CN107573302A - Aryl piperazines compound and its production and use - Google Patents

Aryl piperazines compound and its production and use Download PDF

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CN107573302A
CN107573302A CN201710814200.4A CN201710814200A CN107573302A CN 107573302 A CN107573302 A CN 107573302A CN 201710814200 A CN201710814200 A CN 201710814200A CN 107573302 A CN107573302 A CN 107573302A
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CN107573302B (en
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袁牧
陈洪
叶碧波
杨宗琳
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Abstract

The invention provides a kind of new aryl diethylenediamine compound and its production and use.The invention provides a kind of compound of logical formula (I),

Description

Aryl piperazine compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel aryl piperazine compound and a preparation method and application thereof.
Technical Field
Prostate cancer (PCa) is a disease that is very common in men, second-hand in fatal cancer in men, second-hand in morbidity and mortality to lung cancer. The incidence of PCa in European and American countries is far higher than that in China, Japan and other east Asia countries, and the incidence rate of prostate cancer in China is also increasing, and the prostate cancer has become a global problem.
Clinically, localized disease can be cured by surgical or radiation therapy to ablate or destroy cancer cells. However, metastatic prostate cancer is not curable and androgen ablation therapy becomes the standard therapy. Despite the use of various chemotherapeutic drugs alone or in combination with radiation therapy to treat advanced stage patients, none of the traditional cancer treatments for prostate cancer have been very successful. Other studies have shown that: once tumor cells become hormone-resistant, standard cytotoxic agents have been shown to be less effective in improving treatment outcome or survival for hormone-insensitive prostate cancer, although they may provide some relief from the pain of the patient. Therefore, there is an urgent need to find more effective and safe anti-prostate cancer drugs.
Disclosure of Invention
One of the objects of the present invention is to provide a novel arylpiperazine compound.
The second object of the present invention is to provide a process for producing the novel arylpiperazine compound.
The invention also aims to provide the application of the novel aryl piperazine compound in preparing antitumor drugs.
It is a fourth object of the present invention to provide pharmaceutical formulations comprising novel arylpiperazine compounds.
The inventors have found that the compounds of formula (I) act as novel pharmaceutical active ingredients against prostate cancer.
To achieve the above objects, in one aspect, the present invention provides a compound of the general formula (I),
wherein,
m is 0 or 1;
R1to R5Each independently selected from the group consisting of hydrogen, halogen, amino, hydroxyl, nitro, cyano, aldehyde, sulfonyl, alkyl of 1 to 14 carbon atoms, alkoxy of 1 to 14 carbon atoms, alkenyl of 2 to 14 carbon atoms, alkenyloxy of 2 to 14 carbon atoms, cycloalkyl of 5 to 14 carbon atoms, heterocycloalkyl of 5 to 14 carbon atoms, aryl of 5 to 14 carbon atoms, heteroaryl of 5 to 14 carbon atoms, cycloalkenyloxy of 5 to 14 carbon atoms, heterocycloalkenyloxy of 5 to 14 carbon atoms, cycloalkylalkyl of 5 to 14 carbon atoms, heterocycloalkylalkyl of 5 to 14 carbon atoms, arylalkyl of 5 to 14 carbon atoms, heteroarylalkyl of 5 to 14 carbon atoms, cycloalkenyloxyalkyl of 5 to 14 carbon atoms, heterocycloalkenyloxyalkyl of 5 to 14 carbon atoms, and cycloalkyloxyalkyl of 1 to 14 carbon atomsAminoalkyl, alkylamino of 1 to 14 carbon atoms, acyl of 2 to 14 carbon atoms, ester of 2 to 14 carbon atoms, sulfone of 2 to 14 carbon atoms, acylamino of 2 to 14 carbon atoms, alkoxyacyl of 1 to 14 carbon atoms, thioalkyl of 1 to 14 carbon atoms, haloalkyl of 1 to 14 carbon atoms, haloalkoxy of 1 to 14 carbon atoms, arylalkoxy of 5 to 14 carbon atoms, heteroarylalkoxy of 5 to 14 carbon atoms.
