionally substituted;
L is a linking group, can be the one in following several structure:
R 1independently selected from alkyl, haloalkyl;
R 2independently selected from one or more following group: the alkyl of replacement, the aryl of replacement, the heterocyclic aryl of replacement, halogen, hydroxyl, amino, alkylamino, dialkylamine, acid amides, cyano group, carboxyl, carbalkoxy, alkoxyl group, acyloxy ,=O ,=S ,=NH;
R 3independently selected from hydrogen, the alkyl of replacement, the aryl of replacement;
N is 0,1,2.
Formula I compound of the present invention, one of preferred be have following general formula (II compound a):
Wherein
L is a linking group, can be the one in following several structure:
R 1independently selected from methyl, ethyl, difluoromethyl, 2,2,2-trifluoroethyl;
R 3independently selected from hydrogen, the alkyl of replacement, the aryl of replacement;
R 4, R 5independently selected from: the alkyl of replacement, the aryl of replacement, the heterocyclic aryl of replacement, halogen, hydroxyl, amino, alkylamino, dialkylamine, acid amides, cyano group, carboxyl, carbalkoxy, alkoxyl group, acyloxy;
R 6independently selected from hydrogen, the alkyl of replacement, the aryl of replacement, halogen, hydroxyl, amino, alkylamino, dialkylamine, acid amides, cyano group, carboxyl, carbalkoxy, alkoxyl group, acyloxy ,=O ,=S ,=NH;
N is 0,1,2.
Formula I compound of the present invention, one of preferred be have following general formula (II compound b):
Wherein
L is a linking group, can be the one in following several structure:
R 1independently selected from methyl, ethyl, difluoromethyl, 2,2,2-trifluoroethyl;
R 3independently selected from hydrogen, the alkyl of replacement, the aryl of replacement;
R 7, R 8, R 9independently selected from: the alkyl of replacement, the aryl of replacement, the heterocyclic aryl of replacement, halogen, hydroxyl, amino, alkylamino, dialkylamine, acid amides, cyano group, carboxyl, carbalkoxy, alkoxyl group, acyloxy;
R 10independently selected from hydrogen, the alkyl of replacement, the aryl of replacement, halogen, hydroxyl, amino, alkylamino, dialkylamine, acid amides, cyano group, carboxyl, carbalkoxy, alkoxyl group, acyloxy ,=O ,=S ,=NH;
N is 0,1,2.
Formula I compound of the present invention, one of preferred be have following general formula (II compound c):
Wherein
L is a linking group, can be the one in following several structure:
R 1independently selected from methyl, ethyl, difluoromethyl, 2,2,2-trifluoroethyl;
R 3independently selected from hydrogen, the alkyl of replacement, the aryl of replacement;
R 11, R 12, R 13independently selected from: the alkyl of replacement, the aryl of replacement, the heterocyclic aryl of replacement, halogen, hydroxyl, amino, alkylamino, dialkylamine, acid amides, cyano group, carboxyl, carbalkoxy, alkoxyl group, acyloxy;
R 14independently selected from hydrogen, the alkyl of replacement, the aryl of replacement, halogen, hydroxyl, amino, alkylamino, dialkylamine, acid amides, cyano group, carboxyl, carbalkoxy, alkoxyl group, acyloxy ,=O ,=S ,=NH;
N is 0,1,2.
Formula I compound of the present invention, more preferably certainly:
Formula I compound of the present invention, its molecule can with the salt coordination containing metal ion.Its cationic can be main group metal ion or transition metal ion, and negatively charged ion can be common are machine or inorganic negatively charged ion.Wherein said metal ion is preferably from Zn 2+, Cu 2+, Fe 2+, Fe 3+, Pt 2+, Cr 3+, Ni 2+, Co 2+, Mn 2+, Ag +, Pd 2+, La 3+, Eu 3+, Gd 3+, Ir 3+, Tb 4+, Lu 3+, Ca 2+; Described negatively charged ion is preferably from F -, Cl -, Br -, I -, SO 4 2-, SO 3 2-nO 3 -, PO 4 3-, PO 3 3-, ClO 4 -, ClO 3 -, BrO 4 -, IO 4 -, oxalate denominationby, maleate ion, malate ion, citrate ion, succinic ion.
