CN103172616A - Novel tyrosine kinase inhibitor 1,4-disubstituted-1,2,3-triazole compound and preparation and applications thereof - Google Patents
Novel tyrosine kinase inhibitor 1,4-disubstituted-1,2,3-triazole compound and preparation and applications thereof Download PDFInfo
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- 0 *C1=NC(N)NC=C1 Chemical compound *C1=NC(N)NC=C1 0.000 description 4
- NYPYPOZNGOXYSU-UHFFFAOYSA-N Brc1cccnc1 Chemical compound Brc1cccnc1 NYPYPOZNGOXYSU-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a preparation and applications of a 1,4-disubstituted-1,2,3-triazole compound, and particularly provides a 1,4-disubstituted-1,2,3-triazole compound with a structure shown in the following general formula (I); the compound has a certain inhibitory effect on the growth of K562, KG1a, HCC-1954, the MCF-7 cells, and especially can effectively restrain the survival and growth of KG1a cells, wherein R1 and R2 are selected from H, F, Cl, Br, I, CH3O and CF3; and R3 is selected from CH3O.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, replace-1 in particular to Isosorbide-5-Nitrae-bis-, 2,3-triazole compound, Preparation Method And The Use.
Background technology
Leukemia is the abnormal clone's property malignant disease of a class hemopoietic stem cell.Leukemic generation is all relevant with the self-replacation of leukemia stem/progenitor cells with recurrence, and it has stronger resistance and anti-immune.Therefore stoping the key of leukemia relapse is exactly to eliminate leukemic stem cells.The mankind's acute myeloid leukaemia KG1a cell has the feature of acute myeloid leukaemia stem cell, is the varient of people's acute myeloid leukemia cells in children strain KG1, generally is used as the research of leukemic stem cells.Because the toxic side effect of chemotherapy and radiation is larger, therefore, urgently find a kind of better efficacy, toxic side effect is little, the medicine of the treatment CML of high specificity.
Early 1990s, researchist's expectation suppresses the BCR-ABL fusion gene by the RNA approach and plays a role, but could not effectively treat CML.Along with illustrating of fusion gene structure and expression product, the investigator diversion to the design and development of the small-molecule drug that can directly act on BCR-ABL protein.In recent years, a series of BCR-ABL kinase inhibitor of exploitation have curative effect preferably to CML, such as imatinib, nilotinib etc.But do not have at present a kind of medicine can fundamentally suppress or eliminate leukemic stem cells, reach the effect of thorough healing.Therefore, we come up the research transferred to leukemic stem cells of center of gravity of research, wish to find a kind ofly can restraining effect obviously even thoroughly eliminate the small-molecule drug of stem cell.
In patent of the present invention about the cytoactive testing method of medicine for first with the K562 cell, carrying out general sieve, find out the active testing that active best drug candidate carries out KG1a, MCF-7, HCC-1954 cell.
Summary of the invention
The present invention is optimized the structure of imatinib, has newly synthesized a compounds, with 1,2,3-triazole ring, replaces the amido linkage in imatinib, and with different substituting groups, for Isosorbide-5-Nitrae-bis-replaces-1,2,3-triazole compound.The pharmacologically active result shows, this compounds all has certain restraining effect to the growth of K562, KG1a, MCF-7, HCC-1954 cell, and they can be for other cancers such as prevention or treatment leukemia, mammary cancer.
The invention provides Isosorbide-5-Nitrae-bis-and replace-1,2,3-triazole compound has general formula (I):
Wherein, R
1be selected from
R
2be selected from H, F, Cl, Br, I, CH
3o, CF
3; And
R
3be selected from
cH
3o.