When describing the compounds of the present invention, the terms are to be construed according to the following definitions, unless the context indicates otherwise: the term "aryl" denotes a polyunsaturated, aromatic hydrocarbon-based group having a single ring (i.e., phenyl) or fused (e.g., naphthalene or anthracene) or covalently linked multiple aromatic rings, typically containing 5 to 14 ring atoms, more preferably 5-12, and even more preferably 5-10; and most preferably 5 to 8; wherein at least one ring is aromatic. The aromatic ring may optionally include one to three additional rings (cycloalkyl, heterocyclyl, or heteroaryl) fused thereto. In addition, aryl includes partially hydrogenated derivatives of the carbocyclic ring systems listed herein. Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylene, 5-or 6-tetrahydronaphthyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-azulenyl, 1-or 2-naphthyl, 1-, 2-, or 3-indenyl, 1-, 2-, or 9-anthryl, 1-2-, 3-, 4-, or 5-acenaphthenyl, 1-, 2-, 3-, 4-, or 10-phenanthryl, 1-or 2-pentalenyl, 1,2-, 3-, or 4-fluorenyl, 4-or 5-indanyl, 5-, 6-, 8-azulenyl, 1-or 2-acenaphthenyl, 3-, 4-, or 10-phenanthryl, 1-or 2-pentalenyl, 1,2-, 3-, 7-, or 8-tetrahydronaphthyl, 1,2,3, 4-tetrahydronaphthyl, 1, 4-dihydronaphthyl, dibenzo [ a, d ]]Cycloheptenyl, and 1-, 2-, 3-, 4-, or 5-pyrenyl. The aryl ring can be optionally substituted with one or more substituents, that is, an aryl group which may optionally have one or more substituents at any available point of attachment. Non-limiting examples of such substituents are selected from the group consisting of halogen, hydroxy, oxo, nitro, amino, hydrazine, aminocarbonyl, azido, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxy, -SO2-NH2Aryl, heteroaryl, aralkyl, haloalkyl, haloalkoxy, alkoxycarbonyl, alkylAlkylaminocarbonyl, heteroarylalkyl, alkylsulfonylamino, heterocyclyl, alkylcarbonylaminoalkyl, aryloxy, alkylcarbonyl, acyl, arylcarbonyl, aminocarbonyl, alkylsulfoxide, -SO2RaAlkylthio, carboxy, etc., wherein R isaIs an alkyl or cycloalkyl group.
The term "heteroaryl" denotes a substituent resulting from the replacement of a ring carbon atom in an aryl group as defined above by one or more heteroatoms. The term "heteroaryl" by itself or as part of another group means, but is not limited to, a 5 to 14 carbon-atom aromatic ring or ring system containing 1 to 3 fused or covalently linked rings, typically containing 5 to 14 ring atoms, more preferably 5 to 12, still more preferably 5 to 10; and most preferably 5 to 8; at least one of the rings or ring systems is aromatic, wherein one or more carbon atoms in one or more of these rings can be replaced with oxygen, nitrogen or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Such rings may be fused to aryl, cycloalkyl, heteroaryl or heterocyclyl rings. Non-limiting examples of such heteroaryl groups include: pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, dioxadienyl, thiazinyl, triazinyl, 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 ] imidazolyl, tetrazol [1,5-a ] pyridyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, benzopyranyl, 1(4H) -benzopyranyl, 1(2H) -benzopyranyl, 3, 4-dihydro-1 (2H) -benzopyranyl, isobenzofuranyl, benzothienyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1, 3-benzoxazolyl, 1, 2-benzisoxazolyl, 2, 1-benzisoxazolyl, 1, 3-benzothiazolyl, 1, 2-benzisothiazolyl, 2, 1-benzisothiazolyl, benzotriazolyl, 1,2, 3-benzoxadiazolyl, 2,1, 3-benzoxadiazolyl, 1,2, 3-benzothiadiazolyl, 2,1, 3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo [1,2-a ] pyridinyl, 6-oxo-pyridazin-1 (6H) -yl, 2-oxopyridin-1 (2H) -yl, 6-oxo-pyridazin-1 (6H) -yl, 2-oxopyridin-1 (2H) -yl, 1, 3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl.
The term "alkyl" by itself or as part of another substituent means a compound of formula CxH2x+1Wherein x is a number greater than or equal to 1. Typically, the alkyl groups of the present invention contain 1 to 14 carbon atoms. The alkyl group may be straight or branched chain, and may be substituted as indicated herein. When a subscript is used herein after a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, "C1-C10"is equivalent to C1、C2、C3、C4、C5、C6、C7、C8、C9Or C10。“C1-C14"is equivalent to C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14。“C2-C14”、“C3-C14"etc. are defined similarly and will not be described in detail. Preferably, the alkyl group is C1-C12Alkyl radical, C1-C10Alkyl radical, C1-C8Alkyl radical, C1-C6Alkyl, or C1-C4An alkyl group. Further, for example, C1-C6Alkyl includes all straight chain, branched alkyl groups having 1 to 6 carbon atoms, thus including methyl, ethyl, n-propyl, isopropyl, butyl and its isomers (e.g., n-butyl, isobutyl and tert-butyl), pentyl and its isomers, hexyl and its isomers.
The term "alkoxy" denotes a compound having the formula-ORbWherein R isbIs an alkyl group. Preferably, alkoxy is C1-C14Alkoxy radical, C1-C12Alkoxy radical, C1-C10Alkoxy radical, C1-C8Alkoxy radical, C1-C6Alkoxy, or C1-C4An alkoxy group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.
