CN102532118A - Indolone-containing 4-thiazolidone derivatives and application thereof - Google Patents
Indolone-containing 4-thiazolidone derivatives and application thereof Download PDFInfo
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- CN102532118A CN102532118A CN2010106044378A CN201010604437A CN102532118A CN 102532118 A CN102532118 A CN 102532118A CN 2010106044378 A CN2010106044378 A CN 2010106044378A CN 201010604437 A CN201010604437 A CN 201010604437A CN 102532118 A CN102532118 A CN 102532118A
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- thiazolidone
- indolone
- subunit
- methyne
- 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-thiazolidone analog derivative and the pharmacy acceptable salt thereof that contain indolone, comprise their preparation method and the pharmaceutical composition that contains said compound.The invention still further relates to this verivate and be used for preparing the purposes of the medicine that treats and/or prevents cancer.
Background technology
The compound that contains 4-thiazolidone structure has BA widely, like antibiotic, antimycotic, antiviral, anti-inflammatory, hypoglycemic, cardiac stimulant and antitumor action etc.People such as J.K.Choi have reported to have the inhibiting 5-substituted-phenyl of PRL-3 methyne rhodanine verivate, the compound I C that this series compound external activity is best
50Be 0.9 μ M.People such as N.S.Cutshall have reported one type of N-substituted-phenyl-5-substituted-phenyl methyne rhodanine verivate, 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.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 2 of 4-thiazolidone has obtained a series of compounds, and this compounds has stronger restraining effect to SHP-2.
The 4-thiazolidone analog derivative that contains indolone belongs to one type of new compound, does not have this compound and related activity thereof report in the prior art.
Summary of the invention:
The present invention relates to verivate, 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 said heteroaryl and heterocyclic radical contain 1-3 heteroatoms that is selected from O, N and S, and the individual identical or different R of the optional 1-4 of Ar
1Replace;
R
1Be hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyanic acid, (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-two (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-two (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, cyanic acid, (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-two (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-two (C
1-C
4) alkyl-carbamoyl, (C
1-C
3) alkylenedioxy group;
R
3And R
4Identical or different, be independently selected from hydrogen, C respectively
1-C
10Alkyl, C
3-C
7Naphthenic base, C
2-C
10Thiazolinyl and C
2-C
10Alkynyl, or R
3And R
4Form 5-10 unit heterocyclic radical with the nitrogen-atoms that is connected with them, said heterocyclic radical except with R
3And R
4Outside the nitrogen-atoms that connects, contain 1-4 heteroatoms that is selected from N, O and S, except R
3And R
4Outside the nitrogen-atoms that is connected, optional 1 or 2 carbon-carbon double bond or three key of comprising of said heterocyclic radical;
N is the integer between the 1-4.
The verivate 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 said heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and optional 1-4 the identical or different R of Ar
1Replace;
R
1Be hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyanic acid, (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-two (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-two (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, cyanic acid, (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-two (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-two (C
1-C
4) alkyl-carbamoyl, (C
1-C
3) alkylenedioxy group;
R
3And R
4Identical or different, be independently selected from hydrogen, C respectively
1-C
10Alkyl, C
3-C
7Naphthenic base, C
2-C
10Thiazolinyl and C
2-C
10Alkynyl, or R
3And R
4Form 5-10 unit heterocyclic radical with the nitrogen-atoms that is connected with them, said heterocyclic radical except with R
3And R
4Outside the nitrogen-atoms that connects, contain 1-4 heteroatoms that is selected from N, O and S, except R
3And R
4Outside the nitrogen-atoms that is connected, optional 1 or 2 carbon-carbon double bond or three key of comprising of said heterocyclic radical;
N is the integer between the 1-4.
The present invention is verivate, its geometrical isomer and the pharmacy acceptable salt thereof of following formula I very preferably, wherein,
Ar is a phenyl, and optional 1-4 the identical or different R of Ar
1Replace;
R
1Be hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyanic acid, (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-two (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-two (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, cyanic acid, (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-two (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-two (C
1-C
4) alkyl-carbamoyl, (C
1-C
3) alkylenedioxy group; R
2Be preferably hydrogen, halogen especially; Be preferably hydrogen, fluorine and chlorine atom very especially;
R
3And R
4Identical or different, be independently selected from hydrogen, C respectively
1-C
4Alkyl, or R
3And R
4Form piperidyl, Pyrrolidine base, piperazinyl, 4-N-METHYL PIPERAZINE base, morpholinyl and thio-morpholinyl with the nitrogen-atoms that is connected with them.R
3And R
4Be preferably dimethylamino, diethylin, Pyrrolidine base, piperazinyl, 4-N-METHYL PIPERAZINE base, morpholinyl especially with the nitrogen-atoms that is connected with them;
N is the integer between the 1-4.
