CN109928935B - Anilino pyrimidine compound and medical application thereof - Google Patents
Anilino pyrimidine compound and medical application thereof Download PDFInfo
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Abstract
The invention relates to a pyrimidinamine compound shown as a general formula (I) and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein a substituent R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 Q and n have the meanings given in the description. The invention also relates to application of the compound shown in the general formula (I) in preparation of antitumor drugs, and also relates to application of the compound and pharmaceutically acceptable salts, solvates and prodrugs thereof in preparation and/or prevention and alleviation of cancers caused by tumor cells of human tissues or organs. The cancer is preferably colon cancer, hepatocarcinoma, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, skin cancer, ovarian cancer, cervical cancer, renal cancer, leukemia, prostatic cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal carcinoma or gastric cancer.
Description
Technical Field
The invention belongs to the field of medicine. In particular to an anilino pyrimidine compound and application thereof, in particular to application in preventing and/or treating cancer.
Background
The following three compounds g, h and i were reported to be synthesized in Journal of Chemical Research,1994,412-413, but no compound use was mentioned.
The general formula compound A related to patent WO2005037801A1 is used as an MLR inhibitor and has no tumor reported activity.
The compound B of the general formula related to the patent WO2006/128129A2 has the activity of inhibiting c-Rel.
Despite the numerous patents available, there is a continuing need to develop new anti-cancer compounds to control the risk of cancer to humans. All of the compounds disclosed in the above patents differ significantly from the compounds of the present invention in structure.
Disclosure of Invention
The invention aims to provide anilinopyrimidine compounds with novel structures and application of the anilinopyrimidine compounds in preparation of antitumor drugs.
In order to achieve the purpose, the invention adopts the following technical scheme:
an anilinopyrimidine compound is shown in a general formula (I),
in the formula (I), the compound is shown in the specification,
R 1 selected from halogen, hydroxy, cyanoNitro, amino, C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxy radical, C 3 -C 12 Cycloalkyl radical, C 1 -C 12 Alkylthio radical, C 1 -C 12 Alkylsulfonyl radical, C 1 -C 12 Alkylcarbonyl group, C 1 -C 12 Alkoxycarbonyl, amino substituted by one or more Q groups, C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxy radical, C 3 -C 12 Cycloalkyl, C 1 -C 12 Alkylthio radical, C 1 -C 12 Alkylsulfonyl radical, C 1 -C 12 Alkylcarbonyl or C 1 -C 12 An alkoxycarbonyl group;
n is selected from 0 to 5;
R 2 selected from hydrogen or C 1 -C 6 An alkyl group;
R 3 selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxy radical, C 3 -C 12 Cycloalkyl, heterocyclyl, aryl, heteroaryl, amino substituted by one or more Q groups, C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxy radical, C 3 -C 12 Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 4 selected from hydrogen, halogen, C 1 -C 12 Alkyl or halo C 1 -C 12 An alkyl group;
R 3 and R 4 And may also form, together with the carbon atoms to which they are attached, a 3-6 membered carbocyclic or heterocyclic ring which is unsubstituted or substituted by a plurality of groups: halogen, hydroxy, amino, cyano, nitro, C 1 -C 12 Alkyl, halo C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxy or halo C 1 -C 12 An alkoxy group; and R is 3 And R 4 Not simultaneously selected from hydrogen;
R 5 selected from hydrogen or C 1 -C 6 An alkyl group;
when R is 6 In the absence of the presence of the agent,
R 7 is selected from
R 8 Selected from hydrogen, amino, C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxy radical, C 3 -C 12 Cycloalkyl radical, C 1 -C 12 Alkylthio radical, C 1 -C 12 Alkylsulfonyl radical, C 1 -C 12 Alkylcarbonyl group, C 1 -C 12 Alkoxycarbonyl, amino substituted by one or more Q groups, C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxy radical, C 3 -C 12 Cycloalkyl, C 1 -C 12 Alkylthio radical, C 1 -C 12 Alkyl sulfonyl, C 1 -C 12 Alkylcarbonyl or C 1 -C 12 An alkoxycarbonyl group;
R 9 selected from aryl or heteroaryl, unsubstituted or substituted by one or more Q groups;
further, when n is selected from 0, R 2 、R 4 、R 5 、R 8 Are all selected from hydrogen, R 3 When selected from methyl, R 9 Is not selected from 4-chlorophenyl;
when R is 6 When the air conditioner is in the existence state,
R 6 selected from hydrogen, C 1 -C 12 Alkyl radical, C 3 -C 12 Cycloalkyl, heterocyclyl, aryl, heteroaryl, C substituted by one or more Q groups 1 -C 12 Alkyl radical, C 3 -C 12 Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 7 selected from the group consisting of heterocyclyl, aryl, arylacetyl, heteroaryl, arylmethyl, or heteroarylacetyl, unsubstituted or substituted with one or more Q groups;
q is selected from halogen, hydroxy, amino, cyano, nitro, C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxy radical, C 3 -C 12 Cycloalkyl radical, C 2 -C 12 Alkenyl radical, C 2 -C 12 Alkynyl, amino substituted by one or more of the following groups, C 1 -C 12 Alkyl radical, C 1 -C 12 Alkoxy radical, C 3 -C 12 Cycloalkyl radical, C 2 -C 12 Alkenyl or C 2 -C 12 Alkynyl, the following groups are hydroxy, halogen or alkyl;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
Preferred compounds, in said general formula (I),
R 1 selected from halogen, hydroxy, amino, cyano, nitro, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 3 -C 6 Cycloalkyl, C 1 -C 4 Alkylthio radical, C 1 -C 4 Alkylsulfonyl radical, C 1 -C 4 Alkylcarbonyl group, C 1 -C 4 Alkoxycarbonyl, amino substituted by one or more Q groups, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 4 Alkylthio radical, C 1 -C 4 Alkylsulfonyl radical, C 1 -C 4 Alkylcarbonyl or C 1 -C 4 An alkoxycarbonyl group;
n is selected from 0 to 5;
R 2 selected from hydrogen or C 1 -C 4 An alkyl group;
