CN109320473A - Thiazoleamino benzamide acetogenin and application thereof - Google Patents

Thiazoleamino benzamide acetogenin and application thereof Download PDF

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CN109320473A
CN109320473A CN201811209798.5A CN201811209798A CN109320473A CN 109320473 A CN109320473 A CN 109320473A CN 201811209798 A CN201811209798 A CN 201811209798A CN 109320473 A CN109320473 A CN 109320473A
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alkyl
reaction
added
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alkoxy
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CN109320473B (en
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彭俊梅
刘娟
曹轩
黄红林
贺冬秀
谢志忠
喻翠云
李娜
罗景顺
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University of South China
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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 benzamide acetogenins for having anti-tumor activity, it can be used to prepare anticancer drug, especially as Bcr-Abl tyrosine kinase inhibitor, the Bcr-Abl tyrosine kinase inhibitor of T315I mutation especially can be used as.

Description

Thiazoleamino benzamide acetogenin and application thereof
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a series of thiazoleamino benzamide acetogenins, its system 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 not Patient of the same period understands some and generates drug resistance after long-term use.Drug resistance may be caused by number of mechanisms, wherein Bcr- Abl point mutation is most common be also influence maximum resistance mechanism (Nat Rev Drug Discov, 2007,6 (10): 834-848).
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: a kind of thiazoleamino benzamide acetogenin is provided, it can Bcr-Abl tyrosine kinase inhibitor as 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-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, C1-C6Halogenated alkoxy；
R2Selected from hydrogen, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, C1-C6Halogenated alkoxy；
R3Selected from hydrogen ,-OH ,-NO2,-CN, halogen, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, C1-C6Haloalkoxy Base, C6-C10Aryl C1-C6Alkyl；
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.
Preferably, R3Selected from hydrogen ,-OH, halogen, C1-C4Alkyl, C1-C6Alkoxy, C1-C4Halogenated alkyl, C1-C4Alkyl halide Oxygroup, benzyl, more preferably hydrogen, benzyl.
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、R2、R3Defined as described above with n, R4 is selected from C1-C6Alkyl or C1-C6Halogenated alkyl.
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 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 intermediate thiazoleamino benzoic acid derivative；
Step 4: intermediate thiazoleamino benzoic acid derivative, EDCI, HOBT and dehydrated alcohol are added under condition of ice bath to anti- It answers in bottle, reacts 2-4 h, be addedHydrochloride, DIPEA, DMAP and DMF continue ice bath and react half an hour, it After be changed to react at room temperature, until end of reaction, then be slowly added to ice water while stirring, until solution becomes muddy from clarifying, room Temperature stirring 0.5-1.5 h places into refrigerator and white solid is precipitated, and filtering is dry by obtained solid, obtains compound of formula I；
Step 5: intermediate 4, dehydrated alcohol and distilled water being added into reaction flask, adjust pH most 11-13 with dilute NaOH, and 37 DEG C stirring, reaction process monitor pH, be adjusted to 11-13 in time when lower than 10.TLC monitors reaction process, after completion of the reaction, filtering, Filter residue is abandoned, filtrate is 2-3 with dilute HCl tune pH, is put into refrigerator and solid, filtering, dry compound of formula I is precipitated.
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；
Preferably, in step 4WithMolar ratio be 1-2: 1, preferably 1.5: 1；
Preferably, the pH in step 5 in reaction process is preferably 12, and the pH in last handling process is preferably 2-3, and dilute NaOH is The NaOH aqueous solution of 5%-30%, dilute HCl are the hydrochloric acid solution of 5%-15%.
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 benzamide phenylacetic acid compound with anticancer activity, is widened The range of existing anticancer compound can be used as lead compound and continue to optimize；
(2) the compounds of this invention is to CML cell cycling inhibiting, the K562 cell of resistance to Imatinib (K562/R), human liver cancer cell (HepG-2) and Non-small cell lung carcinoma cell (A549) has good inhibiting effect, 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 bI1 and AbIlT315IIt is effectively combined, has and make well With intensity, it is able to suppress Bcr-AbIlT315IActivity, and then efficiently solve T315I be mutated caused by resistance problems, can be used as The novel B cr-Abl tyrosine kinase inhibitor of anti-T315I 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.
