CN109232467B - Thiazole aminobenzoic acid derivative and application thereof - Google Patents
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Abstract
The invention discloses a thiazolylaminobenzoic acid derivative with antitumor activity, which can be used for preparing an anticancer drug, particularly as a Bcr-Abl tyrosine kinase inhibitor, and particularly as a T315I mutant Bcr-Abl tyrosine kinase inhibitor.
Description
Technical Field
The invention relates to the field of medicinal chemistry, and particularly relates to a series of thiazole aminobenzoic acid derivatives, and a preparation method and application thereof.
Background
Chronic Myeloid Leukemia (CML), a malignant myeloproliferative disease originating from hematopoietic stem cells, accounts for 15% -20% of all leukemias, is the most common myeloproliferative disease. The origin of the disease is from the Bcr-Abl gene formed by fusing the proto-oncogene c-Abl on the chromosome 9 and the Bcr gene on the chromosome 22. Currently, bcr-Abl tyrosine kinase has been demonstrated to be the most ideal molecular target for the treatment of CML (Blood, 1996, 87: 3036-3038, blood, 2000, 96, 343-356). Various efforts have been made by the pharmaceutical workers around the Bcr-Abl tyrosine kinase. Currently, the successfully marketed Bcr-Abl tyrosine kinase inhibitors are imatinib, nilotinib, ladotinib, dasatinib, sulbactam and ponatinib.
Wherein imatinib is a first-generation Bcr-Abl tyrosine kinase inhibitor and is a first-line medicament for treating CML, but a part of patients in different periods can generate drug resistance after long-term administration. Resistance may be caused by a variety of mechanisms, of which Bcr-Abl point mutations are the most common and most influential resistance mechanisms (Nat Rev Drug Discov, 2007, 6 (10): 834-848).
Nilotinib, ladotinib, dasatinib and bosutinib are second generation Bcr-Abl tyrosine kinase inhibitors. Compared with imatinib, the drug resistance produced by most mutants can be solved, but the drug resistance caused by the T315I mutation cannot be effectively solved (Ann Oncol, 2007, 18 (6): 42-46; eur J Cancer, 2010, 46 (10): 1781-1789 Haematologica, 2014, 99 (7): 1191-1196).
Ponatinib is a third-generation Bcr-Abl tyrosine kinase inhibitor and can effectively solve drug resistance caused by T315I mutation (Cancer Cell, 2009, 16 (5): 401-412). However, ponatinib can cause serious and fatal thrombosis and angiostenosis, and can induce complications such as heart disease, myocardial infarction, stroke, limb ischemia and even tissue necrosis (Chinese medicine alert, 2017, 14 (4): 218-221).
The T315I mutation occurs at position 315 in the Bcr-Abl kinase domain, referred to as "gatekeeper", and the threonine (Thr) in the wild-type Bcr-Abl is replaced by isoleucine (Ile). Thr315 in the wild-type Bcr-Abl can form a key hydrogen bond with imatinib, nilotinib and the like, and when the Thr315 is substituted by Ile315, the key hydrogen bond cannot be formed. In addition, ile315 after mutation sterically hinders imatinib to make it effective against wild-type Bcr-Abl and not against Bcr-ablT315I due to its large size (Cancer Cell, 2002, 2 (2): 117-125 Bioorg Med Chem Lett, 2008, 18: 4907-4912. The research on the effect of the ponatinib and Bcr-AblT315I shows that: the alkyne bond in the ponatinib structure does not form hydrogen bonds with both Thr315 and Ile315, and does not sterically hinder Ile315 due to the smaller structure (pharmaceutical advances, 2014, 38 (5): 333-339 cancer Cell, 2009, 16 (5): 401-412.
In earlier work, the inventor designs and synthesizes a series of 2-aminothiazole compounds, and the activity test result shows that the 2-aminothiazole compounds have good antitumor activity (CN 102319244A, CN102675303, CN1080031152A and CN 107459513A). Therefore, the inventor thinks that the 2-aminothiazole group is combined into a molecular structure, and expects to obtain a Bcr-Abl tyrosine kinase inhibitor which can be used as a T315I mutant and reduce toxic and side effects to a human body.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: a class of thiazolylaminobenzoic acid derivatives are provided, which can be used as T315I mutant Bcr-Abl tyrosine kinase inhibitors.
