CN101973989A - Thiazole amide compound and medicinal application thereof for treating malignancy - Google Patents
Thiazole amide compound and medicinal application thereof for treating malignancy Download PDFInfo
- Publication number
- CN101973989A CN101973989A CN 201010503001 CN201010503001A CN101973989A CN 101973989 A CN101973989 A CN 101973989A CN 201010503001 CN201010503001 CN 201010503001 CN 201010503001 A CN201010503001 A CN 201010503001A CN 101973989 A CN101973989 A CN 101973989A
- Authority
- CN
- China
- Prior art keywords
- amide compound
- compound
- thiazole amide
- formula
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Abstract
The invention relates to a thiazole amide compound and the medicinal application thereof for treating malignancy. The thiazole amide compound is an ideal Bcr-Abl and Src protein tyrosine kinase inhibitor and has good effect on malignancy, such as chronic myelogenous leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes, lung cancer, oophoroma, prostatic cancer, soft tissue sarcoma, glioblastoma, and the like, and meanwhile, the invention has the advantages of little dosage and few side effects.
Description
Technical field
The present invention relates to thiazole amide compound and their purposes in the preparation anti-malignant tumor medicine.
Background technology
Protein tyrosine kinase (protein tyrosine kinase, PTK) by phosphorylation activating downstream signal albumen, and then regulating cell reaction.When the signal protein hyperactivity, can cause unusual cell growth and differentiation.Therefore, the unusual regulation and control of Tyrosylprotein kinase and the invasion and attack and the poor prognosis of many tumours have substantial connection, are the key characters of malignant tumour.
Known, the compound of formula (I) expression, N-(2-chloro-6-aminomethyl phenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidyl] amino]-5-thiazole carboxamides (claiming Dasatinib or BMS-354825 again) is a kind of protein tyrosine kinase inhibitor, Src kinase inhibitor for example, and can be used for the treatment of immunity and tumor disease.The compound of formula (I) expression still is BCR/ABL inhibitor and/or ABL inhibitor.The compound that suppresses Scr and/or BCR/ABL can be used for the treatment of cancer, for example CML and ALL.
U.S. Patent number 6,596, the compound and the preparation thereof of 746 pairs of above-mentioned formulas (I) expression are described.U.S. Patent Application Serial 11/051,028 also is described this compound, thinks that wherein this compound is a kind of ideal one crystalline hydrate form.
At present, the compound of formula (I) expression is used to treat the adult patient of all stadium of chronic lymphocytic leukemia that comprise that the imatinib mesylate resistance maybe can not tolerate, and it is had fluid retention, gastrointestinal symptom and bleeding episode etc. by report in clinical study; The most serious side reaction of normal report is heating, pleural effusion, heat generation neutral white) be used for granulocyte leukemia (CML).
Summary of the invention
Technical problem to be solved by this invention is to overcome the deficiencies in the prior art, and a kind of new thiazole amide compound is provided, and it is the less protein tyrosine kinase inhibitor of a kind of side effect.
For solving above technical problem, a kind of technical scheme that the present invention takes is as follows:
A kind of thiazole amide compound and pharmacologically acceptable salt thereof, it has the structure shown in the formula (I),
Wherein,
R
1Be hydrogen or deuterium;
R
2Be hydrogen, C
1-C
6Alkyl;
R
3Be hydrogen, the C of straight or branched
1-C
6Alkyl, perhaps R
3Representative-COO R
4, wherein, R
4C for straight or branched
1-C
6Alkyl.
According to an aspect of the present invention, R
2For being selected from-CH
3,-CH
2CH
3,-CH
2CH
2CH
3,-CH (CH
3) CH
3,-CH
2CH (CH
3)
2,-(CH
2)
3CH
3,-(CH
2)
4CH
3,-(CH
2)
5CH
3,-(CH
2)
2CH (CH
3) CH
3,-CH
2C (CH
3)
3,-C (CH
3)
3And-CH
2CH
2C (CH
3)
3In a kind of.
According to another aspect of the invention, R
3Representative-COOR
4, R wherein
4For being selected from-CH
3,-CH
2CH
3,-CH
2CH
2CH
3,-CH (CH
3) CH
3,-CH
2CH (CH
3)
2,-(CH
2)
3CH
3,-(CH
2)
4CH
3,-(CH
2)
5CH
3,-(CH
2)
2CH (CH
3) CH
3,-CH
2C (CH
3)
3,-C (CH
3)
3And-CH
2CH
2C (CH
3)
3In a kind of.
According to an aspect of the present invention, it provides formula (Ia) or the represented compound of formula (Ib).
