CN102532118B - Indolone-containing 4-thiazolidone derivatives and application thereof - Google Patents
Indolone-containing 4-thiazolidone derivatives and application thereof Download PDFInfo
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- CN102532118B CN102532118B CN201010604437.8A CN201010604437A CN102532118B CN 102532118 B CN102532118 B CN 102532118B CN 201010604437 A CN201010604437 A CN 201010604437A CN 102532118 B CN102532118 B CN 102532118B
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- indolone
- thiazolidone
- subunit
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- dimethylamino
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Abstract
The invention relates to indolone-containing 4-thiazolidone derivatives shown in a general formula I as well as geometrical isomers and pharmaceutically acceptable salts of the indolone-containing 4-thiazolidone derivatives. In the formula I, substituted groups namely Ar, R2, R3, R4 and n are defined in the specification. The invention also relates to application of compounds of the general formula I in preparation of a medicine for treating and/or preventing cancer.
Description
Technical field
The invention belongs to medical technical field, relate to new the 4-Thiazolidinone and the pharmacy acceptable salt thereof that contain indolone, comprise their preparation method and the pharmaceutical composition that contains described compound.The invention still further relates to this derivative for the preparation of the purposes treating and/or preventing in the medicine of cancer.
Background technology
The compound that contains 4-thiazolidone structure has biologic activity widely, as antibacterial, antimycotic, antiviral, anti-inflammatory, hypoglycemic, cardiac stimulant and antitumor action etc.The people such as J.K.Choi have reported to have the inhibiting 5-substituted-phenyl of PRL-3 methyne Rhodanine derivates, the Compound I C that this series compound external activity is best
50be 0.9 μ M.The people such as N.S.Cutshall have reported class N-substituted-phenyl-5-substituted-phenyl methyne Rhodanine derivates, and this compounds has restraining effect to JSP-1, the Compound I C that this compounds external activity is best
50be 1.3 μ M.The people such as A.Geronikaki have reported that thiazole-2-imido grpup, benzo [d] thiazole-2-imido grpup and benzo [d] isothiazole-2-imido grpup are introduced to 2 of 4-thiazolidone has obtained a series of compounds, and this compounds has stronger restraining effect to SHP-2.
The 4-Thiazolidinone that contains indolone belongs to the compound that a class is new, there is no this compound and related activity report thereof in prior art.
summary of the invention:
The present invention relates to derivative, its geometrical isomer and the pharmacy acceptable salt thereof of formula I,
Wherein,
Ar is phenyl, quinolyl, isoquinolyl, naphthyl, 5-6 unit's heteroaryl and 5-6 unit is saturated or the heterocyclic radical of fractional saturation, and described heteroaryl and heterocyclic radical contain 1-3 heteroatoms that is selected from O, N and S, and the optional 1-4 of Ar identical or different R
1replace;
R
1for hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyano group, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, N-(C
1-C
4) alkylamino, N, N-bis-(C
1-C
4) alkylamino, (C
1-C
4) alkyl sulfenyl, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkoxyethyl, (C
1-C
4) alkyl acyl, formamyl, N-(C
1-C
4) alkyl-carbamoyl, N, N-bis-(C
1-C
4) alkyl-carbamoyl, (C
1-C
3) alkylenedioxy group;
R
2optional 1-3 following substituting group is hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyano group, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, N-(C
1-C
4) alkylamino, N, N-bis-(C
1-C
4) alkylamino, (C
1-C
4) alkyl sulfenyl, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkoxyethyl, (C
1-C
4) alkyl acyl, formamyl, N-(C
1-C
4) alkyl-carbamoyl, N, N-bis-(C
1-C
4) alkyl-carbamoyl, (C
1-C
3) alkylenedioxy group;
R
3and R
4identical or different, respectively independently selected from hydrogen, C
1-C
10alkyl, C
3-C
7cycloalkyl, C
2-C
10thiazolinyl and C
2-C
10alkynyl, or R
3and R
4form 5-10 unit heterocyclic radical together with the nitrogen-atoms being connected with them, described heterocyclic radical except with R
3and R
4outside the nitrogen-atoms connecting, contain 1-4 heteroatoms that is selected from N, O and S, except R
3and R
4outside the nitrogen-atoms connecting, described heterocyclic radical optionally comprises 1 or 2 carbon-carbon double bond or three key;
N is the integer between 1-4.
The derivative of the preferred formula I of the present invention, its geometrical isomer and pharmacy acceptable salt thereof, wherein,
Ar is phenyl, 5-6 unit heteroaryl, and described heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and the optional 1-4 of Ar identical or different R
1replace;
R
1for hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyano group, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, N-(C
1-C
4) alkylamino, N, N-bis-(C
1-C
4) alkylamino, (C
1-C
4) alkyl sulfenyl, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkoxyethyl, (C
1-C
4) alkyl acyl, formamyl, N-(C
1-C
4) alkyl-carbamoyl, N, N-bis-(C
1-C
4) alkyl-carbamoyl, (C
1-C
3) alkylenedioxy group;
R
2optional 1-3 following substituting group is hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyano group, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, N-(C
1-C
4) alkylamino, N, N-bis-(C
1-C
4) alkylamino, (C
1-C
4) alkyl sulfenyl, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkoxyethyl, (C
1-C
4) alkyl acyl, formamyl, N-(C
1-C
4) alkyl-carbamoyl, N, N-bis-(C
1-C
4) alkyl-carbamoyl, (C
1-C
3) alkylenedioxy group;
R
3and R
4identical or different, respectively independently selected from hydrogen, C
1-C
10alkyl, C
3-C
7cycloalkyl, C
2-C
10thiazolinyl and C
2-C
10alkynyl, or R
3and R
4form 5-10 unit heterocyclic radical together with the nitrogen-atoms being connected with them, described heterocyclic radical except with R
3and R
4outside the nitrogen-atoms connecting, contain 1-4 heteroatoms that is selected from N, O and S, except R
3and R
4outside the nitrogen-atoms connecting, described heterocyclic radical optionally comprises 1 or 2 carbon-carbon double bond or three key;
N is the integer between 1-4.