Verivate, its geometrical isomer and the pharmacy acceptable salt thereof of the also preferred following formula I of the present invention, wherein,
Ar is a phenyl, and optional 1-4 the identical or different R of Ar
1Replace;
R
1Be hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyanic acid, (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-two (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-two (C
1-C
4) alkyl-carbamoyl, (C
1-C
3) alkylenedioxy group;
R
2Be hydrogen, halogen; Preferred R
2Be hydrogen, chlorine, fluorine;
R
3And R
4Form dimethylamino, diethylin, Pyrrolidine base, piperazinyl, 4-methyl isophthalic acid-piperazinyl, morpholinyl with the nitrogen-atoms that is connected with them;
N is the integer between the 1-4.
The present invention is preferably verivate, its geometrical isomer and the pharmacy acceptable salt thereof of the following formula I of structural formula especially:
3-{5-phenyl methyne-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-(2-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-(3,4-difluorophenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
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 }-6-fluoro-2-indolone;
3-{5-(3,4-difluorophenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-bromo-2-indolone;
3-{5-(2,4 difluorobenzene base methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-(2,4 difluorobenzene base methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-(2,4 difluorobenzene base methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-bromo-2-indolone;
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] Er 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 }-5-bromo-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-bromo-2-indolone;
3-{5-(2-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-the 2-indolone;
3-{5-(2-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-chloro-2-indolone;
3-{5-(3,4-difluorophenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-the 2-indolone;
3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-chloro-2-indolone;
3-{5-(3,4-difluorophenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-(2,4 difluorobenzene base methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-(2,4 difluorobenzene base methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-chloro-2-indolone;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-the 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 }-5-fluoro-2-indolone;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-chloro-2-indolone;
3-{5-(2,4 difluorobenzene base methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-the 2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-chloro-2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-bromo-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-the 2-indolone;
3-{5-(2,5-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-the 2-indolone;
3-{5-(2,5-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
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 }-5-chloro-2-indolone;
3-{5-(2-hydroxy phenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-the 2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-the 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 }-6-fluoro-2-indolone;
3-{5-phenyl methyne-3-[2-(dimethylamino) butyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-phenyl methyne-3-[2-(diethylamino) butyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) butyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-phenyl methyne-3-[3-(1-Pyrrolidine base) propyl group]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-phenyl methyne-3-[3-(piperidino) propyl group]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-phenyl methyne-3-[3-(1-morpholinyl) propyl group]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
Verivate of the present invention can exist with the geometrical isomer form, and these rotamerism forms can be that two keys are configured as 2Z, 5Z, 2Z, 5E, 2E, 5E and 2E, 5Z in the formula I.The present invention had both related to the verivate of single configuration, also related to their mixtures separately.
In addition, the present invention also comprises the prodrug of verivate of the present invention.According to the present invention, prodrug is a general formula
IVerivate, they self possibly have more weak active or even do not have activity, but after administration, (for example through metabolism, solvolysis or other mode) is converted to corresponding biologically active form under physiological condition.
Only if point out in addition, term used herein " halogen " is meant fluorine, chlorine, bromine or iodine atom; " alkyl " is meant the alkyl of straight or branched; " alkylidene group " is meant the alkylidene group of straight or branched; " naphthenic base " is meant and replaces or unsubstituted naphthenic base; Heteroaryl comprises the heteroatoms that contains one or more O of being selected from, N and S; Can be monocycle or polycyclic; The ring-type system is an aromaticity; For example can enumerate imidazolyl, pyridyl, pyrimidyl, (1,2,3)-with (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.Said pharmaceutically acceptable excipient is meant any thinner, auxiliary and/or carrier that can be used for pharmaceutical field.Verivate of the present invention can use with other activeconstituents combinations, as long as they do not produce other unfavorable effect, for example anaphylaxis.
