CN109232467A - Thiazoleamino benzoic acid derivative and application thereof - Google Patents
Thiazoleamino benzoic acid derivative and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The invention discloses a kind of thiazoleamino benzoic acid derivatives for having anti-tumor activity, it can be used to prepare anticancer drug, especially as Bcr-Abl tyrosine kinase inhibitor, especially can be used as the Bcr-Abl tyrosine kinase inhibitor of T315I mutation.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a series of thiazoleamino benzoic acid derivatives, preparation method
And application thereof.
Background technique
Chronic myelocytic leukemia (CML) is a kind of pernicious bone marrow proliferative diseases originating from candidate stem cell, accounts for institute
There is the 15% ~ 20% of leukaemia, is the most common bone marrow proliferative diseases.Its former cancer of root on No. 9 chromosomes of falling ill
The Bcr-Abl gene that Bcr Gene Fusion on gene c-Abl and No. 22 chromosomes is formed.At present, it was verified that Bcr-Abl
Tyrosine kinase is treatment CML optimal molecular target (Blood, 1996,87:3036-3038；Blood, 2000,
96:343-356).Around Bcr-Abl tyrosine kinase, drug workers have carried out various effort.Currently, successfully listing
Bcr-Abl tyrosine kinase inhibitor have Imatinib, nilotinib, draw mostly for Buddhist nun, Dasatinib, Shu Bo for Buddhist nun and Pu Na
For Buddhist nun.
Wherein, Imatinib is first generation Bcr-Abl tyrosine kinase inhibitor, for the first-line drug for treating CML, but it is different when
The patient of phase understands some and generates drug resistance after long-term use.Drug resistance may be caused by number of mechanisms, wherein Bcr-Abl point
It is also to influence maximum resistance mechanism (Nat Rev Drug Discov, 2007,6 (10): 834- that mutation, which is most common,
848).
Nilotinib draws and replaces Buddhist nun, Dasatinib and bosutinib for second generation Bcr-Abl tyrosine kinase inhibitor more.
Compared with Imatinib, it is able to solve the drug resistance that most of mutant generate, but do not can effectively solve caused by T315I mutation
Drug resistance (Ann Oncol, 2007,18 (6): 42-46； Eur J Cancer, 2010, 46 (10): 1781-1789；
Haematologica, 2014,99 (7): 1191-1196).
Ponatinib is third generation Bcr-Abl tyrosine kinase inhibitor, be can effectively solve the problem that resistance to caused by T315I mutation
Medicine (Cancer Cell, 2009,16 (5): 401-412).But Ponatinib can generate serious and lethal thrombus and blood vessel
Stenosis disease, and complication (the Chinese drugs such as heart disease, myocardial infarction, apoplexy, limb ischemia even tissue necrosis can be induced
Warning, 2017,14 (4): 218-221).
T315I mutation occurs 315 that are referred to as " gatekeeper " in Bcr-Abl kinase domain, wild type
Threonine (Thr) in Bcr-Abl is replaced by isoleucine (Ile).Thr315 can be replaced with her horse in wild type Bcr-Abl
Buddhist nun and nilotinib etc. form a crucial hydrogen bond, and after it is replaced by Ile315, this crucial hydrogen bond just can not shape
At.In addition to this, Ile315 after being mutated since volume is larger, can and Imatinib generate steric hindrance, to keep its right
Wild type Bcr-Abl is effectively and to Bcr-AblT315I invalid (Cancer Cell, 2002,2 (2): 117-125；
Bioorg Med Chem Lett, 2008, 18: 4907-4912；Leukemia, 2004,18 (8): 1321-1331).
The effect for studying Ponatinib and Bcr-AblT315I is found: acetylene bond and Thr315 and Ile315 in Ponatinib structure are not
Hydrogen bond is formed, and (pharmacy is in progress, 2014,38 (5): 333- without generating steric hindrance with Ile315 since structure is smaller
339；Cancer Cell, 2009,16 (5): 401-412).
The present inventor designs in previous work, has synthesized serial thiazolamine class compound, active testing
The result shows that its with good anti-tumor activity (CN102319244A, CN102675303, CN1080031152A,
CN107459513A).Thus inventor expects for thiazolamine group being integrated in molecular structure, it is desirable to which accessing can make
For the Bcr-Abl tyrosine kinase inhibitor of T315I mutation, while the toxic side effect to human body can reduce.