In specific embodiment, described Isosorbide-5-Nitrae-bis-replaces-1, and 2,3-triazole compound has general formula (I), wherein R
1be selected from
r
2be selected from H, CF
3, and R
3be selected from
The invention provides a kind of Isosorbide-5-Nitrae-bis-for preparing and replace-1, the method for 2,3-triazole compound, comprise the following steps:
Step a: make formula (II) compound
Through acid amide condensation reaction production (III) compound
Wherein, described acid amide condensation reaction comprise make formula (II) compound under 0～5 ℃ in solvent with condensing agent, acylation catalyst, the alkali admixture activation scheduled time, and add N in mixing solutions, the O-dimethyl hydroxylamine hydrochloride is reacted, obtain formula (III) compound, wherein said solvent is selected from methylene dichloride or chloroform, preferred methylene dichloride, described condensing agent is selected from 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC) or N, N '-DIC (DIC), preferred EDCI, described acylation catalyst is selected from I-hydroxybenzotriazole (HOBt), Dimethylamino pyridine (DMAP), N-hydroxy-succinamide (NHS) or N-hydroxy thiosuccinimide (sulfo-NHS), preferred HOBt, described alkali is selected from the 4-methylmorpholine, triethylamine (TEA), diisopropylethylamine (DIEA) or dimethyl formamide (DMF), preferred 4-methylmorpholine, and the described scheduled time is in the scope of 20 minutes to 1 hour, preferably 20 minutes,
Step b: make formula (III) compound under 0 ℃ in aprotic solvent with reductive agent generation reduction reaction production (IV) compound
Wherein, described aprotic solvent is selected from ether, tetrahydrofuran (THF) or dioxane, preferred tetrahydrofuran (THF), and described reductive agent is selected from metal hydride H
xm
y, wherein M represents metal and alkylate thereof, includes but not limited to LiAlH
4, AlH
3, LiAlH (OEt)
3, (CH
3oCH
2cH
2o) LiAlH
2, Ca[AlH
2(OBu-i)
2]
2, preferred LiAlH
4;
Step c: formula (IV) compound is reacted in solvent with catalyzer under 20～25 ℃, alkaline environment and generate the formula V compound
Wherein, described alkaline environment is provided by salt of wormwood, and described catalyzer is (1-diazo-2-oxo-propyl group)-dimethyl phosphate, described solvent is MeOH: THF (1: 1, v/v) mixture, wherein MeOH mainly plays the hydrotropy effect, and participates in reaction;
Steps d: make formula (VI) compound
At 80～85 ℃, with DPPA, in the trimethyl carbinol, react the scheduled time, then products therefrom reacts production (VII) compound under acidic conditions in solvent
Step e: make formula (VII) compound react the scheduled time with Sodium Nitrite under sour existence in polar solvent under preset temperature, and then with reaction of sodium azide production (VIII) compound
Wherein, described temperature between-20 to 5 ℃, preferably 0～5 ℃, described polar solvent is selected from water, dimethyl formamide or N,N-DIMETHYLACETAMIDE, preferably water, and described acid is selected from hydrochloric acid, and in the scope of the described scheduled time between 5 minutes to 2 hours, preferably 1.5 hours; And
Step f: make formula (V) compound react production (I) compound with formula (VIII) compound under 20～25 ℃ in polar solvent under the existence of catalyzer, wherein, described solvent is selected from water, dimethyl formamide, acetonitrile, ethanol or its combination, preferably CH
3cN: H
2o (1: 1, mixture v/v), and described catalyzer is selected from Cu
2o, CuCN, CuCl, CuI or CuBr etc., preferably Cu
2o,
Wherein, formula (I) is to the R in formula (V)
1there is identical implication, be selected from
Formula (I), (VI), (VII) and (VIII) in R
2there is identical implication, be selected from H, F, Cl, Br, I, CH
3o, CF
3; And
Formula (I), (VI), (VII) and (VIII) in R
3there is identical implication, be selected from
cH
3o.
The invention provides a kind of R in general formula (I) for preparing
1be
r
2h, CF
3, and R
3be
cH
3the Isosorbide-5-Nitrae of O-bis-replaces-1, and the method for 2,3-triazole compound comprises:
Step a: make formula (II) compound
Through acid amide condensation reaction production (III) compound
Wherein, described acid amide condensation reaction comprise make formula (II) compound under 0～5 ℃ in solvent with condensing agent, acylation catalyst, the alkali admixture activation scheduled time, and add N in mixing solutions, the O-dimethyl hydroxylamine hydrochloride is reacted, obtain formula (III) compound, wherein said solvent is selected from methylene dichloride or chloroform, preferred methylene dichloride, described condensing agent is selected from 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC) or N, N '-DIC (DIC), preferred EDCI, described acylation catalyst is selected from I-hydroxybenzotriazole (HOBt), Dimethylamino pyridine (DMAP), N-hydroxy-succinamide (NHS) or N-hydroxy thiosuccinimide (sulfo-NHS), preferred HOBt, described alkali is selected from the 4-methylmorpholine, triethylamine (TEA), diisopropylethylamine (DIEA) or dimethyl formamide (DMF), preferred 4-methylmorpholine, and the described scheduled time is in the scope of 20 minutes to 1 hour, preferably 20 minutes,