In a first aspect, the present invention provides compounds of formula I and pharmaceutically acceptable salts thereof, having the following structure:
I
wherein: r 1 Each independently selected from halogen, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy;
R 2 selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy;
n is selected from 0, 1, 2,3 or 4.
Preferably, R 1 Each independently selected from halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, more preferably methyl, chloro, fluoro, hydroxy, trifluoromethyl; n is selected from 0, 1 or 2, preferably 0 or 1.
Preferably, R 2 Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, more preferably methyl, ethyl, trifluoromethyl.
More preferably, the compounds of formula I according to the present invention are selected from the following compounds:
in another aspect of the invention there is provided a process for the preparation of a compound of formula I, the reaction scheme being as follows:
wherein R is 1 、R 2 And n is as defined above.
The preparation method of the invention specifically comprises the following reaction steps:
the method comprises the following steps: adding ammonium thiocyanate and acetone into a reactor, stirring uniformly, then dropwise adding benzoyl chloride, changing the solution from clear to white turbid liquid, heating to reflux, adding m-aminobenzoic acid in batches, cooling after the reaction is finished, filtering, and drying the obtained solid to obtain 3- (3-benzoyl thiourea) benzoic acid;
step two: adding 3- (3-benzoylthiourea) benzoic acid and an alkaline aqueous solution into a reaction bottle to enable the pH value to be =13, stirring, heating and refluxing until the reaction is finished, cooling to the room temperature, adding dilute hydrochloric acid, adjusting the pH value to 2, standing for 24 hours, separating out a solid, filtering, and drying the solid to obtain 3-carboxyphenylthiourea;
step three: adding 3-carboxyphenylthiourea, substituted 2-Br-1-acetophenone and glacial acetic acid into a reaction bottle, uniformly stirring, heating to reflux, removing insoluble solids in the reaction bottle while the reaction is hot after the reaction is finished, evaporating partial solvent in a rotary manner, cooling for 24 hours at normal temperature in a ventilation kitchen, separating out solids, filtering, and drying the obtained solids to obtain the compound of the formula I.
Preferably, the molar ratio of m-aminobenzoic acid, ammonium thiocyanate and benzoyl chloride in step one is 1:1-1.5:1-1.5, preferably 1:1.2:1.3;
preferably, the alkaline aqueous solution in the second step is a 10% NaOH aqueous solution, and the concentration of dilute hydrochloric acid is 4mol/L;
preferably, the molar ratio of the 3-carboxyphenylthiourea and the substituted 2-Br-1-phenylalkylketone of step three is from 1:1 to 1.2, preferably 1:1.
In another aspect of the present invention, a pharmaceutical composition is provided, which comprises the compound represented by formula I or a pharmaceutically acceptable salt thereof described in the present invention, and a pharmaceutically acceptable carrier or excipient.
In another aspect, the invention relates to the use of a compound according to the invention or a pharmaceutical composition comprising said compound for the manufacture of a medicament for the treatment of a cancer associated with a Bcr-Abl tyrosine kinase, in particular a cancer targeted against a T315I mutated Bcr-Abl tyrosine kinase.
Preferably, the cancer is selected from human chronic myelogenous leukemia, liver cancer (such as HepG-2 cell line), non-small cell lung cancer (such as A549 cell line), more preferably human chronic myeloid leukemia (such as K562 cell line), K562 imatinib-resistant cell line (K562/R cell line).
Defining:
"alkyl" means consisting solely of carbon and hydrogen atoms, containing no unsaturation, and may be a C1-6 alkyl group. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Representative saturated straight chain alkyl groups include, but are not limited to-methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and-n-hexyl; and saturated branched alkyl groups include, but are not limited to-isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methyl-pentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethyl-butyl, and the like. The alkyl group is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl. In a non-limiting embodiment, the substituted alkyl group can be selected from the group consisting of fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.
"alkoxy" means an "alkyl" group attached to the parent molecule through an oxygen atom, wherein "alkyl" has the meaning described above.