The present invention is derivative, its geometrical isomer and the pharmacy acceptable salt thereof of following formula I very preferably, wherein,
Ar is phenyl, and the optional 1-4 of Ar identical or different R
1replace;
R
1for hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyano group, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, N-(C
1-C
4) alkylamino, N, N-bis-(C
1-C
4) alkylamino, (C
1-C
4) alkyl sulfenyl, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkoxyethyl, (C
1-C
4) alkyl acyl, formamyl, N-(C
1-C
4) alkyl-carbamoyl, N, N-bis-(C
1-C
4) alkyl-carbamoyl, (C
1-C
3) alkylenedioxy group;
R
2optional 1-3 following substituting group is hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyano group, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, N-(C
1-C
4) alkylamino, N, N-bis-(C
1-C
4) alkylamino, (C
1-C
4) alkyl sulfenyl, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkoxyethyl, (C
1-C
4) alkyl acyl, formamyl, N-(C
1-C
4) alkyl-carbamoyl, N, N-bis-(C
1-C
4) alkyl-carbamoyl, (C
1-C
3) alkylenedioxy group; R
2be particularly preferably hydrogen, halogen; Be very particularly preferably hydrogen, fluorine and chlorine atom;
R
3and R
4identical or different, respectively independently selected from hydrogen, C
1-C
4alkyl, or R
3and R
4form piperidyl, Pyrrolidine base, piperazinyl, 4-methylpiperazine base, morpholinyl and thio-morpholinyl together with the nitrogen-atoms being connected with them.R
3and R
4be particularly preferably dimethylamino, diethylin, Pyrrolidine base, piperazinyl, 4-methylpiperazine base, morpholinyl with the nitrogen-atoms being connected with them;
N is the integer between 1-4.
Derivative, its geometrical isomer and the pharmacy acceptable salt thereof of the also preferred following formula I of the present invention, wherein,
Ar is phenyl, and the optional 1-4 of Ar identical or different R
1replace;
R
1for hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyano group, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, N-(C
1-C
4) alkylamino, N, N-bis-(C
1-C
4) alkylamino, (C
1-C
4) alkyl sulfenyl, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkoxyethyl, (C
1-C
4) alkyl acyl, formamyl, N-(C
1-C
4) alkyl-carbamoyl, N, N-bis-(C
1-C
4) alkyl-carbamoyl, (C
1-C
3) alkylenedioxy group;
R
2for hydrogen, halogen; Preferred R
2for hydrogen, chlorine, fluorine;
R
3and R
4form dimethylamino, diethylin, Pyrrolidine base, piperazinyl, 4-methyl isophthalic acid-piperazinyl, morpholinyl together with the nitrogen-atoms being connected with them;
N is the integer between 1-4.
The present invention is particularly preferably derivative, its geometrical isomer and the pharmacy acceptable salt thereof of the following formula I of structural formula:
3-{5-phenyl methyne-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(2-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(3,4-difluorophenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(3,4-difluorophenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-(3,4-difluorophenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-(3,4-difluorophenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the bromo-2-indolone of-5-;
3-{5-(2,4 difluorobenzene base methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-(2,4 difluorobenzene base methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(2,4 difluorobenzene base methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the bromo-2-indolone of-5-;
3-{5-(2-hydroxy phenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-(2-hydroxy phenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the bromo-2-indolone of-5-;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the bromo-2-indolone of-5-;
3-{5-(2-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-2-indolone;
3-{5-(2-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-;
3-{5-(3,4-difluorophenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-2-indolone;
3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-;
3-{5-(3,4-difluorophenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-(2,4 difluorobenzene base methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-(2,4 difluorobenzene base methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-2-indolone;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-;
3-{5-(2,4 difluorobenzene base methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the bromo-2-indolone of-5-;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-2-indolone;
3-{5-(2,5-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-2-indolone;
3-{5-(2,5-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-(4-hydroxy phenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-;
3-{5-(2-hydroxy phenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-(4-p-methoxy-phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-phenyl methyne-3-[2-(dimethylamino) butyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-phenyl methyne-3-[2-(diethylamino) butyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) butyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-phenyl methyne-3-[3-(1-Pyrrolidine base) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-phenyl methyne-3-[3-(piperidino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-phenyl methyne-3-[3-(1-morpholinyl) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
Derivative of the present invention can exist with geometrical isomer form, and these rotamerism forms can be that in formula I, two keys are configured as 2Z, 5Z, 2Z, 5E, 2E, 5E and 2E, 5Z.The present invention had both related to the derivative of single configuration, also related to their mixtures separately.
In addition, the present invention also comprises the prodrug of derivative of the present invention.According to the present invention, prodrug is general formula
iderivative, they self may have weak active or even there is no activity, but after administration, under physiological condition, (for example, by metabolism, solvolysis or other mode) is converted to corresponding biologically active form.
Unless otherwise noted, term used herein " halogen " refers to fluorine, chlorine, bromine or iodine atom; " alkyl " refers to the alkyl of straight or branched; " alkylidene group " refers to the alkylidene group of straight or branched; " cycloalkyl " refers to and replaces or unsubstituted cycloalkyl; Heteroaryl comprises the heteroatoms that contains one or more O of being selected from, N and S, can be monocycle or many rings, ring-type system is aromaticity, can enumerate for example imidazolyl, pyridyl, pyrimidyl, (1,2,3)-and (1,2,4)-triazolyl, pyrazinyl, tetrazyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrryl, thiazolyl, benzimidazolyl-, pyridine-imidazole base, benzothienyl, benzothiazolyl, indyl, quinolyl, Pyridopyrimidine base etc.
The present invention includes pharmaceutical composition, said composition contains general formula
i4-thiazolidone compounds, its geometrical isomer and pharmacy acceptable salt thereof as activeconstituents, and pharmaceutically acceptable excipient.Described pharmaceutically acceptable excipient refers to any thinner, auxiliary and/or carrier that can be used for pharmaceutical field.Derivative of the present invention can be used in combination with other activeconstituentss, for example, as long as they do not produce other disadvantageous effect, anaphylaxis.
Pharmaceutical composition of the present invention can be mixed with several formulation, wherein contains some vehicle conventional in pharmaceutical field; For example, oral preparations (as tablet, capsule, solution or suspension); Injectable preparation (as injectable solution or suspension, or injectable dried powder, before injection, add water for injection to use immediately); Topical formulations (for example ointment or solution).
Carrier for pharmaceutical composition of the present invention is the available common type of pharmaceutical field, comprising: the tackiness agent that oral preparations is used, lubricant, disintegrating agent, solubility promoter, thinner, stablizer, suspension agent, non-pigment, correctives etc.; The sanitas that injectable formulation is used, solubilizing agent, stablizer etc.; The matrix that topical formulations is used, thinner, lubricant, sanitas etc.Pharmaceutical preparation can oral administration or parenteral mode (for example intravenously, subcutaneous, intraperitoneal or part) administration, if some drugs is unsettled under stomach condition, can be mixed with enteric coated tablets.
