CN107573302B - Aryl piperazines compound and its preparation method and application - Google Patents
Aryl piperazines compound and its preparation method and application Download PDFInfo
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Abstract
The present invention provides a kind of new aryl diethylenediamine compounds and its preparation method and application.The present invention provides a kind of compound of logical formula (I),
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of new aryl diethylenediamine compound and preparation method thereof and use
On the way.
Technical background
Prostate cancer (PCa) is very common a kind of disease in male, occupies second in male's lethal cancer,
Disease incidence and the death rate are only second to lung cancer.PCa is significantly larger than China, the East Asian countries such as Japan in the generation of American-European countries, and shows
In China, the disease incidence of prostate cancer is also in the trend of growth, and prostate cancer has become global problem.
Clinically, localized disease can be cut off or be destroyed cancer cell by operation or radiotherapy to cure.However, turning
Shifting property prostate cancer cannot cure and androgen ablation therapy becomes standard treatment.Although various chemotherapeutic drugs are used alone
Object treats patients with terminal in conjunction with radiotherapy, but to prostate cancer without any traditional cancer treatment method
It is very successfully.It is other researches show that: once tumour cell become Hormone refractory, for Hormone-refractory prostate cancer
For, the cytotoxic agent of standard can hardly improve treatment results or survival rate, although they can delay to a certain extent
Solve the pain of patient.Therefore, there is an urgent need to find more effective, safe antiprostate cancer.
Summary of the invention
One of the object of the invention is to provide a kind of novel aryl piperazines compound.
The second object of the present invention is to providing the preparation method of above-mentioned novel aryl piperazines compound.
The three of the object of the invention are to provide the purposes of novel aryl piperazines compound in the preparation of antitumor drugs.
The four of the object of the invention are to provide the pharmaceutical preparation containing novel aryl piperazines compound.
Inventors have found that the compound of logical formula (I) plays a role as new antiprostate cancer active constituent.
To achieve the above object, on the one hand, the present invention provides a kind of compound of logical formula (I),
Wherein,
M=0 or 1；
R1To R5It is each independently selected from hydrogen, halogen, amino, hydroxyl, nitro, cyano, aldehyde radical, sulfonyl, 1 to 14 carbon
The alkyl of atom, the alkoxy of 1 to 14 carbon atom, the alkenyl of 2 to 14 carbon atoms, the alkenyloxy group of 2 to 14 carbon atoms, 5
To the naphthenic base of 14 carbon atoms, the Heterocyclylalkyl of 5 to 14 carbon atoms, the aryl of 5 to 14 carbon atoms, 5 to 14 carbon originals
The heteroaryl of son, the cyclenes oxygroup of 5 to 14 carbon atoms, the heterocycle alkenyloxy group of 5 to 14 carbon atoms, 5 to 14 carbon atoms
Cycloalkyl-alkyl, the hetercycloalkylalkyl of 5 to 14 carbon atoms, 5 to 14 carbon atoms aryl alkyl, 5 to 14 carbon atoms
Heteroaryl alkyl, the cyclenes oxygroup alkyl of 5 to 14 carbon atoms, the heterocycle alkenyloxy group alkyl of 5 to 14 carbon atoms, 1 to 14
The aminoalkyl of a carbon atom, the alkylamino of 1 to 14 carbon atom, the acyl group of 2 to 14 carbon atoms, 2 to 14 carbon atoms ester
Base, the sulfuryl of 2 to 14 carbon atoms, the acylamino- of 2 to 14 carbon atoms, the alkoxyacyl of 1 to 14 carbon atom, 1 to 14
The alkylthio of a carbon atom, the halogenated alkyl of 1 to 14 carbon atom, the halogenated alkoxy of 1 to 14 carbon atom, 5 to 14
The heteroarylalkoxy of the alkoxy aryl of carbon atom, 5 to 14 carbon atoms.
When describing the compound of the present invention, unless otherwise indicated by context, otherwise, term is explained according to following definitions:
Term " aryl " indicates to have monocycle (i.e. phenyl) or condensed (such as naphthalene or anthracene) or the multiple aromatic rings covalently connected
How unsaturated, aromatic hydrocarbon radical, generally contain 5 to 14 annular atoms, and more preferable 5-12, more preferred 5-10 are a；With
And most preferably 5-8；Wherein at least one ring is aromatics.The aromatic ring can optionally include one to three condensed with it
Other rings (naphthenic base, heterocycle or heteroaryl).In addition, aryl includes the part hydrogenation derivative for enumerating carbon-loop system herein
Object.The non-limiting example of aryl include phenyl, xenyl, biphenylene, 5- or 6- tetralyl, 1-, 2-, 3-, 4-, 5-,
6-, 7- or 8- azulenyl, 1- or 2- naphthalene, 1-, 2- or 3- indenyl, 1-, 2- or 9- anthryl, 1-2-, 3-, 4- or 5- acenaphthylene
Base, 3-, 4- or 5- acenaphthenyl, 1-, 2-, 3-, 4- or 10- phenanthryl, 1- or 2- pentalene base, 1,2-, 3- or 4- fluorenyl,
4- or 5- indanyl, 5-, 6-, 7- or 8- tetralyl, 1,2,3,4- tetralyl, Isosorbide-5-Nitrae-ihydro naphthyl, dibenzo [a, d]
Cycloheptenyl and 1-, 2-, 3-, 4- or 5- pyrenyl.Aryl rings can be optionally substituted by one or more substituents, that is,
Say can optionally there is the aryl of one or more substituent groups in arbitrarily utilizable tie point.This substituent group
Non-limiting example be selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, amino carbonyl, azido, cyano, alkyl, naphthenic base,
Alkenyl, alkynyl, cycloalkyl-alkyl, alkyl amino, alkoxy ,-SO2-NH2, aryl, heteroaryl, aralkyl, halogenated alkyl is halogenated
Alkoxy, alkoxy carbonyl group, alkyl amino-carbonyl, heteroaryl alkyl, alkyl sulfonyl amino, heterocycle, alkylcarbonylaminoalkyl,
Aryloxy group, alkyl-carbonyl, acyl group, aryl carbonyl, amino carbonyl, alkyl sulfoxide ,-SO2Ra, alkylthio group, carboxyl, etc. wherein RaIt is
Alkyl or cycloalkyl.