"haloalkyl" refers to an alkyl group wherein all hydrogen atoms are partially or fully replaced with a halogen selected from fluoro, chloro, bromo, and iodo. In some embodiments, all hydrogen atoms are each replaced with fluoro groups. In some embodiments, all hydrogen atoms are each replaced with a chloro group. Examples of haloalkyl include-CF 3, -CF2CF2CF3, -CFCl2, -CF2Cl, and the like.
In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt, which is well known in the art. Examples of pharmaceutically acceptable salts are such as hydrochloric, hydrobromic, phosphoric, sulfuric, perchloric, acetic, oxalic, maleic, tartaric, citric, succinic or malonic, acetic, propionic, glycolic, pyruvic, oxalic, lactic, trifluoroacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic, and the like.
"pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coating agents, isotonic and absorption delaying agents and the like. Pharmaceutically acceptable carriers or excipients do not destroy the pharmacological activity of the disclosed compounds and are non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound. The use of such media and agents for pharmaceutically active substances is well known in the art.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention provides a new thiazole amino benzoic acid compound with anticancer activity, widens the range of the existing anticancer compound, and can be continuously optimized as a lead compound;
(2) The compound has good inhibition effect on a CML cell strain K562, has lower toxicity on human normal liver cells L02, and can avoid or reduce toxic and side effects on a human body while inhibiting cancer cells;
(3) The compounds of the invention are capable of interacting with a target tyrosine kinase Abl T315I Effectively combined, has good action strength, and can inhibit Bcr-Abl T315I Can effectively solve the problem of drug resistance caused by the T315I mutation, and can be used as a novel Bcr-Abl tyrosine kinase inhibitor for resisting the T315I mutationAnd (4) preparing the preparation.
Detailed Description
The present invention will be described in detail with reference to examples. In the present invention, the following examples are intended to better illustrate the present invention and are not intended to limit the scope of the present invention. The materials, reagents and the like used in the examples are commercially available unless otherwise specified.
Example 1- [ (5-Ethyl-4-phenylthiazol-2-yl) amino ] benzoic acid
A, step a:
to a 100 mL slant-mouth reaction flask equipped with a mechanical stirring and condensing tube, 11.4341 g (0.12 mol) of ammonium thiocyanate and 20mL of acetone were added, and stirred uniformly by mechanical stirring. 16.8034 g (0.13 mol) of benzoyl chloride were added dropwise (10 min complete) and the solution turned from clear to a cloudy white solution. Heating to reflux, 14.1147 g (0.10 mol) of m-aminobenzoic acid was added in 4 portions, and the progress of the reaction was monitored by TLC (ethyl acetate: petroleum ether = 4). Cooling, filtering and drying the obtained solid to obtain 28.0041 g of light yellow powder 3- (3-benzoyl thiourea) benzoic acid m.p. 184-186 ℃.
To a 100 mL inclined-mouth reaction flask with a condenser tube, 0.9913 g (0.12 mol) of 3- (3-benzoylthioureido) benzoic acid and 33 mL of 10% NaOH were added, pH =13 was measured, magnetic stirring was performed, heating was performed under reflux, TLC (ethyl acetate: petroleum ether = 4) monitored for the progress of the reaction, and the reaction was completed for 4 h. Cooling to room temperature, adding a proper amount of 4mol/L dilute hydrochloric acid, adjusting the pH to 2, standing for 24 hours, precipitating a solid, filtering, drying the obtained solid, and weighing to obtain 0.6142 g of white powder, wherein the yield is 86.72 percent and the m.p. is 186-187 ℃. 1 H NMR（DMSO-D 6 ，400 MHz）, δ：2.51（s，1H，NH）, 3.36（s, 2H, NH 2 ）, 7.43-8.03（m, 4H, C 6 H 4 ），9.89（s, 1H, COOH）。