In addition, present invention also offers the method for synthesis formula I compound.Raw material 5 can obtain with the method described in CN 101139358 or the synthesis of similar method according to Chinese patent CN 101085743 with 6.
If n is 0 in formula I compound, its synthetic method is:
If n is 1 or 2 in formula I compound, its concrete building-up process illustrates by following reaction equation:
this reaction, with corresponding halogenated carboxylic acid, is reacted by the method and CA-4 making acyl chlorides or active ester, is obtained the carboxylicesters of CA-4.Again carboxylicesters and methyl-isochondodendrine or derivatives thereof are synthesized under base catalysis and obtain target product.Finally this product and metal ion complexation are obtained final product.
Compound of the present invention and pharmacy acceptable salt also comprise the form of solvate or hydrate.In general, the form of solvate or hydrate is equal to form that is non-solvated or non-hydrated, contains within the scope of the invention in the lump.Likely there is polycrystal or unbodied form in some compound in the present invention.Generally speaking, all physical form have equal purposes, and contain within the scope of the invention.
The present invention is contained in form of mixtures or all steric isomers of the compounds of this invention in pure form.The definition of the compounds of this invention comprises all possible steric isomer and composition thereof.It comprises racemic form and the optical isomer with given activity be separated very particularly.Racemic form splits by physical method, and described physical method is such as carried out fractional crystallization, separation to diastereomer derivative or is separated by chiral column chromatography.By ordinary method such as optical activity acid form salify then crystallization and obtain independent optical isomer from racemic modification.
The present invention also comprises the prodrug of described compound.Prodrug is a kind of compound derived by parent drug, and it is once enter in body, and prodrug is just parent drug by metabolic transformation.Prodrug is prepared by replacing one or more functional groups of parent drug, and its substituted radical can be discharged parent compound by enzyme catalysis in vivo.Preparation and the use of prodrug can at T.Higuchi and V.Stella, " Pro-drugs as Novel Delivery System ", Vol.14of the A.C.S.SymposiumSerier and Bioreversible Carriers in Drug Design, ed.Edward B.Roche, AmericanPharmaceutical Association and Pergamon Press, finds in 1987.
The invention still further relates to the pharmaceutical composition of the formula I compound that includes effective amount and pharmacologically acceptable carrier, said composition be applicable to local, in intestines or administration outside intestines, can be inorganic or organic, solid-state or liquid state.For oral, especially with tablet or capsule.This tablet or capsule comprise activeconstituents and thinner (as lactose, glucose, sucrose, mannitol, sorbyl alcohol, Mierocrystalline cellulose, glycerol), lubricant (as talcum, stearate), polyoxyethylene glycol.Tablet also can comprise tackiness agent, starch, gelatin, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone, also can comprise disintegrator (as starch, agar, alginic acid and salt thereof), effervescent mixture, or sorbent material if desired, dyestuff, seasonings, sweetener.These compositions can also administered parenterally form or be suitable for the form of injection.The preferred isotonic aqueous solution of this type of formulation or emulsion, as when the lyophilised compositions be only made up of activeconstituents and a kind of carrier (as N.F,USP MANNITOL), this type of solution can be prepared before use.These pharmaceutical compositions can be aseptic, or comprise vehicle, or solubilizing agent, adjustment osmotic pressure salt.
The invention provides a kind of application of medicine in the medicine preparing the treatment disease relevant to tumour comprising formula I compound.Tumour wherein comprises: lung cancer, small cell lung cancer, liver cancer, carcinoma of the pancreas, cancer of the stomach, osteocarcinoma, esophagus cancer, mastocarcinoma, kidney, cholangiocarcinoma, prostate cancer, carcinoma of testis, colorectal carcinoma, ovarian cancer, bladder cancer, cervical cancer, bronchogenic carcinoma, melanoma, gland cancer, syringocarcinoma, papillary carcinoma, papillary carcinoma, squamous cell carcinoma, rodent cancer, adenocarcinoma cystic, glioma, astrocytoma, medulloblastoma, neuroblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, oligodendroglioma, meningioma, neurofibroma, fibrosarcoma, fibroblastoma, fibroma, myxosarcoma, myxocystoma, lipoma, lipoadenoma, chondrosarcoma, chondroma, chondromyoma, chordoma, chorioadenoma, villous vessels knurl, chorioepithelium knurl, chorioblastoma, osteosarcoma, osteoblastoma, osteoclastoma, osteochondrofibroma, osteochondrosarcoma, stock cystoma, osteodentinoma, osteofibroma, the fibrosarcoma of bone, vascular tumor, angiosarcoma, lymphangiosarcoma, lymphangioma, lymphoma, endothelioma, synovioma, synovial sarcoma, mesothelioma, mesocytoma, ewing's tumor, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdosarcoma, kemia, acute myelogenous leukemia, chronic leukemia, polycyth(a)emia, multiple myeloma.
