CN107964027A - Phosphoryl pyrimidine anti-tumor compounds and preparation method thereof and purposes - Google Patents
Phosphoryl pyrimidine anti-tumor compounds and preparation method thereof and purposes Download PDFInfo
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- CN107964027A CN107964027A CN201711289229.1A CN201711289229A CN107964027A CN 107964027 A CN107964027 A CN 107964027A CN 201711289229 A CN201711289229 A CN 201711289229A CN 107964027 A CN107964027 A CN 107964027A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Abstract
The present invention relates to phosphoryl pyrimidine anti-tumor compounds and preparation method thereof and purposes, the phosphoryl pyrimidines are specially the compound shown in logical formula (I), and each substituent of logical formula (I) is defined in the description.The invention further relates to the compound or its pharmaceutically acceptable salt shown in the logical formula (I), or containing its pharmaceutical composition by suppressing focal adhesion kinase, and then tumor disease is treated, be particularly used to treat cancer of pancreas, lung cancer, the purposes of breast cancer；
Description
Technical field
The present invention relates to phosphoryl pyrimidine anti-tumor compounds and preparation method thereof and purposes, belongs to medical science neck
Domain.
Background technology
Protein tyrosine kinase (protein tyrosine kinase, PTKs) is by controlling the signal transduction of cell to lead to
Road adjusts a series of physiological and biochemical procedures such as the growth, differentiation, apoptosis of cell.Receptor type tyrosine kinase is one kind across cell
The relatively large kinases of film, its extracellular domain with ligand binding, transmembrane domain and a zymogenesis-in phosphorylation
Specific tyrosine residue and the intracellular domain for thus influencing cell Proliferation.(such as lung cancer, mammary gland in general human cancer
Cancer, stomach cancer, oophoroma, lymthoma) have found the unconventionality expression of the kinases.Protein tyrosine kinase becomes antitumor drug
One of important target spot of research and development.
Focal adhesion kinase (focal adhesion kinase, FAK) is that one kind is located at focal adhension, by 1028 amino acid
The cytoplasmic tyrosine kinase and skelemin of composition, participate in a variety of acceptor or nonreceptor tyrosine kinase signal paths, including
Oncoprotein Src, vascular endothelial growth factor -3 (VEGFR-3), p53, phosphatidylinositol 3-kinase (PI3K) and Insulin-Like
The biobehavioral such as path, survival, propagation, migration and invasion and attack to cell such as epidermal growth factor -1 (IGF-1) has adjusting to make
With.Some researches show that have the overexpression of FAK in many tumour cells.Therefore, it is new to have become research and development by FAK
The important target of antitumor drug.Research shows, all table is crossed there are FAK in the tumor tissues of most Patients with Pancreatic Cancer
Reach, and Fak inhibitor can reduce the viability of pancreatic cancer cell through a variety of ways, suppress its growth, promote its apoptosis, but
Fak inhibitor only has little effect to normal cell.At present, it is almost into preclinical or clinical research Fak inhibitor
Micromolecular inhibitor, since FAK and many cell signaling proteins have effect, according to the difference of mechanism of action, as FAK
The FAK micromolecular inhibitors of anti-tumor drugs targeting are roughly divided into two major classes：ATP dependent forms and ATP independent forms.ATP is relied on
Type FAK micromolecular inhibitors can disturb the activity of FAK catalysis regions, may influence multiple downstream signaling pathways, cause more
Extensive side effect, and can block if non ATP dependent form FAK micromolecular inhibitors such as allosteric Fak inhibitor specific protein-
Protein interaction (interaction of such as p53 and FAK), so as to suppress the activity of FAK.It is existing at present it is multiple have much treatment before
The FAK micromolecular inhibitors of scape are developed into preclinical and clinical research successively, but there is no such medicine to list.Wherein there is generation
The FAK micromolecular inhibitors of table have：PF-00562271, it is the benzene sulfonate of PF-562271, is a kind of effective, ATP
Competitiveness, reversible Fak inhibitor, IC50For 1.5nM, act on Pyk2 and be compared to be used for low 10 times or so of FAK effects, be compared to use
In more than 100 times of other protein kinase (except some CDKs) high selectivities.Clinical 1 research of positive progress at present (Serrels A.,
et al.Int.J.Cancer,2012,131(2):287-97.).And for example, TAE226 (NVP-TAE226), it is a kind of effective
Fak inhibitor, IC50Most effective to act on Pyk2 for 5.5nM, to InsR, IGF-1R, ALK and c-Met action effects are than it
Weak 10 to 100 times or so.TAE226 shows effective antiproliferative and suppression in testing in vivo and in vitro to a series of malignant tumours
Knurl acts on, there is no at present in relation to its clinical test report (Schultze A., et al.Invest New Drugs, 2010,
28(6):825-33.).In addition, Defactinib (VS-6063, PF-04554878) is a kind of selectivity, and it is orally active
Fak inhibitor.The positive clinic 2 that carries out is studied at present.(Kang Y.,et al.J.Natl.Cancer Inst.,2013,105
(19):1485-95.)
In view for the treatment of cancer there is an urgent need to this area is necessary to develop the better medicine of new effect.
The content of the invention
, should it is an object of the present invention to providing a kind of phosphoryl pyrimidines or its pharmaceutically acceptable salt
Class compound has good antitumor activity.
Another object of the present invention is to provide to contain the phosphoryl pyrimidines or its pharmaceutically acceptable salt
Pharmaceutical composition.
It is still another object of the present invention to provide the phosphoryl pyrimidines or its pharmaceutically acceptable salt, or
The purposes of the composition.
On the one hand, the present invention provides the compound or its pharmaceutically acceptable salt shown in a kind of logical formula (I), the general formula
(I) compound shown in has such as lower structure：
Wherein,
R1Selected from chlorine, fluorine or trifluoromethyl；
R2Selected from methyl, ethyl or cyclopropyl；
R3Selected from methyl, chlorine, fluorine or hydrogen；
R4Selected from methyl or ethyl；
L is selected from-CH2- or-O (CH2)2CH2-；
Y is selected from oxygen ,-NCH3、-NCH2CH3Or-NC (=O) CH3。
As a kind of embodiment of the present invention, the compound shown in logical formula (I) of the present invention has I-1~I-
Structure shown in 16：
Preferably, the compound shown in the logical formula (I) is I-4.