Embodiment 1(3- ((5- methyl 4-phenyl thiazol-2-yl) amino) benzoyl) glycine
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).
Step c:(3- ((5- methyl 4-phenyl thiazol-2-yl) amino) benzoyl) glycine methyl ester
0.4153g(0.003mol is added under condition of ice bath) 3-[(5- ethyl-4- phenyl thiazole-2- base) amino] benzoic acid, 0.5812g(0.003mol) EDCI, 0.4154g(0.003mol) HOBT and 18ml dehydrated alcohol to three-necked flask, reacts about 3h Afterwards, be added 0.2502g(0.002mol) glycine methyl ester hydrochloride, 0.8ml DIPEA, 0.0979g(0.0008mol) DMAP and 18mlDMF continues ice bath and reacts half an hour, is changed to react at room temperature later, TLC(ethyl acetate: petroleum ether=4:1) monitoring reaction Process, about 21 hours end of reaction.It is slowly added to ice water while stirring, until solution becomes muddiness, about 40ml, room from clarifying Temperature stirring 30min, places into refrigerator and white solid is precipitated.Filtering, obtained solid is dry, the white powder of 0.2112 g is obtained, m.p. 135 ~ 137℃。1H NMR(CDCl3, 400 MHz),δ: 1.30(t,J =8.0 Hz, 3H, CH2CH3), 1.41(s, 3H, OCH3), 2.89(q,J=8.0 Hz, 2H, CH2CH3), 4.39(d,J=4.0 Hz, 2H, NHCH2), 7.26-8.00(m, 9H, C6H5, C6H4).
Step d:(3- ((5- methyl 4-phenyl thiazol-2-yl) amino) benzoyl) glycine
(3- ((5- methyl 4-phenyl thiazol-2-yl) amino) benzoyl) glycine methyl ester is added in 50ml three-necked flask 0.1532g(0.4mmol), 15ml dehydrated alcohol and 3ml distilled water, adjusting pH with dilute NaOH is about 12,37 DEG C of stirrings, is reacted Range monitoring pH is adjusted to 12 when lower than 10 in time.TLC (solvent: ethyl acetate: petroleum ether=1:1) monitors reaction process, React about 2h.After completion of the reaction, it filters, abandons filter residue, filtrate is 2-3 with dilute HCl tune Ph, is put into refrigerator and solid is precipitated, filter, do It is dry to obtain 0.0865g yellow powder, yield 56.78 %, m.p. 200-202- DEG C.1H NMR(DMSO-D6, 400 MHz),δ: 1.22 (t,J =8.0 Hz, 3H, CH2CH3), 2.82(q,J=8.0 Hz, 2H, CH2CH3), 3.93(d,J=4.0 Hz, 2H, NHCH2), 7.37-8.07(m, 9H, C6H4, C6H5), 8.87(t,J =4.0 Hz, 1H, CONH), 10.79(s, 1H, COOH).
Embodiment 2 (3- ((5- methyl -4- (p-methylphenyl) thiazol-2-yl) amino) benzoyl) glycine
Operation is same as above, and obtains the brown powder of 0.0934g, yield 61.28%, and m.p.225-228 DEG C.1H NMR(DMSO-D6, 400 MHz),δ: 2.36(s, 3H, CH3), 2.41(s, 3H, CH3), 3.93(d,J=8.0 Hz, 2H, NHCH2), 7.26-8.08(m, 8H, 2 × C6H4), 8.82(t,J=8.0 Hz, 1H, CONH), 10.49(s, 1H, COOH).