Present invention also offers a kind of being used for the treatment of or the test method of Tumor suppression, the method, mainly through In-vivo test in mice, measures the anti-tumor activity of compound.
Embodiment
In order to better understand the present invention, set forth content of the present invention further below in conjunction with embodiment, but content of the present invention is not only confined to the following examples.
It is below the definition of the term that can use in this manual.Except as otherwise noted, the original definition that this patent provides with regard to group or term be applicable to specification sheets in the whole text in described group or term, no matter to be used alone or the part as another group uses.
Unsubstituted alkyl that is that term " alkyl " refers to straight chain or side chain, it has 1-20 carbon atom, preferably 1-6 carbon atom, refers in particular to methyl, ethyl, propyl group (comprising n-propyl and sec.-propyl), butyl (comprising normal-butyl, isobutyl-, the tertiary butyl) etc.
Term " halogen " or " halo " refer to fluorine (fluoro), chlorine (chloro), bromine (bromo), iodine (iodo).
Term " aryl " refers to the aromatic hydrocarbons of monocycle or many rings, such as benzene, naphthalene, anthracene, phenanthrene etc.
Term " heterocyclic aryl " refers to the optional aromatic cyclic groups replaced, and wherein at least contain a carbon atom by other hybrid atom MCM-41, heteroatoms comprises nitrogen, oxygen, sulphur.This nitrogen and sulfur heteroatom also can be optionally oxidized, and nitrogen heteroatom also can be optionally quaternized.This heterocyclic group can connect at any heteroatoms or carbon atom place.Preferred heterocyclic aryl includes but not limited to, pyridine, pyrazine, pyrimidine, pyridazine, triazine, furans, thiophene, imidazoles, triazole, tetrazolium, thiazole, isothiazole, pyrroles, pyrazoles, oxazole, isoxazole, cumarone, benzothiazole, thionaphthene, indoles, quinoline, isoquinoline 99.9, purine, carbazole, benzoglyoxaline, pyrrolopyridine, pyrrolopyrimidine etc.
Term " cycloalkyl " refers to the carbocyclic ring of non-aromatic, comprises monocycle, condensed ring or volution.Cycloalkyl also comprises and has the ring that one or more aromatic nucleus condenses (namely having the key that common), and the cycloalkyl having one or more aromatic nucleus to condense can be connected with other groups by aromatic nucleus or non-aromatic ring part.
Term " Heterocyclylalkyl " refers to nonaromatic heterocycles, and wherein one or more ring member nitrogen atoms are heteroatomss, as oxygen, nitrogen, sulphur atom.Heterocyclylalkyl can comprise monocycle or many rings (if any 2,3,4 fused rings), volution.Preferred Heterocyclylalkyl comprises aziridine, azetidine, tetrahydrofuran (THF), tetramethylene sulfide, tetramethyleneimine, oxazolidine, thiazolidine, isothiazolidine, imidazolidine, pyrazolidine, morpholine, thiomorpholine, piperazine, piperidines etc.Heterocyclylalkyl also comprises the heterocycle having one or more aromatic nucleus and condense, such as 2,3-Dihydrobenzofuranes, 1,3-benzodioxolane, phendioxin, 4-diox, benzenedicarboxamide etc.There is the Heterocyclylalkyl that one or more aromatic nucleus condenses to be connected with other group by aromatic nucleus or non-aromatic ring part.
Term " amide group " refers to group-C (=O) NH-.
Term " cyano group " refers to group-CN.
Term " alkylamino " refers to the amino replaced by an alkyl.
Term " dialkylamine " refers to the amino that group is replaced by two identical or different alkyl.
Term " carboxyl " refers to group-COOH.
Term " alkoxycarbonyl " refers to group-C (=O) OR 15, wherein R 15refer to alkyl.
Term " alkoxyl group " refers to group-OR 16, wherein R 16refer to alkyl.