Term " heteroaryl " indicates to obtain when the ring carbon atom with one or more hetero atom replacements in above-mentioned aryl group
The substituent group arrived.Term " heteroaryl " itself or as another group part indicate but be not limited to 5 to 14 carbon-atom aromatics
Ring or ring system, the ring or ring system contain 1 to 3 ring that is condensed or covalently connecting, generally contain 5 to 14 ring originals
Son, more preferable 5-12, more preferred 5-10；And most preferably 5-8；At least one of the ring or ring system are aromatics,
In these rings one or more in one or more carbon atoms can be nitrogen or sulphur atom replacement with oxygen, wherein nitrogen and sulphur
Hetero atom can be optionally oxidized, and nitrogen heteroatom can be optionally quaternized.This ring can be fused to aryl, ring
Alkyl, heteroaryl or heterocyclic ring.The non-limiting example of this heteroaryl, comprising: pyrrole radicals, furyl, thienyl, pyrazoles
Base, imidazole radicals, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazoles base, thiadiazolyl group, tetrazole radical are disliked
Triazolyl, thiatriazole base, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, oxazines base, Dioxin base, thiazinyl, three
Piperazine base, imidazo [2,1-b] [1,3] thiazolyl, thieno [3,2-b] furyl, thieno [3,2-b] thienyl, thieno
[2,3-d] [1,3] thiazolyl, thieno [2,3-d] imidazole radicals, tetrazolo [1,5-a] pyridyl group, indyl, indolizine base, different Yin
Diindyl base, benzofuranyl, benzopyranyl, 1 (4H)-benzopyranyl, 1 (2H)-benzopyranyl, 3,4- dihydros -1 (2H) -
Benzopyranyl, -1 (2H)-benzopyranyl of 3,4- dihydro, isobenzofuran-base, benzothienyl, isobenzo-thienyl, Yin
Oxazolyl, benzimidazolyl, 1,3- benzoxazolyl, 1,2- benzo isoxazolyl, 2,1- benzo isoxazolyls, 1,3- benzothiazole
Base, 1,2- benzisothia oxazolyl, 2,1- benzisothia oxazolyls, benzotriazole base, 1,2,3- benzoxadiazole base, 2,1,3- benzos
Oxadiazoles base, 1,2,3- diazosulfide base, 2,1,3- diazosulfide bases, thienopyridine base, purine radicals, imidazo [1,
2-a] pyridyl group, 6- oxo-pyridazine -1 (6H)-base, 2- oxo pyridine -1 (2H)-base, 6- oxo-pyridazine -1 (6H)-base, 2- oxygen
For pyridine -1 (2H)-base, 1,3- benzodioxole group, quinolyl, isoquinolyl, cinnoline base, quinazolyl, quinoline
Quinoline base, 7- azaindolyl, 6- azaindolyl, 5- azaindolyl, 4- azaindolyl.
Term " alkyl " itself or a part as other substituent groups refer to formula CxH2x+1Fully saturated hydrocarbon, wherein x
It is greater than or equal to 1 number.Generally, alkyl of the invention includes 1 to 14 carbon atom.Alkyl can be linear chain or branched chain
, and can be substituted as noted herein.When being marked on after carbon atom under used herein, the subscript refers to life
The carbon atom number that the group of name can contain.For example, " C1-C10" it is equal to C1、C2、C3、C4、C5、C6、C7、C8、C9Or C10。
“C1-C14" it is equal to C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14。“C2-C14”、“C3-C14" etc. define class
Seemingly, it repeats no more.It is preferred that alkyl is C1-C12Alkyl, C1-C10Alkyl, C1-C8Alkyl, C1-C6Alkyl or C1-C4Alkyl.Into one
Step ground, for example, C1-C6Alkyl includes all straight chains with 1 to 6 carbon atom, the alkyl of branch, to include methyl, second
Base, n-propyl, isopropyl, butyl and its isomers (such as normal-butyl, isobutyl group and tert-butyl), amyl and its isomers, oneself
Base and its isomers.
Term " alkoxy " indicates there is formula-ORbResidue, wherein RbIt is alkyl.It is preferred that alkoxy is C1-C14Alcoxyl
Base, C1-C12Alkoxy, C1-C10Alkoxy, C1-C8Alkoxy, C1-C6Alkoxy or C1-C4Alkoxy.Alkoxy it is unrestricted
Property example includes methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec- butoxy, t-butoxy,
Amoxy and hexyloxy.
Term " aminoalkyl " indicates one or more CH in alkyl2In H atom by amino or substituted-amino (i.e. amine
Base) alkyl.It is preferred that aminoalkyl is C1-C14Aminoalkyl, C1-C12Aminoalkyl, C1-C10Aminoalkyl, C1-C8Aminoalkyl, C1-C6Ammonia
Alkyl or C1-C4Aminoalkyl.The non-limiting example of aminoalkyl includes aminomethyl, aminoethyl, aminopropyl, ammonia isopropyl, ammonia fourth
Base, ammonia isobutyl group, ammonia sec-butyl, ammonia tert-butyl, ammonia amyl and ammonia hexyl.
Term " alkylamino " indicates that one or two of amino H atom is further substituted with by alkyl or substituted alkyl
Amino.It is preferred that alkylamino is C1-C14Alkylamino, C1-C12Alkylamino, C1-C10Alkylamino, C1-C8Alkylamino, C1-C6Alkane ammonia
Base or C1-C4Alkylamino.The non-limiting example of alkylamino includes methylamino, dimethylamino, ethylamino, lignocaine, the third ammonia
Base, dipropyl amino, isopropylamino, diisopropylaminoethyl, fourth amino, dibutylamino, i-butylamino, two i-butylaminos, sec- fourth ammonia
Base, two sec- fourth amino, tert- fourth amino, two tert- fourth amino, penta amino, two tert- fourth amino, own amino and two own amino.
Term " alkyl acyl " itself or a part as other substituent groups refer to-C (=O) Rc, wherein RcIt is as above
It is defined for alkyl.It is preferred that alkyl acyl is C1-C14Alkyl acyl, C1-C12Alkyl acyl, C1-C10Alkyl acyl, C1-C8
Alkyl acyl, C1-C6Alkyl acyl or C1-C4Alkyl acyl.The non-limiting example of alkyl acyl includes methyl acyl group, second
Alkyl acyl, propyl acyl group, isopropyl alkyl acyl, butane group acyl group, isobutyl alkyl acyl, sec- butane group acyl group, tert- fourth
Alkyl acyl, pentyl acyl group and hexyl acyl group.