3 3- of embodiment ((4- (4- chlorphenyl) -5- methylthiazol -2- base) amino) benzoyl) glycine
Operation is same as above, and obtains the yellow powder of 0.09492g, yield 59.18%, and m.p.238-240 DEG C.1H NMR(DMSO-D6, 400 MHz),δ: 2.43(s, 3H, CH3), 3.91(d,J=8.0 Hz, 2H, NHCH2), 7.26-8.08(m, 8H, 2 × C6H4), 8.75 (t,J=8.0 Hz, 1H, CONH), 10.25(s, 1H, COOH).
Embodiment 4 (3-((4-(4- chlorphenyl) -5- ethyl thiazole -2- base) amino) benzoyl) glycine
Operation is same as above, and obtains the yellow powder of 0.1194g, yield 71.86%, and m.p161-163. DEG C.1H NMR(CDCl3, 400 MHz),δ: 1.28(t,J =8.0 Hz, 3H, CH2CH3), 2.18(q,J=8.0 Hz, 2H, CH2CH3), 4.26(d,J = 8.0 Hz, 2H, NHCH2), 6.95-7.79(m, 9H, 2 × C6H4).
Embodiment 5 (3- ((4- (4- hydroxy phenyl) -5- methylthiazol -2- base) amino) benzoyl) glycine
Operation is same as above, and obtains the yellow powder of 0.0772g, yield 50.36%, and m.p.194-197 DEG C.1H NMR(DMSO-D6, 400 MHz),δ: 2.43(s, 3H, CH3), 3.93(d,J=8.0 Hz, 2H, NHCH2), 7.26-8.08(m, 8H, 2 × C6H4), 8.75 (t,J=8.0 Hz, 1H, CONH), 10.25(s, 1H, COOH).
Embodiment 6 (3-((4-(4- fluorophenyl) -5- methylthiazol -2- base) amino) benzoyl) glycine
Operation is same as above, and obtains the shallow green powder of 0.1528g, yield 80.59%, and m.p.211-213 DEG C.1H NMR(DMSO-D6, 400 MHz),δ: 2.43(s, 3H, CH3), 3.93(d,J=8.0 Hz, 2H, NHCH2), 7.26-8.08(m, 8H, 2 × C6H4), 8.75(tJ=8.0 Hz, 1H, CONH), 10.25(s, 1H, COOH).
Embodiment 7 (3-((5- methyl 4-phenyl thiazol-2-yl) amino) benzoyl) glycine
Operation is same as above, and obtains 0.0962g yellow powder, yield 81.29 %, m.p.283-285 DEG C.1H NMR(DMSO-D6, 400 MHz),δ: 2.44(s, 3H, CH3), 3.93(d,J=8.0 Hz, 2H, NHCH2), 7.69-8.05(m, 9H, C6H4, C6H5), 8.77(tJ=8.0 Hz, 1H, CONH), 10.24(s, 1H, COOH).
Embodiment 8 (3- ((5- methyl -4- (4- (trifluoromethyl) phenyl) thiazol-2-yl) amino) benzoyl) sweet ammonia Acid
Operation is same as above, and obtains 0.1349g yellow powder, yield 81.29 %, m.p.183-186 DEG C.1H NMR(DMSO-D6, 400 MHz),δ: 2.45(s, 3H, CH3), 3.95(d,J=8.0 Hz, 2H, NHCH2), 7.29-8.10(m, 8H, 2 × C6H4), 8.78 (t,J=8.0 Hz, 1H, CONH), 10.27(s, 1H, COOH).
Embodiment 9(3-((5- ethyl-4- phenyl thiazole-2- base) amino) benzoyl) phenylalanine
Operation is same as above, and obtains 0.1182g white powder, yield 62.74%, m.p.199-202 DEG C.1H NMR(DMSO-D6, 400 MHz),δ: 1.24(t,J =8.0 Hz, 3H, CH2CH3) 2.84(q,J=8.0 Hz, 2H, CH2CH3), 3.18(m, 2H, CH2C6H5), 4.63 (m, 1H, CH), 7.16-7.97(m, 14H, 2 × C6H5, C6H4), 8.66(d,J=8.0 Hz, 1H, CONH), 10.27(s, 1H, COOH).