R 3 selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 3 -C 6 Cycloalkyl, heterocyclyl, aryl or heteroaryl, amino substituted by one or more Q groups, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 3 -C 6 Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 4 selected from hydrogen, halogen, C 1 -C 4 Alkyl or halo C 1 -C 4 An alkyl group;
R 3 and R 4 Or together with the carbon atoms to which they are attached, form a 3-to 6-membered carbocyclic or heterocyclic ring which is unsubstituted or substituted by more than one halogen, hydroxy, amino, cyano, nitro, C 1 -C 4 Alkyl, halo C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy or halo C 1 -C 4 An alkoxy group; and R is 3 And R 4 Cannot be simultaneously selected from hydrogen;
R 5 selected from hydrogen or C 1 -C 4 An alkyl group;
when R is 6 In the absence of the presence of the magnetic field,
R 7 is selected from
R 8 Selected from hydrogen, amino, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 4 Alkylthio radical, C 1 -C 4 Alkylsulfonyl radical, C 1 -C 4 Alkylcarbonyl group, C 1 -C 4 Alkoxycarbonyl, amino substituted by one or more Q groups, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 3 -C 6 Cycloalkyl radical, C 1 -C 4 Alkylthio radical, C 1 -C 4 Alkylsulfonyl radical, C 1 -C 4 Alkylcarbonyl or C 1 -C 4 An alkoxycarbonyl group;
R 9 selected from aryl or heteroaryl, unsubstituted or substituted by one or more Q groups;
further, when n is selected from 0, R 2 、R 4 、R 5 、R 8 Are all selected from hydrogen, R 3 When selected from methyl, R 9 Is not selected from 4-chlorophenyl;
when R is 6 When the water-soluble polymer is existed in the water,
R 6 selected from hydrogen, C 1 -C 4 Alkyl radical, C 3 -C 6 Cycloalkyl, heterocyclyl, aryl, heteroaryl, C substituted by one or more Q groups 1 -C 4 Alkyl radical, C 3 -C 6 Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 7 selected from the group consisting of heterocyclyl, arylmethyl, aryl, arylacetyl, heteroaryl, heteroarylacetyl, unsubstituted or substituted with one or more Q groups;
q is selected from halogen, hydroxy, amino, cyano, nitro, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 3 -C 6 Cycloalkyl group, C 2 -C 4 Alkenyl or C 2 -C 4 Alkynyl, amino substituted by one or more of the following groups, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 3 -C 6 Cycloalkyl radical, C 2 -C 4 Alkenyl or C 2 -C 4 Alkynyl, the following groups are hydroxyl, halogen and alkyl;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
Further preferably, in the general formula (I),
R 1 selected from halogen, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, methylthio, methylsulfonyl or cyclopropyl;
n is selected from 0 to 3;
R 2 selected from hydrogen or methyl;
R 3 selected from methyl, ethyl, trifluoromethyl or cyclopropyl;
R 4 selected from hydrogen or C 1 -C 4 An alkyl group;
R 3 and R 4 And may also form, together with the linking carbon atom, a5 or 6 membered carbocyclic ring;
R 5 selected from hydrogen or methyl;
when R is 6 In the absence of the presence of the agent,
R 7 is selected from
R 8 Selected from hydrogen, methyl, ethyl or trifluoromethyl;
R 9 selected from phenyl, pyridyl, thienyl, unsubstituted or substituted with 1-3Q groups;
further, when n is selected from 0, R 2 、R 4 、R 5 、R 8 Are all selected from hydrogen, R 3 When selected from methyl, R 9 Is not selected from 4-chlorophenyl;
when R is 6 When the air conditioner is in the existence state,
R 6 selected from hydrogen or methyl;
R 7 selected from phenylacetyl or benzyl, unsubstituted or substituted with 1 to 3Q groups;
q is selected from halogen, hydroxyl, amino, nitro and C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 3 -C 6 Cycloalkyl radical, C 2 -C 4 Alkenyl radical, C 2 -C 4 Alkynyl, amino substituted by one or more of the following groups, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 3 -C 6 Cycloalkyl radical, C 2 -C 4 Alkenyl or C 2 -C 4 Alkynyl, wherein the following groups are hydroxyl, halogen and alkyl;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
Further preferably, in the general formula (I),
R 1 selected from halogens;
n is selected from 0 to 3;
R 2 selected from hydrogen;
R 3 selected from methyl or trifluoromethyl;
R 4 selected from hydrogen, methyl or n-butyl;
R 3 and R 4 And may also form, together with the linking carbon atom, a5 or 6 membered carbocyclic ring;
R 5 selected from hydrogen or methyl;
when R is 6 In the absence of the presence of the magnetic field,
R 7 is selected from
R 8 Selected from hydrogen, methyl, ethyl or trifluoromethyl;
R 9 selected from phenyl, pyridyl or thienyl, unsubstituted or substituted with 1 to 3Q groups;
further, when n is selected from 0, R 2 、R 4 、R 5 、R 8 Are all selected from hydrogen, R 3 When selected from methyl, R 9 Is not selected from 4-chlorophenyl;
when R is 6 When the water-soluble polymer is existed in the water,
R 6 selected from hydrogen or methyl;
R 7 selected from phenylacetyl or benzyl, unsubstituted or substituted with 1 to 3Q groups;
q is selected from fluorine, chlorine, hydroxyl, nitro, methyl, methoxy, trifluoromethyl or trifluoromethoxy;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
More preferably, in the general formula (I),
R 1 selected from fluorine or chlorine;
n is selected from 0 to 3;
R 2 selected from hydrogen;
R 3 selected from methyl or trifluoromethyl;
R 4 selected from hydrogen;
R 3 and R 4 And may also form a5 membered carbocyclic ring together with the linking carbon atom;
R 5 selected from hydrogen;
when R is 6 In the absence of the presence of the agent,
R 7 is selected from
R 8 Selected from hydrogen or methyl;
R 9 selected from phenyl, unsubstituted or substituted with 1 to 3Q groups;
further, when n is selected from 0, R 2 、R 4 、R 5 、R 8 Are all selected from hydrogen, R 3 When selected from methyl, R 9 Is not selected from 4-chlorophenyl;
when R is 6 When the air conditioner is in the existence state,
R 6 selected from hydrogen;
R 7 selected from o-chlorophenyl acetyl;
q is selected from fluorine, chlorine, hydroxyl, nitro, methyl, methoxy, trifluoromethyl or trifluoromethoxy;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
The compound of the general formula (I) or the salt corresponding to the isomer of the compound is at least one of hydrochloride, sulfate, nitrate, bicarbonate, carbonate, phosphate, formate, acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methylsulfonate, benzoate, citrate, malate, tartrate, maleate, succinate, ascorbate or oxalate.