The another technical scheme that the present invention takes is: thiazole amide compound and the pharmacologically acceptable salt thereof shown in a kind of formula (II),
Wherein,
R
1Be hydrogen or deuterium;
R
2Be hydrogen, C
1-C
6Alkyl;
R
3Be hydrogen, the C of straight or branched
1-C
6Alkyl, perhaps R
3Representative-COO R
4, wherein, R
4C for straight or branched
1-C
6Alkyl.
According to one aspect of the invention, R
2For being selected from-CH
3,-CH
2CH
3,-CH
2CH
2CH
3,-CH (CH
3) CH
3,-CH
2CH (CH
3)
2,-(CH
2)
3CH
3,-(CH
2)
4CH
3,-(CH
2)
5CH
3,-(CH
2)
2CH (CH
3) CH
3,-CH
2C (CH
3)
3,-C (CH
3)
3And-CH
2CH
2C (CH
3)
3In a kind of.
According to another aspect of the invention, R
3Representative-COOR
4, R wherein
4For being selected from-CH
3,-CH
2CH
3,-CH
2CH
2CH
3,-CH (CH
3) CH
3,-CH
2CH (CH
3)
2,-(CH
2)
3CH
3,-(CH
2)
4CH
3,-(CH
2)
5CH
3,-(CH
2)
2CH (CH
3) CH
3,-CH
2C (CH
3)
3,-C (CH
3)
3And-CH
2CH
2C (CH
3)
3In a kind of.
According to an aspect of the present invention, it provides suc as formula (IIa) or (IIb) represented compound.
Should be understood that the present invention's " compound " comprises any kind or all in this class form.
According to the present invention, described pharmacologically acceptable salt includes but not limited to hydrochloride, phosphoric acid salt, vitriol, acetate, maleate, metilsulfate, benzene sulfonate, toluenesulfonate, fumarate, tartrate etc.
Compound of the present invention can be used for preparing anti-malignant tumor medicine, and malignant tumour described here includes but not limited to chronic lymphocytic leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, lung cancer, ovarian cancer, prostate cancer, soft tissue sarcoma and glioblastoma etc.
The preparation of The compounds of this invention can be by the route of synthesis of well-known those the similar methods of chemical field, and particularly compound of the present invention is synthesized in the description that comprises according to this paper.Reagent generally obtains or is easy to use the well-known method preparation of those skilled in the art from commercial source.U.S. Patent number 6,596, the description of the preparation of 746 pairs of Dasatinibs will be incorporated into this paper as a reference.
Because the enforcement of above technical scheme, the present invention compared with prior art has following advantage:
1, the first pass effect of The compounds of this invention is very little, and bioavailability is very high;
2, The compounds of this invention has very high water solubility, can reach 15-20mg/mL, thereby is convenient to prepare its preparation and improves its effective bioavailability.
Description of drawings
Fig. 1 is the graph of a relation that the tumor average volume of formula (Ib) the compound group fate after with tumour transplatation changes;
Fig. 2 is the graph of a relation that the fate of formula (Ib) compound group nude mice mean body weight after with tumour transplatation changes.
Embodiment
Hereinafter, the compound that provides has provided title and structural formula simultaneously, and wherein compound is as the criterion with structural formula, and name is called reference.
The reactive material of Shi Yonging hereinafter, if do not provide the preparation method especially, promptly showing can be directly by commercially available.
The present invention will be further described in detail below in conjunction with specific embodiment, but the present invention is not limited to following examples.
Embodiment 1
Formula (Ia) compound, its chemical name are N-(2-chloro-6-aminomethyl phenyl)-2-[[6-[4-(2-amino-3-methyl-butyl carbonyl)-2,2,3,3,5,5,6,6-eight deuteriums-1-piperazinyl]-2-methyl-4-pyrimidyl] amino]-the 5-thiazole carboxamides.
Embodiment 2
Formula (Ib) compound, its chemical name are N-(2-chloro-6-aminomethyl phenyl)-2-[[6-[4-(2-(N-tertbutyloxycarbonyl) amino)-3-methyl-butyl carbonyl)-2,2,3,3,5,5,6,6-eight deuteriums-1-piperazinyl]-2-methyl-4-pyrimidyl] amino]-the 5-thiazole carboxamides.
Embodiment 3
Formula (IIa) compound, its chemical name are N-(2-chloro-6-aminomethyl phenyl)-2-[[6-[4-(2-amino-3-methyl-butyl carbonyl)-1-piperazinyl]-2-methyl-4-pyrimidyl] amino]-the 5-thiazole carboxamides.
Embodiment 4
Formula (IIb) compound, its chemical name are N-(2-chloro-6-aminomethyl phenyl)-2-[[6-[4-(2-(N-tertbutyloxycarbonyl-amino)-3-methyl-butyl carbonyl)-1-piperazinyl]-2-methyl-4-pyrimidyl] amino]-the 5-thiazole carboxamides.