Structural compounds as implied above are phosphoryl yl pyrimidines class compound, during antitumor activity screening display is of the invention
Compound all has stronger suppression pancreatic cancer cell (Aspc-1 cells, Bxpc-3 cells and Panc-1 cells) multiplication capacity,
The cytoactive relatively low to normal HPDE6-C7 cells shows, indicates that it has relatively low cytotoxicity；Part of compounds is shown
Go out than with reference to medicine TAE226 (CAS：761437-28-9) unexpected more excellent anti-FAK kinase activities.As one kind
The novel molecule of structure, the present invention in compound have exploitation into new and effective Fak inhibitor potentiality, to treatment-related
Tumor disease especially cancer of pancreas, lung cancer and breast cancer have larger application value.
Structure shown in foregoing I-1~I-16 has following title respectively：
(I-1) N- [3- [[the chloro- 2- of 5- [[4- [[(1- morpholines) methoxyl group phosphoryl] methyl]] phenyl] amine -4- pyrimidines
Base] amine] phenyl] -2- formamides；
(I-2) [[[the chloro- 2- of 5- [[4- [[(1- ethyl piperazidines) methoxyl group phosphoryl] methyl]] phenyl] amine -4- is phonetic by 3- by N-
Piperidinyl] amine] phenyl] -2- formamides；
(I-3) [[[the chloro- 2- of 5- [[4- [[(1- methyl piperazines) ethyoxyl phosphoryl] methyl]] phenyl] amine -4- is phonetic by 3- by N-
Piperidinyl] amine] phenyl] -2- formamides；
(I-4) [[[the chloro- 2- of 5- [[4- [[(1- morpholines) methoxyl group phosphoryl] propoxyl group]] phenyl] amine -4- is phonetic by 3- by N-
Piperidinyl] amine] phenyl] -2- formamides；
(I-5) N- [3- [[the fluoro- 2- of 5- [[4- [[(1- morpholines) ethyoxyl phosphoryl] methyl]] phenyl] amine -4- pyrimidines
Base] amine] phenyl] -2- formamides；
(I-6) N- [3- [[5- trifluoromethyls -2- [[4- [[(1- morpholines) methoxyl group phosphoryl] propoxyl group]] phenyl]
Amine -4- pyrimidine radicals] amine] phenyl] -2- formamides；
(I-7) [[[the chloro- 2- of 5- [[4- [[(1- morpholines) methoxyl group phosphoryl] propoxyl group]] phenyl] amine -4- is phonetic by 3- by N-
Piperidinyl] amine] phenyl] -2- ring propionamides；
(I-8) [[[the chloro- 2- of 5- [[4- [[(1- morpholines) methoxyl group phosphoryl] propoxyl group]] phenyl] amine -4- is phonetic by 3- by N-
Piperidinyl] amine] phenyl] -2- acetamides；
(I-9) N- [3- [[the chloro- 2- of 5- [[2- methyl -4- [[(1- morpholines) methoxyl group phosphoryl] propoxyl group]] phenyl]
Amine -4- pyrimidine radicals] amine] phenyl] -2- formamides；
(I-10) N- [3- [[the chloro- 2- of 5- [[the fluoro- 4- of 2- [[(1- morpholines) methoxyl group phosphoryl] propoxyl group]] phenyl]
Amine -4- pyrimidine radicals] amine] phenyl] -2- formamides；
(I-11) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 2- [[(1- morpholines) methoxyl group phosphoryl] propoxyl group]] phenyl]
Amine -4- pyrimidine radicals] amine] phenyl] -2- formamides；
(I-12) N- [3- [[the chloro- 2- of 5- [[2- methyl -4- [[(1- morpholines) methoxyl group phosphoryl] methyl]] phenyl]
Amine -4- pyrimidine radicals] amine] phenyl] -2- formamides；
(I-13) N- [3- [[the chloro- 2- of 5- [[the fluoro- 4- of 2- [[(1- morpholines) methoxyl group phosphoryl] methyl]] phenyl] amine-
4- pyrimidine radicals] amine] phenyl] -2- formamides；
(I-14) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 2- [[(1- morpholines) methoxyl group phosphoryl] methyl]] phenyl] amine-
4- pyrimidine radicals] amine] phenyl] -2- formamides；
(I-15) N- [3- [[the chloro- 2- of 5- [[4- [[(1- morpholines) methoxyl group phosphoryl] methyl]] phenyl] amine -4- pyrimidines
Base] amine] phenyl] -2- acetamides；
(I-16) N- [3- [[the chloro- 2- of 5- [[4- [[(1- acetylpiperazines) methoxyl group phosphoryl] propoxyl group]] phenyl] amine -4-
Pyrimidine radicals] amine] phenyl] -2- formamides.
On the other hand, the present invention provides a kind of pharmaceutical composition, it contains the logical formula (I) institute of the present invention of effective dose
The compound shown or its pharmaceutically acceptable salt, and pharmaceutical carrier.