According to the invention, prodrugs of compounds of formula (I) are derivatives of compounds of formula (I) which may themselves have a weak activity or even no activity, but which, after administration, are converted under physiological conditions (e.g. by metabolism, solvolysis or otherwise) into the corresponding biologically active form.
The compound solvate of the general formula (I) is a compound of the general formula (I) or an isomer thereof, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, dichloromethane, petroleum ether and acetonitrile
The invention further relates to a compound shown in the general formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition containing the compound, and an application of the compound or the pharmaceutically acceptable salt, solvate or prodrug in preparation of medicines for relieving, preventing and/or treating cancer in mammals including human beings. The cancer includes, but is not limited to, colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, ovarian cancer, cervical cancer, renal cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal cancer, gastric cancer, etc.
In the definitions given above for compounds of the general formula (I), the collective terms used generally represent the following substituents:
halogen: refers to fluorine, chlorine, bromine or iodine. Alkyl groups: straight-chain or branched alkyl groups, such as methyl, ethyl, propyl, isopropyl or tert-butyl. Halogenated alkyl groups: straight-chain or branched alkyl groups in which the hydrogen atoms may be partially or completely substituted by halogen atoms, such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, etc. Alkoxy group: straight or branched chain alkyl groups attached to the structure via oxygen atom bonds. A haloalkoxy group: straight-chain or branched alkoxy groups in which the hydrogen atoms may be partially or completely replaced by halogen atoms, such as chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, trifluoroethoxy, etc. Alkylthio groups: straight or branched chain alkyl groups attached to the structure via a sulfur atom. Halogenated alkylthio groups: straight-chain or branched alkylthio groups in which hydrogen atoms in these alkyl groups may be partially or wholly replaced by halogen atoms, such as chloromethylthio, dichloromethylthio, trichloromethylthio, fluoromethylthio, difluoromethylthio, trifluoromethylthio, chlorofluoromethylthio and the like. An alkylamino group: straight or branched chain alkyl, linked to the structure via a nitrogen atom. A haloalkylamino group: straight-chain or branched alkylamino groups, the hydrogen atoms on these alkyl groups may be partially or completely substituted by halogen atoms. Alkenyl: straight-chain or branched alkenes, for example ethenyl, 1-propenyl, 2-propenyl and the different butenyl, pentenyl and hexenyl isomers. Alkenyl also includes polyenes such as 1, 2-allenyl and 2, 4-hexadienyl. Halogenated alkenyl groups: straight or branched chainThe alkenyl group may have a hydrogen atom partially or completely substituted with a halogen atom. Alkynyl: straight-chain or branched alkynes, for example ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. Alkynyl also includes groups consisting of multiple triple bonds, such as 2, 5-hexadiynyl. Halogenated alkynyl group: straight-chain or branched alkynes, in which the hydrogen atoms may be partially or completely replaced by halogen atoms. Alkylcarbonyloxy group: such as CH 3 COO-，CH 3 CH 2 NHCOO-. Alkylcarbonylamino group: such as CH 3 CONH-，CH 3 CH 2 NHCONH-. The aryl moiety in aryl, arylmethyl, aryloxy, arylamino and the like includes phenyl, naphthyl and the like. Heteroaryl is a five or six membered ring containing 1 or more heteroatoms N, O, S. Such as furyl, pyrrolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl and the like.
In the compounds of the invention of the partial general formula I (R) 1 ) n The substituents are listed in Table 1, but do not limit the present invention.
TABLE 1
Note: in the table, "-" indicates n =0.
Some of the compounds may be represented by, but are not limited to, the specific compounds listed in tables 2 and 3.
When R is 6 In the absence of R 7 Is selected from
The compound of the general formula (I) can be represented by the general formula (I-1) shown in Table 2,
TABLE 2
Note: in the table "-" means n =0.
When R is 6 When present, the compounds of formula (I) may be represented by Table 3,
TABLE 3
The compound of the general formula (I-1) to which the present invention relates can be prepared according to the following process. The reaction is as follows, wherein each group is as defined above unless otherwise stated:
a synthetic route of the general formula (I-1):
among them, in a preferred embodiment, the chlorinating agent can be selected from, for example, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, vilesmier-Haack reagent, sulfuryl chloride, and the like.
In a preferred embodiment, the acid can be selected from, for example, oxalic acid (oxalic acid), sulfurous acid, phosphoric acid, pyruvic acid, nitrous acid, hydrofluoric acid, formic acid, benzoic acid, acrylic acid, acetic acid, propionic acid, carbonic acid, and the like.
The reaction is carried out in a solvent, which in a preferred embodiment may be selected from, for example, tetrahydrofuran, acetonitrile, toluene, xylene, benzene, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetone, butanone, or the like.
The reaction temperature in the above reaction may be between room temperature and the boiling temperature of the solvent, and in a preferred embodiment, ranges from 20 to 100 ℃. The reaction time is 30 minutes to 20 hours, and in a preferred embodiment, the reaction time is 1 to 10 hours.
Intermediates II, III, VI and VII in the above reaction are commercial products, intermediate IV is obtained by condensation according to known method, and specific synthesis can be found in WO2008145052 and CN 201010554472.3.
The salts of the compounds of the formula (I) can be prepared from the compounds of the formula (I) and the corresponding acids in a conventional manner. Suitable acids are selected from hydrochloric, sulphuric, nitric, carbonic, phosphoric, formic, acetic, trifluoroacetic, benzenesulfonic, p-toluenesulfonic, methanesulfonic, benzoic, citric, malic, tartaric, maleic, succinic, ascorbic or oxalic acids and the like; further preferred are hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
The invention comprises a preparation prepared by taking the compound contained in the general formula (I) as an active ingredient and a preparation consisting of the preparation. The preparation method comprises the following steps: dissolving the compound covered by the present invention in a water-soluble organic solvent, a nonionic surfactant, a water-soluble lipid, various cyclodextrins, fatty acids, fatty acid esters, phospholipids or a combination thereof to prepare a preparation solution; adding physiological saline to obtain 1-20% carbohydrate. The organic solvent includes polyethylene glycol (PEG), ethanol, propylene glycol or a combination of these solvents.