Step b:3- [ (5-Ethyl-4-phenylthiazol-2-yl) amino ] benzoic acid
3.9432 g (0.02 mol) of 3-carboxyphenylthiourea, 4.5213 g (0.02 mol) of 2-Br-1-phenylbutanone and 20mL of glacial acetic acid were added to a 100 mL inclined-mouth reaction flask with a condenser tube, stirred uniformly, heated to reflux, and reacted for about 24h by monitoring the progress of the reaction by TLC (developing agent: ethyl acetate: petroleum ether = 4). The insoluble solid in the reaction flask was removed while hot and part of the solvent was rotary evaporated. And (3) cooling the mixture for 24 hours at normal temperature in a ventilation kitchen, separating out a solid, filtering, drying the obtained solid, and weighing 5.6.163 g of brown yellow powder, wherein the yield is 66.54 percent and the m.p.229-231 ℃. 1 H NMR（DMSO-D 6 ，400 MHz），δ：1.25（t，3H，J = 8.0 Hz，CH 3 ），2.85（q，2H，J = 8.0 Hz，CH 2 ），7.32-8.27（m，9H，C 6 H 4 ，C 6 H 5 ），10.38（s，1H，COOH）。
Example 2- [ (5-methyl-4- (4-methylaryl) thiazol-2-yl) amino ] benzoic acid
The operation is as in example 1, 2.4358 g of dark green crystals are weighed, the yield is 57.72%, m.p. 257-258 ℃. 1 H NMR（DMSO-D 6 ，400 MHz），δ：2.35（s，3H，CH 3 ），2.42（s，3H，CH 3 ），7.27-8.27（m，8H，2×C 6 H 4 ），10.42（s，1H，COOH）。
Example 3- [ (4- (4-chlorophenyl) -5-methylthiazol-2-yl) amino ] benzoic acid
The same procedure as in example 1 was repeated to give 4.5789 g ofBrown powder, yield 54.19%, m.p. 257-258 ℃. 1 H NMR（DMSO-D 6 ，400 MHz），δ：2.44（s，3H，CH 3 ），7.44-8.27（m，8H，2×C 6 H 4 ），10.40（s，1H，COOH）。
Example 4- [ (4- (4-chlorophenyl) -5-ethylthiazol-2-yl) amino ] benzoic acid
The operation was carried out in the same manner as in example 1 to obtain 4.6573 g of a tan-colored powder, yield 53.10%, m.p. 222-223 ℃. 1 H NMR（DMSO-D 6 ，400 MHz），δ：1.25（s，3H，J = 8.0 Hz，CH 3 ），2.85（q，2H，J = 8.0 Hz，CH 2 ），7.43-7.95（m，8H，2×C 6 H 4 ），10.37（s，1H，COOH）。
Example 5- [ (4- (4-hydroxyphenyl) -5-methylthiazol-2-yl) amino ] benzoic acid
The operation is as in example 1, 2.4358 g of pale green powder are weighed, yield 60.19%, m.p.252-254 ℃. 1 H NMR（DMSO-D 6 ，400 MHz），δ：2.39（s，3H，CH 3 ），6.84-8.26（m，8H，2×C 6 H 4 ），10.34（s，1H，COOH）。
Example 6- [ (4- (4-fluorophenyl) -5-methylthiazol-2-yl) amino ] benzoic acid
In the same manner as in example 1, 1.7584 g of a blue powder was weighed, and the yield was 37.43%, m.p.258 to 259 ℃. 1 H NMR（DMSO-D 6 ，400 MHz），δ：2.43（s，3H，CH 3 ），7.28-7.94（m，8H，2×C 6 H 4 ），10.34（s，1H，COOH）。
Example 7- [ (5-methyl-4- (4- (trifluoromethyl) phenyl) thiazol-2-yl) amino ] benzoic acid
The procedure is as in example 1, (DMSO-D) 6 ，400 MHz），δ：2.45（s，3H，CH 3 ），7.29-8.28（m，8H，2×C 6 H 4 ），10.33（s，1H，COOH）。
Example 8- [ (5-methyl-4-phenylthiazol-2-yl) amino ] benzoic acid
The procedure is as in example 1 to give a tan powder with a yield of 61.13%. m.p.252-254 ℃. 1 H NMR（DMSO-D 6 ，400 MHz），δ：2.45（s，3H，CH 3 ），7.31-8.31（m，9H，C 6 H 4 ，C 6 H 5 ），10.47（s，1H，COOH）。
Example 9 Compounds and target tyrosine kinase Bcr-Abl T315I (PDB: 3IK 3) docking and scoring
Molecular simulation software sybyl is utilized to pair the designed and synthesized compound and a target Bcr-Abl T315I (PDB: 3IK 3) docking was performed. The stronger the docking strength, the better the inhibition effect on the target kinase. The testing steps are as follows (the specific operation of each step can be set according to the software requirement):
2.1 obtaining proteins
Landing address http:// www.rcsb.org/PDB/home/home.do download protein (PDB: 3IK 3); the test compound was saved in the SLN file in mol2 format with chemdream 3D pro.