Pharmaceutical composition of the present invention can be mixed with some kinds of formulations, wherein contains some vehicle commonly used in the pharmaceutical field; For example, oral prepns (like tablet, capsule, solution or suspension); Injectable preparation (like injectable solution or suspension, or injectable dried powder, before injection, adding water for injection can use immediately); Topical formulations (for example ointment or solution).
The carrier that is used for pharmaceutical composition of the present invention is the available common type of pharmaceutical field, comprising: the tackiness agent that oral prepns 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 prepn can oral administration or parenteral mode (for example intravenously, subcutaneous, intraperitoneal or part) administration, if some drugs is unsettled under the stomach condition, can it be mixed with enteric coated tablets.
We have found that The compounds of this invention is external and have had an inhibition tumor cell growth activity that therefore, it can treat and/or prevent the medicine of cancer as preparation.Especially treat the cancer of mammary gland, lung, colon, rectum, stomach, prostate gland, bladder, pancreas and ovary.The compounds of this invention also is supposed to can be used to treat other diseases such as mellitus, fungi infestation, infectation of bacteria, virus infection, chronic inflammatory diseases etc.Expect in addition 4-thiazolidone compounds of the present invention will have leukemia, malignant lymphoma and solid tumor as at tissue like the activity of cancer in liver, kidney, prostate gland and the pancreas and sarcoma scope.
Verivate according to the present invention can be used as activeconstituents and is used for preparation and treats and/or prevents various cancers; The present invention also provides treatment or prevents the method for above-mentioned disease, comprise suffer from or be prone to suffer from this sick patient significant quantity according to verivate of the present invention.General formula
IThe 4-thiazolidone compounds clinical dosage that is used for the patient must rely on the main body of being treated, administration concrete approach, treat severity of disease and is changed, and optimal dose is definite by the concrete patient's of treatment doctor.
Active compound of the present invention can be used as unique cancer therapy drug and uses, and perhaps can unite use with one or more other antitumor drugs.Combination therapy realizes through each being treated component while, order or separating administration.
Following synthetic route A has described general formula of the present invention
IThe preparation of compound, all raw materials all are the method preparation known through the method for describing in these synoptic diagram, through the organic chemistry filed those of ordinary skill or commercially available.All final compound of the present invention all is to prepare through the method for describing in these synoptic diagram or through method similar with it, and these methods are that the organic chemistry filed those of ordinary skill is known.The whole variable factors used in these synoptic diagram such as the definition of hereinafter or like the definition in the claim.
According to general formula of the present invention
ICompound is at general formula
IIn the preparation route of compound, wherein substituent A r, R
1, R
2Has the implication that in specification sheets, provides with n
The preparation route of generalformula
Compound 1 and dithiocarbonic anhydride reacting generating compound 2; Compound 2 generates compound 3 with chloroacetate reaction; Ring-closure reaction takes place and generates compound 4 in compound 3 under sulphuric acid catalysis; The Knoevenagel condensation reaction takes place with substituted benzaldehyde and generates compound 5 in compound 4, and compound 5 generates compound 6 with triethyl orthoformate generation ethylation reaction under the BFEE effect, and compound 6 with compound 7 condensation takes place and generates verivate shown in the formula I.
In the above-mentioned route, raw material
1,7Can be perhaps commercially available through the method preparation that the organic chemistry filed those of ordinary skill is known.
Compound of the present invention carries out antitumor activity screening through external to various tumor cell strains, and the result shows that it has anti-tumor activity.
Embodiment:
Embodiment is intended to set forth rather than limit scope of the present invention.The proton nmr spectra of prepared compound is measured with Bruker ARX-300 among the present invention, and mass spectrum is measured with Agilent 1100 LC/MSD; Agents useful for same is analytical pure or CP.