Term " acyloxy " refers to group-OC (=O) R 17, wherein R 17refer to alkyl.
" replacement " means that the group described subsequently can be replaced by some common groups (as hydrogen, halogen, hydroxyl, amino, sulfydryl, nitro, cyano group, aryl, heterocyclic radical, Heterocyclylalkyl, carboxyl, amide group etc.).
" optionally " means that the event that describes subsequently or situation can occur or not occur, and described description is paraded one's wealth example that wherein said event or situation occur and wherein its example of not occurring.
" pharmaceutically acceptable carrier " used herein comprise any and whole solvents, dispersion medium, dressing, antibacterium and antifungal medicine, etc. blend absorption delay agent etc.Such medium and medicament are used for pharmaceutically active substances and are well known in the art.Unless any conventional media or medicament incompatible with activeconstituents, expected during its application in therapeutic composition.The activeconstituents supplemented also can be incorporated in composition.
Embodiment 1
Step 1:
(Z)-1-(3 is added in 500ml there-necked flask, 4,5-trimethoxyphenyl)-2-(3-amino-4-methoxyl phenyl) ethene (31.5g, 0.1mol), methylene dichloride 300ml, diisopropylethylamine 20ml, stirs, adds 2-chloroacetyl chloride (11.3g under ice bath, 0.1mol), be warmed up to 25 DEG C after adding, reaction 3h, TLC follow the tracks of.After reaction terminates, use sodium bicarbonate aqueous solution, saturated common salt water washing respectively, collect organic phase, anhydrous magnesium sulfate drying, filter, concentrated.The crude product obtained is directly used in the next step.
Step 2:
The crude product that upper step obtains is dissolved in 300ml DMF, adds PdCl 2(17.7g, 0.1mol), tetrabutylammonium chloride (27.8g, 0.1mol), methyl-isochondodendrine (17.2g, 0.1mol), stirs, is heated to 80 DEG C, and reaction 10h, TLC follow the tracks of.After reaction terminates, cooling.Reaction solution is poured in 500ml frozen water, use 300ml dichloromethane extraction respectively 3 times, collect organic phase, anhydrous magnesium sulfate drying, filter, concentrate and obtain crude product.Crude product flash column chromatography is separated, and eluant dichloromethane/methyl alcohol/triethylamine=9/1/0.5, obtains sterling 25g, yield 47.4%.MS(M+1)=528.6。
Embodiment 2
Step 1:1,4,7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, the preparation of 7,10-tetraacethyl (DOTA)
Isosorbide-5-Nitrae is added, 7 in there-necked flask, 10-tetraazacyclododecanand (100g, 0.58mol), deionized water 1000ml, stir, drip the KOH solution of 30%, adjust ph is to 8.5, then Mono Chloro Acetic Acid (263g is added, 2.78mol), then use the KOH solution adjust ph of 30% to 8.5, be heated to 80 DEG C, reaction 24h, maintains pH value in the process between 8.5-9.After reaction terminates, cooling, adds concentrated hydrochloric acid adjust ph to 2, and adularescent precipitation produces, and filters.Filter cake water-ethanol solution weight crystallization, the crystal ethanol obtained, washed with diethylether, dry, obtain DOTA crystal 183g, yield 78%.MS(M+1)=405.4。
Step 2:
DOTA (20g, 0.05mol) is added, thionyl chloride 200ml in the there-necked flask of band stirring and refluxing device, stir, reflux 4h, pressure reducing and steaming thionyl chloride liquid after cooling, add the THF of 100ml drying again, pressure reducing and steaming solvent, obtains solid acid chloride.The solid acid chloride this obtained is dissolved in the methylene dichloride of 250ml drying, add diisopropylethylamine 20ml, stir, under ice bath, add (Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-hydroxyl-4-p-methoxy-phenyl) ethene (4g, 0.0125mol), remove ice bath, be slowly warming up to 30 DEG C, reaction 3h, TLC follow the tracks of.Add frozen water 100ml after reaction terminates, stir 30min, pressure reducing and steaming organic solvent.In aqueous phase, use concentrated hydrochloric acid adjust ph to 2, have solid to separate out, filter and obtain white solid, use ethanol-water solution recrystallization, obtain target product 22.8g, yield 65%.MS(M+1)=703.8。
Embodiment 3