Term " alkylamidoalkyl " itself or a part as other substituent groups refer to-NHC (=O) Rd, wherein RdBe as
It is defined described previously for alkyl.It is preferred that alkylamidoalkyl is C1-C14Alkylamidoalkyl, C1-C12Alkylamidoalkyl, C1-C10Alkyl
Amide groups, C1-C8Alkylamidoalkyl, C1-C6Alkylamidoalkyl or C1-C4Alkylamidoalkyl.The non-limiting reality of alkylamidoalkyl
Example includes methyl amide groups, ethyl group amide groups, propyl amide groups, isopropyl alkylamidoalkyl, butane group amide groups, isobutyl
Alkylamidoalkyl, sec- butane group amide groups, tert- butane group amide groups, pentyl amide groups and hexyl amide groups.
Term " alkoxyacyl " itself or a part as other substituent groups refer to-C (=O) ORe, wherein ReBe as
It is defined described previously for alkyl.It is preferred that alkoxyacyl is C1-C14Alkoxyacyl, C1-C12Alkoxyacyl, C1-C10Alcoxyl
Base acyl group, C1-C8Alkoxyacyl, C1-C6Alkoxyacyl or C1-C4Alkoxyacyl.The non-limiting reality of alkoxyacyl
Example includes first alkoxyacyl, second alkoxyacyl, the third alkoxyacyl, isopropyl alkoxyacyl, fourth alkoxyacyl, isobutyl
Alkoxyacyl, sec- fourth alkoxyacyl, tert- fourth alkoxyacyl, penta alkoxyacyl and own alkoxyacyl.
Term " alkyl ester group " itself or a part as other substituent groups refer to-OC (=O) Rf, wherein RfIt is as preceding
Text is defined for alkyl.It is preferred that alkyl ester group is C1-C14Alkyl ester group, C1-C12Alkyl ester group, C1-C10Alkyl ester group, C1-
C8Alkyl ester group, C1-C6Alkyl ester group or C1-C4Alkyl ester group.The non-limiting example of alkyl ester group includes methyl ester group, second
Base ester base, propyl ester group, isopropyl ester group, butyl ester group, isobutyl group ester group, sec-butyl ester group, tert-butyl ester group, amyl ester
Base and hexyl ester group.
Term " alkylthio " indicates one or more CH in alkyl2In H atom by sulfydryl (- SH) or substituted sulfhydryl
The alkyl of (i.e. alkylthio group).It is preferred that alkylthio is C1-C14Alkylthio, C1-C12Alkylthio, C1-C10Alkylthio, C1-
C8Alkylthio, C1-C6Alkylthio or C1-C4Alkylthio.The non-limiting example of alkylthio includes first alkylthio,
Second alkylthio, rosickyite substituted alkyl, isopropyl alkylthio, fourth alkylthio, isobutyl alkylthio, sec- fourth alkylthio, tert-
Fourth alkylthio, penta alkylthio and own alkylthio.
Term " alkylthio group " indicates the mercapto that the H atom in sulfydryl (- SH) is further substituted with by alkyl or substituted alkyl
Base.It is preferred that alkylthio group is C1-C14Alkylthio group, C1-C12Alkylthio group, C1-C10Alkylthio group, C1-C8Alkylthio group, C1-C6Alkylthio group, or
C1-C4Alkylthio group.The non-limiting example of alkylthio group includes methane sulfenyl, ethane sulfenyl, propane sulfenyl, isopropyl alkylthio group, butane
Sulfenyl, isobutyl alkylthio group, sec- butane sulfenyl, tert- butane sulfenyl, pentane sulfenyl and hexane sulfenyl.
Term " alkyl halide (oxygen) base " indicates one or more CH in alkyl2In the alkane that is optionally substituted by halogen of H atom
(oxygen) base.Halogen is selected from fluorine, chlorine, bromine and iodine.It is preferred that alkyl halide (oxygen) base is C1-C14Alkyl halide (oxygen) base, C1-C12Alkyl halide
(oxygen) base, C1-C10Alkyl halide (oxygen) base, C1-C8Alkyl halide (oxygen) base, C1-C6Alkyl halide (oxygen) base or C1-C4Alkyl halide (oxygen)
Base.The non-limiting example of alkyl halide (oxygen) base includes halide (oxygen) base, halothane (oxygen) base, halogenopropane (oxygen)
Base, halogenated isopropyl alkane (oxygen) base, butyl halide (oxygen) base, halogenated iso-butane (oxygen) base, halogenated sec- butane (oxygen) base, halogenated tert-
Butane (oxygen) base, halogenated pentane (oxygen) base and halogenated hexane (oxygen) base.Further, such as the non-limiting reality of halogenated alkyl
Example include chloro first (oxygen) base, 1- bromo second (oxygen) base, fluoro first (oxygen) base, difluoro first (oxygen) base, fluoroform (oxygen) base, 1,1,
1- trifluoro second (oxygen) base, etc..
Term " naphthenic base " refer to saturation and cricoid alkyl, itself or as another group part indicate but not
It is limited to 5 to 14 carbon-atom cycloaliphatic ring or ring system.Naphthenic base generally contains 5 to 14 annular atoms, more preferable 5-12, more
It is preferred that 5-10；And most preferably 5-8.The non-limiting example of naphthenic base includes cyclopenta, cyclohexyl, 2- or 3- methyl
Cyclopenta, suberyl and 2-, 3- or 4- methylcyclohexyl.
Term " Heterocyclylalkyl " refer to saturation and cricoid alkyl, itself or as another group part indicate but
It is not limited to 5 to 14 carbon-atom cycloaliphatic ring or ring system.Generally contain 5 to 14 annular atoms, more preferable 5-12, more preferably
5-10；And most preferably 5-8；Wherein one or more carbon atoms in the one or more of these rings are by O, N or S atom
Replace, wherein nitrogen and sulfur heteroatom can be optionally oxidized, and nitrogen heteroatom can be optionally quaternized.Heterocyclylalkyl
Non-limiting example include 2- or 3- oxocyclopentyl, 1,2- or 3- azepine cyclopenta, 2- or 3- thia cyclopenta, 2-,
3- or 4- oxacyclohexyl, 1-, 2-, 3- or 4- piperidyl, 2-, 3- or 4- thia cyclohexyl, etc..
Term " cycloalkenyl ", " heterocycloalkenyl ", " cycloalkyl-alkyl ", " hetercycloalkylalkyl ", " cyclenes oxygroup alkyl ",
" heterocycle alkenyloxy group alkyl " is similar with above-mentioned " alkyl " and " (miscellaneous) cycloalkanes (alkene) base ", can have one or more double bonds, but
Do not have armaticity simultaneously, repeats no more.