We have found that the compounds of this invention is external and have had a growth inhibitory activity to tumor cell, and therefore, it can treat and/or prevent as preparation the medicine of cancer.Especially treat the cancer of mammary gland, lung, colon, rectum, stomach, prostate gland, bladder, pancreas and ovary.The compounds of this invention is also supposed to be used for the treatment of other diseases as diabetes, fungi infestation, bacterium infection, virus infection, chronic inflammatory diseases etc.Expect that in addition 4-thiazolidone compounds of the present invention will have leukemia, malignant lymphoma and solid tumor as organized as the activity of the cancer in liver, kidney, prostate gland and pancreas and sarcoma scope.
Derivative according to the present invention can be used as activeconstituents for the preparation for the treatment of and/or preventing various cancers, the present invention also provides treatment or prevents the method for above-mentioned disease, comprise suffer from or easily suffer from this sick patient significant quantity according to derivative of the present invention.General formula
i4-thiazolidone compounds for patient's clinical dosage must rely on the main body that is treated, administration concrete ways, be treated the seriousness of disease and change, and optimal dose is definite by the doctor who treats concrete patient.
Active compound of the present invention can be used as unique cancer therapy drug and uses, or can combine use with one or more other antitumor drugs.Combination therapy realizes by each being treated to component while, order or separating administration.
Synthetic route A has described general formula of the present invention below
ithe preparation of compound, prepared by the method that all raw materials are all methods by describing in these schematic diagram, know by organic chemistry filed those of ordinary skill or commercially available.All final compounds of the present invention are all the methods by describing in these schematic diagram or prepare by similar method, and these methods are that organic chemistry filed those of ordinary skill is known.Whole variable factors of applying in these schematic diagram are as definition below or as the definition in claim.
According to general formula of the present invention
icompound, at general formula
iin the syntheti c route of compound, wherein substituent A r, R
1, R
2there is with n the implication providing in specification sheets
the syntheti c route of generalformulaⅰcompound
Compound 1 and dithiocarbonic anhydride reacting generating compound 2, compound 2 generates compound 3 with chloroacetate reaction, under sulphuric acid catalysis, there is ring-closure reaction and generate compound 4 in compound 3, there is Knoevenagel condensation reaction with substituted benzaldehyde and generate compound 5 in compound 4, compound 5 generates compound 6 with triethyl orthoformate generation ethylation reaction under boron trifluoride diethyl etherate effect, and compound 6 with compound 7, condensation occurs and generates derivative shown in formula I.
In above-mentioned route, raw material
1,7the method preparation that can know by organic chemistry filed those of ordinary skill or commercially available.
Compound of the present invention carries out antitumor activity screening through external to various tumor cell strains, and result shows that it has anti-tumor activity.
embodiment:
Embodiment is intended to set forth rather than limit the scope of the invention.In the present invention, the proton nmr spectra of prepared compound is measured with Bruker ARX-300, and mass spectrum is measured with Agilent 1100 LC/MSD; Agents useful for same is analytical pure or chemical pure.
the structural formula of table 1. embodiment 1-50
| Embodiment | Structural formula | Embodiment | Structural formula |
| 1 | 2 |
 |
|
| 3 |
 |
4 |
 |
| 5 |
 |
6 |
 |
| 7 |
 |
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embodiment 1:
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } preparation of the fluoro-2-indolone of-5-
the preparation of 2-sulfo--3-(dimethyl aminoethyl)-4-thiazolidone
By 8.8g (0.1mol) N, N-dimethyl-ethylenediamine adds in 200mL anhydrous diethyl ether, then drip ether (50mL) solution of dithiocarbonic anhydride 7.6g (0.1mol), drip Bi Jixu and stir 30min, suction filtration, ether washing, after dry, solid is added to reactor, add successively 200mL water, 50mL methyl alcohol.In this suspension, drip the salt of wormwood Mono Chloro Acetic Acid aqueous solution (the salt of wormwood 6.9g (0.05mol) preparing in advance, Mono Chloro Acetic Acid 9.4g (0.1mol), water 40mL), drip and finish, 30 ℃ of reaction 7-8h, filtering insolubles then drips vitriol oil 11mL in reaction solution, drip and finish, 30 ℃ of reaction 10h.React complete by reaction solution evaporate to dryness, to ethanol 100 ml in residual solution, temperature rising reflux 30min, suction filtration while hot,, by filtrate evaporate to dryness, obtain 2-sulfo--3-(dimethyl aminoethyl)-4-thiazolidone 11.0 g, yield 54%.
the preparation of sulfo--3-(dimethyl aminoethyl)-5-(3,4,5-trimethoxyphenyl methyne)-4-thiazolidone
2-sulfo--3-(dimethyl aminoethyl)-4-thiazolidone 2.04g (0.01mol) is added to 15mL ethanol, then add successively 3,4,5-TMB 1.96 (0.01mol), piperidines 0.85g (0.01mol), is warming up to 80 ℃ of reaction 2h, reaction is finished, cooling, separate out solid, suction filtration, the a small amount of washing with alcohol of filter cake, dry, obtain yellow solid 2.0g, yield 52%.
the preparation of ethylmercapto group-3-(dimethyl aminoethyl)-5-(3,4,5-trimethoxyphenyl methyne)-4-thiazoline a tetrafluoro borate
By 2-sulfo--3-(dimethyl aminoethyl)-5-3,4,5-trimethoxyphenyl methyne)-4-thiazolidone 1.67g (0.0044mol) adds 40mL dioxane, then add successively ethyl orthoformate 4.38mL, boron trifluoride ether solution 6.57mL, 80 ℃ of reaction 2h, reaction is finished, cooling, suction filtration, a small amount of dioxane of filter cake, ether washing, dry, obtain yellow solid 1.75g, receive filter 80%.
trimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } preparation of the fluoro-2-indolone of-5-
Under ice bath by 2-ethylmercapto group-3-(dimethyl aminoethyl)-5-(3,4,5-trimethoxyphenyl methyne)-4-thiazoline a tetrafluoro borate 0.61g (1.23mmol) and fluoro-2-indolone 0.19 g of 5-(1.23mmol) add in 4mL acetonitrile successively, drip 0.28mL triethylamine, continue reaction 4h under ice bath, reaction is finished, suction filtration, filter cake is used a small amount of methyl alcohol successively, a small amount of ether washing, obtain solid 0.12g, yield 20%.