Step b: make formula (III) compound under 0 ℃ in aprotic solvent with reductive agent generation reduction reaction production (IV) compound
Wherein, described aprotic solvent is selected from ether, tetrahydrofuran (THF) or dioxane, preferred tetrahydrofuran (THF), and described reductive agent is selected from metal hydride H
xm
y, wherein M represents metal and alkylate thereof, includes but not limited to LiAlH
4, AlH
3, LiAlH (OEt)
3, (CH
3oCH
2cH
2o) LiAlH
2, Ca[AlH
2(OBu-i)
2]
2, preferred LiAlH
4;
Step c: formula (IV) compound is reacted in solvent with catalyzer under 20～25 ℃, alkaline environment and generate the formula V compound
Wherein, described alkaline environment is provided by salt of wormwood, and described catalyzer is (1-diazo-2-oxo-propyl group)-dimethyl phosphate, described solvent is MeOH: THF (1: 1, v/v) mixture, wherein MeOH mainly plays the hydrotropy effect, and participates in reaction;
Steps d: make (VI) compound
At 80～85 ℃, with DPPA, in the trimethyl carbinol, react the scheduled time, then products therefrom reacts production (VII) compound under acidic conditions in solvent
Step e: make formula (VII) compound react the scheduled time with Sodium Nitrite under sour existence in polar solvent under preset temperature, and then with reaction of sodium azide production (VIII) compound
Wherein, described temperature between-20 to 5 ℃, preferably 0～5 ℃, described polar solvent is selected from water, dimethyl formamide or N,N-DIMETHYLACETAMIDE, preferably water, and described acid is selected from hydrochloric acid, and in the scope of the described scheduled time between 5 minutes to 2 hours, preferably 1.5 hours; And
Step f: make formula (V) compound react production (I) compound with formula (VIII) compound under 20～25 ℃ in polar solvent under the existence of catalyzer, wherein, described solvent is selected from water, dimethyl formamide, acetonitrile, ethanol or its combination, preferably CH
3cN: H
2o (1: 1, mixture v/v), and described catalyzer is selected from Cu
2o, CuCN, CuCl, CuI or CuBr etc., preferably Cu
2o,
Wherein, formula (II) is to the R in formula (V)
1be
r in formula (VI), (VII) and formula (VIII)
2be H, CF
3, and the R in formula (VI), (VII) and formula (VIII)
3be
cH
3o.
In specific embodiment, prepare R in general formula (I)
1be
r
2h, CF
3, and R
3be
cH
3the Isosorbide-5-Nitrae of O-bis-replaces-1, and the method for 2,3-triazole compound comprises:
Step a: make formula (II) compound
Activate 20 minutes with EDCI, HOBt, 4-methylmorpholine in methylene dichloride under 0 ℃ after, with N, the condensation reaction of O-dimethyl hydroxylamine hydrochloride generation acid amide, production (III) compound
Step b: make formula (III) compound under 0 ℃ in tetrahydrofuran (THF) with LiAlH
4react, production (IV) compound
Step c: make formula (IV) compound at room temperature with K
2cO
3, (1-diazo-2-oxopropyl)-dimethyl phosphate MeOH: THF (1: 1, v/v) in reaction generate the formula V compound
Steps d: make formula (VI) compound
At 45～50 ℃, with DPPA, in the trimethyl carbinol, react 3 hours, then product at CF
3cOOH: CH
2cl
2react production (VII) compound under=1: 5 conditions
Under 0～5 ℃, in water, with Sodium Nitrite, under the existence of hydrochloric acid, react 1.5 hours, and then with reaction of sodium azide production (VIII) compound
Step e: make formula (V) compound and formula (VII) compound under 25 ℃ at EtOH: H
2o (1: 1, v/v) at Cu
2under the existence of O, reaction generates wherein R
1be
r
2h, CF
3, and R
3be
cH
3the formula of O (I) compound,
Wherein, formula (II) is to the R in formula (V)
1be
r in formula (VI), (VII) and formula (VIII)
2be H, CF
3, and the R in formula (VI), (VII) and formula (VIII)
3be
cH
3o.
The present invention also provides described Isosorbide-5-Nitrae-bis-to replace-1, the application of 2,3-triazole compound in the medicine of other cancers such as preparation prevention or treatment leukemia.This compounds is to the growth of K562 cell and active certain restraining effect all arranged, and the Isosorbide-5-Nitrae-bis-when R1, R2 and R3 are different substituents replaces-1, and 2,3-triazole compound, at 48 hours IC of the inhibition to the K562 cell
50(μ mol/L) and IC
90(μ mol/L) value is (for increasing solvability, embodiment 1 compound carries out biological activity determination by its mesylate form) as shown in following table one, with the positive standard specimen of imatinib.
Having chosen active best compound (embodiment 2) according to table one continues the clones such as KG1a, MCF-7, HCC-1954 have been carried out to the cytoactive test, the IC at 48 hours
50(μ mol/L) and IC
90(μ mol/L) value as shown in Table 2.
Known according to table two, embodiment 2 compounds all have restraining effect preferably to the growth of KG1a, MCF-7, HCC-1954 cell, especially can significantly suppress growth and the survival of KG1a cell, stem cell is had to good restraining effect, thereby this compounds can be mixed with for preventing or treat the medicine of leukemia, mammary cancer.