The term "aminoalkyl" denotes one or more CH in an alkyl group2The H atom in (1) is an alkyl group substituted with an amino group or a substituted amino group (i.e., an amine group). Preferably, aminoalkyl is C1-C14Aminoalkyl radical, C1-C12Aminoalkyl radical, C1-C10Aminoalkyl radical, C1-C8Aminoalkyl radical, C1-C6Aminoalkyl radicals, or C1-C4An aminoalkyl group. Non-limiting examples of aminoalkyl groups include aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, aminoisobutyl, ammonia sec-butyl, ammonia tert-butyl, aminopentyl and aminohexyl.
The term "alkylamino" denotes an amino group wherein one or two H atoms of the amino group are further substituted by an alkyl or substituted alkyl group. Preferably, alkylamino is C1-C14Alkylamino radical, C1-C12Alkylamino radical, C1-C10Alkylamino radical, C1-C8Alkylamino radical, C1-C6Alkylamino, or C1-C4An alkylamino group. Non-limiting examples of alkylamino include methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, isopropylamino, diisopropylamino, butylamino, dibutylamino, isobutylamino, diisobutylamino, sec-butylamino, di-sec-butylamino, tert-butylamino, di-tert-butylamino, pentylamino, di-tert-butylamino, hexylamino and dihexylamino.
The term "alkanoyl" as employed herein or as part of another substituentIs independently-C (═ O) RcWherein R iscAs defined hereinbefore for alkyl. Preferably, the alkanoyl is C1-C14Alkyl acyl radical, C1-C12Alkyl acyl radical, C1-C10Alkyl acyl radical, C1-C8Alkyl acyl radical, C1-C6Alkyl acyl, or C1-C4An alkyl acyl group. Non-limiting examples of alkanoyl groups include alkanoyl, isopropanoyl, butanoyl, isobutanoyl, sec-butanoyl, tert-butanoyl, pentanoyl and hexanoyl.
The term "alkylamido" by itself or as part of another substituent means-NHC (═ O) RdWherein R isdAs defined hereinbefore for alkyl. Preferably, the alkylamide group is C1-C14Alkylamido radical, C1-C12Alkylamido radical, C1-C10Alkylamido radical, C1-C8Alkylamido radical, C1-C6Alkylamido radical, or C1-C4An alkylamide group. Non-limiting examples of alkylamido include methylamido, ethylamido, propylamido, isopropylamido, butylamido, isobutylamido, sec-butylamido, tert-butylamido, pentylamido and hexylamido.
The term "alkoxyacyl" by itself OR as part of another substituent means-C (═ O) OReWherein R iseAs defined hereinbefore for alkyl. Preferably, the alkoxyacyl group is C1-C14Alkoxyacyl radical, C1-C12Alkoxyacyl radical, C1-C10Alkoxyacyl radical, C1-C8Alkoxyacyl radical, C1-C6Alkoxyacyl, or C1-C4An alkoxyacyl group. Non-limiting examples of alkoxyacyl groups include methanoxyacyl, ethanoxyacyl, propanexyacyl, isopropanoxyacyl, butanexyacyl,isocyanatooxyacyl, sec-butoxyacyl, tert-butoxyacyl, pentoxyacyl and hexoxyacyl.
The term "alkyl ester group" by itself or as part of another substituent means-OC (═ O) RfWherein R isfAs defined hereinbefore for alkyl. Preferably, the 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-C4An alkyl ester group. Non-limiting examples of alkyl ester groups include methyl ester groups, ethyl ester groups, propyl ester groups, isopropyl ester groups, butyl ester groups, isobutyl ester groups, sec-butyl ester groups, tert-butyl ester groups, pentyl ester groups, and hexyl ester groups.
The term "thioalkyl" denotes one or more CH in an alkyl group2The H atom in (1) is substituted with a mercapto group (-SH) or an alkyl group substituted with a mercapto group (-alkylthio). Preferably, thioalkyl is C1-C14Thioalkyl, C1-C12Thioalkyl, C1-C10Thioalkyl, C1-C8Thioalkyl, C1-C6Thioalkyl, or C1-C4A thioalkyl group. Non-limiting examples of thioalkyl groups include methylthioalkyl, ethylthioalkyl, propylthioalkyl, isopropylthioalkyl, butylthioalkyl, isobutylthioalkyl, sec-butylthioalkyl, tert-butylthioalkyl, pentylthioalkyl and hexylthioalkyl.
The term "alkylthio" denotes a mercapto group wherein the H atom in the mercapto group (-SH) is further substituted by an alkyl group or a substituted alkyl group. Preferably, alkylthio is C1-C14Alkylthio radical, C1-C12Alkylthio radical, C1-C10Alkylthio radical, C1-C8Alkylthio radical, C1-C6Alkylthio, or C1-C4An alkylthio group. Non-limiting examples of alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthioAlkylthio, isobutylalkylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio.