Compound of the present invention is subjected to due to their purposes in medicine, the salt preferred agents of formula (I) compound
Salt.The compound of the present invention is alkali, wherein required salt form can be prepared by appropriate method known in the art, including with
Mineral acid treatment free alkali, the inorganic acid is such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid；Or swum with organic acid treatment
From alkali, the organic acids such as acetic acid, trifluoroacetic acid, maleic acid, butanedioic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, grass
Acid, hydroxyacetic acid, salicylic acid, pyranose thuja acid (pyranosidy1acid), such as glucuronic acid or galacturonic acid, α-hydroxyl
Base acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or Chinese cassia tree
Acid, sulfonic acid, such as p- toluenesulfonic acids, methanesulfonic acid, ethyl sulfonic acid etc..The embodiment of pharmaceutically acceptable salt includes sulfate, Jiao
Sulfate, disulfate, sulphite, bisulfites, phosphate, chloride, bromide, iodide, acetate, propionic acid
Salt, caprate, caprylate, acrylates, formates, isobutyrate, caproate, enanthate, propionate (propiolates),
Oxalates, malonate, benzoate, chloro benzoate, methyl benzoic acid salt, dinitro-benzoate, hydroxy benzoate,
Methoxy benzoic acid salt, phthalate, phenyl acetate salt, phenylpropionic acid salt, phenylbutyrate (phenylbutrates),
Citrate, lactate, gamma hydroxybutyrate, hydroxyl acetate, tartrate, amygdalate and sulfonate, such as diformazan
Benzene sulfonate, mesylate, propane sulfonic acid salt, naphthalene -1- sulfonate and naphthalene-2-sulfonic acid salt.
The pharmaceutical composition of the present invention usually contains a kind of the compounds of this invention.However, in some embodiments, this hair
Bright pharmaceutical composition, which contains, has more than a kind of compound of the invention.In addition, the pharmaceutical composition of the present invention can also optionally include
One or more other pharmaceutically active compounds.
The present invention also provides the phosphoryl pyrimidines or its pharmaceutically acceptable salt, described pharmaceutical composition
By suppressing focal adhesion kinase, and then suppress the purposes of tumor proliferation.Specifically, which, which predominantly prepares, is used to treat pancreas
Purposes in the medicine of cancer, lung cancer and breast cancer.
The present invention provides shown compound or its pharmaceutically acceptable salt, or pharmaceutical composition of the present invention exists
Prepare the application in focal adhesion kinase inhibitor.
The present invention provides the compound or its pharmaceutically acceptable salt shown in the logical formula (I), or of the present invention
Purposes of the pharmaceutical composition in the medicine for preparing treatment tumour.Preferably, the tumour is selected from cancer of pancreas, lung cancer and breast cancer
One or more, further preferred cancer of pancreas.It is highly preferred that what the purposes was mainly realized by suppressing focal adhesion kinase.
Brief description of the drawings
Fig. 1 changes over time feelings for different disposal of embodiment of the present invention group to the inhibitory action of Aspc-1, Panc-1 cell
Condition.
Fig. 2 is different disposal group Aspc-1 Apoptosis situations of the embodiment of the present invention.
Fig. 3 is different disposal group Aspc-1 cell cycle distributions of the embodiment of the present invention.
Embodiment
The explanation present invention is further described below in conjunction with specific embodiment, but these embodiments are not meant as limiting this hair
Bright scope.
The experimental method of actual conditions is not specified in the embodiment of the present invention, usually according to normal condition, or according to raw material or
Condition proposed by commodity manufacturer.The reagent in specific source is not specified, for the conventional reagent of market purchase.
The preparation of 1 target molecule of embodiment
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, and thin-layered chromatography (TLC) makes
The specification that silicon amine plate uses is 0.15mm-0.2mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4mm-
0.5mm。
The raw material that the present invention uses is mainly purchased from commercially available from Sinopharm Chemical Reagent Co., Ltd., Beijing coupling science and technology
Co., Ltd, Aladdin chemical reagent Co., Ltd, up to companies such as auspicious chemicals.
Refer to aqueous solution without specified otherwise, solution in embodiment.
Without specified otherwise in embodiment, the temperature of reaction is room temperature, is 20 DEG C -30 DEG C.
The technical solution adopted by the present invention is as follows：
Synthetic route, reagent and the condition of compound (I):a)P(OR4)3, such as P (OEt)3Or P (OMe)3,130℃,80–
91%；b)(COCl)2,DMF,60℃；c)THF, 0 DEG C, 92%；d)Fe-NH4Cl,MeOH-H2O, 80 DEG C to rt, 62-
85%；e)SOCl2,1h,60℃；100%；f)R2NH2, NaHCO3, CH3CN, 4h, 0 DEG C；95%；G) N, N- diisopropyl ethyl
(DIPEA), isopropanol (IPA), 6h, 80 DEG C；85%；H) TFA, 2-BuOH, 100 DEG C, 12h, 12-30%.
7 synthesis
6 (5.98mmol, 1.00g) are taken in three-necked bottle, add SOCl2(7.176mmol), when the 80 DEG C of reactions 1 that heat up are small
Afterwards, reaction finishes, and reaction solution removes solvent under reduced pressure, obtains liquid, directly throws in next step；Previous step product (3mmol) is slowly added dropwise
Enter R2NH2(2.94mmol), NaHCO3In the 15ml acetonitrile solutions of (7.5mmol), 0 DEG C reaction, 4 it is small when after react complete.Reaction
Liquid evaporated under reduced pressure, pours into 80ml water and separates out solid, filters, and drying, obtains 7, does not purify and directly reacts in next step.
8 synthesis
Take 7 (2mmol) and NH4Cl (4mmol) adds MeOH-H2O(1:1) in, iron powder (8mmol) is slowly added under stirring,
Heating 60 DEG C, reaction 2 it is small when after, reaction complete, filter while hot, add 200mL water, do not separate out solid, water mutually uses ethyl acetate
Extract (100mL × 3), combined ethyl acetate layer, saturated common salt is washed once, and anhydrous sodium sulfate drying, evaporated under reduced pressure obtains white
Solid 8, does not purify and directly reacts in next step.
9 synthesis
8 (2mmol) and DIPEA (3mmol) are taken, 8mL isopropanols is added, 2,4-, bis- chloro- 5-R is slowly added dropwise under stirring1-
Pyrimidine (such as 2, bis- chloro- 5-FU (2mmol) of 4,5- trichloropyrimidines (2mmol) or 2,4-), be warming up to 80 DEG C reaction 6 it is small when
Afterwards, reaction is completed.Reaction solution evaporated under reduced pressure, solid are added to 20mL saturations NaHCO3In aqueous solution, solid is separated out.Filter, dry
It is dry, white solid 9 is obtained, does not purify and directly reacts in next step.