Summary of the invention
The technical problems to be solved by the present invention are: providing a kind of thiazoleamino benzoic acid derivative, can be used as
The Bcr-Abl tyrosine kinase inhibitor of T315I mutation.
The first aspect of the invention is to provide a kind of compound of Formula I and its pharmaceutically acceptable salt, has as follows
Structure:
I
Wherein: R1It is each independently selected from halogen ,-OH ,-NO2 ,-CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl halide
Base, C1-C6 halogenated alkoxy；
R2Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy；
N is selected from 0,1,2,3 or 4.
Preferably, R1It is each independently selected from halogen ,-OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 halogenated alkyl,
More preferably methyl, chlorine, fluorine, hydroxyl, trifluoromethyl；N is selected from 0,1 or 2, preferably 0 or 1.
Preferably, R2Selected from hydrogen, C1-C4 alkyl, C1-C4 halogenated alkyl, more preferably methyl, ethyl, trifluoromethyl.
It is highly preferred that compound of formula I of the present invention, is selected from following compound:
Another aspect of the present invention provides a kind of the method for preparing compound of formula I, and reaction route is as follows:
；
Wherein, R1、R2It is defined as described above with n.
Preparation method of the invention specifically further includes following reaction step:
Step 1: ammonium thiocyanate and acetone are added into reactor, stirs evenly, chlorobenzoyl chloride is then added dropwise, solution is by clarifying
Become white opacity liquid, be heated to flowing back, gavaculine is added portionwise, to which after completion of the reaction, cooling is filtered, by gained
Solid is dry, obtains 3-(3- benzoylthioureas base) benzoic acid；
Step 2: 3-(3- benzoylthioureas base is added into reaction flask) benzoic acid and alkaline aqueous solution, make pH=13, stirs,
It is heated to reflux, until end of reaction, is cooled to room temperature, dilute hydrochloric acid is added, pH is transferred to 2, stands 24 h, solid is precipitated, is filtered,
Solid is dry, obtain 3- carboxyl phenyl thiocarbamide；
Step 3: 3- carboxyl phenyl thiocarbamide, substituted 2-Br-1- Phenyl ethyl ketone and glacial acetic acid being added into reaction flask, and stirring is equal
It is even, it is heated to flowing back, after completion of the reaction, removes the insoluble solids in reaction flask while hot, rotate partial solvent, be put into ventilating kitchen
Solid is precipitated in 24 h of room temperature cooling, and filtering is dry by obtained solid, obtains compound of formula I.
Preferably, the molar ratio of the gavaculine, ammonium thiocyanate and chlorobenzoyl chloride of step 1 is 1: 1-1.5:
1-1.5, preferably 1: 1.2: 1.3；
Preferably, step 2 alkaline aqueous solution is 10% NaOH aqueous solution, and dilute hydrochloric acid concentration is 4 mol/L；
Preferably, the molar ratio of the 3- carboxyl phenyl thiocarbamide of step 3 and substituted 2-Br-1- phenyl alkyl ketone is 1: 1-
1.2 preferably 1: 1.
Another aspect of the present invention provides a kind of pharmaceutical composition, it includes compound shown in Formulas I of the present invention or
Its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, excipient.
Another aspect of the present invention is related to compound of the present invention or the pharmaceutical composition comprising the compound is being made
Standby treatment and the purposes in the drug of Bcr-Abl tyrosine kinase associated cancer, in particular for the Bcr- of T315I mutation
Abl tyrosine kinase is the cancer of target spot.
Preferably, the cancer is selected from human chronic myelogenous leukemia, liver cancer (such as HepG-2 cell strain), non-small cell lung
Cancer (such as A549 cell strain) is more preferably people's chronic myelogenous leukemia (such as K562 cell strain), the K562 cell strain of resistance to Imatinib
(K562/R cell strain).
Definition:
" alkyl ", which refers to, to be only made of carbon and hydrogen atom, is not contained degree of unsaturation, can is C1-6 alkyl.In some embodiments
In, alkyl has 1 to 6 or 1 to 4 carbon atom.Representative straight chain saturated alkyl includes but is not limited to-methyl ,-ethyl ,-positive third
Base ,-normal-butyl ,-n-pentyl and-n-hexyl；And being saturated branched alkyl includes but is not limited to-isopropyl ,-sec-butyl ,-isobutyl
Base ,-tert-butyl ,-isopentyl, 2- methyl butyl, 3- methyl butyl, 2- Methyl pentyl, 3- methyl amyl, 4- methyl amyl, 2-
Methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2,3- dimethyl-butyl etc..Alkyl is connected by singly-bound
In parent molecule.Unless in addition statement in the description, otherwise alkyl is optionally independently taken including below by one or more
Replace for base: acyl group, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, naphthenic base.In a non-limiting embodiments, take
The alkyl in generation can be selected from methyl fluoride, difluoromethyl, trifluoromethyl, 2- fluoro ethyl, 3- fluoropropyl, hydroxymethyl, 2- hydroxyethyl,
3- hydroxypropyl, benzyl and phenethyl.