(Z)-1-(3,4,5-trimethoxyphenyl)-2-(3-amino-4-methoxyl phenyl) ethene (20g, 63mmol) be dissolved in 200ml methylene dichloride, add diisopropylethylamine 13ml, stir, under ice bath, add 1,1 '-carbonyl dimidazoles (12.3g, 76mmol), DMF (100ml) solution of methyl-isochondodendrine (13g, 76mmol) is added after reacting 1.5h, add rear room temperature reaction to spend the night, TLC follows the tracks of.After reaction terminates, be concentrated into by reaction solution dry, be separated with flash column chromatography, separation condition is eluent: methylene chloride/methanol/triethylamine=9/1/0.5, obtains target product 23g, yield 71%.MS(M+1)=514.6。
Embodiment 4
Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand (20g, 0.116mol) is dissolved in 200mlDMF, add DMF contracting dicarbaldehyde (20.8g, 0.17mol), stir, be heated to 100 DEG C, reaction 2h, after reaction terminates, cool to room temperature.Reaction solution is poured in 500ml water, and at room temperature placement is spent the night.Then use chloroform extraction 3 times, each 200ml, merge organic layer, anhydrous magnesium sulfate drying, pressure reducing and steaming solvent, namely obtains 1-formaldehyde-Isosorbide-5-Nitrae, 7,10-teteaazacyclododecane.
Solid obtained in the previous step is dissolved in 350ml methylene dichloride, adds methyl iodide (49.5g, 0.35mol), potassium hydroxide 20g, be heated to 50 DEG C, stirring reaction 3h.After having reacted, cooling, filters, filtrate is concentrated into dry.By after the solid 200ml dissolve with ethanol that obtains, add the sulphuric acid soln 100ml of 10%, be heated to 50 DEG C, stirring reaction 5h.After reaction terminates, cooling, the potassium hydroxide adjust ph with 10%, to 9.5, adds dichloromethane extraction 3 times, merges organic layer, is concentrated into dry after drying.Flash column chromatography is separated, and separation condition is eluent: methylene chloride/methanol/triethylamine=9/1/0.5, obtains 4,7,10-trimethylammonium-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand 16.7g, yield 60%.MS(M+1)=215.4。
(Z)-1-(3 is added in there-necked flask, 4,5-trimethoxyphenyl)-2-(3-amino-4-methoxyl phenyl) ethene (31.5g, 0.1mol), methylene dichloride 300ml, diisopropylethylamine 20ml, stirs, adds 2-chloroacetyl chloride (11.3g under ice bath, 0.1mol), be warmed up to 25 DEG C after adding, reaction 3h, TLC follow the tracks of.After reaction terminates, use sodium bicarbonate aqueous solution, saturated common salt water washing respectively, collect organic phase, anhydrous magnesium sulfate drying, filter, concentrated.The crude product obtained is directly used in the next step.
The crude product that upper step obtains is dissolved in 300ml DMF, adds PdCl 2(17.7g, 0.1mol), tetrabutylammonium chloride (27.8g, 0.1mol), 4,7,10-trimethylammonium-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand (21.4g, 0.1mol), stirs, is heated to 80 DEG C, and reaction 10h, TLC follow the tracks of.After reaction terminates, cooling.Reaction solution is poured in 500ml frozen water, use 300ml dichloromethane extraction respectively 3 times, collect organic phase, anhydrous magnesium sulfate drying, filter, concentrate and obtain crude product.Crude product flash column chromatography is separated, and eluant dichloromethane/methyl alcohol/triethylamine=9/1/0.5, obtains sterling 25g, yield 47.4%.MS(M+1)=570.7。
According to method similar above, this patent has also prepared following compound:
The preparation of zinc salt title complex
Be dissolved in by 1mmol compound in 100mL dehydrated alcohol, slowly drip the ethanol solution containing 1mmolZn (ClO4) 26H2O, stirring at room temperature 2h, filter, vacuum-drying obtains following several compound respectively:
The preparation of platinum salt complex
1mmol compound is dissolved in 100mL dehydrated alcohol, slowly drips, after adding K2PtCl4 (0.42g, the 1mmol) aqueous solution (5mL), temperature is risen to 50 DEG C of lucifuge reaction 12h.Add acetone (20mL) after reaction solution concentrating under reduced pressure and separate out dark blue precipitate, precipitate with a small amount of washing with acetone 3 times, then after vacuum-drying, obtain following several compound respectively:
Embodiment 60 pharmaceutical formulation
The invention provides several formula of pharmaceutical composition being used for the treatment of or preventing the disease relevant to protein kinase, its pharmaceutical composition has tablet, capsule, injection, aerosol etc.Illustrated compound is represented below with " active compound ".