The synthesis of object (I)
9 (23.44mmol) and trifluoroacetic acid (4.5g, 35.16mmol) is taken to be slowly added into substitution in 2-BuOH (50ml)
Arylamine (5), heat up 100 DEG C, reaction 12 it is small when after, reaction finishes, cooling, pour into saturated sodium bicarbonate solution, separate out solid,
Filter, wash, drying, separates through silica gel column chromatography, obtain target molecule (I).
Target molecule is synthesized according to above method, the physicochemical data of synthesized target molecule is as follows：
(I-1) N- [3- [[the chloro- 2- of 5- [[4- [[(1- morpholines) methoxyl group phosphoryl] methyl]] phenyl] amine -4- pyrimidines
Base] amine] phenyl] -2- formamides；
1H NMR (400MHz, DMSO-d6)δ12.04(s,1H),10.51(s,1H),9.12(s,1H),8.65(s,1H),
8.18 (d, J=4.0Hz, 1H), 7.80-7.42 (m, 4H), 7.29 (s, 1H), 7.15 (s, 2H), 4.06-3.68 (s, 2H),
3.67 (d, J=12.4Hz, 4H), 3.42 (d, J=12.4Hz, 4H), 3.01-2.66 (s, 3H), 1.21 (d, J=6.8Hz,
3H)；HRMS (ESI), C24H28ClN6O4P, [M+H]+theoretical calculation：531.1598, actual measurement：531.1620.
(I-2) [[[the chloro- 2- of 5- [[4- [[(1- ethyl piperazidines) methoxyl group phosphoryl] methyl]] phenyl] amine -4- is phonetic by 3- by N-
Piperidinyl] amine] phenyl] -2- formamides；
1H NMR (400MHz, DMSO-d6)δ12.04(s,1H),10.51(s,1H),9.12(s,1H),8.65(s,1H),
8.18 (d, J=4.0Hz, 1H), 7.80-7.42 (m, 4H), 7.29 (s, 1H), 7.15 (s, 2H), 4.06-3.68 (s, 2H),
3.39 (s, 3H), 2.74 (d, J=6.8Hz, 3H), 2.65 (dd, J=12.4Hz, 4H), 2.49 (dd, J=12.4Hz, 4H),
2.40 (m, 2H), 1.55 (t, J=8.0,3H)；HRMS (ESI), C26H33ClN7O3P, [M+H]+theoretical calculation：558.2071, it is real
Survey：558.3071.
(I-3) [[[the chloro- 2- of 5- [[4- [[(1- methyl piperazines) ethyoxyl phosphoryl] methyl]] phenyl] amine -4- is phonetic by 3- by N-
Piperidinyl] amine] phenyl] -2- formamides；
1H NMR (400MHz, DMSO-d6)δ12.05(s,1H),10.51(s,1H),9.12(s,1H),8.65(s,1H),
8.18 (d, J=4.0Hz, 1H), 7.80-7.42 (m, 4H), 7.29 (s, 1H), 7.15 (s, 2H), 4.06-3.68 (m, 2H),
3.40 (s, 2H), 2.74 (d, J=6.8Hz, 3H), 2.65 (dd, J=12.4Hz, 4H), 2.49 (dd, J=12.4Hz, 4H),
2.27 (s, 3H), 1.55 (t, J=8.0,3H)；HRMS (ESI), C26H33ClN7O3P, [M+H]+theoretical calculation：558.2071, it is real
Survey：558.3045.
(I-4) [[[the chloro- 2- of 5- [[4- [[(1- morpholines) methoxyl group phosphoryl] propoxyl group]] phenyl] amine -4- is phonetic by 3- by N-
Piperidinyl] amine] phenyl] -2- formamides；
1H NMR (400MHz, DMSO-d6) δ 12.05 (s, 1H), 10.39 (s, 1H), 9.09 (s, 1H), 8.63 (d, J=
4.6Hz, 1H), 8.16 (d, J=8.2Hz, 1H), 7.63 (d, J=8.0Hz, 1H), 7.56-7.41 (m, 3H), 7.27 (t, J=
8.0Hz, 1H), 6.82 (d, J=8.0Hz, 2H), 4.20 (t, J=4.4Hz, 2H), 4.10-3.75 (m, 4H), 3.52 (t, J=
4.4Hz, 4H), 3.01 (d, J=2.6Hz, 4H), 2.80 (s, 3H), 2.77 (d, J=4.0Hz, 3H)；HRMS (ESI),
C26H32ClN6O5P, [M+H]+theoretical calculation：575.1860, actual measurement：575.1920.
(I-5) N- [3- [[the fluoro- 2- of 5- [[4- [[(1- morpholines) ethyoxyl phosphoryl] methyl]] phenyl] amine -4- pyrimidines
Base] amine] phenyl] -2- formamides；
1H NMR (400MHz, DMSO-d6)δ12.04(s,1H),10.51(s,1H),9.12(s,1H),8.65(s,1H),
8.18 (d, J=4.0Hz, 1H), 7.80-7.42 (m, 4H), 7.29 (s, 1H), 7.15 (s, 2H), 4.06-3.68 (s, 2H),
3.67 (d, J=12.4Hz, 4H), 3.42 (d, J=12.4Hz, 4H), 3.01-2.66 (s, 3H), 2.56 (s, 2H), 1.21 (d, J
=6.8Hz, 3H)；HRMS (ESI), C25H30FN6O4P, [M+H]+theoretical calculation：529.2050, actual measurement：529.3015.