It may be noted that carbon atom number can be equally independently varied in above-mentioned each substituent group of definition.For example, by " 1 to 14
A carbon atom ", " 2 to 14 carbon atoms " or " 5 to 14 carbon atoms " are changed to " 1 to 12 carbon atom ", " 2 to 12 respectively
Carbon atom " or " 5 to 12 carbon atoms "；Alternatively, " 1 to 10 carbon atom ", " 2 to 10 carbon atoms " or " 5 to 10 carbon originals
Son "；Alternatively, " 1 to 8 carbon atom ", " 2 to 8 carbon atoms " or " 5 to 8 carbon atoms "；Alternatively, " 1 to 6 carbon atom ", " 2
To 6 carbon atoms " or " 5 to 8 carbon atoms ".
Further, the compound of logical formula (I) according to the present invention, wherein
M=0 or 1；
R1To R5It is each independently selected from hydrogen, halogen, amino, hydroxyl, nitro, cyano, aldehyde radical, sulfonyl, 1 to 14 carbon
The alkyl of atom, the alkoxy of 1 to 14 carbon atom, the halogenated alkyl of 1 to 14 carbon atom, 1 to 14 carbon atom it is halogenated
Alkoxy, the aryl of 5 to 14 carbon atoms, the heteroaryl of 5 to 14 carbon atoms, the aryl alkyl of 5 to 14 carbon atoms, 5 to
The heteroaryl alkyl of 14 carbon atoms, the alkoxy aryl of 5 to 14 carbon atoms, 5 to 14 carbon atoms heteroarylalkoxy.
Further, the compound of logical formula (I) according to the present invention, wherein
M=0 or 1；
R1To R5Be each independently selected from hydrogen, cyano, the alkyl of 1 to 14 carbon atom, 1 to 14 carbon atom alkoxy,
The halogenated alkoxy of the halogenated alkyl of 1 to 14 carbon atom, 1 to 14 carbon atom.
Further, the compound of logical formula (I) according to the present invention, wherein
M=0 or 1；
R1To R5It is each independently selected from hydrogen, cyano, the alkyl of 1 to 4 carbon atom, the alkoxy of 1 to 4 carbon atom, 1
To the halogenated alkyls of 4 carbon atoms, the halogenated alkoxy of 1 to 4 carbon atom.
Further, the compound of logical formula (I) according to the present invention, wherein
M=0 or 1；
R1To R5It is each independently selected from hydrogen, cyano, methyl, methoxyl group, ethyl, ethyoxyl, trifluoromethyl.
Unless otherwise indicated by context, term " the compounds of this invention " can broadly indicate to include logical formula (I) compound
With any derivative.Tautomer, enantiomter, the diastereo-isomerism of term " derivative " expression the compounds of this invention
Body, racemic modification, metabolin, prodrug, hydrate, solvate and its salt and their quaternized nitrogen analog, etc.
Deng.
For example, the compounds of this invention can exist in the form of different tautomers, the tautomer includes
But it is not limited to geometric isomer, conformer, E/Z- isomers, three-dimensional chemical isomer, and corresponding in change of the invention
Close the isomers of identical substituent group present on the different position of ring present in object.All this possible tautomers and
Its mixture is included within the scope of the present invention.
The compounds of this invention can serve as in chirality containing one or more asymmetric carbon atoms, the asymmetric carbon atom
The heart can lead to different optical forms (such as enantiomter, diastereoisomer and racemic modification).The present invention includes
All may configuration this optical forms of whole and its mixture.
The quaternized nitrogen analog of the compounds of this invention indicates the present invention that one of them or several N atoms are quaternized
Compound.
The hydrate and solvate of the compounds of this invention indicate hydrone or solvent molecule to crystallize or non-crystalline forms
Participate in being formed the substance of the compounds of this invention solid form.
The salt of the compounds of this invention includes the pharmaceutically acceptable salt of formula (I) compound represented.It is pharmaceutically acceptable
Salt include, wherein it is applicable, derived from pharmaceutically acceptable inorganic and organic acid acid addition salts such as hydrogen chlorate, hydrobromic acid
Salt, sulfate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, 4- methoxy benzoic acid
Salt, 2- or 4-HBA salt, 4- chloro benzoate, benzene sulfonate, nicotinate, mesylate, ascorbate, acetic acid
Salt, succinate, lactate, glutarate, gluconate, hydroxyl naphthalene carboxylate, oleate and amino-acid salt, common amino
Hydrochlorate refer to glycinate, alanine salt, phenylalanine salt, aspartate, aspartate, methionine salt, lysine salt,
Tryptophan salt, glutamate and threonine salt etc.；And the salt prepared from pharmaceutically acceptable inorganic and organic base, it is derived from inorganic base
Salt include aluminium, ammonium, calcium, copper, iron, ferrous iron, lithium, magnesium, manganese, sub- manganese, potassium, sodium, zinc and bismuth salt, be particularly preferred to be ammonium, calcium,
Magnesium, potassium, sodium salt.Salt derived from pharmaceutically acceptable organic base includes primary, secondary and tertiary amine, cyclic amine such as arginine glycine betaine, choline
Deng salt.
The derivative of the compounds of this invention can also be further to its metabolin and prodrug.These forms are this fields
Known to technical staff.
It is studied through Preliminary pharmacological, anticancer experiment in vitro, as the result is shown: some compounds show good antitumor work
Property, novel anti-tumor drug can be developed.
Preferred compounds of the invention has the structure of following compounds 5,6,7,8,9,10,11,12,13,14:
Further, preferred compounds of the invention has the structure of compound 6,10；Most preferably, of the invention preferred
Compound has the structure of compound 6.Above compound has three kinds of human prostate cancer cell lines PC-3, LNCaP, DU145
Preferable extracorporeal anti-tumor cell activity, simultaneously for normal prostate epithelial cell WPMY-1 selectivity with higher.
And the compound for occurring this situation in the prior art is relatively fewer.
On the other hand, the present invention provides the preparation methods of above-mentioned novel aryl piperazines compound.
Formula (I) compound of the invention can be to be prepared in a manner known in the art.For example, following methods can be passed through
Preparation: raw material 4- (bromoethane) phenylacetic acid 1 is reduced into intermediate 2 by borane dimethyl sulphide complex compound first, secondly intermediate 2
It reacts to obtain intermediate 3 with 6- hydroxyl -1-tetralone under base catalysis, intermediate 3 is under base catalysis and to toluene sulphur again
The intermediate 4 of acyl chloride reaction generation hydroxyl protection；Last intermediate 4 and corresponding aryl piperazines class compound generation nucleophilic displacement of fluorine are anti-
It should obtain corresponding compound 5-14.
Reaction route is as follows:
The preparation process of intermediate 2 of the present invention is as follows:
The preparation process of intermediate 2 includes:
4- (bromoethane) phenylacetic acid reacts to obtain intermediate 2 with borane dimethyl sulphide complex compound (BMS) at normal temperature.