MS (ESI) m/z:500.6 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.06(s ,6H), 2.10(s, 6H), 2.41-2.49(m, 4H), 3.76(s ,6H), 3.87(s ,6H), 3.90(s ,6H), 4.33(t, 2H), 4.88(t, 2H), 6.83-7.03(m, 4H), 7.05(s, 2H), 7.07(s, 2H), 7.41 (d, 1H, J=10.5Hz),7.50 (d, 1H, J=9.9Hz), 7.69(s, 1H), 7.83 (s, 1H), 10.68 (s, 1H), 10.79(s, 1H)。
According to the method for embodiment 1, select the known raw material of those skilled in the art and reagent, make respectively the compound of embodiment 2-49.When mentioning specific reaction raw materials, it should be understood that be proficient in that the technician in this field can be according to embodiment need to select suitable raw material and reagent.
embodiment 2:3-{5-(4-p-methoxy-phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-
MS (ESI) m/z: 440.1(M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.01(s , 6H), 2.12(s, 6H), 2.41-2.44(t, 2H), 2.48(t, 2H), 3.84(s, 3H), 3.85(s, 3H), 4.33-4.35(t, 2H), 4.83-4.85(t, 2H), 6.69-6.71 (m, 1H), 6.72-6.74(m, 1H), 6.78-6.82(m, 1H), 6.84-6.88(m, 1H), 7.14-7.16(m, 4H), 7.51-7.53(m, 1H) , 7.65-7.67(d, 2H,
J= 6 Hz), 7.69(s, 1H), 7.72-7.74(d, 2H,
J= 6 Hz) , 7.77-7.80(m, 1H), 7.81(s, 1H), 10.79 (s, 1H), 11.00(s, 1H)。
embodiment 3:3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-methyl-2-indolone
MS (ESI) m/z: 422.5 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.04(s , 6H), 2.17 (s, 6H), 2.32 (s, 3H), 2.40-2.46(m, 7H), 4.37 (t, 2H), 4.86 (t, 2H), 6.82-7.78 (m, 16H), 10.35 (s, 2H) 10.55 (s, 1H), 10.75(s, 1H)。
embodiment 4:3-{5-(3,4-difluorophenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-
MS (ESI) m/z:446.4 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.05(s ,6H), 2.08(s, 6H), 2.39-2.49(m, 4H), 4.33(t, 2H), 4.86(t, 2H), 6.83-6.91(m, 2H), 7.01-7.07(m, 2H), 7.42-7.94 (m, 10H ), 10.71 (s, 1H), 10.92(s, 1H)。
embodiment 5:3-{5-(3,4-difluorophenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-methyl-2-indolone
MS (ESI) m/z:442.5 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.05(s ,6H), 2.08(s, 6H), 2.28-2.47(m, 10H), 4.36(t, 2H), 4.86(t, 2H), 6.67-7.90(m, 14H), 10.58 (s, 1H), 10.79(s, 1H)。
embodiment 6:3-{5-(3,4-difluorophenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-
MS (ESI) m/z:446.5 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.01(s ,6H), 2.07(s, 6H), 2.43(t, 4H), 4.35(t, 2H), 4.84(t, 2H), 6.69-6.87(m, 4H), 7.55-7.86(m, 10H ), 10.85 (s, 1H), 11.07(s, 1H)。
embodiment 7:3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-2-indolone
MS (ESI) m/z: 408.5 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 1.98(s , 6H ,2×CH
3), 2.07 (s, 6H, 2×CH
3), 2.41-2.49(m, 4H, 2×CH
2), 4.36 (t, 2H, CH
2), 4.87 (t, 2H, CH
2), 6.98-7.76 (m, 18H, 2×CH and arom), 10.36 (s, 2H, 2×OH) 10.65 (s, 1H, NH), 10.85(s, 1H, NH)。
embodiment 8:3-{5-(2,4 difluorobenzene base methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-
MS (ESI) m/z:446.5 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.02(s ,6H ,2×CH
3), 2.08(s, 6H, 2×CH
3), 2.39-2.48(m, 4H, 2×CH
2), 4.34(t, 2H, CH
2), 4.83(t, 2H, CH
2), 6.69-6.88(m, 4H, arom), 7.34-7.88(m, 10H, arom and 2×CH ), 10.86 (s, 1H, NH), 11.07(s, 1H, NH)。
embodiment 9:3-{5-(2-hydroxy phenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-2-indolone
MS (ESI) m/z: 450.5 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 1.07(t, 6H), 1.18(t, 6H), 2.00 (t, 2H), 2.14(t, 2H), 2.90-3.20 (m, 12H), 4.35 (t, 2H), 4.52 (t, 2H), 6.89-7.85 (m, 16H), 8.20(s, 1H), 8.23(s, 1H), 9.00(s, 2H) 10.66 (s, 1H), 10.89(s, 1H)。
embodiment 10:3-{5-(4-hydroxy phenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-
MS (ESI) m/z: 485.0 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 1.09(t, 6H), 1.18(t, 6H), 2.03 (t, 2H), 2.15(t, 2H), 2.95-3.20 (m, 12H), 4.30 (t, 2H), 4.47 (t, 2H), 6.86-7.76 (m, 14H), 8.19(s, 1H), 8.26(s, 1H), 8.99(s, 2H) 10.77 (s, 1H), 11.01(s, 1H)。
embodiment 11:3-{5-(2-hydroxy phenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-methyl-2-indolone
MS (ESI) m/z:464.6 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ:1.07 (t, 6H), 1.18 (t, 6H), 2.00 (b, 2H),2.14(b, 2H), 2.35(s, 3H), 2.36(s, 3H), 2.90 -3.19 (m, 12H), 4.37(t, 2H), 4.52(t, 2H), 6.76 (d, 1H, J=3.9Hz), 6.82 (d, 1H, J=3.9Hz), 6.89-6.93(m, 2H) 6.95(d, 1H, J=6Hz), 7.01 (d, 1H, J=3Hz), 7.13-7.17(m, 2H), 7.25-7.30(m, 3H), 7.49-7.51 (m, 2H), 7.67 (s, 1H), 8.12(s, 1H), 8.23(s, 1H), 9.00(b, 2H), 10.51 (s, 1H), 10.75 (s, 1H)。
embodiment 12:3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-methyl-2-indolone
MS (ESI) m/z:450.5 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.05(s ,6H), 2.06(s ,6H), 2.32-2.46(m, 10H), 4.36(t, 2H), 4.86(t, 2H), 6.15(s, 2H), 6.16(s, 2H), 6.76 -6.82 (m, 2H), 6.96 -7.01 (m, 2H), 7.14-7.37(m, 7H), 7.55 (s, 1H), 7.74(s, 1H), 7.78(s, 1H) , 10.54 (s, 1H), 10.74(s, 1H)。