Present embodiment provides the preparation method of the compound that a kind of following formula represents,
Wherein, R
2, R
4Definition is with the summary of the invention part.
This compound can prepare by the synthetic route that following equation is represented:
Below with R in the formula
2Be sec.-propyl, R
4For the compound of tertiary butyl representative also is that formula (Ib) compound is an example, describe its preparation process in detail.
The preparation process of formula (Ib) compound comprises the steps:
(1), preparation 1-tertbutyloxycarbonyl-deuterium is for piperazine: at room temperature, while stirring with sodium hydroxide (0.78g, 19.5mmol) aqueous solution of 1mL slowly is added drop-wise to deuterium for piperazine hydrochloride (3.25g, 19.4mmol) in, reacted about 5 minutes, and then dropping 250mL methyl alcohol, stir after 30 minutes, being reflected at the cryosel bath stirred 30 minutes for following-20 ℃, slowly drip simultaneously the methanol solution (4.25g of tert-Butyl dicarbonate, 19.5mmol) about 50mL, be placed on room temperature reaction 1 hour, concentrate, add water and stir 15 minutes after-filtration, filtrate is used dichloromethane extraction, the organic phase anhydrous sodium sulfate drying, and filtering and concentrating also obtains clear crystal in vacuum-drying and is 1-tertbutyloxycarbonyl-deuterium for piperazine.
(2), preparation N-(2-chloro-6-aminomethyl phenyl)-2-[[6-[4-tertbutyloxycarbonyl-2,2,3,3,5,5,6,6-eight deuteriums-1-piperazinyl]-2-methyl-4-pyrimidyl] amino]-the 5-thiazole carboxamides: while stirring with 1-tertbutyloxycarbonyl-deuterium for piperazine (2.1g, 10.8mmol) and N, N-diisopropylethylamine (2.8g 21.7mmol) slowly is added drop-wise to N-(2-chloro-6-methyl-phenyl)-2-[(6-chloro-2-methyl-4-pyrimidyl) amino]-5 thiazole carboxamides (3.6g, 9.1mmol) in the dimethyl sulfoxide (DMSO) 100mL solution, be heated to 115 ℃, under agitation reacted 18 hours, cool to room temperature adds water has precipitation to separate out, at room temperature stir filtration in 15 minutes, obtain light brown powder with ethyl acetate rinse, after obtain pure light brown product with re-crystallizing in ethyl acetate again and be N-(2-chloro-6-aminomethyl phenyl)-2-[[6-[4-tertbutyloxycarbonyl-2,2,3,3,5,5,6,6-eight deuteriums-1-piperazinyl]-2-methyl-4-pyrimidyl] amino]-the 5-thiazole carboxamides.
Compound to preparation has carried out hydrogen nuclear magnetic resonance
1H NMR (400MHz, d6-DMSO) and mass spectrometric measurement, the result is as follows:
1Absorption peak in the H NMR spectrogram: 11.50 (s, 1H), 9.87 (s, 1H), 8.22 (s, 1H), 7.40 (m, 1H), 7.27 (m, 2H), 6.01 (s, 1H), 2.40 (s, 3H), 2.44 (s, 3H) .1.42 (s, 9H); M/s:[MH]+: 552.
(3), preparation N-(2-chloro-6-aminomethyl phenyl)-2-[[6-(2,2,3,3,5,5,6,6-eight deuteriums-1-piperazinyl)-and 2-methyl-4-pyrimidyl] amino]-the 5-thiazole carboxamides: at room temperature, (2.4g is in 100mL dichloromethane solution 4.4mmol) while stirring the 5mL trifluoroacetic acid slowly to be added drop-wise to step (2) gained compound, reacted 2 hours, solvent spun off obtain light brown powder, clean with saturated sodium hydrogen carbonate solution again and stirred 15 minutes, filter and promptly get N-(2-chloro-6-aminomethyl phenyl)-2-[[6-(2,2,3,3,5,5,6,6-eight deuteriums-1-piperazinyl)-2-methyl-4-pyrimidyl] amino]-5-thiazole carboxamides (1.95g, 99.2%).
Compound to preparation has carried out hydrogen nuclear magnetic resonance
1H NMR (400MHz, d6-DMSO) and mass spectrometric measurement, the result is as follows:
1Absorption peak in the H NMR spectrogram: 9.88 (s, 1H), 8.22 (s, 1H), 7.41 (d, 1H), 7.27 (m, 2H), 6.01 (s, 1H), 2.40 (s, 3H), 2.24 (s, 3H).