(I-6) N- [3- [[5- trifluoromethyls -2- [[4- [[(1- morpholines) methoxyl group phosphoryl] propoxyl group]] phenyl]
Amine -4- pyrimidine radicals] amine] phenyl] -2- formamides；
1H NMR (400MHz, DMSO-d6) δ 12.05 (s, 1H), 10.39 (s, 1H), 9.09 (s, 1H), 8.63 (d, J=
4.6Hz, 1H), 8.16 (d, J=8.2Hz, 1H), 7.63 (d, J=8.0Hz, 1H), 7.56-7.41 (m, 3H), 7.27 (t, J=
8.0Hz, 1H), 6.82 (d, J=8.0Hz, 2H), 4.20 (t, J=4.4Hz, 2H), 4.10-3.75 (m, 4H), 3.52 (t, J=
4.4Hz, 4H), 3.01 (d, J=2.6Hz, 4H), 2.80 (s, 3H), 2.77 (d, J=4.0Hz, 3H)；HRMS (ESI),
C27H32F3N6O5P, [M+H]+theoretical calculation：609.2124, actual measurement：609.3125.
(I-7) [[[the chloro- 2- of 5- [[4- [[(1- morpholines) methoxyl group phosphoryl] propoxyl group]] phenyl] amine -4- is phonetic by 3- by N-
Piperidinyl] amine] phenyl] -2- ring propionamides；
1H NMR (400MHz, DMSO-d6) δ 12.05 (s, 1H), 10.39 (s, 1H), 9.09 (s, 1H), 8.63 (d, J=
4.6Hz, 1H), 8.16 (d, J=8.2Hz, 1H), 7.63 (d, J=8.0Hz, 1H), 7.56-7.41 (m, 3H), 7.27 (t, J=
8.0Hz, 1H), 6.82 (d, J=8.0Hz, 2H), 4.20 (t, J=4.4Hz, 2H), 4.10-3.75 (m, 4H), 3.52 (t, J=
4.4Hz, 4H), 3.01 (d, J=2.6Hz, 4H), 2.80 (s, 3H), 2.32 (m, 1H), 1.15 (m, 4H)；HRMS (ESI),
C28H34ClN6O5P, [M+H]+theoretical calculation：601.2017, actual measurement：601.2022.
(I-8) [[[the chloro- 2- of 5- [[4- [[(1- morpholines) methoxyl group phosphoryl] propoxyl group]] phenyl] amine -4- is phonetic by 3- by N-
Piperidinyl] amine] phenyl] -2- acetamides；
1H NMR (400MHz, DMSO-d6) δ 12.05 (s, 1H), 10.39 (s, 1H), 9.09 (s, 1H), 8.63 (d, J=
4.6Hz, 1H), 8.16 (d, J=8.2Hz, 1H), 7.63 (d, J=8.0Hz, 1H), 7.56-7.41 (m, 3H), 7.27 (t, J=
8.0Hz, 1H), 6.82 (d, J=8.0Hz, 2H), 4.20 (t, J=4.4Hz, 2H), 4.10-3.75 (m, 4H), 3.67 (t, J=
4.4Hz, 4H), 3.45 (d, J=2.6Hz, 4H), 3.39 (s, 3H), 3.24 (m, 2H), 2.80 (t, J=4.4Hz, 3H)；HRMS
(ESI), C27H34Cl2N6O5P, [M+H]+theoretical calculation：589.2017, actual measurement：589.2034.
(I-9) N- [3- [[the chloro- 2- of 5- [[2- methyl -4- [[(1- morpholines) methoxyl group phosphoryl] propoxyl group]] phenyl]
Amine -4- pyrimidine radicals] amine] phenyl] -2- formamides；
1H NMR (400MHz, DMSO-d6) δ 12.05 (s, 1H), 10.39 (s, 1H), 9.09 (s, 1H), 8.63 (d, J=
4.6Hz, 1H), 8.16 (d, J=8.2Hz, 1H), 7.63 (d, J=8.0Hz, 1H), 7.56-7.41 (m, 3H), 7.27 (t, J=
8.0Hz, 1H), 6.82 (s, 1H), 4.20 (t, J=4.4Hz, 2H), 4.10-3.75 (m, 4H), 3.52 (t, J=4.4Hz, 4H),
3.01 (d, J=2.6Hz, 4H), 2.80 (s, 3H), 2.77 (d, J=4.0Hz, 3H), 2.35 (s, 3H)；HRMS (ESI),
C27H34ClN6O5P, [M+H]+theoretical calculation：589.2017, actual measurement：589.3010.
(I-10) N- [3- [[the chloro- 2- of 5- [[the fluoro- 4- of 2- [[(1- morpholines) methoxyl group phosphoryl] propoxyl group]] phenyl]
Amine -4- pyrimidine radicals] amine] phenyl] -2- formamides；
1H NMR (400MHz, DMSO-d6) δ 12.05 (s, 1H), 10.39 (s, 1H), 9.09 (s, 1H), 8.63 (d, J=
4.6Hz, 1H), 8.16 (d, J=8.2Hz, 1H), 7.63 (d, J=8.0Hz, 1H), 7.56-7.41 (m, 3H), 7.27 (t, J=
8.0Hz, 1H), 6.82 (s, 1H), 4.20 (t, J=4.4Hz, 2H), 4.10-3.75 (m, 4H), 3.52 (t, J=4.4Hz, 4H),
3.01 (d, J=2.6Hz, 4H), 2.80 (s, 3H), 2.77 (d, J=4.0Hz, 3H)；HRMS (ESI), C26H31ClN6O5P, [M+
H]+theoretical calculation：593.1766, actual measurement：593.1663.
(I-11) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 2- [[(1- morpholines) methoxyl group phosphoryl] propoxyl group]] phenyl]
Amine -4- pyrimidine radicals] amine] phenyl] -2- formamides；
1H NMR (400MHz, DMSO-d6) δ 12.05 (s, 1H), 10.39 (s, 1H), 9.09 (s, 1H), 8.63 (d, J=
4.6Hz, 1H), 8.16 (d, J=8.2Hz, 1H), 7.63 (d, J=8.0Hz, 1H), 7.56-7.41 (m, 3H), 7.27 (t, J=
8.0Hz, 1H), 6.82 (s, 1H), 4.20 (t, J=4.4Hz, 2H), 4.10-3.75 (m, 4H), 3.52 (t, J=4.4Hz, 4H),
3.01 (d, J=2.6Hz, 4H), 2.80 (s, 3H), 2.77 (d, J=4.0Hz, 3H)；HRMS (ESI), C26H31Cl2N6O5P, [M+
H]+theoretical calculation：609.1471, actual measurement：609.1456.