" alkoxy " refers to that " alkyl " is connected by oxygen atom with parent molecule, determines as described above wherein " alkyl " has
Justice.
" halogenated alkyl " refers to wherein all hydrogen moieties or all by selected from fluoro base, chloro base, bromo base and iodine
The alkyl of the halogen displacement of Dai Ji.In some embodiments, all hydrogen atoms are all respectively replaced by fluoro base.In some implementations
In scheme, all hydrogen atoms are all respectively replaced by chloro base.The example of halogenated alkyl include-CF3 ,-CF2CF3 ,-
CF2CF2CF3 ,-CFCl2 ,-CF2Cl etc..
In certain embodiments, pharmaceutically acceptable form is pharmaceutically acceptable salt, pharmaceutically acceptable
Salt is well known in the art.The example of pharmaceutically acceptable salt is such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, high chlorine
Acid, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, acetic acid, propionic acid, glycolic, pyruvic acid,
Oxalic acid, lactic acid, trifluoroacetic acid, Loprazolam, ethane sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid etc..
" pharmaceutically acceptable carrier " or " pharmaceutically acceptable excipient " includes any and all solvents, dispersion Jie
Matter, covering, isotonic agent and absorption delaying agent etc..Pharmaceutically acceptable carrier or excipient do not destroy disclosed compound
Pharmacological activity, and be nontoxic when to be enough to deliver the dosage application of the compound of therapeutic dose.Pharmaceutically active substance
The use of the medium and reagent is in the art well known.
Compared with prior art, the beneficial effects of the present invention are:
(1) the present invention provides a new class of thiazoleamino benzoic acid derivatives with anticancer activity, have widened existing anti-
The range of chemical compound for treating cancer can be used as lead compound and continue to optimize；
(2) the compounds of this invention has good inhibiting effect to CML cell cycling inhibiting, has simultaneously for human normal liver cell L 02
There is lower toxicity, while inhibiting cancer cell, can be avoided or reduce the toxic side effect to human body；
(3) the compounds of this invention can be with target tyrosine kinase A blT315IIt is effectively combined, there is good action intensity,
It is able to suppress Bcr-AblT315IActivity, and then efficiently solve T315I be mutated caused by resistance problems, can be used as anti-T315I
The novel B cr-Abl tyrosine kinase inhibitor of mutation.
Specific embodiment
The contents of the present invention are illustrated below by embodiment.In the present invention, following embodiment is in order to more preferable
Ground illustrates the present invention, is not for limiting the scope of the invention.Material used in embodiment, reagent etc., such as without special theory
It is bright, it is commercially available.
1 3- of embodiment [(5- ethyl -4- phenyl thiazole -2- base) amino] benzoic acid
Step a:
11.4341 g(0.12 mol are added in angle reaction flask of 100 mL with mechanical stirring and condenser pipe) ammonium thiocyanate
With 20 mL acetone, stirred evenly by mechanical stirring.16.8034 g(0.13 mol are added dropwise) chlorobenzoyl chloride (10 min are dripped off),
Solution becomes white opacity liquid from clarifying.It is heated to flowing back, point 4 crowdes of 14.1147 g(0.10 mol of addition) gavaculine,
TLC(ethyl acetate: petroleum ether=4:1) monitoring reaction course, 8 h end of reaction.Cooling, filtering is dry by obtained solid,
Obtain the pale yellow powder 3-(3- benzoylthioureas base of 28.0041 g) benzoic acid, 184 ~ 186 DEG C of m.p..