m/z：[MH]
+＝452。
(4); preparation formula (Ib) compound: at room temperature; while stirring with 2-(1H-benzo trisazo-L-1-yl)-1; 1; 3; 3-tetramethyl-urea Tetrafluoroboric acid ester (TBTU) (0.8g; 2.5mmol) be added drop-wise to uncle's 2-fourth oxanamide base-3 Methylbutanoic acid (0.43g; 2.0mmol) N; among the dinethylformamide 10mL; under same condition, stirred 30 minutes; the back slowly adds N under nitrogen protection; N-diisopropylethylamine (0.64g; 5.0mmol); stirred 30 minutes under the same condition; postcooling to 0 ℃; slowly drip step (3) gained compound (0.75g, N 1.66mmol), dinethylformamide solution 5mL to this reaction system; after dropwising; return to stirring at room and reacted about 18 hours, after reaction finishes, to wherein adding water; use ethyl acetate extraction; with saturated sodium chloride solution washing, add anhydrous sodium sulfate drying again, filtering and concentrating vacuum-drying gets thick product; after obtaining white powder (0.54g, 50.0%), 1: 19 mistake of methyl alcohol and methylene dichloride column purification is formula (Ib) compound.
Compound to preparation has carried out hydrogen nuclear magnetic resonance
1H NMR (400MHz, d6-DMSO) and mass spectrometric measurement, the result is as follows:
1Absorption peak in the H NMR spectrogram: 11.64 (s, 1H), 9.89 (s, 1H), 8.22 (s, 1H), 7.40 (d, J=8.8Hz, 1H), 7.27 (m, 2H), 6.89 (d, J=8.8Hz, 1H), 6.06 (s, 1H), 4.27 (m, 1H), 2.43 (s, 3H), 2.24 (s, 3H), 1.99 (m, 1H), 1.38 (s, 9H), 6.86 (d, J=6.4Hz, 6H).
m/z：[MH]
+＝651。
Embodiment 6
Present embodiment provides the preparation method of the compound that a kind of following formula represents,
In the formula, R
2Definition is with embodiment 5, and the compound that the compound that this formula is represented can embodiment 5 preparations is a raw material, reacts to obtain under the trifluoroacetic acid effect.With R in the formula
2The compound of representing for sec.-propyl is an example, and its concrete preparation process is as follows:
At room temperature, while stirring the 0.1mL trifluoroacetic acid slowly is added drop-wise to formula (Ib) compound (35mg, 0.054mmol) the 1mL dichloromethane solution in, reacted 1 hour, solvent spun off obtain light brown powder, clean with saturated sodium hydrogen carbonate solution again and stirred 15 minutes, filter and promptly obtain target product (21mg, 70.9%).
Compound to preparation has carried out hydrogen nuclear magnetic resonance
1H NMR (400MHz, d6-DMSO) and mass spectrometric measurement, the result is as follows:
1Absorption peak in the H NMR spectrogram: 9.88 (s, 1H), 8.22 (s, 1H), 7.29 (d, J=6.0Hz, 1H), 7.25 (m, 2H), 6.07 (s, 1H), 2.43 (s, 3H), 2.24 (s, 3H), 1.75 (m, 1H), 0.90 (d, J=6.4Hz, 3H), 0.82 (d, J=6.8Hz, 3H).
m/z：[MH]
+＝551。
Present embodiment provides a kind of N-(2-chloro-6-aminomethyl phenyl)-2-[[6-[4-(2-(N-butyl ester base-amino)-3-methyl-butyl carbonyl)-2,2,3,3,5,5,6,6-eight deuteriums-1-piperazinyl]-2-methyl-4-pyrimidyl] amino]-preparation method of 5-thiazole carboxamides mesylate (being the mesylate of formula (Ib) compound), specific as follows:
At room temperature, while stirring with methylsulfonic acid (18mg, (100mg is in 5mL methanol solution 0.184mmol) 0.187mmol) slowly to be added drop-wise to formula (Ib) compound, reacted 1 hour, removing desolvates obtains the mesylate (yield 89%) that white powder 105mg is formula (Ib) compound.
Embodiment 8
Present embodiment provides a kind of N-(2-chloro-6-aminomethyl phenyl)-2-[[6-[4-(2-(N-butyl ester base-amino)-3-methyl-butyl carbonyl)-2,2,3,3,5,5,6,6-eight deuteriums-1-piperazinyl]-2-methyl-4-pyrimidyl] amino]-preparation method of 5-thiazole carboxamides mesylate (being the Citrate trianion of formula (Ib) compound), specific as follows:
At room temperature, while stirring with citric acid (the monohydrate) (39mg of 1ml, 0.185mmol) methanol solution slowly is added drop-wise to (100mg, 0.184mmol) the 5mL methanol solution in, be heated to 80C then, reacted 1 hour, temperature drops to room temperature, removing desolvates obtains white powder, and with the anhydrous diethyl ether washing, 118mg is Citrate trianion (yield 88.7%) again.