(I-12) N- [3- [[the chloro- 2- of 5- [[2- methyl -4- [[(1- morpholines) methoxyl group phosphoryl] methyl]] phenyl]
Amine -4- pyrimidine radicals] amine] phenyl] -2- formamides；
1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),10.51(s,1H),9.12(s,1H),8.65(s,1H),
8.18 (d, J=4.0Hz, 1H), 7.80-7.42 (m, 4H), 7.29 (s, 1H), 7.15 (s, 1H), 4.06-3.68 (s, 2H),
3.67 (d, J=12.4Hz, 4H), 3.42 (d, J=12.4Hz, 4H), 3.01-2.66 (s, 3H), 2.35 (s, 3H), 1.21 (d, J
=6.8Hz, 3H)；HRMS (ESI), C25H30ClN6O4P, [M+H]+theoretical calculation：545.1755, actual measurement：545.1754.
(I-13) N- [3- [[the chloro- 2- of 5- [[the fluoro- 4- of 2- [[(1- morpholines) methoxyl group phosphoryl] methyl]] phenyl] amine-
4- pyrimidine radicals] amine] phenyl] -2- formamides；
1H NMR (400MHz, DMSO-d6)δ12.04(s,1H),10.51(s,1H),9.12(s,1H),8.65(s,1H),
8.18 (d, J=4.0Hz, 1H), 7.80-7.42 (m, 4H), 7.29 (s, 1H), 7.16 (s, 1H), 4.06-3.68 (s, 2H),
3.67 (d, J=12.4Hz, 4H), 3.42 (d, J=12.4Hz, 4H), 3.01-2.66 (s, 3H), 1.21 (d, J=6.8Hz,
3H)；HRMS (ESI), C24H27ClFN6O4P, [M+H]+theoretical calculation：549.1504, actual measurement：549.1503.
(I-14) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 2- [[(1- morpholines) methoxyl group phosphoryl] methyl]] phenyl] amine-
4- pyrimidine radicals] amine] phenyl] -2- formamides；
1H NMR (400MHz, DMSO-d6)δ12.11(s,1H),10.51(s,1H),9.12(s,1H),8.65(s,1H),
8.18 (d, J=4.0Hz, 1H), 7.80-7.42 (m, 4H), 7.29 (s, 1H), 7.15 (s, 1H), 4.06-3.68 (s, 2H),
3.67 (d, J=12.4Hz, 4H), 3.52 (d, J=12.4Hz, 4H), 3.01-2.66 (s, 3H), 1.21 (d, J=6.8Hz,
3H)；HRMS (ESI), C24H27Cl2N6O4P, [M+H]+theoretical calculation：565.1208, actual measurement：565.1210.
(I-15) N- [3- [[the chloro- 2- of 5- [[4- [[(1- morpholines) methoxyl group phosphoryl] methyl]] phenyl] amine -4- pyrimidines
Base] amine] phenyl] -2- acetamides；
1H NMR (400MHz, DMSO-d6)δ12.04(s,1H),10.51(s,1H),9.12(s,1H),8.65(s,1H),
8.18 (d, J=4.0Hz, 1H), 7.80-7.42 (m, 4H), 7.29 (s, 1H), 7.15 (s, 2H), 4.06-3.68 (s, 2H),
3.67 (d, J=12.4Hz, 4H), 3.42 (d, J=12.4Hz, 4H), 3.01-2.66 (s, 3H), 2.57 (m, 2H), 1.21 (d, J
=6.8Hz, 3H)；HRMS (ESI), C25H30ClN6O4P, [M+H]+theoretical calculation：545.1755, actual measurement：545.1745.
(I-16) N- [3- [[the chloro- 2- of 5- [[4- [[(1- acetylpiperazines) methoxyl group phosphoryl] propoxyl group]] phenyl] amine -4-
Pyrimidine radicals] amine] phenyl] -2- formamides；
1H NMR (400MHz, DMSO-d6) δ 12.05 (s, 1H), 10.39 (s, 1H), 9.09 (s, 1H), 8.63 (d, J=
4.6Hz, 1H), 8.16 (d, J=8.2Hz, 1H), 7.63 (d, J=8.0Hz, 1H), 7.56-7.41 (m, 3H), 7.27 (t, J=
8.0Hz, 1H), 6.82 (d, J=8.0Hz, 2H), 4.20 (t, J=4.4Hz, 2H), 3.39 (s, 3H), 3.32 (d, J=2.6Hz,
4H), 2.81 (d, J=2.6Hz, 4H), 2.74 (d, J=4.0Hz, 3Hz), 2.5 (m, 4H), 2.02 (s, 3H)；HRMS (ESI),
C28H35ClN7O5P, [M+H]+theoretical calculation：615.2126, actual measurement：615.2120.
Method of the target molecule into salt
The preparation method of inorganic acid salt：Take target molecule (1mmol) to be dissolved in 10mL absolute methanols, under ice bath, slowly drip
Add the 5mL absolute methanol solutions of inorganic acid (1mmol), be added dropwise, stirred 30 minutes at a temperature of this, then first is evaporated off in room temperature
Alcohol, up to the inorganic acid salt of target molecule.
The preparation method of acylate：Take target molecule (1mmol) to be dissolved in 10mL absolute methanols, under ice bath, slowly drip
Add the 5mL dry ethers of organic acid (1mmol), be added dropwise, stirred 30 minutes at a temperature of this, then solvent is evaporated off in room temperature,
Up to the acylate of target molecule.
The preparation of two target molecule mixtures
The above-mentioned two target molecule of equimolar amounts (1mmol) is taken to be stirred at room temperature 10 minutes in absolute methanol (5mL),
Solvent is evaporated off in room temperature, up to the mixture of target molecule.