2.2 introduction of protein the protein to be docked was introduced according to the software protocol.
2.3 protein preparation
2.4 analysis of protein Structure and preparation for docking
2.5 testing other settings
2.6 specifying ligands to dock and submit work
2.7 browsing results of Surflex-Dock
After finishing all interaction docking operations, the scoring result will actively pop up in the Results Browser dialog box by Application>Docking Suite>The Analyze Results may be read in batch runs and the jobname selected in the upper right corner of the dialog box. Click View details these chemical structures and Bcr-Abl T315I Map of the docking of the kinases.
The scoring results were as follows:
the scoring results show that the compounds of the present application are directed to Bcr-Abl T315I The kinase has certain binding ability and can inhibit Bcr-Abl T315I The activity of (3) and further effectively solving the problem of drug resistance caused by the T315I mutation, and can be used as a novel Bcr-Abl tyrosine kinase inhibitor for resisting the T315I mutation.
Example 10 in vitro antitumor Activity assay
The cell strain is selected from human chronic myelogenous leukemia cell (K562) and human normal liver cell (L02).
The K562 cells, K562/R cells and L02 cells were cultured in 1640 medium containing 1% diabody and 10% FBS, respectively, in 5-percent CO 2 And subcultured once every 2 days in a saturated humidity incubator at 37 ℃.
Selecting K562 cells and K562/R cells in logarithmic growth phase, and preparing them in 1640 medium containing 10% FBS at a concentration of 4X 10 4 The cells were suspended in a volume of one mL/mL and plated in 96-well plates, and 100. Mu.l of the cell suspension was added to each well. In 5% of CO 2 And after continuously culturing for 24h in a saturated humidity incubator at 37 ℃, adding 100 mu M culture medium with the compound concentration of 8, 16, 32, 64 and 128 mu M respectivelyL (with 3 auxiliary wells), continuously culturing for 48h, adding 20. Mu.L MTS, placing in an incubator for culturing for 4h, and measuring absorbance (OD) at 490nm with a microplate reader. Replicate 3 times in parallel.
Selecting L02 cells in logarithmic growth phase, and preparing the cells in a medium containing 10% FBS at a concentration of 5X 10 4 Perml of cell suspension, seeded into 96-well plates, and 100. Mu.L of cell suspension was added per well. In 5% of CO 2 Continuously culturing for 24h in a saturated humidity incubator at 37 ℃, removing the culture solution, adding 200 mu L of culture medium (provided with 3 auxiliary holes) with the compound concentration of 8, 16, 32, 64 and 128uM respectively, continuously culturing for 48h, adding 20 mu L of MTT, placing in the incubator for culturing for 4h, carefully discarding the culture medium, adding 150uL of DMAO into each hole, placing on a shaking table, shaking at low speed and in a dark place for 10min to completely dissolve crystals, and measuring the absorbance value (OD) at 490nm by using an enzyme-labeling instrument. Replicate 3 times in parallel.
The cell viability (cell viability) calculation formula is as follows: cell viability = (OD) Drug -OD Blank )/(OD Control -OD Blank )×100%
The test results were as follows:
as can be seen from the table above, the compound has good inhibition effect on the CML cell strain K562, has lower toxicity on the normal human liver cells L02, and can avoid or reduce toxic and side effects on human bodies while inhibiting cancer cells.
Claims (13)
1. A compound of formula I, or a pharmaceutically acceptable salt thereof, having the structure:
wherein: r 1 Each independently selected from halogen, -OH, -NO 2 、-CN、C 1 -C 6 An alkyl group,C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl, C 1 -C 6 A haloalkoxy group;
R 2 is selected from C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl, C 1 -C 6 A haloalkoxy group;
n is selected from 0, 1, 2,3 or 4;
while the compounds of formula I are not:
2. a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, R 1 Each independently selected from halogen, -OH, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 A haloalkyl group; n is selected from 0, 1 or 2.
3. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, R 1 Each independently selected from methyl, chloro, fluoro, hydroxy, trifluoromethyl; n is selected from 0 or 1.
4. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, R 2 Selected from ethyl and trifluoromethyl.
5. A compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structure:
6. a process for the preparation of a compound of formula I according to claim 1, which reaction scheme is as follows:
wherein R is 1 、R 2 And n is as defined in claim 1.
7. The method of claim 6, comprising the reaction steps of:
the method comprises the following steps: adding ammonium thiocyanate and acetone into a reactor, stirring uniformly, then dropwise adding benzoyl chloride, changing the solution from clear to white turbid liquid, heating to reflux, adding m-aminobenzoic acid in batches, cooling after the reaction is finished, filtering, and drying the obtained solid to obtain 3- (3-benzoyl thiourea) benzoic acid;
step two: adding 3- (3-benzoyl thiourea) benzoic acid and an alkaline aqueous solution into a reaction bottle to ensure that the pH is =13, stirring, heating and refluxing until the reaction is finished, cooling to room temperature, adding dilute hydrochloric acid, adjusting the pH to 2, standing for 24h, separating out a solid, filtering, and drying the solid to obtain 3-carboxyphenyl thiourea;
step three: adding 3-carboxyphenylthiourea, substituted 2-Br-1-phenylalkyl ketone and glacial acetic acid into a reaction bottle, uniformly stirring, heating to reflux, removing insoluble solids in the reaction bottle while the reaction bottle is hot after the reaction is finished, carrying out rotary evaporation on part of the solvent, cooling for 24 hours at normal temperature in a ventilated kitchen, separating out solids, filtering, and drying the obtained solids to obtain the compound shown in the formula I.
8. The method of claim 7, wherein:
the mol ratio of m-aminobenzoic acid, ammonium thiocyanate and benzoyl chloride in the first step is 1-1.5;
the second step is to use 10% NaOH aqueous solution as the alkaline aqueous solution, and the concentration of the dilute hydrochloric acid is 4mol/L;
the molar ratio of the 3-carboxyphenylthiourea to the substituted 2-Br-1-phenylalkyl ketone in the third step is 1-1.2.
9. The method of claim 8, wherein:
the mol ratio of m-aminobenzoic acid, ammonium thiocyanate and benzoyl chloride in the first step is 1.2;
and the molar ratio of the 3-carboxyphenylthiourea to the substituted 2-Br-1-phenylalkyl ketone in the third step is 1.
10. A pharmaceutical composition comprising a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient.
11. Use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 10 for the manufacture of a medicament for the treatment of cancer, said cancer being human chronic myeloid leukemia.
12. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer, wherein: the cancer is human chronic myeloid leukemia;
the structure of the compound of formula I is as follows:
wherein: r 1 Each independently selected from halogen, -OH, -NO 2 、-CN、C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl, C 1 -C 6 A haloalkoxy group;
R 2 selected from hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkyl, C 1 -C 6 A haloalkoxy group;
n is selected from 0, 1, 2,3 or 4.
13. Use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer, wherein: the cancer is human chronic myeloid leukemia; the structure of the compound is as follows:
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| CN102558088A (en) * | 2010-12-31 | 2012-07-11 | 中国科学院上海药物研究所 | Biphenyl methylene-2-sulpho-4-thiazolone compound as well as preparation method and application thereof |
| CN102675303A (en) * | 2011-10-19 | 2012-09-19 | 湖南大学 | 4-alkyl-2-arylamino-5-(1,2,4-triazole-1-group) thiazole and application thereof to preparation of medicaments for resisting cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558088A (en) * | 2010-12-31 | 2012-07-11 | 中国科学院上海药物研究所 | Biphenyl methylene-2-sulpho-4-thiazolone compound as well as preparation method and application thereof |
| CN102675303A (en) * | 2011-10-19 | 2012-09-19 | 湖南大学 | 4-alkyl-2-arylamino-5-(1,2,4-triazole-1-group) thiazole and application thereof to preparation of medicaments for resisting cancer |
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| "Design, synthesis and broad-spectrum Bcr-Abl inhibitory activity of novel thiazolamide-benzamide derivatives";Juan Liu et al.;《RSC Adv.》;20190115;第9卷;第2092-3001页 * |
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