The preparation process of intermediate 3 of the present invention is as follows:
The preparation process of intermediate 3 includes:
2- (4- (bromomethyl) phenyl) ethanol (intermediate 2) is under potassium carbonate catalysis, with 6- hydroxyl -1- four
Hydrogen naphthalenone reacts to obtain intermediate 3).
The preparation process of intermediate 4 of the present invention is as follows:
The preparation process of intermediate 4 includes: intermediate 3 under triethylamine catalysis, reacts to obtain with paratoluensulfonyl chloride
Mesosome 4.
The preparation process of the compounds of this invention 5-14 is as follows:
The preparation process of compound 5-14 includes: that intermediate 4 reacts to obtain compound with corresponding aryl piperazines class compound
5-14。
On the other hand, the use the present invention provides the above-mentioned aryl piperazines compound of the present invention in the preparation of antitumor drugs
On the way.
In accordance with the purpose of the invention, wherein the tumour is prostate cancer.
For medicinal usage, the compounds of this invention can be formulated as the form of pharmaceutical preparation or pharmaceutical composition, the medicine
Object preparation or pharmaceutical composition include at least one the compounds of this invention and at least one pharmaceutically acceptable carrier, diluent
Or excipient and/or auxiliary agent, and optionally include the compound of other one or more pharmaceutical actives.
In another aspect, the present invention provides a kind of pharmaceutical preparation, including the above-mentioned aryl piperazines compound of the present invention.
Pharmaceutical preparation of the invention can be the form suitable for oral administration, be suitable for use in local administration (including eye)
Form is suitable for use in through sucking, by skin patch, waits the form of administrations by suppository by implantation material.It is this to be suitable for
Form of medication (such as solid, semisolid or liquid, depend on administration mode) and method and carrier for its preparation, it is dilute
Release agent and excipient.
Pharmaceutical preparation of the invention includes tablet, pill, powder, lozenge, pouch, cachet, suspension, lotion, solution,
Syrup, aerosol, ointment, creme, lotion, soft hard gelatin capsule, suppository, drops, the solution and nothing of sterile injection
Bacterium bag fills powder.For the administration of pill form and/or for being continuously administered, carrier, excipient, and dilution can be used
Agent is prepared, the carrier, and excipient and diluent itself are to be suitable for this preparaton, such as lactose, glucose, sucrose, mountain
Pears alcohol, mannitol, starch, gum arabic, calcium phosphate, alginates, bassora gum, gelatin, calcium silicates, microcrystalline cellulose, poly- second
Vinyl pyrrolidone, polyethylene glycol, cellulose, sterile water, methylcellulose, methyl-and propylhydroxy benzoate, talcum,
Magnesium stearate, edible oil, vegetable oil and mineral oil or its suitable mixture.The preparaton can be optionally containing other
The substance of pharmaceutical active and the other materials generally used in pharmaceutical formulation, such as lubricant, wetting agent, emulsification and suspending
Agent, dispersing agent, disintegrating agent, filler, filler, preservative, sweetener, corrigent, flowing regulator, release agent, etc..Described group
Closing object can also be formulated to, and provide the quick of the active compound wherein contained, the lasting or release that delays, such as
Using liposome or hydrophilic high mol matrix based on Native Gel or the polymer of synthesis.In order to enhance drug according to the present invention
The solubility and/or stability of the compound of composition, can advantageously use α-, β-or gamma-cyclodextrin or they spread out
Biology.
In addition, cosolvent such as alcohols solvent can improve the solubility and/or stability of compound.In Aquo-composition
Preparation in, be added the salt of the compound of the present invention can be it is preferably, reason is that salt is conducive to the dissolution of increased water
Degree.
Pharmaceutical preparation can be to be prepared in a manner known in the art, and it is at least one according to the present invention to be usually directed to mixing
Compound and one or more pharmaceutically acceptable carriers, preferably carry out under sterile conditions.
Logical formula (I) compound provided by the present invention has carried out Preliminary pharmacological research (anti tumor activity in vitro test),
As the result is shown: some compounds show good anti-tumor activity, can further develop as novel anti-tumor drug.With
Control compound Naftopidil is compared, and extracorporeal anti-tumor cell activity is suitable, even higher；Simultaneously relative to control compound
Selectivity is higher.
Specific embodiment
The invention will be further elucidated with reference to specific embodiments.It should be understood that these embodiments are merely to illustrate this hair
It is bright rather than limit the scope of the invention.In addition, it should also be understood that, after reading the contents of the present invention, those skilled in the art
The present invention can be made various changes or modifications, such equivalent forms are equally fallen within defined by the application the appended claims
Range.
It will be helpful to understand the present invention by following embodiments, but cannot limit the scope of the invention.
Embodiment 1: the preparation of intermediate 5
100mg (0.22mmol) intermediate 4,59.8mg (0.26mmol) 1- (4- trifluoro are added in 25mL round-bottomed flask
Aminomethyl phenyl) piperazine, 182mg (1.32mmol) potassium carbonate, 15mL acetonitrile reacts 16h at 86 DEG C, and TLC shows raw material reaction
Completely.Stop reaction, filters, concentration.Crude product is purified by silica gel column chromatography, eluant, eluent: V (ethyl acetate): V (petroleum ether)=
1:3 obtains 35.2mg white solid, yield: 33%.M.p.:165-166℃；MS(ESI,m/z):509.2[M+1]+；8.01 (d,
J=8.7Hz, 1H), 7.35 (d, J=8.0Hz, 2H), 7.26 (d, J=3.6Hz, 2H), 7.00-6.94 (m, 2H), 6.90 (d, J
=4.3Hz, 2H), 6.88 (dd, J=4.7,1.9Hz, 1H), 6.78 (d, J=2.3Hz, 1H), 5.08 (s, 2H), 3.16 (t, J
=4.9Hz, 4H), 2.92 (t, J=6.0Hz, 2H), 2.87 (dd, J=9.7,6.5Hz, 2H), 2.71 (t, J=4.9Hz, 4H),
2.68 (dd, J=9.8,6.6Hz, 2H), 2.61 (t, J=6.5Hz, 2H), 2.11 (t, J=6.4Hz, 2H)；13C NMR
(126MHz, CDCl3) δ inppm:197.18,162.73,153.26,146.96,140.26,134.08,129.69,129.05,
127.77,126.53,126.42,126.39,114.53,113.66,113.60,77.29,77.03,76.78,69.93,
60.21,52.91,47.97,38.91,33.27,30.17,23.37.Fusing point test is surveyed with aFisherJohns hot-stage
Determine instrument (thermometer does not correct).All target compounds (hydrochloride)1HNMR,13C NMR Switzerland Bruker AVANCE
AV-400NB measurement, TMS do internal standard.Mass spectrum (ESI) is measured with Thremo DSQ mass spectrograph.It is the same below.