embodiment 13:3-{5-(2-hydroxy phenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the bromo-2-indolone of-5-
MS (ESI) m/z:528.1(M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ:1.08 (t, 6H), 1.18 (t, 6H), 1.93-2.21 (m, 4H), 2.85 -3.24 (m, 12H), 4.29(t, 2H), 4.48(t, 2H), 6.82-6.94 (m, 4H), 7.09-7.20 (m, 2H), 7.25-7.36(m, 4H), 7.46-7.52(m, 3H), 7.86 (s, 1H), 8.19(s, 1H), 8.25(s, 1H), 8.99(s, 2H), 10.77 (s, 1H), 11.01 (s, 1H)。
embodiment 14:3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-
MS (ESI) m/z:454.4 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.02(s ,12H), 2.39-2.48(m, 4H), 4.35(t, 2H), 4.84(t, 2H),6.16(s, 4H) 6.72 -6.84 (m, 4H), 7.15-7.33 (m, 6H), 7.51-7.56 (m, 2H), 7.68(s, 1H), 7.79(s, 1H) , 10.81 (s, 1H), 11.03(s, 1H)。
embodiment 15:3-{5-(2,5-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-
MS (ESI) m/z: 470.6 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.00(s , 6H), 2.09(s, 6H), 2.34 -2.49(m, 4H), 3.79(s, 6H), 3.85(s, 6H) 4.33 (t, 2H), 4.83(t, 2H), 6.74 -7.66 (m, 12H), 7.90(s, 1H), 7.96(s, 1H)10.82 (s, 1H), 11.00 (s, 1H)。
embodiment 16:3-{5-(2,5-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-2-indolone
MS (ESI) m/z: 452.1 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.07(s ,12H) ,2.34 -2.49(m, 4H), 3.80 (s, 3H), 3.81 (s, 3H), 3.87(s, 3H), 3.89(s, 3H), 4.40 (t, 2H), 4.87(t, 2H), 6.88 -7.72 (m, 14H), 7.91(s, 1H), 7.98(s, 1H), 10.70 (s, 1H), 10.85(s, 1H)。
embodiment 17:3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-2-indolone
MS (ESI) m/z:478.5(M+H)
+;
1H NMR (300 MHz, DMSO-
d6)0.75(t, 6H),0.85 (t, 6H), 1.67-1.78 (m, 4H), 2.19 -2.42 (m, 12H), 4.32(t, 2H), 4.66(t, 2H), 6.15(s, 2H), 6.16(s, 2H), 6.86-6.93 (m, 2H), 6.97-7.09 (m, 2H), 7.14-7.35 (m, 8H), 7.47(d, 1H, J=6.0Hz), 7.68(s, 1H), 7.78(s, 1H), 7.80(d, 1H, J=6.0Hz), 10.63 (s, 1H), 10.84 (s, 1H)。
embodiment 18:3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-2-indolone
MS (ESI) m/z:436.2 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.02(s , 6H), 2.10(s, 6H), 2.41 -2.49(m, 4H), 4.37 (t, 2H), 4.87(t, 2H), 6.15(s, 4H), 6.88 -7.79 (m, 16H), 10.66 (s, 1H), 10.87 (s, 1H)。
embodiment 19:3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-methyl-2-indolone
MS (ESI) m/z:492.2(M+H)
+;
1H NMR (300 MHz, DMSO-
d6)0.77(t, 6H),0.85 (t, 6H), 1.68-1.77 (m, 4H), 2.22 -2.42 (m, 18H), 4.32(t, 2H), 4.65(t, 2H), 6.15(s, 2H), 6.16(s, 2H), 6.75-7.55 (m, 12H), 7.67(s, 1H), 7.77(s, 1H), 10.51 (s, 1H), 10.73 (s, 1H)。
embodiment 20:3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-
MS (ESI) m/z:496.6(M+H)
+;
1H NMR (300 MHz, DMSO-
d6)0.76(t, 6H), 0.87 (t, 6H), 1.73-1.75 (m, 4H), 2.19 -2.46 (m, 12H), 4.29(t, 2H), 4.64(t, 2H), 6.15(s, 2H), 6.16(s, 2H), 6.83-6.90 (m, 2H), 6.97-7.03(m, 2H) 7.15-7.17(m, 2H), 7.25-7.60(m, 6H), 7.70(s, 1H), 7.80(s, 1H), 10.62 (s, 1H), 10.85 (s, 1H)。
embodiment 21:3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-
MS (ESI) m/z:496.6(M+H)
+;
1H NMR (300 MHz, DMSO-
d6)1.08 (t, 6H), 1.19 (t, 6H), 1.93-2.18 (m, 4H), 2.88 -3.23 (m, 12H), 4.31(t, 2H), 4.47(t, 2H), 6.17(s, 2H), 6.18(s, 2H), 6.69-7.87(m, 14H), 10.85 (s, 1H), 11.09 (s, 1H)。
embodiment 22:3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-
MS (ESI) m/z:512.1(M+H)
+;
1H NMR (300 MHz, DMSO-
d6)0.78 (t, 6H),0.85 (t, 6H), 1.69-1.82 (m, 4H), 2.20 -2.42 (m, 12H), 4.27(t, 2H), 4.62(t, 2H), 6.16(s, 2H), 6.17(s, 2H), 6.85(d, 1H, J=8.4Hz), 6.89(d, 1H, J=8.1Hz) 7.14-7.34(m, 8H), 7.42(d, 1H, J=1.5Hz), 7.68(d, 1H, J=1.8Hz), 7.70(s, 1H), 7.82(s, 1H), 10.75 (s, 1H), 10.97 (s, 1H)。
embodiment 23:3-{5-(3,4-difluorophenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-
MS (ESI) m/z:488.1(M+H)
+;
1H NMR (300 MHz, DMSO-
d6)1.04 (t, 6H),1.18 (t, 6H), 1.90-2.21 (m, 4H), 2.80 -3.24 (m, 12H), 4.31(t, 2H), 4.48(t, 2H), 6.85-7.98(m, 14H), 10.75 (s, 1H), 10.97 (s, 1H)。
embodiment 24:3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-2-indolone
MS (ESI) m/z:452.2 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.05(s , 6H), 2.07 (s, 6H), 2.41-2.47(t, 4H), 3.80 (s, 3H), 3.81 (s, 3H), 3.87(s, 3H), 3.89 (s, 3H), 4.35(t, 2H), 4.84(t, 2H), 6.72 -7.56 (m, 12H), 7.91(s, 1H), 7.98(s, 1H) , 10.81 (s, 1H), 11.00(s, 1H)。
embodiment 25:3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-
MS (ESI) m/z:470.1 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.01(s , 6H), 2.09 (s, 6H), 2.38-2.47(t, 4H), 3.80 (s, 3H), 3.81 (s, 3H), 3.87(s, 3H), 3.89 (s, 3H), 4.35(t, 2H), 4.84(t, 2H), 6.72 -7.56 (m, 12H), 7.91(s, 1H), 7.98(s, 1H) , 10.81 (s, 1H), 11.00(s, 1H)。
embodiment 26:3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-