The compounds covered in the general formula (I) and the salts and prodrugs thereof are used for preparing anti-tumor medicaments or medicinal preparations for treating, preventing or relieving tumors, and the active ingredients of the medicaments are one or more than two pyrimidinamine compounds shown in the general formula (I). Is especially suitable for treating or relieving cancer caused by tumor cells in human tissues or organs. The cancer is preferably colon cancer, hepatocarcinoma, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, ovarian cancer, cervical cancer, renal cancer, leukemia, prostatic cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal carcinoma or gastric cancer.
The compound synthesized by the invention can be used as an active component of an anti-tumor medicament, can be used independently, and can also be used together with other anti-tumor and anti-virus medicaments. The combination therapy of the present invention involves the use of at least one compound of the present invention and its active derivatives in combination with one or more other anti-tumor anti-viral agents to increase overall efficacy. The dosage and administration time of the combination should be determined according to the most reasonable therapeutic effect obtained under different conditions.
The pharmaceutical formulation contemplated includes an effective dose of the compound of formula (I). An "effective amount" as used herein refers to the amount of the compound required to produce a therapeutic effect in the subject being treated. The effective dose or dosages may be varied by the experiential person according to the recommendations of the individual case. For example, the types of tumors to be treated are different, and the use of drugs is different; whether the composition is used together with other treatment methods such as other antitumor drugs or antiviral drugs, etc., the dosage can be changed. Can be made into any available dosage form. If certain compounds have basic or acidic properties and can form non-toxic acids or salts, the salt forms of the compounds can be used. Pharmaceutically acceptable organic acid salts include physiologically acceptable negative ion salts such as p-toluenesulfonate, methanesulfonate, acetate, benzoate, citrate, malate, tartrate, maleate, succinate, ascorbate or glycerophosphate salts and the like; inorganic salts that may be used include chloride, bromide, fluoride, iodide, sulfate, nitrate, bicarbonate, carbonate, or phosphate, and the like; basic compounds such as amines with suitable acids can be prepared in the form of the salts; the carboxylic acid compounds may form usable salts with alkali metals or alkaline earth metals.
The compounds encompassed in the general formula (I) in the present invention are generally easily dissolved in organic solvents, water-soluble solvents, and mixed solvents of organic solvents and water-soluble solvents with water. The water-soluble solvent is preferably alcohol, polyethylene glycol, N-methyl-2-pyrrolinone, N-dimethylacetamide, N-dimethylformamide, dimethylsulfoxide, acetonitrile, or a combination thereof. The alcohol is preferably methanol, ethanol, isopropanol, glycerol or ethylene glycol. The compounds of the present invention may be formulated by mixing with conventional formulation vehicles. Dissolving the compound in water-soluble organic solvent, aprotic solvent, water-soluble lipid, cyclodextrin, fatty acid, phospholipid or their mixture to obtain medicinal solution; adding physiological saline to obtain 1-20% carbohydrate, such as glucose water solution. The formulations thus prepared are stable and useful in animals and in clinical settings.
The product medicine prepared by using the compound in the general formula (I) as an active ingredient can be administrated by oral or parenteral routes, and also can be administrated by a medicine pump transplanted in vivo and other methods, wherein the parenteral route administration refers to perfusion, subcutaneous intradermal, intramuscular, intravenous, intraarterial, intraatrial, intrasynovial, intrasternal, intrathecal, wound site, intracranial injection or instillation technology and the like. The technical personnel mix the components by a conventional method to finally obtain the required medicament form. Can be made into tablet, pill, capsule, granule, syrup, injection, lyophilized powder for injection, emulsion, powder, lyophilized powder, dripping pill, emulsion suspension, aqueous suspension, water solution, colloid solution, sustained release preparation, nanometer preparation, or other dosage forms for animal or clinical use.
The compound in the general formula (I) is used for preparing a medicine for treating or relieving cancer of a certain tissue or organ. The cancer includes but is not limited to colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, ovarian cancer, cervical cancer, renal cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal cancer or gastric cancer.
Detailed Description
The following specific examples are provided to further illustrate the invention, but the invention is not limited to these examples. (all materials are commercially available unless otherwise noted)
Synthetic examples
Example 1: preparation of Compound 30
The method comprises the following steps: phenylguanidine (0.1mol, 13.5 g) is dissolved in 100mL of absolute ethyl alcohol, ethyl trifluoroacetoacetate (0.12mol, 22.08g) is added for reflux reaction for 5h, the reaction is stopped, after cooling to room temperature, 300mL of ice water is added, stirring is carried out for 30min, suction filtration is carried out, a filter cake is washed by water and dried, and 18.6g of off-white solid is obtained.
Step two: dissolving the intermediate a (0.05mol, 12.75g) in 100mL acetonitrile, adding phosphorus oxychloride (0.25 mol, 23mL), slowly dropwise adding N, N-diisopropylethylamine (0.005mol, 0.8 mL), refluxing for 6h after finishing dripping, stopping reaction, cooling to room temperature, adding 300mL of ice water, stirring for 30min, performing suction filtration, washing a filter cake with water, and drying to obtain 8.76g of a light brown solid.
Step three: dissolving the intermediate b (0.02mol, 5.5 g) in 50mL of absolute ethanol, adding 85% hydrazine hydrate (0.06mol, 2.9 mL), reacting at room temperature for 4h, stopping the reaction, adding 150mL of ice water, stirring for 30min, carrying out suction filtration, washing a filter cake with water, and drying to obtain 4.9g of a white solid.