The term "haloalkoxy" denotes one or more CH's in an alkyl group2An alkyl (oxy) group in which the H atom is substituted with a halogen. Halogen is selected from fluorine, chlorine, bromine and iodine. Preferably, the haloalkane (oxy) group is C1-C14Alkyl (oxy) halide, C1-C12Alkyl (oxy) halide, C1-C10Alkyl (oxy) halide, C1-C8Alkyl (oxy) halide, C1-C6Alkyl (oxy) halide, or C1-C4Alkyl (oxy) halide group. Non-limiting examples of the haloalkanyl (oxy) group include a methyl (oxy) halide group, an ethyl (oxy) halide group, a propane (oxy) halide group, an isopropanyl (oxy) halide group, a butane (oxy) halide group, an isobutane (oxy) halide group, a sec-butane (oxy) halide group, a tert-butane (oxy) halide group, a pentane (oxy) halide group, and a hexane (oxy) halide group. Further, for example, non-limiting examples of the haloalkyl group include a chloromethyloxy group, a 1-bromoethoxy (oxy) group, a fluoromethoxy (oxy) group, a difluoromethoxy (oxy) group, a trifluoromethyl (oxy) group, a 1,1, 1-trifluoroethyl (oxy) group, and the like.
The term "cycloalkyl" refers to a saturated and cyclic alkyl group, by itself or as part of another group, representing but not limited to an aliphatic ring or ring system of 5 to 14 carbon-atoms. Cycloalkyl groups generally contain 5 to 14 ring atoms, more preferably 5 to 12, still more preferably 5 to 10; and most preferably 5-8. Non-limiting examples of cycloalkyl groups include cyclopentyl, cyclohexyl, 2-, or 3-methylcyclopentyl, cycloheptyl, and 2-, 3-, or 4-methylcyclohexyl.
The term "heterocycloalkyl" refers to a saturated and cyclic alkyl group, by itself or as part of another group, representing but not limited to an aliphatic ring or ring system of 5 to 14 carbon-atoms. Generally containing 5 to 14 ring atoms, more preferably 5 to 12, still more preferably 5 to 10; and most preferably 5 to 8; wherein one or more carbon atoms in one or more of these rings are substituted with O, N or S atoms, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Non-limiting examples of heterocycloalkyl include 2-, or 3-oxocyclopentyl, 1,2-, or 3-oxocyclopentyl, 2-, 3-, or 4-oxocyclohexyl, 1-, 2-, 3-, or 4-oxocyclohexyl, and the like.
The terms "cycloalkenyl", "heterocycloalkenyl", "cycloalkylalkyl", "heterocycloalkylalkyl", "cycloalkenyloxyalkyl", "heterocycloalkenyloxyalkyl" may, like the abovementioned "alkyl" and "(hetero) cycloalkyl (en) yl", have one or more double bonds, but at the same time are not aromatic and are not described in any further detail.
It is to be noted that the number of carbon atoms in each substituent defined above may likewise vary independently. For example, from "1 to 14 carbon atoms", "2 to 14 carbon atoms", or "5 to 14 carbon atoms" to "1 to 12 carbon atoms", "2 to 12 carbon atoms", or "5 to 12 carbon atoms", respectively; or "1 to 10 carbon atoms", "2 to 10 carbon atoms", or "5 to 10 carbon atoms"; or "1 to 8 carbon atoms", "2 to 8 carbon atoms", or "5 to 8 carbon atoms"; alternatively, "1 to 6 carbon atoms", "2 to 6 carbon atoms", or "5 to 8 carbon atoms".
Further, the compound of the general formula (I) according to the present invention, wherein,
m is 0 or 1;
R1to R5Each independently selected from the group consisting of hydrogen, halogen, amino, hydroxyl, nitro, cyano, aldehyde, sulfonyl, alkyl of 1 to 14 carbon atoms, alkoxy of 1 to 14 carbon atoms, haloalkyl of 1 to 14 carbon atoms, haloalkoxy of 1 to 14 carbon atoms, aryl of 5 to 14 carbon atoms, heteroaryl of 5 to 14 carbon atoms, arylalkyl of 5 to 14 carbon atoms, heteroarylalkyl of 5 to 14 carbon atoms, arylalkoxy of 5 to 14 carbon atoms, heteroarylalkoxy of 5 to 14 carbon atoms.
Further, the compound of the general formula (I) according to the present invention, wherein,
m is 0 or 1;
R1to R5Each independently selected from hydrogen, cyano, alkyl of 1 to 14 carbon atoms, alkoxy of 1 to 14 carbon atoms, haloalkyl of 1 to 14 carbon atoms, haloalkoxy of 1 to 14 carbon atoms.
Further, the compound of the general formula (I) according to the present invention, wherein,
m is 0 or 1;
R1to R5Each independently selected from hydrogen, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, haloalkoxy of 1 to 4 carbon atoms.
Further, the compound of the general formula (I) according to the present invention, wherein,
m is 0 or 1;
R1to R5Each independently selected from hydrogen, cyano, methyl, methoxy, ethyl, ethoxy, trifluoromethyl.
Unless the context indicates otherwise, the term "compounds of the invention" may be broadly interpreted to include compounds of formula (I) and any derivatives. The term "derivative" refers to tautomers, enantiomers, diastereomers, racemates, metabolites, prodrugs, hydrates, solvates and salts thereof of the compounds of the present invention, as well as their quaternized nitrogen analogs, and the like.