The structural formula of table 1. embodiment 1-50
| Embodiment | Structural formula | Embodiment | Structural formula |
| 1 |
 |
2 |
 |
| 3 | 4 |
 |
|
| 5 | 6 |
 |
|
| 7 | 8 |
 |
|
| 9 |
 |
10 |
 |
| 11 |
 |
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Embodiment 1:
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-preparation of 5-fluoro-2-indolone
The preparation of 2-sulfo--3-(dimethyl aminoethyl)-4-thiazolidone
With 8.8g (0.1mol) N, the N-dimethyl-ethylenediamine adds in the 200mL anhydrous diethyl ether, drips ether (50mL) solution of dithiocarbonic anhydride 7.6g (0.1mol) then, drips Bi Jixu and stirs 30min; Suction filtration, the ether washing is after the drying; Solid is added reactor drum, add 200mL water successively, 50mL methyl alcohol.In this suspension, drip the salt of wormwood Mono Chloro Acetic Acid aqueous solution (salt of wormwood 6.9g (0.05mol), Mono Chloro Acetic Acid 9.4g (0.1mol), water 40mL) for preparing in advance; Drip and finish, 30 ℃ of reaction 7-8h, filtering insolubles; In reaction solution, drip vitriol oil 11mL then, drip and finish, 30 ℃ of reaction 10h.Reaction finishes the reaction solution evaporate to dryness, ethanol 100 ml in residual solution, and temperature rising reflux 30min, suction filtration while hot,, the evaporate to dryness of will filtrate must 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 15mL ethanol, add 3,4 successively then, 5-TMB 1.96 (0.01mol); Piperidines 0.85g (0.01mol) is warming up to 80 ℃ of reaction 2h, and reaction is finished, cooling; Separate out solid, suction filtration, filter cake washs with small amount of ethanol; Drying gets 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
With 2-sulfo--3-(dimethyl aminoethyl)-5-3,4,5-trimethoxyphenyl methyne)-4-thiazolidone 1.67g (0.0044mol) adding 40mL dioxane, add ethyl orthoformate 4.38mL then successively; Boron trifluoride ether solution 6.57mL, 80 ℃ of reaction 2h, reaction is finished, cooling; Suction filtration, filter cake are used a small amount of dioxane, the ether washing; Drying gets yellow solid 1.75g, receives filter 80%.
The trimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-preparation of 5-fluoro-2-indolone
Under the ice bath 2-ethylmercapto group-3-(dimethyl aminoethyl)-5-(3,4,5-trimethoxyphenyl methyne)-4-thiazoline a tetrafluoro borate 0.61g (1.23mmol) and 5-fluoro-2-indolone 0.19 g (1.23mmol) are added in the 4mL acetonitrile successively; Drip the 0.28mL triethylamine, ice bath continues reaction 4h down, and reaction is finished; Suction filtration, filter cake are used small amount of methanol successively, a small amount of ether washing; Get 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 known raw material of those skilled in the art and reagent, make the compound of embodiment 2-49 respectively.When mentioning specific reaction raw materials, it should be understood that the technician who is proficient in this field can select proper raw material and reagent according to the needs of embodiment.
Embodiment 2:3-{5-(4-p-methoxy-phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone
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 }-5-fluoro-2-indolone
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 }-6-fluoro-2-indolone
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 }-the 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 }-6-fluoro-2-indolone
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 }-the 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 }-5-chloro-2-indolone
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] Er 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 }-5-bromo-2-indolone
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] Er Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone
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 }-6-fluoro-2-indolone
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 }-the 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] Er Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-the 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] Er Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-the 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] Er 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] Er Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone
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] Er Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone
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] Er Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-chloro-2-indolone
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 }-5-fluoro-2-indolone
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 }-the 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 }-5-fluoro-2-indolone
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 }-6-fluoro-2-indolone
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 }-5-chloro-2-indolone
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 }-6-fluoro-2-indolone
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 }-6-fluoro-2-indolone
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 }-5-chloro-2-indolone
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 }-the 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 }-5-fluoro-2-indolone
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 }-6-fluoro-2-indolone
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 }-5-chloro-2-indolone
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 }-the 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 }-5-fluoro-2-indolone
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 }-6-fluoro-2-indolone
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 }-5-chloro-2-indolone
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 }-5-bromo-2-indolone
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] Er Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-bromo-2-indolone
MS?(ESI)?m/z:514.0?(M+H)
+。
Embodiment 44:3-{5-(2-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone
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 }-5-bromo-2-indolone
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 }-5-fluoro-2-indolone
MS?(ESI)?m/z:446.1?(M+H)
+。
Embodiment 47:3-{5-(3,4-difluorophenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-bromo-2-indolone
MS?(ESI)?m/z:506.4?(M+H)
+。
Embodiment 48:3-{5-phenyl methyne-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone
MS?(ESI)?m/z:410.5?(M+H)
+
。
Embodiment 49:3-{5-(2-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone
MS?(ESI)?m/z:426.4?(M+H)
+。
Embodiment 50:3-{5-phenyl methyne-3-[2-(dimethylamino) butyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone
MS?(ESI)?m/z:438.2?(M+H)
+。
Embodiment 51:3-{5-phenyl methyne-3-[2-(diethylamino) butyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone
MS?(ESI)?m/z:466.6?(M+H)
+。
Embodiment 52:3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) butyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone
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 }-5-fluoro-2-indolone
MS?(ESI)?m/z:450.5?(M+H)
+。
Embodiment 54:3-{5-phenyl methyne-3-[3-(piperidino) propyl group]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone
MS?(ESI)?m/z:464.6.?(M+H)
+。
Embodiment 55:3-{5-phenyl methyne-3-[3-(1-morpholinyl) propyl group]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone
MS?(ESI)?m/z:466.5?(M+H)
+。
The pharmacological research of product of the present invention
To according to following formula of the present invention
IThe 4-thiazolidone analog derivative that contains indolone carried out the anti tumor activity in vitro screening.