Step four: dissolving o-chloroacetophenone (0.005mol, 0.77g) in 15mL of absolute ethanol, sequentially adding the intermediate c (0.005mol, 1.4 g) and 98% glacial acetic acid (0.0002mol, 0.01mL), heating to 65 ℃ for reaction for 3h, stopping the reaction, adding 30mL of ice water, stirring for 30min, carrying out suction filtration, washing a filter cake with water, and drying to obtain 1.07g of a white solid. Melting point 204.3-206.3 ℃.
1 H NMR(300MHz,DMSO-d6)δ10.65(s,1H),9.74(s,1H),7.89(d,J＝6.9Hz,2H), 7.69(s,1H),7.46(s,1H),7.31(d,J＝7.5Hz,4H),7.04–6.94(m,1H),6.88(s,1H),2.40 (s,3H).
Example 2: preparation of Compound 7
Intermediate c was prepared as in example 1. The preparation method of the compound 7 comprises the following steps:
p-fluorobenzaldehyde (0.005mol, 0.69g) is dissolved in 15mL of absolute ethyl alcohol, the intermediate c (0.005mol, 1.4 g) and 98% glacial acetic acid (0.0002mol, 0.01mL) are sequentially added, the reaction is stopped after 3 hours of room temperature reaction, 30mL of ice water is added, the mixture is stirred for 30 minutes, the filtration is carried out, a filter cake is washed by water and dried, and 1.69g of light yellow solid is obtained. The melting point is 156.8-158.8 ℃.
1 H NMR(400MHz,DMSO-d 6 )δ11.62(s,1H),9.67(s,1H),8.18(s,1H),7.77(dd,J ＝8.5,5.7Hz,4H),7.32–7.18(m,4H),6.94(t,J＝7.3Hz,2H).
Example 3: preparation of Compound 79
The method comprises the following steps: dissolving 2, 4-dichloroguandine (0.05mol, 10.15g) in 100mL of absolute ethanol, adding ethyl trifluoroacetoacetate (0.05mol, 9.2g), refluxing for 5h, stopping the reaction, cooling to room temperature, adding 300mL of ice water, stirring for 30min, carrying out suction filtration, washing a filter cake with water, and drying to obtain 13.24g of off-white solid.
Step two: dissolving the intermediate a (0.03mol, 9.69g) in 100mL of acetonitrile, adding phosphorus oxychloride (0.15 mol, 14mL), slowly dropwise adding N, N-diisopropylethylamine (0.003mol, 0.5 mL), refluxing for 6h, stopping reaction, cooling to room temperature, adding 200mL of ice water, stirring for 30min, carrying out suction filtration, washing a filter cake with water, and drying to obtain 7.49g of a light brown solid.
Step three: dissolving the intermediate b (0.02mol, 6.82g) in 50mL of absolute ethanol, adding 85% hydrazine hydrate (0.06mol, 2.9 mL), reacting at room temperature for 4h, stopping the reaction, adding 150mL of ice water, stirring for 30min, performing suction filtration, washing a filter cake with water, and drying to obtain 6.02g of a white solid.
Step four: dissolving o-chloroacetophenone (0.005mol, 0.77g) in 15mL of absolute ethanol, sequentially adding the intermediate c (0.005mol, 1.69g) and 98% glacial acetic acid (0.0002mol, 0.01mL), heating to 65 ℃ for reaction for 3h, stopping the reaction, adding 30mL of ice water, stirring for 30min, carrying out suction filtration, washing a filter cake with water, and drying to obtain 1.48g of light yellow solid. Melting point 203.9-205.9 ℃.
1 H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.91(s,1H),7.82(d,J＝8.7Hz,1H), 7.62(d,J＝2.3Hz,1H),7.50–7.47(m,1H),7.44(dd,J＝4.6,2.4Hz,1H),7.41–7.35(m, 3H),6.82(s,1H),2.29(s,3H).
Example 4: preparation of Compound 115
The method comprises the following steps: phenylguanidine (0.1mol, 13.5 g) is dissolved in 100mL of absolute ethyl alcohol, ethyl acetoacetate (0.12mol, 15.6 g) is added, reflux reaction is carried out for 5h, the reaction is stopped, after cooling to room temperature, 300mL of ice water is added, stirring is carried out for 30min, suction filtration is carried out, a filter cake is washed by water and dried, and 14.86g of off-white solid is obtained.
Step two: dissolving the intermediate a (0.05mol, 10.05g) in 100mL acetonitrile, adding phosphorus oxychloride (0.25 mol, 23mL), slowly dropwise adding N, N-diisopropylethylamine (0.005mol, 0.8 mL), refluxing for 6h after finishing dripping, stopping reaction, cooling to room temperature, adding 300mL of ice water, stirring for 30min, performing suction filtration, washing a filter cake with water, and drying to obtain a light brown solid 7.39g.
Step three: dissolving the intermediate b (0.02mol, 4.38g) in 50mL of absolute ethyl alcohol, adding 85% hydrazine hydrate (0.06mol, 2.9 mL), reacting at room temperature for 4h, stopping the reaction, adding 150mL of ice water, stirring for 30min, performing suction filtration, washing a filter cake with water, and drying to obtain 3.82g of a white solid.
Step four: dissolving o-chloroacetophenone (0.005mol, 0.77g) in 15mL of absolute ethanol, sequentially adding the intermediate c (0.005mol, 1.08g) and 98% glacial acetic acid (0.0002mol, 0.01mL), heating to 65 ℃ for reaction for 3h, stopping the reaction, adding 30mL of ice water, stirring for 30min, carrying out suction filtration, washing a filter cake with water, and drying to obtain 0.24g of white-like solid. Melting point 141.4-143.4 ℃.
1 H NMR(400MHz,DMSO-d 6 )δ9.83(s,1H),9.09(s,1H),7.83(d,J＝7.7Hz,2H), 7.50–7.45(m,2H),7.39–7.36(m,2H),7.23–7.17(m,2H),6.85(t,J＝7.3Hz,1H), 6.39(s,1H),2.30(s,3H),2.19(s,3H).
Example 5: preparation of Compound 161
The method comprises the following steps: dissolving 2,3, 4-trifluoro-phenylguanidine carbonate (0.05mol, 11g) in 100mL of absolute ethanol, adding 2-oxocyclopentane-1-carboxylic acid ethyl ester (0.05mol, 7.8g), refluxing for 5h, stopping reaction, cooling to room temperature, adding 300mL of ice water, stirring for 30min, filtering, washing a filter cake with water, and drying to obtain 10.75g of off-white solid.