For example, the compounds of the invention may exist in the form of different tautomers including, but not limited to, geometric isomers, conformational isomers, E/Z-isomers, stereochemical isomers, and isomers corresponding to the same substituents present at different positions of the rings present in the compounds of the invention. All such possible tautomers and mixtures thereof are included within the scope of the present invention.
The compounds of the invention may contain one or more asymmetric carbon atoms which act as chiral centers, which may result in different optically active forms (e.g., enantiomers, diastereomers, and racemates). The present invention encompasses all such optically active forms of all possible configurations, as well as mixtures thereof.
Quaternized nitrogen analogs of the compounds of the invention means compounds of the invention in which one or several N atoms are quaternized.
Hydrates and solvates of the compounds of the invention mean substances in which water molecules or solvent molecules participate in crystalline or amorphous form to form the solid forms of the compounds of the invention.
Salts of the compounds of the present invention include pharmaceutically acceptable salts of the compounds of formula (I). Pharmaceutically acceptable salts include, among others, the acid addition salts applicable and derived from pharmaceutically acceptable inorganic and organic acids such as hydrochloride, hydrobromide, sulfate, phosphate, maleate, fumarate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2-or 4-hydroxybenzoate, 4-chlorobenzoate, benzenesulfonate, nicotinate, methanesulfonate, ascorbate, acetate, succinate, lactate, glutarate, gluconate, hydroxynaphthalene carboxylate, oleate and amino acid salts, the usual amino acid salts being glycinate, alanate, phenylalanine, aspartate, methionine, lysine, tryptophan, glutamate and threonine, etc.; and salts prepared from pharmaceutically acceptable inorganic and organic bases, including aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, and bismuth salts, with ammonium, calcium, magnesium, potassium, sodium salts being particularly preferred. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, cyclic amines such as arginine betaine, choline, and the like.
The derivatives of the compounds of the present invention may further relate to metabolites and prodrugs thereof. These forms are well known to those skilled in the art.
The results of preliminary pharmacological studies and in vitro anti-tumor experiments show that: some compounds have good anti-tumor activity and can be developed into novel anti-tumor drugs.
Preferred compounds of the invention have the following structure of compounds 5, 6, 7, 8, 9, 10, 11, 12, 13, 14:
further, preferred compounds of the present invention have the structure of compounds 6, 10; most preferably, preferred compounds of the present invention have the structure of compound 6. The compound has good in-vitro anti-tumor cell activity on three human prostate cancer cell lines of PC-3, LNCaP and DU145, and has high selectivity on normal prostate epithelial cells WPMY-1. And relatively few compounds of the prior art have been shown to be such.
In another aspect, the present invention provides a method for preparing the above novel arylpiperazine compound.
The compounds of formula (I) of the present invention may be prepared in a manner known in the art. For example, it can be prepared by the following method: firstly, reducing a raw material 4- (bromoethane) phenylacetic acid 1 into an intermediate 2 by a borane dimethyl sulfide complex, secondly, reacting the intermediate 2 with 6-hydroxy-1-tetralone under the catalysis of alkali to obtain an intermediate 3, and secondly, reacting the intermediate 3 with p-toluenesulfonyl chloride under the catalysis of alkali to generate a hydroxyl protected intermediate 4; finally, the intermediate 4 and the corresponding aryl piperazine compound are subjected to nucleophilic substitution reaction to obtain the corresponding compound 5-14.
The reaction scheme is as follows:
the preparation process of the intermediate 2 in the invention is as follows:
the preparation process of the intermediate 2 comprises the following steps:
4- (bromoethane) phenylacetic acid reacts with borane dimethyl sulfide complex (BMS) at normal temperature to obtain an intermediate 2.
The preparation process of the intermediate 3 in the invention is as follows:
the preparation process of the intermediate 3 comprises the following steps:
2- (4- (bromomethyl) phenyl) ethanol (intermediate 2) reacts with 6-hydroxy-1-tetralone under the catalysis of potassium carbonate to obtain an intermediate 3).
The preparation process of intermediate 4 of the invention is as follows:
the preparation process of the intermediate 4 comprises the following steps: and reacting the intermediate 3 with p-toluenesulfonyl chloride under the catalysis of triethylamine to obtain an intermediate 4.
The preparation of compounds 5-14 of the present invention is as follows:
the preparation process of the compounds 5-14 comprises the following steps: the intermediate 4 reacts with corresponding aryl piperazine compounds to obtain compounds 5-14.
On the other hand, the invention provides the application of the aryl piperazine compound in preparing antitumor drugs.
The use according to the invention, wherein the tumour is prostate cancer.
For pharmaceutical use, the compounds of the invention may be formulated in the form of a pharmaceutical formulation or a pharmaceutical composition comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more other pharmaceutically active compounds.
In a further aspect, the present invention provides a pharmaceutical formulation comprising the above-described arylpiperazine compound of the present invention.