0.9913 g(0.12 mol is added in angle reaction flask of 100 mL with condenser pipe) 3-(3- benzoylthioureas
Base) 10% NaOH of benzoic acid and 33 mL, pH=13 are measured, magnetic agitation is heated to reflux, TLC(ethyl acetate: petroleum ether=
4:1) monitor its reaction process, 4 h end of reaction.It is cooled to room temperature, suitable 4 mol/L dilute hydrochloric acid is added, pH is transferred to 2,
Stand 24 h, solid be precipitated, filtering is dry by obtained solid, weigh 0.6142 g white powder, yield is 86.72 %,
m.p. 186 ~ 187 ℃。 1H NMR(DMSO-D6, 400 MHz),δ: 2.51(s, 1H, NH), 3.36(s, 2H, NH2),
7.43-8.03(m 4H, C6H4), 9.89(s, 1H, COOH).
Step b:3- [(5- ethyl -4- phenyl thiazole -2- base) amino] benzoic acid
3.9432 g(0.02 mol are added in angle reaction flask of 100 mL with condenser pipe) 3- carboxyl phenyl thiocarbamide, 4.5213
G(0.02mol) 2-Br-1- phenyl butanone and 20mL glacial acetic acid, stir evenly, and are heated to flowing back, TLC (solvent: acetic acid second
Ester: petroleum ether=4:1) monitoring reaction process, reacts about 24 h.The insoluble solids in reaction flask are removed while hot, rotate part
Solvent.It is put into 24 h of room temperature cooling in ventilating kitchen, solid is precipitated, filtering is dry by obtained solid, weighs to obtain 5.6.163 g
Brownish-yellow powder, yield are 66.54 %, m.p.229 ~ 231 DEG C.1H NMR(DMSO-D6, 400 MHz),δ: 1.25(t, 3H,J=8.0 Hz, CH3), 2.85(q, 2H,J=8.0 Hz, CH2), 7.32-8.27(m, 9H, C6H4, C6H5), 10.38(s, 1H,
COOH).
2 3- of embodiment [(5- methyl -4- (4- methyl aryl) thiazol-2-yl) amino] benzoic acid
Operation with embodiment 1, weigh 2.4358 g green crystals, yield be 57.72 %, 257 ~ 258 DEG C of m.p..1H NMR(DMSO-D6, 400 MHz),δ: 2.35(s, 3H, CH3), 2.42(s, 3H, CH3), 7.27-8.27(m, 8H, 2 ×
C6H4), 10.42(s, 1H, COOH).
3 3- of embodiment [(4- (4- chlorphenyl) -5- methylthiazol -2- base) amino] benzoic acid
Operation obtains the brown powder of 4.5789 g with embodiment 1, and yield is 54.19 %, and 257 ~ 258 DEG C of m.p..1H
NMR(DMSO-D6, 400 MHz),δ: 2.44(s, 3H, CH3), 7.44-8.27(m, 8H, 2 × C6H4), 10.40(s, 1H,
COOH).
4 3- of embodiment [(4- (4- chlorphenyl) -5- ethyl thiazole -2- base) amino] benzoic acid
Operation obtains the yellowish-brown powder of 4.6573 g with embodiment 1, and yield is 53.10 %, and 222 ~ 223 DEG C of m.p..1H
NMR(DMSO-D6, 400 MHz),δ: 1.25(s, 3H,J=8.0 Hz, CH3), 2.85(q, 2H,J=8.0 Hz, CH2),
7.43-7.95(m 8H, 2 × C6H4), 10.37(s, 1H, COOH).
5 3- of embodiment [(4- (4- hydroxy phenyl) -5- methylthiazol -2- base) amino] benzoic acid
Operation with embodiment 1, weigh 2.4358 g shallow green powder, 60.19 % of yield, m.p.252 ~ 254 DEG C.1H
NMR(DMSO-D6, 400 MHz),δ: 2.39(s, 3H, CH3), 6.84-8.26(m, 8H, 2 × C6H4), 10.34(s, 1H,
COOH).
Embodiment 6 3-[(4-(4- fluorophenyl)-5- methylthiazol-2- base) amino] benzoic acid
Operation with embodiment 1, weigh 1.7584 g blue powder, yield be 37.43 %, m.p.258 ~ 259 DEG C.1H
NMR(DMSO-D6, 400 MHz),δ: 2.43(s, 3H, CH3), 7.28-7.94(m, 8H, 2 × C6H4), 10.34(s, 1H,
COOH).
Embodiment 7 3-[(5- methyl-4- (4- (trifluoromethyl) phenyl) thiazol-2-yl) amino] benzoic acid
Operation is the same as embodiment 1, (DMSO-D6, 400 MHz),δ: 2.45(s, 3H, CH3), 7.29-8.28(m, 8H, 2 × C6H4),
10.33(s, 1H, COOH).