Injection (a) （50mg/ml）
Active substance 5.0%w/v
1M sodium chloride solution 15.0%w/v
0.1M hydrochloric acid soln regulates pH to 7.6
PEG400 4.5%w/v
Add water to 100%
Injection (b) (10mg/ml) buffered soln (pH6)
Active substance 1.0%w/v
Sodium phosphate 2.26%w/v
Citric acid 0.38%w/v
PEG400 3.5%w/v
Add water to 100%
The efficacy experiment of embodiment 61 Nude Mice
BALB/cA-nude nude mouse, in 6-7 week, ♀, purchased from Shanghai Slac Experimental Animal Co., Ltd..Nude mouse is subcutaneous inoculates Human hepatocarcinoma Bel-7402 cell, colon cancer cell line HT-29, SGC-7901 cell and Non-small Cell Lung Cancer A 549 respectively, treats that tumor growth is to 100-250mm 3after, by animal random packet (d0).Survey 2-3 knurl volume weekly, claim mouse heavy, record data.Gross tumor volume (V) calculation formula is:
V=1/2 × a × b2 wherein a, b represents length and width respectively;
T/C (%)=(T-T0)/(C-C0) × 100 wherein T, C are the gross tumor volume at the end of experiment; Gross tumor volume when T0, C0 are experiment beginning.
Institute's test agent is all become desired concn with 50%PEG400 distilled water diluting.Application method is administration every day 1 time, and abdominal injection, is used in conjunction 21 days.Test the curative effect of compound to the Nude Mice of people liver cancer Bel-7402, SGC-7901 cell and Non-small Cell Lung Cancer A 549 shown in embodiment 1,3,4,34,36,37,47,49,50 respectively, its result is as shown in table 2.
The curative effect of the multiple cancer cells Nude Mice of table 2 active compound
Conclusion: illustrated compound significantly suppresses the growth of people liver cancer Bel-7402, SGC-7901 cell and Non-small Cell Lung Cancer A 549 Nude Mice under test conditions, and especially its metal complexes has the effect of more obvious inhibition tumor cell.

Claims (10)

1. the compound represented containing logical formula I below or pharmacy acceptable salt or its prodrug
Wherein
A ring represents the macrocyclic polyamine compound that can be optionally substituted;
L is a linking group, can be the one in following several structure:
R 1independently selected from alkyl, haloalkyl;
R 2independently selected from one or more following group: the alkyl of replacement, the aryl of replacement, the heterocyclic aryl of replacement, halogen, hydroxyl, amino, alkylamino, dialkylamine, acid amides, cyano group, carboxyl, carbalkoxy, alkoxyl group, acyloxy ,=O ,=S ,=NH;
R 3independently selected from hydrogen, the alkyl of replacement, the aryl of replacement;
N is 0,1,2.
2. compound according to claim 1, (II a) to have following general formula
Wherein
L is a linking group, can be the one in following several structure:
R 1independently selected from methyl, ethyl, difluoromethyl, 2,2,2-trifluoroethyl;
R 3independently selected from hydrogen, the alkyl of replacement, the aryl of replacement;
R 4, R 5independently selected from: the alkyl of replacement, the aryl of replacement, the heterocyclic aryl of replacement, halogen, hydroxyl, amino, alkylamino, dialkylamine, acid amides, cyano group, carboxyl, carbalkoxy, alkoxyl group, acyloxy;
R 6independently selected from hydrogen, the alkyl of replacement, the aryl of replacement, halogen, hydroxyl, amino, alkylamino, dialkylamine, acid amides, cyano group, carboxyl, carbalkoxy, alkoxyl group, acyloxy ,=O ,=S ,=NH;
N is 0,1,2.