In table one: embodiment 1 to 7, the compound of preparation was at 48 hours IC of the inhibition to the K562 cell
50and IC
90value
Table two: the IC that the compound of choosing records three kinds of different clones in 48 hours
50and IC
90value
Isosorbide-5-Nitrae of the present invention-bis-replaces-1, and 2,3-triazole compound can for example, be mixed to form pharmaceutical preparation according to conventional medicine compounding process and pharmaceutical carrier or vehicle (pharmaceutically acceptable carrier and vehicle).Can be by described 1,4-bis-replaces-1,2, the 3-triazole compound is blended in any oral dosage form commonly used as activeconstituents, described oral dosage form comprises tablet, capsule and liquid preparation (for example elixir and suspensoid), wherein comprises the material of tinting material, correctives, stablizer and taste masking.For mixing oral dosage form, described 1,4-bis-replaces-1, and 2,3-triazole compound can for example, mix to help compressing tablet and incapsulate as activeconstituents with various conventional tablet materials (starch, calcium carbonate, lactose, sucrose and Si Liaodengji dicalcium phosphate feed grade).Described Isosorbide-5-Nitrae-bis-can be replaced to-1,2,3-triazole compound pharmaceutically acceptable sterile liquid carrier for example dissolves or suspendible in sterilized water, aseptic organic solvent or both mixtures.Liquid vehicle can be the carrier that is applicable to injection, such as physiological saline, propylene glycol or Aqueous Solutions of Polyethylene Glycol.In other cases, micronized activeconstituents can also be dispersed in the aqueous solution of starch or Xylo-Mucine or for example be dispersed in, in suitable oil (peanut oil) and make.Liquid pharmaceutical formulation (referring to sterile solution or suspensoid) can be for intravenous injection, intramuscular injection, peritoneal injection or subcutaneous injection.
The present invention also provides a kind of pharmaceutical composition, and this pharmaceutical composition comprises at least one Isosorbide-5-Nitrae of the present invention-bis-as activeconstituents and replaces-1,2,3-triazole compound.In addition, described pharmaceutical composition can also comprise that one or more are inorganic or organic, pharmaceutically acceptable carrier or the vehicle of solid or liquid.Term " pharmaceutically acceptable " refers to additive or the composition that can tolerate and usually can not produce allergy or similarly untoward reaction (such as dizziness etc.) when being administered to animal such as Mammals (such as the mankind) on physiology.Pharmaceutical carrier and vehicle can include but not limited to thinner, for example lactose, glucose, seminose and/or glycerine; Lubricant; Polyoxyethylene glycol; Tackiness agent, for example magnesium aluminum silicate, starch, gelatin, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone; And, if necessary, also comprise disintegrating agent, for example starch, agar, Lalgine or its salt are as sodium alginate; And/or sorbent material, tinting material, sanitas, stablizer, correctives and sweeting agent.
Embodiment
Below with characteristics, be further described to various aspects of the present invention.
Shortenings used herein is generally well-known to those skilled in the art, or can be understandable according to rudimentary knowledge.
The starting raw material adopted in the preparation of the compounds of this invention is known, that can prepare according to currently known methods or commercially available acquisition.
The invention still further relates to new intermediate and/or starting raw material.Particularly preferably with those identical or similar reaction conditionss and the new intermediate mentioned in embodiment.
Intermediate and end product can carry out aftertreatment and/or purifying according to conventional methods, and described ordinary method comprises regulates pH, extraction, filtration, drying, concentrated, chromatography, grinding, crystallization etc.
In addition, the compounds of this invention can also be prepared by the alternative of the whole bag of tricks known in the art or methods described herein.
The following example only, for illustrating the present invention, limits the invention never in any form.
Embodiment 1 (2-methyl-5-{1-[4-(4-methyl-piperazine-1-ylmethyl)-phenyl]-[1,2,3] triazole-4-yl }-phenyl)-preparation of (4-pyridin-3-yl-pyrimidine-2-base)-amine
Step 1.1:N-methoxyl group-N-methyl-4-methyl-2-[(4-pyridin-3-yl-pyrimidine-2-base)-amido] preparation of benzamide
Get tri-mouthfuls of round-bottomed flasks of 50ml, add solvent C H
2cl
2(20ml), under 0 ℃, add successively 4-methyl-2-[(4-pyridin-3-yl-pyrimidine-2-base)-amido] phenylformic acid (1.00g, 3.26mmol), HOBt (0.49g, 3.63mmol), EDCI (0.69g, 3.60mmol), 4-methylmorpholine (0.99g, 9.79mmol), 0 ℃ of reaction system maintenance is constant, stirs 20min.Then add N, O-dimethyl hydroxylamine hydrochloride (0.47g, 4.82mmol), keep temperature-resistant, continues reaction 3h.Pass through TLC monitoring reaction process in reaction process.Reaction finishes, and reaction solution is joined to the saturated NaHCO of 30ml
3in solution, with methylene dichloride (3x100ml) extraction, merge organic phase, organic phase is washed with saturated common salt, Na
2sO
4drying, filter, and concentrated, purification by silica gel column chromatography obtains light yellow solid 1.02g, and productive rate is 89.52%.