Step two: dissolving the intermediate a (0.03mol, 8.43g) in 100mL of acetonitrile, adding phosphorus oxychloride (0.15 mol, 14mL), slowly and dropwise adding N, N-diisopropylethylamine (0.003mol, 0.5 mL), after dropwise addition, carrying out reflux reaction for 6 hours, stopping the reaction, cooling to room temperature, adding 200mL of ice water, stirring for 30min, carrying out suction filtration, washing a filter cake with water, and drying to obtain 6.92g of light brown solid.
Step three: dissolving the intermediate b (0.02mol, 5.98g) in 50mL of absolute ethanol, adding 85% hydrazine hydrate (0.06mol, 2.9 mL), reacting at room temperature for 4h, stopping the reaction, adding 150mL of ice water, stirring for 30min, performing suction filtration, washing a filter cake with water, and drying to obtain 5.16g of an off-white solid.
Step four: p-fluorobenzaldehyde (0.005mol, 0.62g) is dissolved in 15mL of absolute ethanol, the intermediate c (0.005mol, 1.48g) and 98% glacial acetic acid (0.0002mol, 0.01mL) are sequentially added, the reaction is stopped at room temperature for 3h, 30mL of ice water is added, the mixture is stirred for 30min, the filtration is carried out, a filter cake is washed by water and dried, and 1.31g of white-like solid is obtained. Melting point 216.9-218.9 ℃.
1 H NMR(600MHz,DMSO-d6)δ10.98(s,1H),8.72(s,1H),8.09(s,1H),7.67(dd,J ＝8.4,5.7Hz,3H),7.26(dt,J＝23.8,9.1Hz,3H),3.09(s,2H),2.71(t,J＝7.8Hz,2H), 2.01(p,J＝7.7Hz,2H).
Example 6: preparation of Compound 167
Intermediate c was prepared as in example 1. Compound 167 was prepared as follows:
the method comprises the following steps: O-Chlorobenzoic acid (0.02mol, 3.2 g) was dissolved in 20mL of dichloromethane, sulfoxide chloride (0.04mol, 2.9mL) and N, N-dimethylformamide (0.0002 mol, 0.01mL) were sequentially added thereto, and the reaction was stopped after reacting for 2 hours at room temperature, followed by concentration under reduced pressure for use.
Step two: dissolving 2-chlorobenzoyl chloride (0.002mol, 0.35g) in 10mL of absolute ethyl alcohol, sequentially adding the intermediate c (0.002mol, 0.54g) and 98% glacial acetic acid (0.0002mol, 0.01mL), reacting at room temperature for 3h, stopping the reaction, adding 30mL of water and 3X 10mL of ethyl acetate for extraction, combining organic phases, and concentrating under reduced pressure to obtain oily liquid. Adopting petroleum ether: ethyl acetate =10, column chromatography purification, and concentration under reduced pressure gave 0.54g of a pale yellow solid. Melting point 213.3-215.3 ℃.
1 H NMR(400MHz,DMSO-d6)δ10.60(d,J＝31.8Hz,1H),9.86(s,1H),9.69(s, 1H),7.74(s,2H),7.59–7.36(m,4H),7.20(d,J＝22.2Hz,2H),6.94(t,J＝7.3Hz,1H), 6.44(d,J＝17.0Hz,1H).
Other compounds of the invention may be prepared by reference to the above examples.
The physical and nuclear magnetic data of some of the compounds are as follows:
compound 2: melting point 160.1-162.1 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ11.89(s,1H),9.73 (s,1H),8.60(s,1H),8.06(dd,J＝5.8,3.7Hz,1H),7.77(d,J＝8.0Hz,2H),7.51–7.46 (m,1H),7.40(dd,J＝5.9,3.5Hz,2H),7.29–7.22(m,2H),6.95(t,J＝7.3Hz,2H).
Compound 4: the melting point is 155.6-157.6 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ11.73(s,1H),9.73 (s,1H),8.21(s,1H),7.78(d,J＝8.4Hz,4H),7.52(d,J＝8.2Hz,2H),7.30(t,J＝7.9Hz, 2H),6.98(t,J＝7.3Hz,2H).
Compound 9: melting point 112.5-114.5 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ11.85(s,1H),9.76 (s,1H),8.30(s,1H),8.10(d,J＝7.7Hz,1H),8.05(s,1H),7.85–7.75(m,3H),7.70(t,J ＝7.6Hz,1H),7.30(t,J＝7.9Hz,2H),6.99(t,J＝7.3Hz,2H).
Compound 12: melting point 204.7-206.7 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ11.47(s,1H),9.90 (s,1H),9.66(s,1H),8.13(s,1H),7.80(d,J＝7.3Hz,2H),7.58(d,J＝8.4Hz,2H),7.32– 7.25(m,2H),6.97(t,J＝7.3Hz,1H),6.91(s,1H),6.85(d,J＝8.6Hz,2H).
Compound 17: melting Point 122.7-124.7 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ11.76(s,1H),9.75 (s,1H),8.24(s,1H),7.89(d,J＝8.8Hz,2H),7.80(d,J＝5.2Hz,2H),7.45(d,J＝8.2Hz, 2H),7.30(t,J＝7.9Hz,2H),6.99(t,J＝7.3Hz,2H).
Compound 19: melting point 125.8-127.8 ℃.1H NMR (300mhz, dmso-d 6) δ 10.65 (s, 1H), 9.74 (s, 1H), 7.89 (d, J =8.0hz, 2h), 7.68 (d, J =7.9hz, 1h), 7.46 (t, J =6.9hz, 1h), 7.30 (t, J =8.0hz, 4h), 6.98 (t, J =7.5hz, 1h), 6.88 (s, 1H).
Compound 20: melting point 141.5-143.5 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ11.54(s,1H),9.67 (s,1H),8.15(s,1H),7.80(d,J＝7.9Hz,2H),7.34(s,1H),7.32–7.27(m,2H),7.26– 7.22(m,1H),7.03(d,J＝8.4Hz,1H),7.01–6.91(m,2H),3.84(s,3H),3.81(s,3H).