2 target molecule biological evaluation of embodiment
1st, in vitro to receptor tyrosine kinase inhibitory activity test method
(1) kinase assay buffer is prepared
1. melting kinase assay buffer (Kinase Detection Buffer) in room temperature, precipitation has been seen whether.
2. if there is precipitation, just (Kinase Detection Buffer) is incubated at 37 DEG C 15 minutes and often shaken,
Dissolving precipitation.Alternatively, carefully siphoning away supernatant, precipitation is removed.
(2) kinase assay reagent is prepared
1. using preceding at equilibrium at room temperature kinase assay buffer (Kinase Detection Buffe) and kinase assay bottom
Thing (Kinase Detection Substrate).
2. kinase assay buffer (Kinase Detection Buffer) is all poured into equipped with kinase assay substrate
In the brown bottle of (Kinase Detection Substrate), freeze-dried powder substrate is dissolved, kinase assay has thus been made
Reagent.
Mixed 3. gently shaking, being vortexed or overturning, become homogeneous solution, substrate should dissolve in 1 minute.
4. kinase assay reagent should use immediately after preparing, or packing is stored in -20 DEG C, it is believed that the reagent prepared passes through
Freeze thawing Posterior circle signal activity is not all lost several times.
(3) standard curve that ATP changes into ADP is made
1. the Ultra provided with 1 × kinase reaction buffer solution (kinase reaction buffer) dilution kit
Pure ATP and ADP, are made 50 μM of ADP of 900 μ L 50 μM of ATP and 500 μ L.
2. by 50 μM of ATP and 50 μM of ADP solution that previous step prepares by being mixed table 1 Suo Shi in 384 orifice plate A1-A12,
The concentration of the ATP and ADP of each conversion percentages are simulated, is mixed.
Table 1. prepares 50 μM of series A TP+ADP standard items
3. the ADP-Glo of 5 μ L is added per holeTMReagent terminates kinase reaction.In incubation at room temperature 40 minutes.
4. 10 μ L kinase assays reagents (Kinase Detection Reagent) are added per hole changes into ATP by ADP, and
Luciferase and luciferin are introduced to detect ATP.
5. in incubation at room temperature 30-60 minutes, measure fluorescent with multi-function microplate reader and record fluorescent value.
6. draw the standard curve that ATP changes into ADP.
(4) IC of kinase inhibitor is determined50Value
1. prepare 1 × kinase reaction buffer solution (kinase reaction according to promega kit specifications
Buffer), 2.5 × 50ng/ μ L kinases and 2.5 × 0.5 μ g/ μ L substrates and 125 μM of ATP.
2. 3 μ 1 × kinase reactions of L buffer solutions (kinase reaction buffer), 2 μ L are added in no enzyme control wells
2.5 × 0.5 μ g/ μ L substrates and 125 μM of ATP.1 μ L 1 × kinase reaction buffer solutions (kinase is added in negative control hole
Reaction buffer), 2 μ L 2.5 × 50ng/ μ L kinases, 2 μ L, 2.5 × 0.5 μ g/ μ L substrates and 125 μM of ATP.Testing
Add 1 μ L 5 × medicine to be measured in hole, 2 μ L 2.5 × 50ng/ μ L kinases, 2 μ L, 2.5 × 0.5 μ g/ μ L substrates and 125 μM
ATP。
3. mixing tablet, it is incubated 60 minutes.
4. the ADP-Glo of 5 μ L is added per holeTMReagent terminates kinase reaction.In incubation at room temperature 40 minutes.
5. 10 μ L kinase assays reagents (Kinase Detection Reagent) are added per hole changes into ATP by ADP, and
Luciferase and luciferin are introduced to detect ATP.In incubation at room temperature 30-60 minutes, measure fluorescent with multi-function microplate reader and remember
Record fluorescent value.
6. interpretation of result, the results are shown in Table 2.
2nd, FAK high expressing cells growth experiment (CCK-8 detection methods) is suppressed
(1) cell type and selection：Aspc-1 cells, Bxpc-3 cells and Panc-1 cells (human pancreatic cancer cell, FAK
The high expression of kinases), HPDE6-C7 cells.
(2) cell inoculation：Exponential phase cell is collected, concentration of cell suspension is adjusted, with every hole 4 × 103A cell, often
100 μ L of pore volume are inoculated into 96 orifice plates, and every group sets 3 multiple holes (edge hole is filled with sterile PBS)；
(3) cell culture：After cell inoculation, control group is cultivated with 10%FBS RPMI-1640, and experimental group is respectively with 10 μ L
Tae226 (1.25-40 μm of ol/L), the variant medicine (1.25-40 μm of ol/L) of various concentrations gradient are intervened, 37 DEG C, 5%CO2
Continue to cultivate (empirically requiring to cultivate different time respectively) in incubator；
(4) colour generation：Two groups of cells add 10 μ L CCK-8 solution (5mg/ml) after 48h is cultivated, and training is terminated after 4h
Support, in low-speed oscillation 10min on shaking table, crystallization is fully dissolved；
(5) colorimetric：Each hole shading value (OD values) is measured on enzyme-linked immunosorbent assay instrument, 450nm wavelength is selected, with acellular
The zeroing of i.e. RPMl-1640 nutrient solutions blank well, survey the absorbance in each hole.Experiment is in triplicate；
(6) result is recorded：Inhibitory rate of cell growth=(one experimental group absorbance of control group absorbance)/control group is inhaled
Shading value × 100%, cell proliferation rate=(experimental group absorbance/control group absorbance) × 100；
(7) cell growth curve is drawn：Using the time as abscissa, inhibiting rate/proliferation rate draws cell growth for ordinate
Curve.Figure is done for inhibitor concentration in GraphPad Prism mapping softwares in GraphPad softwares, so as to by log
[inhibitor] estimates IC relative to reaction, variable slope model50。
Test result is as shown in table 2, and table 2 shows that obtained compound is suppressing FAK kinases and anti-tumour cell proliferative
In active effect.