Embodiment 9
Present embodiment provides the preparation method of the compound that a kind of following formula represents,
Wherein, R
2, R
4Definition is with the summary of the invention part.
This preparation method comprises the steps:
(1), by the synthetic N-(2-chloro-6-deuterium is for methyl-phenyl) of following synthetic route-2-[(6-chloro-2-methyl-4-pyrimidyl) amino]-5 thiazole carboxamides
(2), with step (1) gained N-(2-chloro-6-deuterium is for methyl-phenyl)-2-[(6-chloro-2-methyl-4-pyrimidyl) amino]-5 thiazole carboxamides are raw material, by obtaining target product with embodiment 5 steps (2) to the identical method of step (4).
The test of pesticide effectiveness
One, tumour cell inhibition test:
1, test method
(1), compound: earlier test compounds is dissolved among the 100%DMSO in the in vitro study, redilution is to desired concn, and the final concentration of DMSO is 0.1%.The DMSO of 0.1% (v/v) is added substratum as solvent control, totally 9 concentration gradients, repeated test secondary.
(2), tumor cell line: the tumour cell of surveying ties up in RPMI1 0 substratum that contains 10% foetal calf serum, in 5%CO
2, cultivate in 37 ℃ of incubators.The tumour cell of surveying is: 1) A375, melanoma (Melanoma) tumour cell; 2) A673, neck struma oncocyte; 3) HepG2, tumor cell of liver; 4) U87, neurospongioma (Glioma) tumour cell; 5) K562, leukemia (Leukemia) tumour cell; 6) MDA-MB-231, the breast cancer tumour cell; 7) A549 and H460, the nonsmall-cell lung cancer tumour cell; 8) HT29, the colorectal carcinoma cell; 9) PC-3, the prostate cancer tumour cell; 10) Mia-PaCa-2, the pancreatic tumour cell.
(3), CellTiter-Glo cytoactive fluoroscopic examination test: cell inoculation in 96 orifice plates, 3000 cells in every hole, and at 5%CO
2, overnight incubation in 37 ℃ of humidification incubators.After adding test compounds in the hand-hole in second day, hatched again 72 hours.Use the CellTiter-Glo cytoactive fluorescence detection reagent kit of Promega company to detect cell activity.Calculate IC
50(compare to make the cell growth be subjected to 50% suppress required drug level, use the nonlinear regression analysis of GraphPad Prism software to calculate) with the DMSO control group.
(4), sample analysis:
1) contains and add the detection reagent for preparing in 96 orifice plates of 100 μ L cell culture mediums and carry out viable cell and detect, do not have cell (only containing substratum) to contrast as a setting in the plate hole, have only substratum not have detection reagent as experiment contrast.Hatch according to culture scheme.
2) the about 30min of balance plank and test sample under the room temperature.
3) add equal-volume (100 μ L) CellTiter-Glo
TMReagent mixes 2min gently on the vortice, incubated at room 10min makes luminous signal stable.CellTiter-Glo
TMThe luciferase test kit unites to use quantitatively to be provided easily and fast a kind of and the sensitive method as viable count, realizes by quantitative ATP, and it is the semiochemicals in the viable cell metabolism.CellTiter-Glo
TMThe viable cell detection kit adopts luciferase to do to detect thing, because there is not the interference of endogenous luciferase in the mammalian cell, and the steady glow type signal that uses the UltraGlow luciferase to generate in the test kit, the transformation period surpasses 4h.The luminous signal of overlength is that many plates provide the foundation with batch detection.Luciferase needs the participation of ATP in the luminescence process, has the respiration of metabolic activity cell and other vital movement processes can produce ATP.In cell culture medium, add equal-volume CellTiter-Glo
TMReagent is measured luminous value, and the ATP amount is directly proportional in optical signal and the system, and ATP and viable count positive correlation.
4) plate is put into the multi-functional luminosity meter of Modulus microwell plate, clicked " Start " and begin to detect, after detection finished, take off data can show that run into other problems in detecting, the problem introduction of please refer to obtains more information with the Excel tabulated form.
5) detect to finish just can to carry out data analysis and calculate 50% inhibition concentration IC by Excel
50
2, test-results
See also table 1.
Table 1
As seen, each compound of test has all showed inhibition activity in various degree to various tumour cells from table 1, has particularly shown that for wild-type BCR-ABL (K562) cell strain growth significant inhibition is active.
Two, the restraining effect of human leukemia tumour cell transplanted tumor in nude mice test
1, test method: 20 of nude mices (male, 6 ages in week), inoculation K562 human leukemia tumour cell treats that the knurl average-volume reaches 300mm
3The time, be divided into 2 groups at random, be respectively control group and 10mg/kg/ days formula (Ib) compound dosage group, successive administration 10 days, vein or subcutaneous injection.Write down twice tumour size and body weight weekly from medication treatment beginning in first day.If medication caused＞20% dead and/or 20% would lose weight only then think ' toxic '.With formula (l * w
2) calculate the weight of tumour, the wherein each minimum and maximum size of measuring (mm) of l and w representative.Draw graph of a relation and the nude mice mean body weight that the fate of tumor average volume after with tumour transplatation change respectively according to result calculated and change the graph of a relation that changes with the fate after the tumour transplatation.