The anti tumor activity in vitro test
(1) with 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 poured into then add nutrient solution in the centrifuge tube to stop digestion.With centrifuge tube centrifugal 3 min under 1300r/min, add 5 mL nutrient solutions gently after the abandoning supernatant, piping and druming mixing cell is drawn in the 10 μ L cell suspensions adding cell counting count board and is counted, and the adjustment cell concn is 10
4Individual/hole.Removing the A1 hole in 96 orifice plates is that blank well does not add the extracellular, and all the other all add 100 uL cell suspensions.96 orifice plates are put into incubator cultivate 24h.
(2) with 50 μ L dmso solution given the test agent, add an amount of nutrient solution then, make sample dissolution become 2 mg/mL soups.In 24 orifice plates, be 100,20,4,0.8 then with diluted sample, 0.16 μ g/mL.Each concentration adds 3 holes, and wherein two row, two row cell growing ways are affected by environment bigger on every side, only uses as blank cell hole.96 orifice plates are put into incubator cultivate 72
H
(3) band medicine nutrient solution in 96 orifice plates is discarded; With phosphate buffer solution (PBS) cell is washed twice; In every hole, add after MTT (tetrazole) (0.5 mg/mL) 100 μ L put into incubator 4h, discard MTT solution, add DMSO 99.8MIN. 100 μ L.Vibration is fully dissolved survivaling cell and MTT reaction product Jia Za on the magnetic force vibrator, puts into ELIASA and measures the result, can obtain medicine IC through the Bliss method
50Value.
The extracorporeal anti-tumor cytoactive result of compound sees table 2.
?
The extracorporeal anti-tumor cytoactive result of table 2. compound
"/" do not carry out active testing
Claims (8)
1. the verivate 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 said heteroaryl and heterocyclic radical contain 1-3 heteroatoms that is selected from O, N and S, and the individual identical or different R of the optional 1-4 of Ar
1Replace;
R
1Be hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyanic acid, (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-two (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-two (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, cyanic acid, (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-two (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-two (C
1-C
4) alkyl-carbamoyl, (C
1-C
3) alkylenedioxy group;
R
3And R
4Identical or different, be independently selected from hydrogen, C respectively
1-C
10Alkyl, C
3-C
7Naphthenic base, C
2-C
10Thiazolinyl and C
2-C
10Alkynyl, or R
3And R
4Form 5-10 unit heterocyclic radical with the nitrogen-atoms that is connected with them, said heterocyclic radical except with R
3And R
4Outside the nitrogen-atoms that connects, contain 1-4 heteroatoms that is selected from N, O and S, except R
3And R
4Outside the nitrogen-atoms that is connected, optional 1 or 2 carbon-carbon double bond or three key of comprising of said heterocyclic radical;
N is the integer between the 1-4.
2. the verivate of the formula I of claim 1, its geometrical isomer and pharmacy acceptable salt thereof,
Wherein,
Ar is phenyl, 5-6 unit heteroaryl, and said heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and optional 1-4 the identical or different R of Ar
1Replace.