The pharmaceutical formulations of the present invention may be in a form suitable for oral administration, for topical administration (including ophthalmic), for administration by inhalation, by dermal patch, by implant, by suppository, and the like. Such suitable administration forms (e.g. solid, semi-solid or liquid, depending on the mode of administration) as well as methods and carriers, diluents and excipients for their preparation.
Pharmaceutical formulations of the present invention include tablets, pills, powders, lozenges, sachets, cachets, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders for administration in pill form and/or for continuous administration may be formulated with carriers, excipients, and diluents that are themselves suitable for use in such formulations, such as lactose, glucose, sucrose, sorbitol, mannitol, starches, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, sterile water, methylcellulose, methyl-and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof.
In addition, co-solvents such as alcoholic solvents may improve the solubility and/or stability of the compounds. In the formulation of aqueous compositions, the addition of salts of the compounds of the invention can be more suitable, since the salts favor increased aqueous solubility.
Pharmaceutical formulations may be prepared in a manner known in the art, and typically involve mixing at least one compound according to the invention and one or more pharmaceutically acceptable carriers, preferably under sterile conditions.
The compound of the general formula (I) provided by the invention is subjected to preliminary pharmacological research (in vitro antitumor activity test), and the result shows that: some compounds have good anti-tumor activity and can be further developed into novel anti-tumor drugs. Compared with a control compound Naftopidil, the in vitro anti-tumor cell activity is equivalent to or even higher; while being more selective relative to control compounds.
Detailed Description
The invention will be further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications can be made by those skilled in the art after reading the contents of the present invention, and those equivalents also fall within the scope of the invention defined by the appended claims.
The following examples will aid understanding of the present invention, but are not intended to limit the scope of the present invention.
Example 1: preparation of intermediate 5
A25 mL round bottom flask was charged with 100mg (0.22mmol) of intermediate 4, 59.8mg (0.26mmol) of 1- (4-trifluoromethylphenyl) piperazine, 182mg (1.32mmol) of potassium carbonate, 15mL of acetonitrile and reacted at 86 ℃ for 16h, TLC showed complete reaction of starting material. The reaction was stopped, filtered and concentrated. The crude product was purified by silica gel column chromatography eluting with: v (ethyl acetate): V (petroleum ether) ═ 1:3, 35.2mg of white solid was obtained, yield: 33 percent. 165: 166 ℃ in M.p.; 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) Delta. 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. Melting point was determined using an aFisher Johns hot-stage determinator (thermometer uncorrected). Of all the target compounds (hydrochlorides)1HNMR，13C NMR was measured using Bruker AVANCEAV-400NB, Switzerland, TMS as an internal standard. Mass spectra (ESI) were determined on a Thremo DSQ mass spectrometer. The same is as follows.
Example 2: preparation of Compound 6
Reaction of intermediate 4 with 1- (2, 5-dimethylphenyl) piperazine, synthesis and test conditions were the same as in example 1. 41.2mg of white solid are obtained, yield: 40 percent. M.p. 145-146 deg.C; MS (ESI, M/z) 469.2[ M +1 ]]+；1HNMR(500MHz，CDCl3)δinppm: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)δin 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。
Example 3: preparation of Compound 7
The reaction, synthesis and test conditions of intermediate 4 and 1- (3-methylphenyl) piperazine were the same as in example 1. 64.9mg of white solid are obtained, yield: 65 percent. M.p. 132-; MS (ESI, M/z) 455.1[ M +1 ]]+；1H NMR(500MHz，CDCl3)δinppm: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)δin 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。
Example 4: preparation of Compound 8
The reaction of intermediate 4 with 1- (4-methylphenyl) piperazine, the synthesis procedure and the test conditions were the same as in example 1. 89.9mg of white solid are obtained, yield: 87 percent. 159 ℃ and 160 ℃ in M.p.; MS (ESI, M/z) 476.1[ M +1 ]]+；1H NMR(500MHz，CDCl3)δinppm: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)δinppm: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。
Example 5: preparation of Compound 9
The reaction of intermediate 4 with 1- (4-methoxyphenyl) piperazine, the synthesis procedure and the test conditions were the same as in example 1. 54.2mg of white solid are obtained, yield: 41 percent. 167-; MS (ESI, M/z) 471.1[ M +1 ]]+；1H NMR(500MHz，CDCl3)δinppm: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)δinppm: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。
Example 6: preparation of Compound 10
The reaction of intermediate 4 with 1- (3-methoxyphenyl) piperazine, the synthesis procedure and the test conditions were the same as in example 1. Yield 72.4mg white solid: 76 percent. 149: 150 ℃ in M.p.; MS (ESI, M/z) 471.2[ M +1 ]]+；1H NMR(500MHz，CDCl3)δinppm: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)δinppm: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。