2, result: referring to Fig. 1 and Fig. 2, the test of human leukemia tumour cell transplanted tumor in nude mice shows that The compounds of this invention has extremely strong restraining effect to the leukemia tumour, and the nude mice tumour promptly disappears or completely dissolve after with a course of treatment of The compounds of this invention treatment substantially.Simultaneously, nude mice mean body weight result of variations shows that the general toxicity of The compounds of this invention is very little, and its resistance is very high.
Similar with Dasatinib, compound of the present invention can be used for but is not limited to treat chronic myelocytic leukemia (CML), and it can combine with dissimilar pharmaceutical salts and make oral preparations (tablet or capsule etc.).The tablet made from The compounds of this invention or capsule can be taken once a day or repeatedly.The compounds of this invention also can be made compound preparation with other its medicine combinations.
The foregoing description only is explanation technical conceive of the present invention and characteristics, and its purpose is to allow the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences that spirit is done according to the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (10)
1. thiazole amide compound and pharmacologically acceptable salt thereof, it is characterized in that: described thiazole amide compound has the structure shown in the formula (I),
Wherein,
R
1Be hydrogen or deuterium;
R
2Be hydrogen, C
1-C
6Alkyl;
R
3Be hydrogen, the C of straight or branched
1-C
6Alkyl, perhaps R
3Representative-COOR
4, wherein, R
4C for straight or branched
1-C
6Alkyl.
2. thiazole amide compound according to claim 1 and pharmacologically acceptable salt thereof is characterized in that: described R
2For being selected from-CH
3,-CH
2CH
3,-CH
2CH
2CH
3,-CH (CH
3) CH
3,-CH
2CH (CH
3)
2,-(CH
2)
3CH
3,-(CH
2)
4CH
3,-(CH
2)
5CH
3,-(CH
2)
2CH (CH
3) CH
3,-CH
2C (CH
3)
3,-C (CH
3)
3And-CH
2CH
2C (CH
3)
3In a kind of.
3. thiazole amide compound according to claim 1 and pharmacologically acceptable salt thereof is characterized in that: described R
3Representative-COOR
4, R wherein
4For being selected from-CH
3,-CH
2CH
3,-CH
2CH
2CH
3,-CH (CH
3) CH
3,-CH
2CH (CH
3)
2,-(CH
2)
3CH
3,-(CH
2)
4CH
3,-(CH
2)
5CH
3,-(CH
2)
2CH (CH
3) CH
3,-CH
2C (CH
3)
3,-C (CH
3)
3And-CH
2CH
2C (CH
3)
3In a kind of.
4. thiazole amide compound according to claim 1 and pharmacologically acceptable salt thereof is characterized in that: its structural formula is suc as formula (I is a) or shown in (I b).
5. thiazole amide compound and pharmacologically acceptable salt thereof, it is characterized in that: described thiazole amide compound has the structure shown in the formula (II),
Wherein,
R
1Be hydrogen or deuterium;
R
2Be hydrogen, C
1-C
6Alkyl;
R
3Be hydrogen, the C of straight or branched
1-C
6Alkyl, perhaps R
3Representative-COO R
4, wherein, R
4C for straight or branched
1-C
6Alkyl.
6. thiazole amide compound according to claim 5 and pharmacologically acceptable salt thereof is characterized in that: described R
2For being selected from-CH
3,-CH
2CH
3,-CH
2CH
2CH
3,-CH (CH
3) CH
3,-CH
2CH (CH
3)
2,-(CH
2)
3CH
3,-(CH
2)
4CH
3,-(CH
2)
5CH
3,-(CH
2)
2CH (CH
3) CH
3,-CH
2C (CH
3)
3,-C (CH
3)
3And-CH
2CH
2C (CH
3)
3In a kind of.
7. thiazole amide compound according to claim 5 and pharmacologically acceptable salt thereof is characterized in that: described R
3Representative-COOR
4, R wherein
4For being selected from-CH
3,-CH
2CH
3,-CH
2CH
2CH
3,-CH (CH
3) CH
3,-CH
2CH (CH
3)
2,-(CH
2)
3CH
3,-(CH
2)
4CH
3,-(CH
2)
5CH
3,-(CH
2)
2CH (CH
3) CH
3,-CH
2C (CH
3)
3,-C (CH
3)
3And-CH
2CH
2C (CH
3)
3In a kind of.