1H-NMR(400MHz，CDCl
3)：δppm?9.27(d，J＝1.2HZ，1H)，8.74(d，J＝3.6HZ，1H)，8.58(d，J＝1.2HZ，1H)，8.53(d，J＝5.2HZ，1H)，8.44(d，J＝8.0HZ，1H)，7.40-7.47(m，2H)，7.30(s，1H)，7.22(d，J＝5.2HZ，1H)，7.02(s，1H)，3.65(s，3H)，3.41(s，3H)，2.43(s，3H)。
Step 1.2:4-methyl-2-[(4-pyridin-3-yl-pyrimidine-2-base)-amido] preparation of phenyl aldehyde
Get tri-mouthfuls of round-bottomed flasks of 25ml, add THF (15ml), under 0 ℃, add successively the product (0.80g, 2.29mmol) obtained in step 1.1, LiAlH
4(0.26g, 6.87mmol), 0 ℃ of reaction system maintenance is constant, continues reaction 3h.Pass through TLC monitoring reaction process in reaction process.Reaction finishes, reaction solution is added drop-wise in the saturated NaOH aqueous solution, can see and have a large amount of white flosss to generate, with EA extraction (30ml) three times, saturated common salt washing (10ml) three times, merge organic phase, anhydrous magnesium sulfate drying, concentrated, purification by silica gel column chromatography obtains yellow solid 0.59g, and productive rate is 88.75%.
1H-NMR(400MHz，CDCl
3)：δppm?10.05(s，1H)，9.28(d，J＝1.2HZ，1H)，8.85(s，1H)，8.76(dd，J＝1.2，4.8HZ，1H)，8.57(d，J＝5.2HZ，1H)，8.47(d，J＝8.0HZ，1H)，7.58(dd，J＝1.6，8.0HZ，1H)，7.51(dd，J＝4.8，8.0HZ，1H)，7.42(d，?J＝8.0HZ，1H)，7.27(s，1H)，7.14(s，1H)，2.48(s，3H)。
Step 1.3:{4-methyl-2-[(4-pyridin-3-yl-pyrimidine-2-base)-amido] phenyl } preparation of acetylene
Get three mouthfuls of round-bottomed flasks of 25ml drying, at room temperature, add successively K
2cO
3(0.28g, 2.00mmol), product (the 0.29g obtained in step 1.2,1.00mmol), (1-diazo-2-oxopropyl)-dimethyl phosphate (0.19g, 1.00mmol), finally by MeOH-THF, (volume ratio is 1: 1,14ml) join in reaction system, continue reaction 6h under room temperature.Pass through TLC monitoring reaction process in reaction process.Reaction finishes, and by reacting liquid filtering, removes K
2cO
3solid, add the 20ml ultrapure water, with EA extraction (3x30), saturated common salt washing (3x10ml), merges organic phase, and anhydrous magnesium sulfate drying, concentrate and obtain yellow solid 0.21g, and productive rate is 73.32%.
The MS:[M+H of this compound]
+287.25;
1h-NMR (400MHz, CDCl
3): δ ppm9.28 (s, 1H), 8.75 (d, J=4.0HZ, 1H), (8.54 d, J=5.2HZ, 1H), 8.41 (d, J=8.0HZ, 1H), 8.35 (s, 1H), (7.47 dd, J=4.8,7.6HZ, 1H), (7.24-7.21 m, 3H), 7.04 (s, 1H), (3.08 s, 1H), 2.39 (s, 3H).
The preparation of step 1.4:4-(4-methyl-piperazinyl-1-ylmethyl) aniline
Get tri-mouthfuls of round-bottomed flasks of 50ml, add solvent t-BuOH (20ml), under 0 ℃, add successively 4-[(4-methyl-piperazinyl-1-yl) methyl]-phenylformic acid (1.00g, 4.27mmol), DPPA (1.41g, 5.12mmol), Et
3n (0.86g, 8.54mmol), 0 ℃ of reaction system maintenance is constant, stirs 20min.Be warming up to 82 ℃, continue reaction 3h.Pass through TLC monitoring reaction process in reaction process.Reaction finishes, and reaction solution directly is spin-dried for, and adds the 30ml aqueous solution, with EA extraction (3x30ml), merges organic phase, and anhydrous magnesium sulfate drying is concentrated, then product at CF
3cOOH: CH
2cl
2under=1: 5 (24ml) condition, reaction is 2 hours, then by reaction solution washing (2x25ml), combining water layer, regulate water layer pH value to 9, be extracted with ethyl acetate water layer (3x30ml), merge organic phase, anhydrous magnesium sulfate drying, concentrated, obtain faint yellow solid 0.59g, productive rate is 67.30%.
The MS:[M+H of this compound]
+206.2;
1h-NMR (400MHz, D
2o): δ ppm 7.08 (d, J=8.4HZ, 2H), 6.74 (d, J=8.4HZ, 2H), 3.35 (s, 2H), 2.57 (s, 8H), 2.12 (s, 3H).