Embodiment 10(3-((5- methyl -4-(p-methylphenyl) thiazol-2-yl) amino) benzoyl) phenylalanine
Operation is same as above, and obtains 0.1183g white powder, yield 62.79%, m.p.223-225 DEG C.1H NMR(DMSO-D6, 400 MHz),δ: 2.37(s, 3H, CH3), 2.45(s, 3H, CH3), 3.10(m, 2H, CH2C6H5), 4.65 (m, 1H, CH), 7.07-7.98 (m, 13H, 2 × C6H4, C6H5), 8.66(d,J =8.0,1H, CONH), 10.21(s, 1H, COOH).
Embodiment 11(3-((4-(4- chlorphenyl) -5- methylthiazol -2- base) amino) benzoyl) phenylalanine
Operation is same as above, and obtains 0.1401g white powder, yield 71.34%, m.p.237-239 DEG C.1H NMR(DMSO-D6, 400 MHz),δ: 2.50(s, 3H, CH3), 3.8(m, 2H, CH2C6H5), 4.62 (m, 1H, CH), 7.17-7.95(m, 13H, 2 × C6H4, C6H5), 8.65(d,J =8.0,1H, CONH), 10.29(s, 1H, COOH).
Embodiment 12(3-((4-(4- chlorphenyl)-5- ethyl thiazole-2- base) amino) benzoyl) phenylalanine
Operation is same as above, and obtains 0.1280g white powder, yield 66.03%, m.p192-194. DEG C.1H NMR(DMSO-D6, 400 MHz),δ: 1.23(t,J =8.0 Hz, 3H, CH2CH3) 2.84(q,J=8.0 Hz, 2H, CH2CH3), 3.07(m, 2H, CH2C6H5), 4.13 (m, 1H, CH), 7.19-7.92(m, 13H, 2 × C6H4, C6H5), 7.98(s, 1H, CONH), 10.59(s, 1H, COOH).
Embodiment 13 (3- ((4- (4- hydroxy phenyl) -5- methylthiazol -2- base) amino) benzoyl) phenylalanine
Operation is same as above, and obtains 0.1048g white powder, yield 55.37%, m.p.156-158 DEG C.1H NMR(DMSO-D6, 400 MHz),δ: 2.39(3,3H, CH3), 3.11(m, 2H, CH2C6H5), 4.62 (m, 1H, CH), 6.83-7.94(m, 13H, 2 × C6H4, C6H5), 8.65(d,J =8.0,1H, CONH), 10.18(s, 1H, COOH).
Embodiment 14(3-((4-(4- fluorophenyl)-5- methylthiazol-2- base) amino) benzoyl) phenylalanine
Operation is same as above, and obtains 0.1289g white powder, yield 67.82%, m.p.228-130 DEG C.1H NMR(DMSO-D6, 400 MHz),δ: 2.45(s, 3H, CH3), 3.11(m, 2H, CH2C6H5), 4.62 (m, 1H, CH), 7.20-7.96(m, 13H, 2 × C6H4, C6H5), 8.65(d,J =8.0,1H, CONH), 10.24(s, 1H, COOH).
Embodiment 15(3-((5- methyl 4-phenyl thiazol-2-yl) amino) benzoyl) phenylalanine
Operation is same as above, and obtains 0.1190g white powder, yield 63.18%, m.p.207-210 DEG C.1H NMR(DMSO-D6, 400 MHz),δ: 2.47(3,3H, CH3), 3.11(m, 2H, CH2C6H5), 4.62 (m, 1H, CH), 7.20-7.98(m, 14H, 2 × C6H5, C6H4), 8.65(d,J =8.0,1H, CONH), 10.26(s, 1H, COOH).