Example 7: preparation of Compound 11
The reaction of intermediate 4 with 1- (2-methylphenyl) piperazine, the synthesis procedure and the test conditions were the same as in example 1. 59.9mg of white solid are obtained, yield: and 64 percent. 149: 150 ℃ in M.p.; MS (ESI, M/z) 455.1[ M +1 ]]+；；1H NMR(500MHz，CDCl3)δinppm: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)δinppm: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。
Example 8: preparation of Compound 12
The reaction, synthesis and test conditions of intermediate 4 with 1- (2-ethoxyphenyl) piperazine were the same as in example 1. 58.6mg of white solid are obtained, yield: and 55 percent. M.p. 141-142 ℃; MS (ESI, M/z) 485.2[ M +1 ]]+；1HNMR(500MHz，CDCl3)δinppm: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)δinppm: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。
Example 9: preparation of Compound 13
The reaction, synthesis and test conditions of intermediate 4 with 4-phenylpiperazine were the same as in example 1. 65.4mg of white solid are obtained, yield: 51 percent. 163-164 ℃ in M.p.; MS (ESI, M/z):441.1[ M +1 ]]+；1H NMR(500MHz,CDCl3)δinppm: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)δin 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。
Example 10: preparation of Compound 14
The reaction of intermediate 4 with 1- (2-benzonitrile) piperazine, the synthesis procedure and the test conditions were the same as in example 1. Yield 32mg of white solid: 82 percent. M.p. 173-174 ℃; MS (ESI, M/z) 466.2[ 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)δin 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。
Example 11: in vitro anti-tumor cell activity assay
The CCK-8 kit was purchased from the institute of Homon chemistry, Japan.
Preparation of target cells: resuscitation and culture of human prostate cancer cell lines PC-3, LNCaP, DU145 and normal prostate epithelial cell WPMY-1. The specific method comprises the following steps:
a. respectively taking out cold storage tubes of the human prostate cancer cell lines PC-3, LNCaP, DU145 and normal prostate epithelial cells WPMY-1 from a liquid nitrogen tank, rapidly placing the cold storage tubes into a 37 ℃ water bath tank, continuously shaking the cold storage tubes to rapidly melt the cold storage tubes, and transferring the cold storage tubes into a centrifuge tube in an aseptic operation;
b. adding DMEM complete culture solution into centrifuge tubes of PC-3 cells and WPMY-1 cells to 10mL, F12 complete culture medium into centrifuge tubes of LNCaP cells to 10mL, 1640 complete culture medium into centrifuge tubes of DU145 cells to 10mL, centrifuging for 5min at 1000rmp, and discarding supernatant.
c. Respectively adding 3-4mL of DMEM complete culture medium into PC-3 and WPMY-1 cells, blowing and beating the cells to uniformly mix the cells, transferring the cells into a culture bottle, adding 3-4mL of F12 complete culture medium into LNCaP cells, blowing and beating the cells to uniformly mix the cells, transferring the cells into the culture bottle, adding 3-4mL of 1640 complete culture medium into DU145 cells, blowing and beating the cells to uniformly mix the cells, transferring the cells into the culture bottle, and adding 5% CO2Culturing at 37 ℃;
d. and (5) observing the growth condition of the cells, replacing the culture solution in time and separating the culture solution into bottles.
And (6) counting the cells. The specific method comprises the following steps:
a. selecting cells in logarithmic phase, digesting with pancreatin, respectively terminating the corresponding complete culture medium, transferring into a centrifuge tube, and adding the corresponding complete culture medium to 10 mL;
b. dropping 10 μ L of cell suspension into the groove at one side of the counting plate, counting the total number of cells in four large lattices under a microscope, dividing by 4, and multiplying by 104I.e. byThe number of cells contained in each ml of culture medium;
c. adjusting the cell count to 1X 105cells/mL。
Preparing an aryl piperazine compound solution: adding the aryl piperazine compound into a DMSO solvent, adjusting the initial concentration to 10mmol, configuring the concentration to 1mmol for later use, and storing at 4 ℃.
The test method is as follows: (1) human prostate cancer cell lines PC-3, LNCaP, DU145 and normal prostate epithelial cells WPMY-1100 μ L (1X 10) were added to each well of 96-well plate5cells/mL), incubated overnight at 37 ℃. (2) Discard solution, add 100 μ L of subjects at different concentrations, control 100 μ L of DMEM complete medium, and continue culturing for 24 h. (3) Adding 10 mu L of CCK-8 detection reagent into each well, and continuously culturing for 20min to 1 h. (4) And measuring the OD value of each hole under the condition of 450nm by using a microplate reader. (5) Calculating an inhibition rate: percent tumor cell inhibition [ (% average OD value measured in control group-average OD value measured in drug-added group)/average OD value measured in control group]X 100%. (6) The IC was determined by plotting the inhibition versus the logarithm of the drug concentration50The value: with lgc as the abscissa and the suppression ratio as the ordinate, IC was obtained50The value is obtained. Table 1 shows the results of the in vitro antitumor cell activities of the compounds of the present invention.
TABLE 1
Note: >50 represents between 50 and 100; >100 represents above 100.