The preparation of step 1.5:1-azido--4-(4-methyl-piperazinyl-1-ylmethyl) benzene
Get tri-mouthfuls of round-bottomed flasks of 100ml and add water 15ml, under 0 ℃, add successively 4-(4-methyl-piperazinyl-1-ylmethyl) aniline (0.37g, 1.81mmol) and NaNO
2(0.25g, 3.62mmol), fully stir, and then slowly drips HCl (0.19g, 5.41mmol), is added dropwise to complete the temperature of rear maintenance reaction system between 0～5 ℃, reacts 1.5 hours.And then slowly drip NaN
3the aqueous solution of (0.14g, 2.17mmol), can produce a large amount of foams in the dropping process.Maintain the temperature at after being added dropwise to complete between 0～5 ℃, continue reaction 3 hours.After reaction finishes, by methylene dichloride reaction solution for (3x80ml) extraction, merge organic phase, with saturated aqueous common salt (3x10ml) washing, through anhydrous magnesium sulfate drying, filter, concentrate, by residue through silica gel column chromatography (CH
2cl
2: MeOH=20: 1) purifying, obtain yellow solid 0.38g, productive rate is 90.77%.
The MS:[M+H of this compound]
+232.3;
1h-NMR (400MHz, CDCl
3): δ ppm7.30 (d, J=8.4HZ, 2H), 7.01 (d, J=8.4HZ, 2H), 3.59 (s, 2H), 3.01 (s, 4H), 2.79 (s, 4H), 2.68 (s, 3H).
Step 1.6:(2-methyl-5-{1-[4-(4-methyl-piperazine-1-ylmethyl)-phenyl]-[1,2,3] triazole-4-yl }-phenyl)-preparation of (4-pyridin-3-yl-pyrimidine-2-base)-amine
Get tri-mouthfuls of round-bottomed flasks of 25ml, at room temperature, add successively CH
3cN-H
2o (20ml), the compound (0.20g, 0.70mmol) of step 1.3, the compound (0.19g, 0.84mmol) of step 1.5, then add Cu
2o (0.19g, 1.00mmol), monitor reaction process by TLC in reaction process.Keep the airtight continuation reaction of reaction system 12 hours.After question response finishes, reacting liquid filtering is spin-dried for concentrated, by residue through silica gel column chromatography (CH
2cl
2: MeOH=8: 1) purifying, obtain faint yellow solid 0.23g, productive rate is 63.51%.
MS：[M+H]
+518.3；
1H-NMR(600MHz，CDCl
3)：δppm?9.34(s，1H)，8.91(s，1H)，8.74(dd，J＝1.8，4.8HZ，1H)，8.55-8.52(m，2H)，8.21(s，1H)，7.79(d，J＝8.4HZ，2H)，7.62(dd，J＝1.8，7.8HZ，1H)，7.52(d，J＝8.4HZ，2H)，7.46(dd，J＝4.8，7.8HZ，1H)，7.33(d，J＝7.8HZ，1H)，7.22(d，J＝5.4HZ，1H)，7.14(s，1H)，3.60(s，2H)，2.54(s，8H)，2.42(s，3H)，2.33(s，3H)；
13C-NMR(600MHz，CDCl
3)：δppm?162.5，160.7，159.2，151.6，148.6，148.4，139.3，138.0，136.1，134.7，132.7，131.0，130.2，128.9，128.2，123.8，120.7，120.3，118.7，117.4，106.2，62.3，55.2，53.1，46.0，18.0。Its mesylate
1h-NMR (400MHz, D
2o): δ ppm 8.10-8.05 (m, 1H), 7.84-7.72 (m, 3H), 7.51-7.49 (m, 1H), 7.33-7.28 (m, 1H), 7.21 (s, 2H), (6.99-6.90 m, 3H), 6.43-6.40 (m, 1H), (6.12-5.94 m, 2H), 3.79 (s, 2H), (3.35 s, 4H), 3.02-3.01 (m, 4H), (2.87 s, 3H), 2.70 (s, 6H).
Embodiment 2N-(2-methyl-5-{1-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl }-1H-[1,2,3]-triazole-4-yl } phenyl)-preparation of 4-(pyridin-3-yl) pyrimidine-2-amine
With 3-trifluoromethyl-4-[(4-methylpiperazine-1-yl) methyl] aniline replaces 4-(4-methyl-piperazinyl-1-ylmethyl) aniline in embodiment 1, adopt the method identical with embodiment 1 to prepare this compound, the ultimate yield of target product is 55.02%.