Embodiment 16 (3- ((5- methyl -4- (4- (trifluoromethyl) phenyl) thiazol-2-yl) amino) benzoyl) phenylpropyl alcohol Propylhomoserin
Operation is same as above, and obtains 0.1586g white powder, yield 56.47%, m.p.193-196 DEG C.1H NMR(DMSO-D6, 400 MHz),δ: 2.46(s, 3H, CH3), 3.08(m, 2H, CH2C6H5), 4.62 (m, 1H, CH), 7.17-8.66(m, 13H, 2 × C6H4, C6H5), 8.65(d,J =8.0,1H, CONH), 10.21(s, 1H, COOH).
17 compound of embodiment and target tyrosine kinase A bl (PDB:2GQG) and Bcr-AblT315I(PDB:3IK3) into Row docking marking
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
Other settings of 2.5 detections
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 formula and Abl and Bcr-AblT315IPair of kinases Map interlinking.
Result of giving a mark is as follows:
Compound number Abl(2GQG) AblT315I(3IK3)
Embodiment 1 6.7384 4.1356
Embodiment 2 7.7483 4.5895
Embodiment 3 7.0082 5.1886
Embodiment 4 7.0082 4.4911
Embodiment 5 7.8749 6.4907
Embodiment 6 5.4287 4.1189
Embodiment 7 9.9196 4.3985
Embodiment 8 8.0825 5.0091
Embodiment 9 9.6593 6.7628
Embodiment 10 11.0930 8.2173
Embodiment 11 6.0868 6.7832
Embodiment 12 7.3708 6.2569
Embodiment 13 10.1033 8.0148
Embodiment 14 7.0016 7.3846
Embodiment 15 9.6431 8.2938
Embodiment 16 6.9344 8.7044
The compound of marking the application as the result is shown is for Abl kinases and Bcr-AblT315IKinases has good binding ability, It is able to suppress Abl and Bcr-AblT315IActivity, and then efficiently solve T315I be mutated caused by resistance problems, can be used as anti- The novel B cr-Abl tyrosine kinase inhibitor of T315I mutation.
18 target protein kinase activity test result of embodiment
ADP-GloTMKinase assay
1 instrument and reagent
Workbench Purifying Equipment Co., Ltd., Suzhou
Biotek Instrument Ltd. of the microplate reader U.S.
Liquid-transfering gun U.S. ThermoFisher SCIENTIFIC
Shift its woods Bell's instrument manufacturing Co., Ltd of shaking table China Haimen
Complete white 384 orifice plate Germany Greiner
ADP-GloTMThe Beijing+ABL Kinase Enzyme System Promega() Bioisystech Co., Ltd
ADP-GloTM+ABLT315IThe Beijing Kinase Enzyme System Promega() Bioisystech Co., Ltd
The preparation of 2 kinase assay buffers
Configuring kinase buffer liquid and/or kinase assay reagent, kinase assay reagent to specifications should use immediately after preparing, or Person's packing is stored in -20 DEG C.The reagent prepared detects signal after freeze thawing several times and does not lose.
3 production ATP-ADP standard conversion curves
3.1 dilute reagent with 1X kinase reaction buffer (kit provides 5X kinase reaction buffer, need to dilute in advance) Ultra the Pure ATP and ADP that box provides, are made 1ml 1mM ATP and 500ul 1mM ADP(1ml 1mM ATP: taking 1 X kinase buffer liquid of 100ulATP, 900ul is made into；500ul 1mM ADP: 50ul ADP, 450ul 1X kinase buffer liquid are taken It is made into).
3.2 are added to 1ml 1mM ATP and 500ul 1mM ADP that the first step prepares by table 3 the EP pipe of 0.2 ml A1-A12 is mixed in hole, this is 1mM series.
3.3 are diluted to 25 μM of series in the hole B1-B12, for making the ATP-ADP transformation standard curve of ABL1.
3.4 are diluted to 5 μM of series in the hole C1-C12, for making ABLT315IATP-ADP transformation standard curve.