Embodiment 2: the preparation of compound 6
The reaction of intermediate 4 and 1- (2,5- 3,5-dimethylphenyl) piperazine, synthesis process and test condition are the same as embodiment 1.?
41.2mg white solid, yield: 40%.M.p.:145-146℃；MS(ESI,m/z):469.2[M+1]+；1HNMR (500MHz,
CDCl3) δ inppm:8.01 (d, J=8.7Hz, 1H), 7.35 (d, J=8.0Hz, 2H), 7.26 (d, J=3.6Hz, 2H),
7.00-6.94 (m, 2H), 6.90 (d, J=4.3Hz, 2H), 6.88 (dd, J=4.7,1.9Hz, 1H), 5.08 (s, 2H), 3.16
(t, J=4.9Hz, 4H), 2.92 (t, J=6.0Hz, 2H), 2.87 (dd, J=9.7,6.5Hz, 2H), 2.71 (t, J=4.9Hz,
4H), 2.68 (dd, J=9.8,6.6Hz, 2H), 2.61 (t, J=6.5Hz, 2H), 2.11 (t, J=6.4Hz, 2H), 1.67 (m,
6H)；13C NMR (126MHz, CDCl3) δ in ppm:197.21,175.15,162.73,150.96,146.95,139.92,
136.18,134.14,130.8,129.69,129.22,129.08,127.80,126.51,123.97,119.81,113.68,
113.59,77.28,77.02,76.77,69.91,59.98,53.35,51.09,38.90,32.62,30.16,23.36,
21.74,21.18,17.43.
Embodiment 3: the preparation of compound 7
Intermediate 4 is reacted with 1- (3- aminomethyl phenyl) piperazine, and synthesis process and test condition are the same as embodiment 1.?
64.9mg white solid, yield: 65%.M.p.:132-133℃；MS(ESI,m/z):455.1[M+1]+；1H NMR (500MHz,
CDCl3) δ inppm:8.01 (d, J=8.7Hz, 1H), 7.35 (d, J=8.0Hz, 2H), 7.26 (d, J=3.6Hz, 2H),
7.00-6.94 (m, 2H), 6.90 (d, J=4.3Hz, 2H), 6.88 (dd, J=4.7,1.9Hz, 1H), 6.78 (d, J=2.3Hz,
1H), 5.08 (s, 2H), 3.16 (t, J=4.9Hz, 4H), 2.92 (t, J=6.0Hz, 2H), 2.87 (dd, J=9.7,6.5Hz,
2H), 2.71 (t, J=4.9Hz, 4H), 2.68 (dd, J=9.8,6.6Hz, 2H), 2.61 (t, J=6.5Hz, 2H), 2.11 (t, J
=6.4Hz, 2H), 1.62 (m, 3H)；13C NMR (126MHz, CDCl3) δ in ppm:197.16,162.73,151.31,
146.93,140.36,138.80,134.01,129.68,129.06,128.96,127.74,126.51,120.70,116.95,
113.67,113.59,113.22,77.28,77.23,77.03,76.77,69.93,60.33,53.25,49.19,38.90,
33.25,30.16,23.36,21.78.
Embodiment 4: the preparation of compound 8
Intermediate 4 is reacted with 1- (4- aminomethyl phenyl) piperazine, and synthesis process and test condition are the same as embodiment 1.?
89.9mg white solid, yield: 87%.M.p.:159-160℃；MS(ESI,m/z):476.1[M+1]+；1H NMR (500MHz,
CDCl3) δ inppm:8.01 (d, J=8.7Hz, 1H), 7.35 (d, J=8.0Hz, 2H), 7.26 (d, J=3.6Hz, 2H),
7.00-6.94 (m, 2H), 6.90 (d, J=4.3Hz, 2H), 6.88 (dd, J=4.7,1.9Hz, 1H), 6.78 (d, J=2.3Hz,
1H), 5.08 (s, 2H), 3.16 (t, J=4.9Hz, 4H), 2.92 (t, J=6.0Hz, 2H), 2.87 (dd, J=9.7,6.5Hz,
2H), 2.71 (t, J=4.9Hz, 4H), 2.68 (dd, J=9.8,6.6Hz, 2H), 2.61 (t, J=6.5Hz, 2H), 2.11 (t, J
=6.4Hz, 2H), 1.60 (m, 3H)；13C NMR (126MHz, CDCl3) δ inppm:197.16,162.73,149.20,
146.93,140.42,133.99,129.68,129.64,129.30,129.05,127.74,126.51,116.43,113.67,
113.59,77.28,77.02,76.77,69.94,60.35,53.26,49.71,38.90,33.30,30.16,23.36,
20.42。
Embodiment 5: the preparation of compound 9
Intermediate 4 is reacted with 1- (4- anisyl) piperazine, and synthesis process and test condition are the same as embodiment 1.?
54.2mg white solid, yield: 41%.M.p.:167-168℃；MS(ESI,m/z):471.1[M+1]+；1H NMR (500MHz,
CDCl3) δ inppm:8.01 (d, J=8.7Hz, 1H), 7.35 (d, J=8.0Hz, 2H), 7.26 (d, J=3.6Hz, 2H),
7.00-6.94 (m, 2H), 6.90 (d, J=4.3Hz, 2H), 6.88 (dd, J=4.7,1.9Hz, 1H), 6.78 (d, J=2.3Hz,
1H), 5.08 (s, 2H), 3.76 (s, 3H), 3.16 (t, J=4.9Hz, 4H), 2.92 (t, J=6.0Hz, 2H), 2.87 (dd, J=
9.7,6.5Hz, 2H), 2.71 (t, J=4.9Hz, 4H), 2.68 (dd, J=9.8,6.6Hz, 2H), 2.61 (t, J=6.5Hz,
2H), 2.11 (t, J=6.4Hz, 2H), 1.62 (m, 3H)；13C NMR (126MHz, CDCl3) δ inppm:197.155,
162.725,153.924,146.934,145.586,140.231,134.061,129.679,129.06,127.76,
126.514,118.292,114.464,113.67,113.591,77.284,77.030,76.775,69.925,60.240,
55.570,53.264,50.514,38.907,33.134,30.162,29.699,23.365,14.122.
Embodiment 6: the preparation of compound 10
Intermediate 4 is reacted with 1- (3- anisyl) piperazine, and synthesis process and test condition are the same as embodiment 1.?