The MS:[M+H of this compound]+586.21;
1h NMR (400MHz, DMSO-D6): δ ppm9.43 (s, 1H), 9.29 (d, J=2.0HZ 1H), (9.08 s, 1H), 8.68 (dd, J=1.6,4.8HZ, 1H), 8.55 (d, J=5.2HZ, 1H), 8.48 (d, J=8.0HZ, 1H), 8.27 (d, J=9.2HZ, 3H), 7.98 (d, J=8.4HZ, 1H), (7.66 dd, J=1.6,6.0HZ, 1H), (7.52 dd, J=4.8,2.8HZ, 1H), (7.47 d, J=5.2HZ, 1H), 7.39 (d, J=8.0HZ, 1H), 3.69 (s, 2H), (2.56-2.50 m, 8H), 2.32 (s, 6H);
13c-NMR (400MHz, DMSO-D6): δ ppm 162.0,161.6,160.0,151.9, and 148.6,148.1,138.9,138.0,136.0,134.8,132.9,132.6,131.4,129.2,128.9,128.4,125.6,124.3,124.0,122.9,122.4,121.8,119.9,117.7,108.2,57.5,54.7,52.4,45.3,18.5.
Embodiment 3 (2-methyl-5-{1-[4-(piperidin-1-yl methyl)-phenyl]-[1,2,3] triazole-4-yl }-phenyl)-preparation of (4-pyridin-3-yl-pyrimidine-2-base)-amine
Replace 4-(4-methyl-piperazinyl-1-ylmethyl) aniline in embodiment 1 with 4-(piperidines-1-methyl) aniline, adopt the method identical with embodiment 1 to prepare this compound, the ultimate yield of target product is 55.94%.
The MS:[M+H of this compound]+503.17;
1h NMR (400MHz, CDCl3): δ ppm9.34 (s, 1H), 8.92 (s, 1H), (8.75 d, J=4.0HZ, 1H), 8.56-8.53 (m, 2H), (8.21 s, 1H), 7.79 (d, J=8.4HZ, 2H), 7.62 (dd, J=1.2,7.6HZ, 1H), 7.52 (d, J=8.4HZ, 2H), (7.47 dd, J=4.8,7.6HZ, 1H), (7.34 d, J=7.6HZ, 1H), 7.23 (d, J=5.2HZ, 1H), 7.13 (s, 1H), (3.58 s, 2H), 2.45-2.43 (m, 7H), (1.66-1.60 m, 4H), 1.52-1.45 (m, 2H);
13c-NMR (400MHz, CDCl
3): δ ppm 162.5,160.6,159.2,151.6, and 148.6,148.5,139.3,137.9,136.0,134.8,132.7,131.0,130.4,128.9,128.2,123.8,120.8,120.3,118.7,117.4,108.3,63.0,54.5,25.9,24.2,18.0.
Embodiment 4 (2-methyl-5-{1-[4-(morpholine-1-ylmethyl)-phenyl]-[1,2,3] triazole-4-yl }-phenyl)-preparation of (4-pyridin-3-yl-pyrimidine-2-base)-amine
Replace 4-(4-methyl-piperazinyl-1-ylmethyl) aniline in embodiment 1 with 4-morpholine methyl aniline, adopt the method identical with embodiment 1 to prepare this compound, the ultimate yield of target product is 61.29%.
The MS:[M+H of this compound]
+505.25;
1h NMR (400MHz, CDCl
3): δ ppm9.35 (s, 1H), 8.91 (s, 1H), 8.74 (s, 1H), 8.53 (t, 2H), 8.21 (s, 1H), (7.79 d, J=8.4HZ, 2H), 7.60 (dd, J=1.2,7.6HZ, 1H), 7.52 (d, J=8.4HZ, 2H), 7.46 (dd, J=2.4,7.2HZ, 1H), 7.32 (d, J=8.0HZ, 1H), (7.21 d, J=5.2HZ, 1H), 7.16 (s, 1H), 3.75 (t, J=4.4HZ, 4H), (3.58 t, J=4.4HZ, 2H), 2.49 (t, J=4.0HZ, 4H), 2.42 (s, 3H);
13c-NMR (400MHz, CDCl
3): δ ppm 162.5,160.6,159.2,151.5, and 148.6,148.5,138.8,137.9,136.1,134.8,131.0,130.3,128.8,128.2,120.8,120.4,118.7,117.4,108.2,67.0,62.7,53.6,18.0.
Embodiment 5 N-(2-methyl-5-[1-(4-morpholinyl phenyl)-1H-[1,2,3]-triazole-4-yl] phenyl)-4-(pyridin-3-yl) pyrimidine-2-amine
Replace 4-(4-methyl-piperazinyl-1-ylmethyl) aniline in embodiment 1 with 4-(4-morpholinyl) aniline, adopt the method identical with embodiment 1 to prepare this compound, the ultimate yield of target product is 68.96%.