3. compound according to claim 1, (II b) to have following general formula
Wherein
L is a linking group, can be the one in following several structure:
R 1independently selected from methyl, ethyl, difluoromethyl, 2,2,2-trifluoroethyl;
R 3independently selected from hydrogen, the alkyl of replacement, the aryl of replacement;
R 7, R 8, R 9independently selected from: the alkyl of replacement, the aryl of replacement, the heterocyclic aryl of replacement, halogen, hydroxyl, amino, alkylamino, dialkylamine, acid amides, cyano group, carboxyl, carbalkoxy, alkoxyl group, acyloxy;
R 10independently selected from hydrogen, the alkyl of replacement, the aryl of replacement, halogen, hydroxyl, amino, alkylamino, dialkylamine, acid amides, cyano group, carboxyl, carbalkoxy, alkoxyl group, acyloxy ,=O ,=S ,=NH;
N is 0,1,2.
4. compound according to claim 1, (II c) to have following general formula
Wherein
L is a linking group, can be the one in following several structure:
R 1independently selected from methyl, ethyl, difluoromethyl, 2,2,2-trifluoroethyl;
R 3independently selected from hydrogen, the alkyl of replacement, the aryl of replacement;
R 11, R 12, R 13independently selected from: the alkyl of replacement, the aryl of replacement, the heterocyclic aryl of replacement, halogen, hydroxyl, amino, alkylamino, dialkylamine, acid amides, cyano group, carboxyl, carbalkoxy, alkoxyl group, acyloxy;
R 14independently selected from hydrogen, the alkyl of replacement, the aryl of replacement, halogen, hydroxyl, amino, alkylamino, dialkylamine, acid amides, cyano group, carboxyl, carbalkoxy, alkoxyl group, acyloxy ,=O ,=S ,=NH;
N is 0,1,2.
5. the compound according to any one of claim 1-4, preferably certainly:
6. compound according to claim 1, its molecule can with the salt coordination containing metal ion; Its cationic can be main group metal ion or transition metal ion, and negatively charged ion can be common are machine or inorganic negatively charged ion.
7. compound according to claim 6, described metal ion is preferably from Zn 2+, Cu 2+, Fe 2+, Fe 3+, Pt 2+, Cr 3+, Ni 2+, Co 2+, Mn 2+, Ag +, Pd 2+, La 3+, Eu 3+, Ir 3+, Gd 3+, Tb 4+, Lu 3+, Ca 2+.
8. compound according to claim 6, described negatively charged ion is preferably from F -, Cl -, Br -, I -, SO 4 2-, SO 3 2-, NO 3 -, PO 4 3-, PO 3 3-, ClO 4 -, ClO 3 -, BrO 4 -, IO 4 -, oxalate denominationby, maleate ion, malate ion, citrate ion, succinic ion.
9. a pharmaceutical composition, is characterized in that, it contains the compound as described in any one of claim 1-8 for the treatment of significant quantity and pharmaceutically acceptable carrier.
10. the compound as described in any one of claim 1-8 is being prepared in antitumor drug or the application for the treatment of in preparation in the medicine of the disease relevant to tumour;
Described various tumour comprises: lung cancer, small cell lung cancer, liver cancer, carcinoma of the pancreas, cancer of the stomach, osteocarcinoma, esophagus cancer, mastocarcinoma, kidney, cholangiocarcinoma, prostate cancer, carcinoma of testis, colorectal carcinoma, ovarian cancer, bladder cancer, cervical cancer, bronchogenic carcinoma, melanoma, gland cancer, syringocarcinoma, papillary carcinoma, papillary carcinoma, squamous cell carcinoma, rodent cancer, adenocarcinoma cystic, glioma, astrocytoma, medulloblastoma, neuroblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, oligodendroglioma, meningioma, neurofibroma, fibrosarcoma, fibroblastoma, fibroma, myxosarcoma, myxocystoma, lipoma, lipoadenoma, chondrosarcoma, chondroma, chondromyoma, chordoma, chorioadenoma, villous vessels knurl, chorioepithelium knurl, chorioblastoma, osteosarcoma, osteoblastoma, osteoclastoma, osteochondrofibroma, osteochondrosarcoma, stock cystoma, osteodentinoma, osteofibroma, the fibrosarcoma of bone, vascular tumor, angiosarcoma, lymphangiosarcoma, lymphangioma, lymphoma, endothelioma, synovioma, synovial sarcoma, mesothelioma, mesocytoma, ewing's tumor, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdosarcoma, kemia, acute myelogenous leukemia, chronic leukemia, polycyth(a)emia, multiple myeloma.
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