Compound 31: melting point 123-125 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.65(s,1H),9.75(s, 1H),8.06–7.75(m,4H),7.55–7.45(m,2H),7.32(t,J＝7.9Hz,2H),7.03–6.86(m, 2H),2.40(s,3H).
Compound 32: melting point 139.7-141.7 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.62(s,1H),9.75 (s,1H),7.89(d,J＝7.0Hz,4H),7.51(d,J＝8.4Hz,2H),7.31(t,J＝7.8Hz,2H),7.03– 6.90(m,2H),2.40(s,3H).
Compound 33: melting point 121.6-123.6 deg.C. 1 H NMR(500MHz,DMSO-d 6 )δ10.66(s,1H),9.75 (s,1H),7.89(s,2H),7.49(s,1H),7.38–7.20(m,5H),7.02–6.95(m,1H),6.88(s,1H), 2.46–2.38(m,3H).
Compound 37: melting point 154-156 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.72(s,1H),9.77(s, 1H),8.21–8.10(m,2H),7.90(s,2H),7.78(d,J＝8.2Hz,1H),7.71(t,J＝7.8Hz,1H), 7.30(t,J＝7.9Hz,2H),7.01–6.92(m,2H),2.46(s,3H).
Compound 39: melting point 203.2-205.2 ℃. 1 H NMR(500MHz,DMSO-d 6 )δ10.80(s,1H),9.75 (s,1H),7.85(d,J＝7.8Hz,3H),7.62(d,J＝7.7Hz,1H),7.31(t,J＝7.9Hz,3H),6.96 (ddt,J＝22.0,15.2,7.2Hz,4H),2.47(s,3H).
Compound 41: the melting point is 137-139 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.42(s,1H),9.65(s, 1H),7.82(d,J＝7.9Hz,2H),7.32(d,J＝6.7Hz,1H),7.23(dd,J＝6.6,2.6Hz,5H),6.93 (t,J＝7.3Hz,1H),6.76(s,1H),2.34(d,J＝11.5Hz,6H).
Compound 42: melting point 176-178 ℃. 1 H NMR(300MHz,Chloroform-d)δ8.53(s,1H),7.60 –7.53(m,3H),7.45(dd,J＝8.5,5.4Hz,2H),7.32(t,J＝7.9Hz,3H),6.89–6.78(m,2H), 1.64(s,3H),1.26(s,3H).
Compound 46: melting point 134.4-136.4 ℃. 1 H NMR(300MHz,CDCl3)δ8.28(s,1H),7.63– 7.54(m,4H),7.38–7.30(m,2H),7.13(s,1H),7.10–7.03(m,3H),2.27(s,3H).
Compound 48: melting point 152.8-154.8 ℃. 1 H NMR(600MHz,DMSO-d6)δ10.52(s,1H),9.70 (s,1H),7.89(s,2H),7.46(s,1H),7.39(s,1H),7.30(t,J＝7.7Hz,2H),7.05–6.89(m, 3H),3.83(s,3H),3.81(s,3H),2.39(s,3H).
Compound 49: melting point 119.4-121.4 deg.C. 1 H NMR(400MHz,DMSO-d 6 )δ10.61(s,1H),9.70 (s,1H),7.83(d,J＝7.9Hz,2H),7.64(d,J＝2.0Hz,1H),7.52–7.43(m,2H),7.25(t,J＝ 7.7Hz,2H),6.93(t,J＝7.3Hz,1H),6.80(s,1H),2.33(s,3H).
Compound 50: melting Point 107.7-109.7 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ10.69(s,1H),9.75 (s,1H),7.88(d,J＝7.5Hz,2H),7.73(t,J＝8.2Hz,1H),7.53(dd,J＝11.2,2.0Hz,1H), 7.39(d,J＝8.3Hz,1H),7.30(t,J＝7.9Hz,2H),6.98(t,J＝7.3Hz,1H),6.88(s,1H), 2.38(s,3H).
Compound 79: melting point 136.3-138.3 ℃. 1 H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.91 (s,1H),7.82(d,J＝8.7Hz,1H),7.62(d,J＝2.3Hz,1H),7.50–7.47(m,1H),7.44(dd,J ＝4.6,2.4Hz,1H),7.41–7.35(m,3H),6.82(s,1H),2.29(s,3H).
Compound 81: melting point 154.3-156.3 ℃. 1 H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.91 (s,1H),7.84(d,J＝8.7Hz,1H),7.64–7.56(m,2H),7.40(td,J＝9.8,9.3,2.1Hz,2H), 7.27–7.20(m,2H),6.87(s,1H),2.30(d,J＝2.5Hz,3H).
Compound 162: melting point 172-174 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ11.12(s,1H),8.71 (s,1H),8.17(s,1H),8.05–7.84(m,2H),7.80–7.56(m,3H),7.33–7.18(m,1H),3.20– 2.96(m,2H),2.84–2.64(m,2H),2.09–1.96(m,2H).
Compound 163: melting point 217.2-219.2 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.61(s,1H),8.55 (s,1H),7.81–7.74(m,1H),7.48–7.41(m,2H),7.38–7.34(m,2H),7.21–7.15(m,1H), 2.90(t,J＝7.4Hz,2H),2.63(t,J＝7.8Hz,2H),2.26(s,3H),1.85(q,J＝7.7Hz,2H).
Other compounds shown in the general formula (I) can also be obtained according to the preparation method, and pharmaceutically acceptable salts of the compounds shown in the general formula (I) can also be obtained by reacting with corresponding salts.
Determination of antitumor Activity
Example 7: the in vitro test for tumor cell inhibition (MTT assay) was as follows:
the human cancer tumor cell line: human lung cancer A-549, human colon cancer HT-29, etc.
The inhibition rate of 2 concentrations of test samples on the growth of each human cancer cell is determined by a conventional MTT method by adopting an in vitro cell culture technology.