MS (ESI) m/z:470.1 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.09(s , 6H), 2.13 (s, 6H), 2.50(t, 4H), 3.80 (s, 3H), 3.85 (s, 3H), 3.86(s, 3H), 3.91 (s, 3H), 4.30(t, 2H), 4.86(t, 2H), 6.83 -7.36 (m, 10H), 7.73(s, 1H), 7.80(s, 1H), 7.92(s, 1H), 7.98(s, 1H) , 10.80 (s, 1H), 10.98(s, 1H)。
embodiment 27:3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-
MS (ESI) m/z:486.1 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.01(s , 6H), 2.08 (s, 6H), 2.43(t, 4H), 3.80 (s, 3H), 3.81 (s, 3H), 3.87(s, 3H), 3.89 (s, 3H), 4.38(t, 2H), 4.87(t, 2H), 6.88 -7.22 (m, 10H), 7.51(d, 1H, J=6Hz), 7.68(d, 1H, J=6Hz), 7.91(s, 1H), 7.98(s, 1H) , 10.66 (s, 1H), 10.84(s, 1H)。
embodiment 28:3-{5-(3,4-difluorophenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-
MS (ESI) m/z:488.5(M+H)
+;
1H NMR (300 MHz, DMSO-
d6) 1.09-1.24(m, 12H), 2.01 -2.21 (m, 4H), 3.07(br s, 12H), 4.48(t, 4H), 6.71-6.92(m, 4H), 7.56-7.94(m, 10H), 10.89 (s, 2H)。
embodiment 29:3-{5-(2,4 difluorobenzene base methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-
MS (ESI) m/z:488.5(M+H)
+;
1H NMR (300 MHz, DMSO-
d6) 0.76 (t, 6H), 0.88 (t, 6H), 1.73 (t, 4H), 2.10 -2.46 (m, 12H), 4.29(t, 2H), 4.60(t, 2H), 6.71-7.88(m, 14H), 10.83 (s, 1H), 11.05 (s, 1H)。
embodiment 30:3-{5-(2,4 difluorobenzene base methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-
MS (ESI) m/z:504.1(M+H)
+;
1H NMR (300 MHz, DMSO-
d6) 0.79 (t, 6H), 0.88 (t, 6H), 1.78 (t, 4H), 2.20 -2.46 (m, 12H), 4.27(t, 2H), 4.61(t, 2H), 6.79-7.86(m, 14H), 10.83 (s, 1H), 11.02 (s, 1H)。
embodiment 31:3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-2-indolone
MS (ESI) m/z:524.2 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6) 0.75 (t, 6H), 0.86(t, 6H,), 1.68-1.78 (m, 4H), 2.22 -2.40 (m, 12H), 3.75 (s, 6H), 3.85 (s, 3H), 3.86(s, 3H), 3.88 (s, 3H), 3.89 (s, 3H), 4.32(t, 2H), 4.67(t, 2H), 6.86-7.03(m, 4H), 7.05 (s, 4H), 7.12-7.21 (s, 2H), 7.45 (d, 1H, J=9Hz), 7.68(s, 1H), 7.71(d, 1H, J=6Hz), 7.80(s, 1H), 10.63 (s, 1H), 10.75(s, 1H)。
embodiment 32:3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-methyl-2-indolone
MS (ESI) m/z:538.7 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6) 0.78 (t, 6H), 0.88(t, 6H), 1.71-1.77 (m, 4H), 2.18 -2.47 (m, 18H), 3.76 (s, 6H), 3.85 (s, 3H), 3.86(s, 3H), 3.90 (s, 3H), 3.91 (s, 3H), 4.32(t, 2H), 4.67(t, 2H), 6.74-7.03(m, 4H), 7.04 (s, 2H), 7.08 (s, 2H), 7.25 (s, 1H), 7.56 (s, 1H), 7.67(s, 1H), 7.77(s, 1H), 10.52 (s, 1H), 10.64(s, 1H)。
embodiment 33:3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-
MS (ESI) m/z:542.6 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6) 0.76 (t, 6H), 0.87(t, 6H), 1.74 (t, 4H), 2.24 -2.44 (m, 12H), 3.76 (s, 6H), 3.85 (s, 3H), 3.86(s, 3H), 3.88 (s, 3H), 3.89 (s, 3H), 4.30(t, 2H), 4.66(t, 2H), 6.82-7.03 (m, 4H), 7.06 (s, 2H), 7.08 (s, 2H), 7.27-7.31(m, 1H), 7.48-7.52(m, 1H), 7.71(s, 1H), 7.83(s, 1H), 10.65 (s, 1H), 10.76(s, 1H)。
embodiment 34:3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-
MS (ESI) m/z:542.2 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6) 0.75 (t, 6H), 0.86(t, 6H), 1.70 (t, 4H), 2.21 -2.40 (m, 12H), 3.75 (s, 6H), 3.85 (s, 3H), 3.86(s, 3H), 3.88 (s, 3H), 3.89 (s, 3H), 4.30(t, 2H), 4.64(t, 2H), 6.68-6.90 (m, 4H), 7.05 (s, 4H), 7.46-7.50(m, 1H), 7.69(s, 1H), 7.71-7.73(s, 1H), 7.80(s, 1H), 10.78 (s, 1H), 10.91(s, 1H)。
embodiment 35:3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-
MS (ESI) m/z:558.2 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6) 0.78 (t, 6H), 0.88(t, 6H), 1.75 (t, 4H), 2.23 -2.45 (m, 12H), 3.76 (s, 6H), 3.86 (s, 6H), 3.90 (s, 6H), 4.26(t, 2H), 4.64(t, 2H), 6.81-7.68 (m, 10H), 7.70(s, 1H), 7.79(s, 1H) 10.75 (s, 1H), 10.87(s, 1H)。
embodiment 36:3-{5-(2,4 difluorobenzene base methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-2-indolone
MS (ESI) m/z:470.6 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6) 0.76(t, 6H), 0.87(t, 6H), 1.74 (t, 4H), 2.19 -2.44 (m, 12H), 4.32 (t, 2H), 4.65(t, 2H), 6.86-7.78 (m, 16H), 10.67 (s, 1H), 10.89(s, 1H)。
embodiment 37:3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-
MS (ESI) m/z:426.5 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.04(s , 6H), 2.07(s, 6H), 2.40 -2.49(m, 4H), 4.34 (t, 2H), 4.87(t, 2H), 6.83 -7.66 (m, 14H), 7.69(s, 1H), 7.81(s, 1H), 10.36 (s, 2H), 10.65 (s, 1H), 10.87 (s, 1H)。
embodiment 38:3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-
MS (ESI) m/z:426.4 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.01(s , 6H), 2.09(s, 6H), 2.42 -2.49(m, 4H), 4.34 (t, 2H), 4.85(t, 2H), 6.72 -7.78 (m, 16H), 10.36 (s, 2H), 10.80 (s, 1H), 11.01 (s, 1H)。
embodiment 39:3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-