As can be seen from the comparison, the in vitro anti-tumor cell activity of the representative compound of the general formula (I) is equivalent to or even higher than that of the control compound Naftopidil aiming at three human prostate cancer cell lines, namely PC-3, LNCaP and DU 145; while being more selective relative to control compounds. In particular, the compounds 6 and 10 have better in vitro anti-tumor cell activity on three human prostate cancer cell lines, namely PC-3, LNCaP and DU 145; meanwhile, the polypeptide has higher selectivity on normal prostate epithelial cells WPMY-1.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention shall fall within the protection scope of the present invention.

Claims (10)

1. A compound of the general formula (I),
wherein,
m is 0 or 1;
R1to R5Each independently selected from the group consisting of hydrogen, halogen, amino, hydroxyl, nitro, cyano, aldehyde, sulfonyl, alkyl of 1 to 14 carbon atoms, alkoxy of 2 to 14 carbon atomsAlkenyl, alkenyloxy of 2 to 14 carbon atoms, cycloalkyl of 5 to 14 carbon atoms, heterocycloalkyl of 5 to 14 carbon atoms, aryl of 5 to 14 carbon atoms, heteroaryl of 5 to 14 carbon atoms, cycloalkenyloxy of 5 to 14 carbon atoms, heterocycloalkenyloxy of 5 to 14 carbon atoms, cycloalkylalkyl of 5 to 14 carbon atoms, heterocycloalkylalkyl of 5 to 14 carbon atoms, arylalkyl of 5 to 14 carbon atoms, heteroarylalkyl of 5 to 14 carbon atoms, cycloalkenyloxyalkyl of 5 to 14 carbon atoms, heterocycloalkenyloxyalkyl of 5 to 14 carbon atoms, aminoalkyl of 1 to 14 carbon atoms, alkylamino of 1 to 14 carbon atoms, acyl of 2 to 14 carbon atoms, ester of 2 to 14 carbon atoms, sulfone of 2 to 14 carbon atoms, amido of 2 to 14 carbon atoms, alkoxyacyl of 1 to 14 carbon atoms, Thioalkyl of 1 to 14 carbon atoms, haloalkyl of 1 to 14 carbon atoms, haloalkoxy of 1 to 14 carbon atoms, arylalkoxy of 5 to 14 carbon atoms, heteroarylalkoxy of 5 to 14 carbon atoms.
2. The compound of claim 1, wherein,
m is 0 or 1;
R1to R5Each independently selected from the group consisting of hydrogen, halogen, amino, hydroxyl, nitro, cyano, aldehyde, sulfonyl, alkyl of 1 to 14 carbon atoms, alkoxy of 1 to 14 carbon atoms, haloalkyl of 1 to 14 carbon atoms, haloalkoxy of 1 to 14 carbon atoms, aryl of 5 to 14 carbon atoms, heteroaryl of 5 to 14 carbon atoms, arylalkyl of 5 to 14 carbon atoms, heteroarylalkyl of 5 to 14 carbon atoms, arylalkoxy of 5 to 14 carbon atoms, heteroarylalkoxy of 5 to 14 carbon atoms.
3. The compound of claim 2, wherein,
m is 0 or 1;
R1to R5Each independently selected from hydrogen, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, haloalkoxy of 1 to 4 carbon atoms.
4. The compound of claim 3, wherein,
m is 0 or 1;
R1to R5Each independently selected from hydrogen, cyano, alkyl of 1 to 14 carbon atoms, alkoxy of 1 to 14 carbon atoms, haloalkyl of 1 to 14 carbon atoms, haloalkoxy of 1 to 14 carbon atoms.
5. The compound of claim 4, wherein the compound is selected from compounds 5-14 having the following structure:
6. the compound of claim 5, wherein said compound is selected from compounds 6 and 10.
7. A process for preparing a compound of claim 5, comprising the steps of: firstly, reducing a raw material 4- (bromoethane) phenylacetic acid 1 into an intermediate 2 by a borane dimethyl sulfide complex, secondly, reacting the intermediate 2 with 6-hydroxy-1-tetralone under the catalysis of alkali to obtain an intermediate 3, and secondly, reacting the intermediate 3 with p-toluenesulfonyl chloride under the catalysis of alkali to generate a hydroxyl protected intermediate 4; finally, the intermediate 4 and the corresponding aryl piperazine compound are subjected to nucleophilic substitution reaction to obtain a corresponding compound 5-14;
8. use of a compound according to any one of claims 1 to 6 in the preparation of an anti-neoplastic drug.
9. The use of claim 8, wherein the tumor is prostate cancer.
10. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 6.
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Publication number Priority date Publication date Assignee Title
CN111269211A (en) * 2018-12-05 2020-06-12 浙江京新药业股份有限公司 Preparation method of benzothiophene derivative
CN111269211B (en) * 2018-12-05 2021-07-02 浙江京新药业股份有限公司 Preparation method of benzothiophene derivative

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