The cells were removed from the incubator, washed twice with PBS solution, digested with 0.25% trypsin solution, added with medium to stop digestion, centrifuged, pipetted to form a cell suspension, and counted under an inverted microscope. Cells were formulated at a concentration of 5x10 4 The method comprises the steps of adding 100 mu L of cells into each well of a 96-well plate, placing the 96-well plate in 5% carbon dioxide, culturing the 96-well plate in humidified air at 37 ℃ overnight, adding the compound obtained in the embodiment to be tested and diluted into two different concentration gradients of 20 mu g/mL and 2 mu g/mL, adding MTT after the compound is acted for 48 hours, reacting for 4 hours, reducing MTT tetrazolium (tetrazole) components by living cells to generate formazan (formazan), adding DMSO to dissolve the formazan, and measuring the light absorption values of 490nm and 630nm on a 96-well plate reader.
Cytostatic rate = (1-absorbance of experimental group/absorbance of control group) × 100%
Some of the test results are as follows:
TABLE 4 inhibition of growth of human lung carcinoma cells A-549 and human colon carcinoma cells HT-29 by compounds
Example 8: the in vitro assay for tumor cell inhibition (MTT assay) was as follows:
the human cancer tumor cell line: human lung cancer A-549, human colon cancer HT-29, human embryonic kidney cell HEK-293, human epidermal cancer cell A-431, human cervical cancer cell Hela, human prostate cancer cell PC-3, human ovarian cancer cell SK-OV-3, etc.
The inhibition rate of 5 concentrations of test samples on the growth of each human cancer cell was determined by the conventional MTT method using the in vitro cell culture technique.
The cells were removed from the incubator, washed twice with PBS, digested with 0.25% trypsin, added to the medium to stop digestion, centrifuged, pipetted to form a cell suspension, and counted under an inverted microscope. Cells were formulated at a concentration of 5x10 4 The cells are suspended in a 96-well plate, 100 mu L of cells are added into each well of the 96-well plate, the 96-well plate is placed in 5% carbon dioxide and incubated overnight at 37 ℃ in humidified air, the compounds obtained in the above-mentioned examples are added and diluted to five different concentration gradients of 40 mu g/mL, 8 mu g/mL, 1.6 mu g/mL, 0.32 mu g/mL and 0.064 mu g/mL, after 48h of reaction, MTT is added, after 4h of reaction, MTT tetrazolium (tetrazole) is reduced by living cells to produce formazan (formazan), then DMSO is added to dissolve formazan, and finally the absorbance at 490nm,630nm is measured on a 96-well plate reader.
Cytostatic rate = (1-absorbance of experimental group/absorbance of control group) × 100%
Then according to the inhibition rate of the 5 concentration test samples, calculating the IC by a GraphPad Prism6 software by a nonlinear regression method 50 The value is obtained.
Some of the test results are as follows:
TABLE 5 cytotoxic Activity of Compounds on human tumor cells
TABLE 6 cytotoxic Activity of Compounds on human tumor cells
As can be seen from the data in tables 4-6, the anilinopyrimidine compound has good anti-tumor activity, and particularly has excellent inhibitory activity on lung cancer A549 and colon cancer HT 29. Part of the compounds also have good inhibitory effect on epidermal cancer A-431, cervical cancer Hela, prostatic cancer PC-3 and ovarian cancer SK-OV-3.
In addition, the anilinopyrimidine compound also has good in-vivo anti-tumor activity, and the tumor inhibition rate of the compound 9 on colon cancer of nude mice reaches more than 30%.
The above-described embodiments of the present invention should not be construed as limiting the scope of the present invention. Any other corresponding changes and modifications made according to the technical idea of the present invention should be included in the protection scope of the claims of the present invention.
Claims (8)
1. An anilino pyrimidine compound is characterized in that: the compound is shown in a general formula (I-1),
in the formula (I), the compound is shown in the specification,
R 1 selected from halogens;
n is selected from 0 to 3;
R 2 selected from hydrogen;
R 3 is selected from trifluoromethyl;
R 4 selected from hydrogen;
R 5 selected from hydrogen;
R 8 selected from hydrogen, methyl, ethyl or trifluoromethyl;
R 9 selected from phenyl, pyridyl or thienyl, unsubstituted or substituted with 1 to 3Q groups;
further, when n is selected from 0, R 2 、R 4 、R 5 、R 8 Are all selected from hydrogen, R 3 When selected from methyl, R 9 Is not selected from 4-chlorophenyl;
q is selected from fluorine, chlorine, hydroxyl, nitro, methyl, methoxy, trifluoromethyl or trifluoromethoxy;
or salts of the compounds shown in the general formula (I-1).
2. The anilinopyrimidine compound according to claim 1, characterized in that: in the general formula (I-1),
R 1 selected from fluorine or chlorine;
n is selected from 0 to 3;
R 2 selected from hydrogen;
R 3 is selected from trifluoromethyl;
R 4 selected from hydrogen;
R 5 selected from hydrogen;
R 8 selected from hydrogen or methyl;
R 9 selected from phenyl unsubstituted or substituted by 1 to 3Q groups;
further, when n is selected from 0, R 2 、R 4 、R 5 、R 8 Are all selected from hydrogen, R 3 When selected from methyl, R 9 Is not selected from 4-chlorophenyl;
q is selected from fluorine, chlorine, hydroxyl, nitro, methyl, methoxy, trifluoromethyl or trifluoromethoxy;
or a salt of the compound shown in the general formula (I-1).
3. The compound of claim 1 or 2, wherein: the salt of the compound of the general formula I-1 is at least one of hydrochloride, sulfate, nitrate, bicarbonate, carbonate, phosphate, formate, acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate, citrate, malate, tartrate, maleate, succinate, ascorbate or oxalate.
4. Use of a compound according to claim 1, wherein: the application of the compound shown in the general formula (I-1) in preparing medicines for treating cell proliferation diseases.
5. Use of a compound according to claim 4, wherein: the cell proliferation diseases are selected from cancer, infection, inflammation or autoimmune diseases.
6. Use of a compound according to claim 5, characterized in that: the cancer is selected from colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, skin cancer, ovarian cancer, cervical cancer, renal cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal carcinoma or gastric cancer.
7. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or 2, together with one or more pharmaceutically acceptable carriers or excipients.
8. The pharmaceutical composition according to claim 7, for use in the preparation of a medicament for the treatment of a cell proliferative disorder.
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