2. compound of table suppresses kinase activity and antiproliferation
a:IC50：Half effective inhibition concentration .b:Aspc-1, Bxpc-3, Panc-1 are typical pancreatic cancer cell, FAK kinases
Altimeter reaches；HPDE6-C7 people's Normal Pancreas ductal epithelial cell.
Meanwhile this experiment finds the Aspc-1 of compound I-4, Panc-1 cytoactives have very big with time and concentration
Relation, as shown in Figure 1, with the increase of concentration, cell survival rate reduces, and the Aspc-1 after especially 72h, Panc-1 cells are in medicine
When thing concentration is up to 8 μm of ol/L, hence it is evident that higher than 48h, thus provable medicine belongs to concentration and time dependence medicine.
3rd, Apoptosis and cell cycle (flow cytometry)
(1) experiment material and reagent
Aspc-1 cells, RAPI, DMEM basal medium (Hyclone companies, cat:SH30022.01B), FBS tires ox blood
(GIBCO companies, cat clearly:16400-044), dual anti-(Beijing Xia Si bio tech ltd, prospec cat:
SV30010), low speed centrifuge (upper sea cowry grace bio tech ltd, cat:TDZ4B-WS), CO2Incubator (is won in Shanghai
News, cat:BC-J160S), superclean bench (winning news model SW-CJ-2FD in Shanghai), is inverted fluorescent electronic microscope (Leica
DMI3000B)。
(2) experimental method
1. expand culture Aspc-1 cells；
2. drug-treated：With various concentrations drug-treated cell 48 it is small when.
3. collected by trypsinisation of the cell without EDTA after drug-treated, PBS washings cell twice, collects cell 1~5
×105Cell；
4. add the AnnexinV Binding Buffer suspension cells of 500uL；
5. after adding 5uL AnnexinV-FITC mixings, adding 5uLPropidium Iodide, (cycle detection only adds 5ul
Propidium Iodide), mix；
6. lucifuge, room temperature reaction 10min；
7. with flow cytomery (Ex=488nm；Em=530nm) the situation in Apoptosis and cycle.
Shown in test result below figure 2 and Fig. 3, lower Fig. 2 and Fig. 3 shows obtained compound I-4 under various concentrations
Cause the result of Aspc-1 Apoptosis.
Above bioactivity the result shows that, the present invention in I-4 inside and outside action effect it is notable, be mainly manifested in following several
A aspect:(1) I-4 has strong inhibition effect, IC to FAK kinases50Only 4.65nM, hence it is evident that better than reference compound TAE226
(6.79nM).(2) antiproliferation result discloses, to the IC of Aspc-1 and Bxpc-3 cells50Respectively 1.66 μM and
0.57 μM, hence it is evident that relatively low to normal HPDE6-C7 cells shows better than reference compound TAE226 (6.73 μM, 1.03 μM)
Cytoactive (IC5020 μM of ＞), indicate its relatively low cytotoxicity.(3) flow cytometer showed the results show I-4 can make Aspc-1 cells
Apoptosis rate substantially increase (91.9%) and by cell-cycle arrest in the G2/M phases, in dose dependent.Indicate that this quasi-molecule has
The potentiality into new and effective Fak inhibitor may be greatly developed, are had to treatment-related tumor disease especially cancer of pancreas larger
Application value.
The above is only the preferred embodiments of the present invention, it is noted that for the ordinary skill people of the art
For member, without departing from the technical principles of the invention, some improvements and modifications can also be made, these improvements and modifications
Also it should be regarded as protection scope of the present invention.
Claims (9)
1. compound or its pharmaceutically acceptable salt shown in a kind of logical formula (I), the compound shown in the logical formula (I) have
Such as lower structure：
Wherein,
R1Selected from chlorine, fluorine or trifluoromethyl；
R2Selected from methyl, ethyl or cyclopropyl；
R3Selected from methyl, chlorine, fluorine or hydrogen；
R4Selected from methyl or ethyl；
L is selected from-CH2- or-O (CH2)2CH2-；
Y is selected from oxygen ,-NCH3、-NCH2CH3Or-NC (=O) CH3。
2. compound or its pharmaceutically acceptable salt shown in logical formula (I) according to claim 1, wherein, it is described logical
Compound shown in formula (I) has the structure shown in I-1~I-16：
3. compound or its pharmaceutically acceptable salt shown in logical formula (I) according to claim 1, wherein, it is described logical
Compound shown in formula (I) is I-4.
4. a kind of pharmaceutical composition, it contains the change led to any one of the claims 1 to 3 of effective dose shown in formula (I)
Compound or its pharmaceutically acceptable salt, and pharmaceutical carrier.
5. lead to the compound or its pharmaceutically acceptable salt shown in formula (I) any one of claims 1 to 3, or right
It is required that application of the pharmaceutical composition in focal adhesion kinase inhibitor is prepared described in 4.
6. lead to the compound or its pharmaceutically acceptable salt shown in formula (I) any one of claims 1 to 3, or right
It is required that purposes of the pharmaceutical composition in the medicine for preparing treatment tumour described in 4.
7. purposes according to claim 6, wherein, the tumour is selected from cancer of pancreas, lung cancer, one kind or more in breast cancer
Kind.
8. purposes according to claim 7, wherein, the tumour is cancer of pancreas.
9. the purposes according to any one of claim 6~8, wherein, the purposes is mainly by suppressing focal adhesion kinase
Realize.
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| CN106565782A (en) * | 2016-10-10 | 2017-04-19 | 大连医科大学 | Phosphoryl pyrimidine compound, composition and use |
| CN107235931A (en) * | 2017-07-11 | 2017-10-10 | 大连医科大学 | New pyrimidine anti-tumor compounds and preparation method thereof and purposes |
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| CN106565782A (en) * | 2016-10-10 | 2017-04-19 | 大连医科大学 | Phosphoryl pyrimidine compound, composition and use |
| CN107235931A (en) * | 2017-07-11 | 2017-10-10 | 大连医科大学 | New pyrimidine anti-tumor compounds and preparation method thereof and purposes |
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