72.4mg white solid, yield: 76%.M.p.:149-150℃；MS(ESI,m/z):471.2[M+1]+；1H NMR (500MHz,
CDCl3) δ inppm:8.01 (d, J=8.7Hz, 1H), 7.35 (d, J=8.0Hz, 2H), 7.26 (d, J=3.6Hz, 2H),
7.00-6.94 (m, 2H), 6.90 (d, J=4.3Hz, 2H), 6.88 (dd, J=4.7,1.9Hz, 1H), 6.78 (d, J=2.3Hz,
1H), 5.08 (s, 2H), 3.78 (s, 3H), 3.16 (t, J=4.9Hz, 4H), 2.92 (t, J=6.0Hz, 2H), 2.87 (dd, J=
9.7,6.5Hz, 2H), 2.71 (t, J=4.9Hz, 4H), 2.68 (dd, J=9.8,6.6Hz, 2H), 2.61 (t, J=6.5Hz,
2H), 2.11 (t, J=6.4Hz, 2H)；13C NMR (126MHz, CDCl3) δ inppm:197.16,162.73,160.60,
152.61,146.93,134.05,129.80,129.68,129.0,127.76,126.51,113.67,113.59,108.90,
104.49,102.57,77.28,77.23,77.02,76.77,69.93,60.27,55.19,53.14,48.99,38.91,
33.21,30.16,29.70,23.36.
Embodiment 7: the preparation of compound 11
Intermediate 4 is reacted with 1- (2- aminomethyl phenyl) piperazine, and synthesis process and test condition are the same as embodiment 1.?
59.9mg white solid, yield: 64%.M.p.:149-150℃；MS(ESI,m/z):455.1[M+1]+；；1H NMR
(500MHz, CDCl3) δ inppm:8.01 (d, J=8.7Hz, 1H), 7.35 (d, J=8.0Hz, 2H), 7.26 (d, J=3.6Hz,
2H), 7.00-6.94 (m, 2H), 6.90 (d, J=4.3Hz, 2H), 6.88 (dd, J=4.7,1.9Hz, 1H), 6.78 (d, J=
2.3Hz, 1H), 5.08 (s, 2H), 3.16 (t, J=4.9Hz, 4H), 2.92 (t, J=6.0Hz, 2H), 2.87 (dd, J=9.7,
6.5Hz, 2H), 2.71 (t, J=4.9Hz, 4H), 2.68 (dd, J=9.8,6.6Hz, 2H), 2.61 (t, J=6.5Hz, 2H),
2.11 (t, J=6.4Hz, 2H), 1.63 (m, 3H)；13C NMR (126MHz, CDCl3) δ inppm:197.15,162.73,
151.37,146.93,134.01,132.60,131.06,129.68,129.06,127.76,126.59,126.51,123.21,
119.03,113.67,113.59,77.27,77.22,77.02,76.77,69.94,60.44,53.71,51.61,38.90,
33.27,30.16,23.36,17.86.
Embodiment 8: the preparation of compound 12
Intermediate 4 is reacted with 1- (2- ethoxyl phenenyl) piperazine, and synthesis process and test condition are the same as embodiment 1.?
58.6mg white solid, yield: 55%.M.p.:141-142℃；MS(ESI,m/z):485.2[M+1]+；1HNMR (500MHz,
CDCl3) δ inppm:8.01 (d, J=8.7Hz, 1H), 7.35 (d, J=8.0Hz, 2H), 7.26 (d, J=3.6Hz, 2H),
7.00-6.94 (m, 2H), 6.90 (d, J=4.3Hz, 2H), 6.88 (dd, J=4.7,1.9Hz, 1H), 6.78 (d, J=2.3Hz,
1H), 5.08 (s, 2H), 3.16 (t, J=4.9Hz, 4H), 2.92 (t, J=6.0Hz, 2H), 2.87 (dd, J=9.7,6.5Hz,
2H), 2.71 (t, J=4.9Hz, 4H), 2.68 (dd, J=9.8,6.6Hz, 2H), 2.61 (t, J=6.5Hz, 2H), 2.11 (t, J
=6.4Hz, 2H)；1.82 (m, 2H), 1.54 (m, 3H)；13C NMR (126MHz, CDCl3) δ inppm:197.17,162.74,
151.55,146.94,141.20,140.32,134.02,129.68,129.08,127.76,126.51,122.84,121.02,
118.20,113.68,113.59,112.47,77.28,77.23,77.03,76.77,69.94,63.56,60.36,53.37,
50.36,38.91,33.10,30.16,23.36,14.95.
Embodiment 9: the preparation of compound 13
Intermediate 4 is reacted with 4- phenylpiperazine, and synthesis process and test condition are the same as embodiment 1.It is solid to obtain 65.4mg white
Body, yield: 51%.M.p.:163-164℃；MS(ESI,m/z):441.1[M+1]+；1H NMR(500MHz,CDCl3)δin
Ppm:8.01 (d, J=8.7Hz, 1H), 7.35 (d, J=8.0Hz, 2H), 7.26 (d, J=3.6Hz, 2H), 7.00-6.94 (m,
2H), 6.90 (d, J=4.3Hz, 2H), 6.88 (dd, J=4.7,1.9Hz, 1H), 6.78 (d, J=2.3Hz, 1H), 5.08 (s,
2H), 3.16 (t, J=4.9Hz, 4H), 2.92 (t, J=6.0Hz, 2H), 2.87 (dd, J=9.7,6.5Hz, 2H), 2.71 (t, J
=4.9Hz, 4H), 2.68 (dd, J=9.8,6.6Hz, 2H), 2.61 (t, J=6.5Hz, 2H), 2.11 (dt, J=12.6,
6.4Hz, 3H)13C NMR (126MHz, CDCl3) δ in ppm:197.16,162.73,151.25,146.93,140.34,
134.02,129.68,129.12,129.06,127.75,126.51,119.79,116.09,113.67,113.59,77.28,
77.23,77.03,76.77,69.93,60.30,53.21,49.11,38.90,33.25,30.16,23.36.