8. thiazole amide compound according to claim 5 and pharmacologically acceptable salt thereof is characterized in that: the structural formula of described thiazole amide compound is (IIa) or (IIb).
In the claim 1 to 8 described thiazole amide compound of each claim and pharmacologically acceptable salt thereof in the purposes of preparation in the anti-malignant tumor medicine.
In the claim 1 to 8 described thiazole amide compound of each claim and pharmacologically acceptable salt thereof in the purposes that suppresses aspect the tumor proliferation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010503001XA CN101973989B (en) | 2010-05-17 | 2010-09-29 | Thiazole amide compound and medicinal application thereof for treating malignancy |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010173515 | 2010-05-17 | ||
| CN201010173515.3 | 2010-05-17 | ||
| CN201010503001XA CN101973989B (en) | 2010-05-17 | 2010-09-29 | Thiazole amide compound and medicinal application thereof for treating malignancy |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101973989A true CN101973989A (en) | 2011-02-16 |
| CN101973989B CN101973989B (en) | 2012-07-18 |
Family
ID=43452109
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010105030486A Expired - Fee Related CN101948467B (en) | 2010-05-17 | 2010-09-29 | Thiazoleamide compound and use thereof for the preparation of anti-malignant tumor medicines |
| CN201010503001XA Expired - Fee Related CN101973989B (en) | 2010-05-17 | 2010-09-29 | Thiazole amide compound and medicinal application thereof for treating malignancy |
| CN2010105030560A Expired - Fee Related CN101967142B (en) | 2010-05-17 | 2010-09-29 | Thiazoleamide compound and medical application thereof in treating malignant tumor |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010105030486A Expired - Fee Related CN101948467B (en) | 2010-05-17 | 2010-09-29 | Thiazoleamide compound and use thereof for the preparation of anti-malignant tumor medicines |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010105030560A Expired - Fee Related CN101967142B (en) | 2010-05-17 | 2010-09-29 | Thiazoleamide compound and medical application thereof in treating malignant tumor |
Country Status (1)
| Country | Link |
|---|---|
| CN (3) | CN101948467B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012395A (en) * | 2013-01-04 | 2013-04-03 | 南京优科生物医药有限公司 | Preparation method of heterocyclic benzene compound |
| CN103172627A (en) * | 2011-12-26 | 2013-06-26 | 南京优科生物医药有限公司 | Heterocyclic benzopyrimidine or quinoline compound and applications thereof |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102391263B (en) * | 2011-09-13 | 2013-05-29 | 济南德爱医药技术有限公司 | Deuteroacetyl-containing kinase inhibitor |
| EA201892726A1 (en) * | 2013-03-15 | 2019-04-30 | Консерт Фармасьютикалс, Инк. | DEUTERED PALBOCYCLIB |
| CN103319476B (en) * | 2013-06-13 | 2015-12-02 | 济南德爱医药技术有限公司 | A kind of kinase inhibitor |
| CN106749223B (en) * | 2015-11-25 | 2019-12-20 | 中国科学院广州生物医药与健康研究院 | Tyrosine kinase inhibitor and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006099474A1 (en) * | 2005-03-15 | 2006-09-21 | Bristol-Myers Squibb Company | 'n-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamides metabolites |
| CN101018547A (en) * | 2004-07-19 | 2007-08-15 | 默克公司 | Histone deacetylase inhibitors |
| CN101591357A (en) * | 2008-11-20 | 2009-12-02 | 杜晓敏 | One group is suppressed the kinase whose phosphate/phosphate ester compounds of BCR-ABL |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3222619A1 (en) * | 1999-04-15 | 2017-09-27 | Bristol-Myers Squibb Holdings Ireland | Cyclic protein tyrosine kinase inhibitors |
| CN1980909B (en) * | 2004-02-06 | 2010-08-25 | 布里斯托尔-迈尔斯·斯奎布公司 | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
-
2010
- 2010-09-29 CN CN2010105030486A patent/CN101948467B/en not_active Expired - Fee Related
- 2010-09-29 CN CN201010503001XA patent/CN101973989B/en not_active Expired - Fee Related
- 2010-09-29 CN CN2010105030560A patent/CN101967142B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101018547A (en) * | 2004-07-19 | 2007-08-15 | 默克公司 | Histone deacetylase inhibitors |
| WO2006099474A1 (en) * | 2005-03-15 | 2006-09-21 | Bristol-Myers Squibb Company | 'n-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamides metabolites |
| CN101591357A (en) * | 2008-11-20 | 2009-12-02 | 杜晓敏 | One group is suppressed the kinase whose phosphate/phosphate ester compounds of BCR-ABL |
Non-Patent Citations (2)
| Title |
|---|
| 《Drug Metabolism and Disposition》 20081231 He, Kan et al. Lacteal secretion, fetal and maternal tissue distribution of dasatinib in rats 第2564-2570页 1-9 第36卷, 第12期 2 * |