3.5 move the A1- of 5ul to 384 orifice plates from 25 μM matched, 5 μM of ATP+ADP series 0.2ml EP pipe B1-B12 A12,B1-B12；0.2ml EP pipe C1-C12 moves C1-C12, D1-D12 of the 5ul to 384 orifice plates.
3.6 incubation at room temperature 40min.
5ul ADP-Glo is added in the every hole of 3.7 384 orifice platesTMReagent terminates kinase reaction, while exhausting unconverted ATP leaves behind ADP.
3.8 press table 4, are incubated at room temperature certain time.
ADP is converted ATP by 3.9 addition 10ul kinase assay reagents, and introduces luciferase and fluorescein to detect ATP (10ul kinase assay reagent is added in the every hole 384 orifice plate A1-A12, B1-B12.
Be incubated at room temperature 30-60min, incubation time length depend on kinase reaction process used in ATP concentration (all for 30min), it is detected with Chemiluminescence Apparatus.
4 optimization kinase reaction conditions
The dosage that the amount of kinases is referred to specification uses (ABLT315IFor 1.4ng, ABL1 1ng).
5 utilize ADP-GloTMKinase assay screening compounds step
5.1 reagents prepare
Drug dilution: 8 1.5ml EP pipes are taken, No. 2-8 plus distilled water 600ul, No. 1 adds distilled water 1110.18ul, testization Close object 9.22ul, sesquialter dilution.
Drug concentration are as follows: 248 16 32 64 128 256 (μM ol/L)
DMSO dilution: 8 1.5ml EP pipes are taken, No. 2-8 plus distilled water 600ul, No. 1 adds distilled water 1110.18ul, DMSO 9.22ul, sesquialter dilution.
1X Buffer: taking 1.5ml EP to manage, and adds 800ul distilled water, and 5 X Buffer, 0.5ul DTT of 200ul is mixed It is even, (dosage can be first calculated before preparing).
62.5 μM of ATP: taking 1.5ml EP to manage, add 397.5ul 1X Buffer, 2.5ul Ultra Pure ATP, mixes It is even.
12.5 μM of ATP: taking 1.5ml EP to manage, add 200ul 1X Buffer, then plus 25 μM of ATP preparing take 50ul, mix It is even.
2.5ng/ul ABL1 protein kinase: taking 1.5ml EP to manage, add 117.0ul 1X Buffer, add 3.0ul ABL1, Active is mixed.
3.5ng/ul ABLT315IProtein kinase: it takes 1.5ml EP to manage, adds 115.8ul 1X Buffer, add 4.2ul ABLT315I, Active, mixing.
5.2 ABLT315IKinase assay
1. 0.2ml EP is taken to manage, it is denoted as 1., substrate is not added, add 18ul 3.5ng/ul ABLT315IProtein kinase, 18ul 1X Buffer, 36 12.5 μM of ul ATP are mixed, for use.
2. 0.2ml EP is taken to manage, it is denoted as 2., adds 90 ul 3.5ng/ul ABLLT315IProtein kinase, 90 ul substrates, 180 12.5 μM of ATP of ul are mixed, for use.
3. take 8 0.2ml EP pipe (No. 1 EP pipe), from low to high plus 2ul DMSO
8 0.2ml EP pipe (No. 2 EP pipes) is taken, from low to high plus 2ul DMSO
8 0.2ml EP pipe (3-6 EP pipe) is taken, from low to high plus 2ul compound (4 compounds)
3. No. 1 0.2ml EP pipe, every hole adds 8ul 0.2ml 1. EP pipe solution, and 2-6 0.2ml EP pipe, 2. every hole adds 8ul 0.2ml EP pipe solution mixes, goes to 384 orifice plates, every hole 5ul.
5. being incubated at room temperature 60min.
6. 5ul ADP-Glo is added in every holeTM, it is incubated for 40min.
7. 10ul kinase assay reagent is added in every hole, it is incubated for 30min, detection.
The protein kinase B cr-Abl of part of compoundsT315IIt is active as shown in the table:
ND:Not detected.