8 3- of embodiment [(5- methyl 4-phenyl thiazol-2-yl) amino] benzoic acid
Operation obtains brownish-yellow powder with embodiment 1, and yield is 61.13 %.m.p.252 ~ 254 ℃.1H NMR(DMSO-D6,
400 MHz),δ: 2.45(s, 3H, CH3), 7.31-8.31(m, 9H, C6H4, C6H5), 10.47(s, 1H, COOH).
9 compound of embodiment and target tyrosine kinase Bcr-AblT315I(PDB:3IK3) docking marking is carried out
Using molecular simulation software sybyl to the compound and target Bcr-Abl of designed synthesisT315I(PDB:3IK3) it carries out
Docking.Docking intensity is stronger, and it is better for the inhibitory effect of target kinases to show.Following (the specific behaviour of each step of testing procedure
Work can be configured according to software requirement):
2.1 obtain albumen
Log in network address http://www.rcsb.org/pdb/home/home.do downloading albumen (PDB:3IK3)；By quasi- testization
Object is closed to be stored in it in SLN file with mol2 format with chemdream 3D pro.
2.2 import the albumen that albumen imports quasi- docking according to software operating method.
2.3 protein prepare
2.4 analysis protein structures simultaneously prepare to dock
2.5 detecting other settings
The 2.6 specified ligands to be docked and submission work
The result of 2.7 browsing Surflex-Dock
After terminating all interaction docking operations, marking result can be popped up actively in Results Browser dialog box,
With Application > Docking Suite > Analyze Results can run in batches in read as a result, and in dialog box
The upper right corner selects jobname.Clicking View can be in detail refering to these chemical structural formulas and Bcr-AblT315IThe docking scheme of kinases.
Result of giving a mark is as follows:
The compound of marking the application as the result is shown is for Bcr-AblT315IKinases has certain binding ability, is able to suppress
Bcr-AblT315IActivity, and then efficiently solve resistance problems caused by T315I is mutated, can be used as the new of anti-T315I mutation
Type Bcr-Abl tyrosine kinase inhibitor.
The test of 10 anti tumor activity in vitro of embodiment
Cell strain selects people's chronic myelogenous leukemia cell (K562), Human normal hepatocyte (L02).
K562 cell, K562/R cell and L02 cell are incubated at containing 1% dual anti-and 10%FBS 1640 culture mediums respectively
Containing 5%CO2, in 37 DEG C of saturated humidity incubator, passage in 2 days is primary.
K562 cell, the K562/R cell for choosing logarithmic growth phase, being made into concentration with 1640 culture mediums containing 10%FBS is 4
×104The cell suspension of/mL is inoculated into 96 well culture plates, and 100 μ L cell suspensions are added in every hole.In 5%CO2, 37 DEG C of saturation
After continuing culture for 24 hours in humidified incubator, it is separately added into the 100 μ L of culture medium that compound concentration is 8,16,32,64,128 μM
(3 secondary orifices of setting), continue after cultivating 48h, 20 μ L MTS are added, after being put into incubator culture 4h, with microplate reader in 490nm wave
Strong point measures absorbance value (OD).It is repeated 3 times in parallel.
The L02 cell for choosing logarithmic growth phase, being made into concentration with the culture medium containing 10%FBS is 5 × 104The cell of/mL is outstanding
Liquid is inoculated into 96 well culture plates, and 100 μ L cell suspensions are added in every hole.In 5%CO2, 37 DEG C of saturated humidity incubator relaying
After continuous culture for 24 hours, move and abandon culture solution, then be separately added into compound concentration be 8,16,32,64, the 200 μ L(of culture medium of 128uM sets
Set 3 secondary orifices), continue after cultivating 48h, 20 μ L MTT are added, after being put into incubator culture 4h, carefully discard culture medium, every hole
Be added 150uL DMAO, set low speed on shaking table, be protected from light shaking 10min make crystallization dissolution completely, with microplate reader at 490nm wavelength
It measures absorbance value (OD).It is repeated 3 times in parallel.
Cell survival rate (cell viability) calculation formula is as follows: Cell viability=(ODDrug-ODBlank)/
(ODControl-ODBlank )×100%
Test result is as follows:
As seen from the above table, the compounds of this invention has good inhibiting effect for CML cell cycling inhibiting, simultaneously for people's normal hepatocytes
There is cell L02 lower toxicity can be avoided or reduce the toxic side effect to human body while inhibiting cancer cell.