3. the verivate of the formula I of claim 2, its geometrical isomer and pharmacy acceptable salt thereof,
Wherein,
Ar is a phenyl, and optional 1-4 the identical or different R of Ar
1Replace;
R
3And R
4Identical or different, be independently selected from hydrogen, C respectively
1-C
4Alkyl, or R
3And R
4Form piperidyl, Pyrrolidine base, piperazinyl, 4-methyl isophthalic acid-piperazinyl, morpholinyl and thio-morpholinyl with the nitrogen-atoms that is connected with them.
4. the verivate of the formula I of claim 3, its geometrical isomer and pharmacy acceptable salt thereof,
Wherein,
R
2Be hydrogen, halogen;
R
3And R
4Form dimethylamino, diethylin, Pyrrolidine base, piperazinyl, 4-methyl isophthalic acid-piperazinyl, morpholinyl with the nitrogen-atoms that is connected with them.
5. the verivate of the formula I of claim 4, its geometrical isomer and pharmacy acceptable salt thereof,
Wherein,
R
2Be hydrogen, chlorine, fluorine;
R
3And R
4Form dimethylamino, diethylin, Pyrrolidine base, piperazinyl, 4-methyl isophthalic acid-piperazinyl, morpholinyl with the nitrogen-atoms that is connected with them.
6. the verivate 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 }-5-fluoro-2-indolone;
3-{5-(2-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-(3,4-difluorophenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
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 }-6-fluoro-2-indolone;
3-{5-(3,4-difluorophenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-bromo-2-indolone;
3-{5-(2,4 difluorobenzene base methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-(2,4 difluorobenzene base methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-(2,4 difluorobenzene base methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-bromo-2-indolone;
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] Er 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 }-5-bromo-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-bromo-2-indolone;
3-{5-(2-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-the 2-indolone;
3-{5-(2-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-methyl-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-chloro-2-indolone;
3-{5-(3,4-difluorophenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-the 2-indolone;
3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-(2,4-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-chloro-2-indolone;
3-{5-(3,4-difluorophenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-(2,4 difluorobenzene base methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-(2,4 difluorobenzene base methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-chloro-2-indolone;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-the 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 }-5-fluoro-2-indolone;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-(3,4,5-trimethoxyphenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-5-chloro-2-indolone;
3-{5-(2,4 difluorobenzene base methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-the 2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-chloro-2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-5-bromo-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-the 2-indolone;
3-{5-(2,5-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-the 2-indolone;
3-{5-(2,5-Dimethoxyphenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-6-fluoro-2-indolone;
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 }-5-chloro-2-indolone;
3-{5-(2-hydroxy phenyl methyne)-3-[3-(diethylamino) propyl group]-4-thiazolidone-2-subunit }-the 2-indolone;
3-{5-(4-hydroxy phenyl methyne)-3-[2-(dimethylamino) ethyl]-4-thiazolidone-2-subunit }-the 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 }-6-fluoro-2-indolone;
3-{5-phenyl methyne-3-[2-(dimethylamino) butyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-phenyl methyne-3-[2-(diethylamino) butyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-[(benzo [d-1,3] Er Yang oxane-4-yls) methyne]-3-[2-(dimethylamino) butyl]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-phenyl methyne-3-[3-(1-Pyrrolidine base) propyl group]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-phenyl methyne-3-[3-(piperidino) propyl group]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone;
3-{5-phenyl methyne-3-[3-(1-morpholinyl) propyl group]-4-thiazolidone-2-subunit }-5-fluoro-2-indolone.
7. a medicinal compsns comprises any one described 4-thiazolidone analog derivative, its geometrical isomer and pharmacy acceptable salt thereof that contains indolone of claim 1-6 as activeconstituents and pharmaceutically acceptable excipient.
8. 4-thiazolidone analog derivative that contains indolone of any one and geometrical isomer thereof and pharmacy acceptable salt thereof treat and/or prevent the application in the medicine of various cancers in preparation among the claim 1-6.
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| CN104387378A (en) * | 2014-11-24 | 2015-03-04 | 沈阳药科大学 | New 4-thiazolidone derivative and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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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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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104387378A (en) * | 2014-11-24 | 2015-03-04 | 沈阳药科大学 | New 4-thiazolidone derivative and application thereof |
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