MS (ESI) m/z:442.1 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.07(s , 12H), 2.39 -2.49(m, 4H), 4.31 (t, 2H), 4.84(t, 2H), 6.90 -7.82 (m, 16H), 10.38(s, 2H), 10.78 (s, 1H), 10.98 (s, 1H)。
embodiment 40:3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the bromo-2-indolone of-5-
MS (ESI) m/z:486.4 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 2.08(s , 12H), 2.40 -2.49(m, 4H), 4.30 (t, 2H), 4.83(t, 2H), 6.86 -7.82 (m, 16H), 10.38(s, 2H), 10.79 (s, 1H), 10.99 (s, 1H)。
embodiment 41:3-{5-(4-hydroxy phenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-methyl-2-indolone
MS (ESI) m/z: 464.6 (M+H)
+;
1H NMR (300 MHz, DMSO-
d6)
δ: 0.98(t, 6H), 1.15(t, 6H), 1.91 (t, 2H), 2.09(t, 2H), 2.33(s, 3H), 2.39(s, 3H), 2.70 -3.20 (m, 12H), 4.34 (t, 2H), 4.49(t, 2H), 6.80-7.77 (m, 16H), 8.99(s, 2H) 10.57 (s, 1H), 10.77(s, 1H)。
embodiment 42:3-{5-(2-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-methyl-2-indolone
MS (ESI) m/z:422.5 (M+H)
+。
embodiment 43:3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the bromo-2-indolone of-5-
MS (ESI) m/z:514.0 (M+H)
+。
embodiment 44:3-{5-(2-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-
MS (ESI) m/z:425.5 (M+H)
+
。
embodiment 45:3-{5-(2,4 difluorobenzene base methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the bromo-2-indolone of-5-
MS (ESI) m/z:506.0 (M+H)
+。
embodiment 46:3-{5-(2,4 difluorobenzene base methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-
MS (ESI) m/z:446.1 (M+H)
+。
embodiment 47:3-{5-(3,4-difluorophenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the bromo-2-indolone of-5-
MS (ESI) m/z:506.4 (M+H)
+。
embodiment 48:3-{5-phenyl methyne-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-
MS (ESI) m/z:410.5 (M+H)
+
。
embodiment 49:3-{5-(2-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-
MS (ESI) m/z:426.4 (M+H)
+。
embodiment 50:3-{5-phenyl methyne-3-[2-(dimethylamino) butyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-
MS (ESI) m/z:438.2 (M+H)
+。
embodiment 51:3-{5-phenyl methyne-3-[2-(diethylamino) butyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-
MS (ESI) m/z:466.6 (M+H)
+。
embodiment 52:3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) butyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-
MS (ESI) m/z:482.2 (M+H)
+。
embodiment 53:3-{5-phenyl methyne-3-[3-(1-Pyrrolidine base) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-
MS (ESI) m/z:450.5 (M+H)
+。
embodiment 54:3-{5-phenyl methyne-3-[3-(piperidino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-
MS (ESI) m/z:464.6. (M+H)
+。
embodiment 55:3-{5-phenyl methyne-3-[3-(1-morpholinyl) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-
MS (ESI) m/z:466.5 (M+H)
+。
the pharmacological research of product of the present invention
To according to above formula of the present invention
ithe 4-Thiazolidinone that contains indolone carried out anti tumor activity in vitro screening.
anti tumor activity in vitro test
(1) by HT29(human colon cancer cell), MDA-MB-231 (human breast cancer cell), and three kinds of cell strains of H460 (non-small cell lung cancer cell) recover respectively and go down to posterity 2-3 time stable after, with trypsin solution (0.25%), it is digested bottom culturing bottle.Cell dissociation buffer is poured in centrifuge tube and then added nutrient solution to stop digestion.By centrifuge tube centrifugal 3 min under 1300r/min, after abandoning supernatant, add gently 5 mL nutrient solutions, piping and druming mixes cell, and absorption 10 μ L cell suspensions add in cell counting count board to be counted, and adjusting cell concn is 10
4individual/hole.In 96 orifice plates, except A1 hole is that blank well does not add extracellular, all the other all add 100 uL cell suspensions.96 orifice plates are put into incubator and cultivate 24h.
(2) with 50 μ L dmso solution given the test agent, then add appropriate nutrient solution, make sample dissolution become 2 mg/mL liquids.Then in 24 orifice plates, by diluted sample, be 100,20,4,0.8,0.16 μ g/mL.Each concentration adds 3 holes, and wherein around two row two row cell growing ways are affected by environment larger, only as blank cell hole, uses.96 orifice plates are put into incubator and cultivate 72
h.
(3) will in 96 orifice plates, be with medicine nutrient solution to discard, with phosphate buffer solution (PBS), cell is rinsed twice, in every hole, adding MTT(tetrazole) (0.5 mg/mL) 100 μ L put into after incubator 4h, discard MTT solution, add dimethyl sulfoxide (DMSO) 100 μ L.On magnetic force vibrator, vibration is fully dissolved survivaling cell and MTT reaction product formazan, puts into microplate reader measurement result, by Bliss method, can obtain medicine IC
50value.