Claims (10)
1. a kind of compound of formula I or its pharmaceutically acceptable salt, have the following structure:
I
Wherein: R1It is each independently selected from halogen ,-OH ,-NO2、-CN、C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl,
C1-C6Halogenated alkoxy；
R2Selected from hydrogen, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, C1-C6Halogenated alkoxy；
N is selected from 0,1,2,3 or 4.
2. compound of formula I as described in claim 1 or its pharmaceutically acceptable salt, R1Be each independently selected from halogen ,-OH,
C1-C4Alkyl, C1-C4Alkoxy, C1-C4Halogenated alkyl, preferably methyl, chlorine, fluorine, hydroxyl, trifluoromethyl；N is selected from 0,1 or 2,
Preferably 0 or 1.
3. compound of formula I as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, R2Selected from hydrogen, C1-C4 alkyl, C1-
C4 halogenated alkyl, preferably methyl, ethyl, trifluoromethyl.
4. compound of formula I as claimed in claim 1 or 2 is selected from following compound:
。
5. a kind of method for preparing compound of formula I as described in claim 1, reaction route are as follows:
；
Wherein, R1、R2It is as described in claim 1 with the definition of n.
6. preparation method as claimed in claim 5, it is characterised in that including following reaction step:
Step 1: ammonium thiocyanate and acetone are added into reactor, stirs evenly, chlorobenzoyl chloride is then added dropwise, solution is by clarifying
Become white opacity liquid, be heated to flowing back, gavaculine is added portionwise, to which after completion of the reaction, cooling is filtered, by gained
Solid is dry, obtains 3-(3- benzoylthioureas base) benzoic acid；
Step 2: 3-(3- benzoylthioureas base is added into reaction flask) benzoic acid and alkaline aqueous solution, make pH=13, stirs,
It is heated to reflux, until end of reaction, is cooled to room temperature, dilute hydrochloric acid is added, pH is transferred to 2, stands 24 h, solid is precipitated, is filtered,
Solid is dry, obtain 3- carboxyl phenyl thiocarbamide；
Step 3: 3- carboxyl phenyl thiocarbamide, substituted 2-Br-1- phenyl alkyl ketone and glacial acetic acid, stirring are added into reaction flask
Uniformly, it is heated to flowing back, after completion of the reaction, removes the insoluble solids in reaction flask while hot, rotate partial solvent, be put into ventilating kitchen
Solid is precipitated in middle 24 h of room temperature cooling, and filtering is dry by obtained solid, obtains compound of formula I.
7. preparation method as claimed in claim 6, it is characterised in that:
The molar ratio of the gavaculine of step 1, ammonium thiocyanate and chlorobenzoyl chloride is 1: 1-1.5: 1-1.5, preferably
1 : 1.2 : 1.3；
Step 2 alkaline aqueous solution is 10% NaOH aqueous solution, and dilute hydrochloric acid concentration is 4 mol/L；
The molar ratio of the 3- carboxyl phenyl thiocarbamide of step 3 and substituted 2-Br-1- phenyl alkyl ketone is 1: 1-1.2；Preferably
1 : 1。
8. a kind of pharmaceutical composition, it includes compound shown in the Formulas I of any one of claim 1-5 or its is pharmaceutically acceptable
Salt and pharmaceutically acceptable carrier, excipient.
9. compound of any of claims 1-5 or pharmaceutical composition according to any one of claims 8 treat cancer in preparation
Purposes in the drug of disease, it is preferable that the cancer be using Bcr-Abl tyrosine kinase as the cancer of target spot, in particular for
The Bcr-Abl tyrosine kinase of T315I mutation is the cancer of target spot.
10. purposes as claimed in claim 9, which is characterized in that the cancer be selected from human chronic myelogenous leukemia, liver cancer,
Non-small cell lung cancer is preferably people's chronic myelogenous leukemia, the K562 cell strain of resistance to Imatinib.
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| WO2021178488A1 (en) * | 2020-03-03 | 2021-09-10 | PIC Therapeutics, Inc. | Eif4e inhibitors and uses thereof |
| CN115515685A (en) * | 2020-03-03 | 2022-12-23 | 皮克医疗公司 | EIF4E inhibitor and application thereof |
| US11753403B2 (en) | 2020-03-03 | 2023-09-12 | PIC Therapeutics, Inc. | EIF4E inhibitors and uses thereof |
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