The test of 19 anti tumor activity in vitro of embodiment
Cell strain selects people's chronic myelogenous leukemia cell (K562), and the K562 cell of resistance to Imatinib (K562/R), human liver cancer is thin Born of the same parents (HepG-2), Non-small cell lung carcinoma cell (A549), Human normal hepatocyte (L02).
1) K562 cell, K562/R cell, HepG-2 cell, A549 cell and L02 cell are respectively with dual anti-and 10% containing 1% 1640 culture mediums of FBS are incubated at containing 5%CO2, in 37 DEG C of saturated humidity incubator, passage in 2 days is primary.K562/R cell is used It is based on containing 5%CO containing 1% dual anti-and 10%FBS, 4 μM of ol/L 1640 cultures2, in 37 DEG C of saturated humidity incubator, pass within 2-3 days In generation, 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.
HepG-2 cell, A549 cell, the L02 cell for choosing logarithmic growth phase, are made into dense with the culture medium containing 10%FBS Degree is 5 × 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℃ Saturated humidity incubator in continue culture for 24 hours after, move abandon culture solution, then be separately added into compound concentration be 8,16,32,64, 3 secondary orifices are arranged in the 200 μ L(of culture medium of 128uM), continue after cultivating 48h, 20 μ L MTT are added, are put into incubator culture 4h Afterwards, culture medium is discarded, 150uL DMAO is added in every hole, sets low speed on shaking table, is protected from light shaking 10min and makes crystallization dissolution completely, uses Microplate reader measures absorbance value (OD) at 490nm wavelength.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 CML cell cycling inhibiting and the K562 cell of resistance to Imatinib (K562/R) good Good inhibiting effect, i.e., equally have good inhibitory activity for the K562 cell with imatinib-resistant；It is right simultaneously There is lower toxicity in human normal liver cell L 02, while inhibiting cancer cell, can be avoided or reduce and is secondary to the poison of human body Effect.

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；
R3Selected from hydrogen ,-OH ,-NO2,-CN, halogen, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl, C1-C6Haloalkoxy Base, C6-C10Aryl C1-C6Alkyl；
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；R3Selected from hydrogen ,-OH, halogen, C1-C4Alkyl, C1-C6Alkoxy, C1- C4Halogenated alkyl, C1-C4Halogenated alkoxy, benzyl, preferably hydrogen, benzyl.
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、R2、R3As described in claim 1 with the definition of n, R4 is selected from C1-C6Alkyl or C1-C6Halogenated alkyl.
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 (i.e. intermediate 1)；
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 (i.e. intermediate 2)；
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 intermediate thiazoleamino benzoic acid derivative (3)；
Step 4: intermediate thiazoleamino benzoic acid derivative, EDCI, HOBT and dehydrated alcohol are added under condition of ice bath to anti- It answers in bottle, reacts 2-4 h, be addedHydrochloride, DIPEA, DMAP and DMF continue ice bath and react half an hour, it After be changed to react at room temperature, until end of reaction, then be slowly added to ice water while stirring, until solution becomes muddy from clarifying, room Temperature stirring 0.5-1.5 h places into refrigerator and white solid is precipitated, and filtering is dry by obtained solid, obtains intermediate 4;
Step 5: intermediate 4, dehydrated alcohol and distilled water being added into reaction flask, adjust pH most 11-13 with dilute NaOH, and 37 DEG C stirring, reaction process monitor pH, be adjusted to 11-13 in time when lower than 10；TLC monitors reaction process, after completion of the reaction, filtering, Filter residue is abandoned, filtrate is 1-4 with dilute HCl tune pH, is put into refrigerator and solid, filtering, dry compound of formula I is precipitated.
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；
PH in step 5 in reaction process is preferably 12, and the pH in last handling process is preferably 2-3, and dilute NaOH is 5%-30%'s NaOH aqueous solution, dilute HCl are the hydrochloric acid solution of 5%-15%.
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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