| 《Registry》 20091025 ACS 1189998-96-6 1-9 , 2 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103172627A (en) * | 2011-12-26 | 2013-06-26 | 南京优科生物医药有限公司 | Heterocyclic benzopyrimidine or quinoline compound and applications thereof |
| CN103172627B (en) * | 2011-12-26 | 2015-11-18 | 南京优科生物医药有限公司 | Heterocyclic pyrimidinium benzene or pyridine benzene-like compounds and application thereof |
| CN103012395A (en) * | 2013-01-04 | 2013-04-03 | 南京优科生物医药有限公司 | Preparation method of heterocyclic benzene compound |
| CN103012395B (en) * | 2013-01-04 | 2015-05-13 | 南京优科生物医药有限公司 | Preparation method of heterocyclic benzene compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101948467B (en) | 2012-07-25 |
| CN101967142B (en) | 2012-05-30 |
| CN101967142A (en) | 2011-02-09 |
| CN101948467A (en) | 2011-01-19 |
| CN101973989B (en) | 2012-07-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101973989B (en) | Thiazole amide compound and medicinal application thereof for treating malignancy | |
| CN103570727B (en) | A kind of N-benzyl couroupitine A derivative and its preparation method and application | |
| CN102295635B (en) | Antitumor medicament tetralin amide compounds and pharmaceutically acceptable salts thereof as well as preparation method and application of antitumor medicament tetralin amide compounds | |
| CN102838590B (en) | Amino quinazoline derivative and application thereof in preparation of antineoplastic drugs | |
| JPS5835995B2 (en) | Naphthalimides, their production methods and their uses | |
| US20070244110A1 (en) | Treatment of prostate cancer, melanoma or hepatic cancer | |
| CN105254615A (en) | Phenylaminopyrimidine derivatives and their use in preparation of drugs for resisting cancers | |
| CN107245075A (en) | Simultaneously [3,4 d] pyrimidines and its salt and the application of 2,4,6 3 substituted pyridines | |
| CN106660970B (en) | Quinazoline derivatives | |
| CN102066362B (en) | Dihydroindolinone derivatives | |
| CN104774221B (en) | Metal complexes of quinolinone derivatives, synthesis method and applications thereof | |
| CN109071462A (en) | Quinazoline derivant or its salt and the pharmaceutical composition comprising it | |
| CN104262263B (en) | N,6 diphenylpyrimidine-4-amine Bcr-Abl inhibitors as well as preparation method and application thereof | |
| CN104725431B (en) | Cobalt (II) complex of quinolinone derivative, and synthesis method and application thereof | |
| CN104817535A (en) | Quinolinone derivative, and synthetic method and application thereof | |
| CN102603712A (en) | S-type and R-type tetrahydro-naphthalene amides antitumor compound and pharmaceutically acceptable salt or pro-drug thereof, preparation method and application | |
| CN112004801B (en) | Crystal form and salt form of c-MET inhibitor and preparation method thereof | |
| CN103864720B (en) | Derived from phenyl acrylic acid farnesyl thio-salicylic acid derivative and preparation method and purposes | |
| WO2012139487A1 (en) | Pegylated derivatives of camptothecin compounds | |
| CN105566145A (en) | Amino acid derivative and application thereof | |
| CN107129465B (en) | Aryl guanidine compound and preparation method and application thereof | |
| CN105272933B (en) | 5 naphthyl 2 amino benzo [d] oxazole derivative and its production and use | |
| CN115304605B (en) | Oxetane derivatives with antitumor activity, and preparation method and application thereof | |
| TWI788444B (en) | Crystal form of fgfr4 inhibitor and its preparation method thereof | |
| CN102702116B (en) | 4-(3-chloro-4-methoxylanilino)-6-(3-amidophenyl)quinazoline compound or pharmaceutically-acceptable salt thereof and preparation methods and applications thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: SUZHOU DEPU MEDICAL TECHNOLOGY CO., LTD. Free format text: FORMER OWNER: SUZHOU BORUT PHARMACEUTICALS INC. Effective date: 20121225 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 215125 SUZHOU, JIANGSU PROVINCE TO: 215123 SUZHOU, JIANGSU PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20121225 Address after: Xinghu Street Industrial Park of Suzhou city in Jiangsu province 215123 No. 218 building A2 room 323 Patentee after: Suzhou General Medical Technology Co Ltd Address before: Xinghu Street Industrial Park of Suzhou city in Jiangsu province 215125 No. 218 building A2 room 327 Patentee before: Suzhou Borui Parmaceuticals, Inc. |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120718 Termination date: 20140929 |
|
| EXPY | Termination of patent right or utility model |