Embodiment 10: the preparation of compound 14
Intermediate 4 is reacted with 1- (2- benzonitrile) piperazine, and synthesis process and test condition are the same as embodiment 1.It is white to obtain 32mg
Color solid, yield: 82%.M.p.:173-174℃；MS(ESI,m/z):466.2[M+1]+；1H NMR (500MHz, CDCl3)δ
In ppm:8.01 (d, J=8.7Hz, 1H), 7.35 (d, J=8.0Hz, 2H), 7.26 (d, J=3.6Hz, 2H), 7.00-6.94
(m, 2H), 6.90 (d, J=4.3Hz, 2H), 6.88 (dd, J=4.7,1.9Hz, 1H), 6.78 (d, J=2.3Hz, 1H), 5.08
(s, 2H), 3.16 (t, J=4.9Hz, 4H), 2.92 (t, J=6.0Hz, 2H), 2.87 (dd, J=9.7,6.5Hz, 2H), 2.71
(t, J=4.9Hz, 4H), 2.68 (dd, J=9.8,6.6Hz, 2H), 2.61 (t, J=6.5Hz, 2H), 2.11 (dt, J=12.6,
6.4Hz, 3H)；13C NMR (126MHz, CDCl3) δ in ppm:196.15,161.72,154.63,145.92,139.30,
133.34,133.00,132.79,128.66,128.03,126.74,125.49,120.77,117.63,117.44,112.66,
112.57,105.01,76.26,76.21,76.00,75.75,68.92,59.14,52.11,50.48,37.89,32.23,
29.14 22.35.
Embodiment 11: extracorporeal anti-tumor cell activity test
CCK-8 kit is purchased from Japanese colleague's chemistry institute.
The preparation of target cell: human prostate cancer cell line PC-3, LNCaP, DU145 and normal prostate epithelial cell
The recovery and cultivation of WPMY-1.The specific method is as follows:
A. human prostate cancer cell line PC-3, LNCaP, DU145 and normal prostate are taken out from liquid nitrogen container respectively
The cold of epithelial cell WPMY-1 deposits pipe, is placed in 37 DEG C of water baths rapidly, is kept stirred and is allowed to dissolve rapidly, and sterile working moves into
In centrifuge tube；
B. respectively plus DMEM complete culture solution is trained completely to the centrifuge tube of PC-3 cell and WPMY-1 cell to 10mL, F12
Base is supported to the centrifuge tube of LNCaP cell to 10mL, 1640 complete mediums to the centrifuge tube of DU145 cell to 10mL, 1000rmp
It is centrifuged 5min, abandons supernatant.
C. PC-3, WPMY-1 cell move into culture bottle after adding DMEM complete medium 3-4mL piping and druming to mix cell respectively
In, LNCaP cell moves into culture bottle after adding the F12 complete medium piping and druming of 3-4mL to mix cell, and DU145 cell adds 3-
The 1640 complete mediums piping and druming of 4mL moves into culture bottle after mixing cell, 5%CO2, 37 DEG C of cultures；
D. cell growth status is observed, replaces culture solution, sub-bottle in time.
Cell count.The specific method is as follows:
A. logarithmic growth phase cell, pancreatin digestion are chosen, corresponding complete medium is terminated, is moved into centrifuge tube,
Add corresponding complete medium to 10mL；
B. 10 μ L cell suspensions is taken to instill in the groove of tally side, counted under microscope four big lattice total number of cells,
Divided by 4, multiply 104, cell number contained by as every milliliter of culture solution；
C. cell number is adjusted to 1 × 105cells/mL。
The configuration of aryl piperazines compound solution: taking aryl piperazines compound that DMSO solvent is added, and adjustment initial concentration is
10mmol, configuration concentration are that 1mmol is stand-by, 4 DEG C of preservations.
Test method is as follows: (1) human prostate cancer cell line PC-3, LNCaP, DU145 and just is added in each hole of 96 orifice plates
Normal prostate epithelial cell WPMY-1100 μ L (1 × 105Cells/mL), 37 DEG C of overnight incubations.(2) liquid is abandoned, is added different dense
The 100 μ L of study subject of degree, control plus 100 μ L of DMEM complete medium, continue culture for 24 hours.(3) CCK-8 detection is added in each hole
10 μ L of reagent continues to cultivate 20min to 1h.(4) every hole OD value is measured under microplate reader 450nm.(5) calculate inhibiting rate: tumour is thin
Born of the same parents' inhibiting rate %=[average OD of (mean OD value of control group measurement-dosing group measurement mean OD value)/control group measurement
Value] × 100%.(6) it is mapped with logarithm of the inhibiting rate to drug concentration, acquires IC50Value: using lgc as abscissa, inhibiting rate is vertical
Coordinate acquires IC50Value.Table 1 is the extracorporeal anti-tumor cell activity result of the compounds of this invention.
Table 1
Note: > 50 indicate between 50 and 100；> 100 indicate 100 or more.
By comparing above as can be seen that for three kinds of human prostate cancer cell lines PC-3, LNCaP, DU145, the present invention
Logical formula (I) representative compound is compared with control compound Naftopidil, and extracorporeal anti-tumor cell activity is suitable, even more
It is high；It is higher relative to control compound selectivity simultaneously.Especially, three kinds of human prostate cancer cell line PC- of compound 6 and 10 pair
3, LNCaP, DU145 have preferable extracorporeal anti-tumor cell activity；Simultaneously for normal prostate epithelial cell WPMY-1
Selectivity with higher.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., is all included in the scope of protection of the present invention.
Claims (5)
1. a kind of compound, wherein the compound is selected from the compound 6 with following structures:
2. a kind of method for preparing compound described in claim 1, which comprises the steps of: raw material 4- (bromine first
Methyl) phenylacetic acid 1 by borane dimethyl sulphide complex compound is reduced into intermediate 2, secondly intermediate 2 under base catalysis with 6- hydroxyl
Base -1-tetralone reacts to obtain intermediate 3, and intermediate 3, which reacts under base catalysis with paratoluensulfonyl chloride, again generates hydroxyl
The intermediate 4 of protection；Last intermediate 4 occurs nucleophilic substitution with corresponding aryl piperazines class compound and obtains corresponding chemical combination
Object 6；
3. the purposes of compound according to claim 1 in the preparation of antitumor drugs.
4. purposes according to claim 3, wherein the tumour is prostate cancer.
5. a kind of pharmaceutical preparation, which is characterized in that including compound according to claim 1.
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| CN105061352A (en) * | 2015-07-29 | 2015-11-18 | 广州市广金投资管理有限公司 | Aryl piperazine derivatives (III), salt thereof, preparation method, and application |
| CN105175360A (en) * | 2015-09-06 | 2015-12-23 | 洛阳师范学院 | Ether aryl piperazine derivatives, and salts, preparation methods and application thereof |
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| CN105061352A (en) * | 2015-07-29 | 2015-11-18 | 广州市广金投资管理有限公司 | Aryl piperazine derivatives (III), salt thereof, preparation method, and application |
| CN105175360A (en) * | 2015-09-06 | 2015-12-23 | 洛阳师范学院 | Ether aryl piperazine derivatives, and salts, preparation methods and application thereof |
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