The extracorporeal anti-tumor cytoactive of compound the results are shown in Table 2.
the extracorporeal anti-tumor cytoactive result of table 2. compound
"/" is not carried out active testing
Claims (8)
1. the derivative of formula I, its geometrical isomer and pharmacy acceptable salt thereof,
Wherein,
Ar is phenyl, quinolyl, isoquinolyl, naphthyl, 5-6 unit's heteroaryl and 5-6 unit is saturated or the heterocyclic radical of fractional saturation, and described heteroaryl and heterocyclic radical contain 1-3 heteroatoms that is selected from O, N and S, and Ar is optionally by 1-4 identical or different R
1replace;
R
1for hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyano group, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, N-(C
1-C
4) alkylamino, N, N-bis-(C
1-C
4) alkylamino, (C
1-C
4) alkyl sulfenyl, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkoxyethyl, (C
1-C
4) alkyl acyl, formamyl, N-(C
1-C
4) alkyl-carbamoyl, N, N-bis-(C
1-C
4) alkyl-carbamoyl;
R
2optional 1-3 following substituting group is hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyano group, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, N-(C
1-C
4) alkylamino, N, N-bis-(C
1-C
4) alkylamino, (C
1-C
4) alkyl sulfenyl, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkoxyethyl, (C
1-C
4) alkyl acyl, formamyl, N-(C
1-C
4) alkyl-carbamoyl, N, N-bis-(C
1-C
4) alkyl-carbamoyl;
R
3and R
4identical or different, respectively independently selected from hydrogen, C
1-C
10alkyl, C
3-C
7cycloalkyl, C
2-C
10thiazolinyl and C
2-C
10alkynyl, or R
3and R
4form 5-10 unit heterocyclic radical together with the nitrogen-atoms being connected with them, described heterocyclic radical except with R
3and R
4outside the nitrogen-atoms connecting, contain 1-4 heteroatoms that is selected from N, O and S, except R
3and R
4outside the nitrogen-atoms connecting, described heterocyclic radical optionally comprises 1 or 2 carbon-carbon double bond or three key;
N is the integer between 1-4.
2. the derivative of the formula I of claim 1, its geometrical isomer and pharmacy acceptable salt thereof,
Wherein,
Ar is phenyl, 5-6 unit heteroaryl, and described heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and Ar is optionally by 1-4 identical or different R
1replace.
3. the derivative of the formula I of claim 2, its geometrical isomer and pharmacy acceptable salt thereof,
Wherein,
Ar is phenyl, and Ar is optionally by 1-4 identical or different R
1replace;
R
3and R
4identical or different, respectively independently selected from hydrogen, C
1-C
4alkyl, or R
3and R
4form piperidyl, Pyrrolidine base, piperazinyl, morpholinyl and thio-morpholinyl together with the nitrogen-atoms being connected with them.
4. the derivative of the formula I of claim 3, its geometrical isomer and pharmacy acceptable salt thereof,
Wherein,
R
2for hydrogen, halogen;
R
3and R
4form dimethylamino, diethylin, Pyrrolidine base, piperazinyl, morpholinyl together with the nitrogen-atoms being connected with them.
5. the derivative of the formula I of claim 4, its geometrical isomer and pharmacy acceptable salt thereof,
Wherein,
R
2for hydrogen, chlorine, fluorine;
R
3and R
4form dimethylamino, diethylin, Pyrrolidine base, piperazinyl, morpholinyl together with the nitrogen-atoms being connected with them.
6. the derivative of the formula I of claim 1, its geometrical isomer and pharmacy acceptable salt thereof:
3-{5-phenyl methyne-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(2-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(3,4-difluorophenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(3,4-difluorophenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-(3,4-difluorophenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-(3,4-difluorophenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the bromo-2-indolone of-5-;
3-{5-(2,4 difluorobenzene base methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-(2,4 difluorobenzene base methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(2,4 difluorobenzene base methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the bromo-2-indolone of-5-;
3-{5-(2-hydroxy phenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-(2-hydroxy phenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the bromo-2-indolone of-5-;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the bromo-2-indolone of-5-;
3-{5-(2-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-2-indolone;
3-{5-(2-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-;
3-{5-(3,4-difluorophenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-2-indolone;
3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-;
3-{5-(3,4-difluorophenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-(2,4 difluorobenzene base methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-(2,4 difluorobenzene base methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-2-indolone;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-;
3-{5-(2,4 difluorobenzene base methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the bromo-2-indolone of-5-;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-2-indolone;
3-{5-(2,5-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-2-indolone;
3-{5-(2,5-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-(4-hydroxy phenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit } the chloro-2-indolone of-5-;
3-{5-(2-hydroxy phenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-(4-p-methoxy-phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-6-;
3-{5-phenyl methyne-3-[2-(dimethylamino) butyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-phenyl methyne-3-[2-(diethylamino) butyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-[(benzo [d-1,3] bis-Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) butyl]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-phenyl methyne-3-[3-(1-Pyrrolidine base) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-phenyl methyne-3-[3-(piperidino) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-;
3-{5-phenyl methyne-3-[3-(1-morpholinyl) propyl group]-4-thiazolidone-2-subunit } the fluoro-2-indolone of-5-.
7. a medicinal compositions, the derivative, its geometrical isomer and the pharmacy acceptable salt thereof that comprise the formula I of claim 1-6 described in any one are as activeconstituents and pharmaceutically acceptable excipient.
8. in claim 1-6, the derivative of the formula I of any one and geometrical isomer thereof and pharmacy acceptable salt thereof treat and/or prevent the application in the medicine of cancer in preparation.
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| CN101007801A (en) * | 2006-01-27 | 2007-08-01 | 上海恒瑞医药有限公司 | Pyrrole substituted 2-dihydromolindone derivative, its preparation method and medical uses |
| CN101195601A (en) * | 2006-12-04 | 2008-06-11 | 江苏先声药物研究有限公司 | 2-dihydro indolone derivant, preparation method and application thereof |
| CN101381348A (en) * | 2008-10-17 | 2009-03-11 | 山东大学 | Thiazolidone derivates and application thereof in preparing anti-lung cancer medicine |
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| CN101007801A (en) * | 2006-01-27 | 2007-08-01 | 上海恒瑞医药有限公司 | Pyrrole substituted 2-dihydromolindone derivative, its preparation method and medical uses |
| CN101195601A (en) * | 2006-12-04 | 2008-06-11 | 江苏先声药物研究有限公司 | 2-dihydro indolone derivant, preparation method and application thereof |
| CN101381348A (en) * | 2008-10-17 | 2009-03-11 | 山东大学 | Thiazolidone derivates and application thereof in preparing anti-lung cancer medicine |
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