The MS:[M+H of this compound]
+491.13;
1h NMR (400MHz, CDCl
3): δ ppm 9.34 (s, 1H), 8.90 (s, 1H), 8.75 (dd, J=1.6,4.8HZ, 1H), 8.56 (d, J=5.2HZ, 2H), 8.14 (s, 1H), 7.72 (d, J=9.2HZ, 2H), 7.61 (dd, J=1.6,8.0HZ, 1H), 7.48 (dd, J=4.8,7.6HZ, 1H), 7.34 (d, J=8.0HZ, 1H), (7.23 d, J=4.8HZ, 1H), 7.10 (s, 1H), 7.04 (d, J=9.2HZ, 2H), (3.92 t, J=4.8HZ, 4H), 3.26 (t, J=4.8HZ, 4H), 2.43 (s, 3H);
13c-NMR (400MHz, CDCl3): δ ppm 162.5,160.6,159.1,151.4, and 148.4,148.2,137.9,135.0,131.0,129.6,129.0,128.2,121.7,120.8,118.8,117.4,115.8,108.2,66.7,48.9,18.0.
Embodiment 6 N-(5-[1-(4-(diethylin) phenyl]-1H-1,2,3-[triazole]-the 4-yl)-the 2-aminomethyl phenyl)-4-(pyridin-3-yl) pyrimidine-2-amine
Use N, the N-diethyl p-phenylenediamine replaces 4-(4-methyl-piperazinyl-1-ylmethyl) aniline in embodiment 1, adopts the method identical with embodiment 1 to prepare this compound, and the ultimate yield of target product is 63.19%.
The MS:[M+H of this compound]
+477.19;
1h NMR (400MHz, CDCl
3): δ ppm9.32 (s, 1H), 8.87 (s, 1H), (8.47 s, 1H), 8.57 (dd, J=2.8,8.4HZ, 1H), 8.55 (d, 1H), (8.08 s, 1H), 7.61 (d, J=8.8HZ, 3H), 7.48 (dd, J=4.8,7.6HZ, 1H), 7.33 (d, J=7.6HZ, 1H), (7.23 d, J=5.2HZ, 1H), 7.12 (s, 1H), 6.78 (d, J=8.4HZ, 2H), (3.44 q, J=7.2HZ, 4H), 2.43 (s, 3H), 1.23 (t, J=6.8HZ, 6H);
13c-NMR (400MHz, CDCl
3): δ ppm 162.5,160.7,159.2,151.5, and 148.4,147.9,137.8,134.9,131.0,129.3,128.1,122.3,120.8,118.8,117.6,111.7,108.2,44.7,18.0,12.5.
Embodiment 7 N-(2-methyl-5-(1-(4-(Pyrrolidine-1-ylmethyl) phenyl)-1H-[1,2,3]-triazole-4-yl) phenyl)-4-(pyridin-3-yl) pyrimidine-2-amine
Replace 4-(4-methyl-piperazinyl-1-ylmethyl) aniline in embodiment 1 with 1-PAB tetramethyleneimine, adopt the method identical with embodiment 1 to prepare this compound, the ultimate yield of target product is 65.10%.
The MS:[M+H of this compound]
+489.18;
1h NMR (400MHz, CDCl
3): δ ppm9.35 (s, 1H), 8.93 (s, 1H), 8.75 (dd, J=1.2,4.8HZ, 1H), 8.56-8.52 (m, 2H), (8.22 s, 1H), 7.79 (d, J=8.4HZ, 2H), 7.62 (dd, J=1.6,8.0HZ, 1H), 7.54 (d, J=8.4HZ, 2H), (7.48 dd, J=4.8,8.0HZ, 1H), (7.33 d, J=8.0HZ, 1H), 7.23 (d, J=4.8HZ, 1H), 7.13 (s, 1H), (3.72 s, 2H), 2.58 (m, 4H), (2.43 s, 3H), 1.86-1.83 (m, 4H);
13c-NMR (400MHz, CDCl
3): δ ppm 162.5,160.6,159.2,151.6, and 148.5,148.5,140.1,137.9,136.0,134.8,132.7,131.0,130.1,128.8,128.2,123.8,120.8,120.4,118.6,117.4,108.3,60.0,54.2,23.5,18.0.
the pharmacologically active part of detecting
The present invention adopts MTT colorimetric method for determining cytoactive.
The MTT colorimetry is a kind of method that detects cell survival and growth.Its detection principle is that the succinodehydrogenase in the viable cell plastosome can make exogenous MTT be reduced to water-insoluble bluish voilet crystallization first a ceremonial jade-ladle, used in libation (Formazan) and be deposited in cell, and dead cell is without this function.First a ceremonial jade-ladle, used in libation in dimethyl sulfoxide (DMSO) (DMSO) energy dissolved cell, measure its absorbance value with enzyme-linked immunosorbent assay instrument at 490nm wavelength place, can indirectly reflect viable cell quantity.In certain cell count scope, the amount that the crystallization of first a ceremonial jade-ladle, used in libation forms is directly proportional to cell count.
The MTT full name is 3-(4,5)-dimethylthiahiazo (z-y1)-3,5-di phenytetrazoliumromide, chemistry 3-(4,5-dimethylthiazole-2)-2 by name, 5-phenylbenzene tetrazole bromine salt, commodity are called tetrazolium bromide, are a kind of dyestuffs of yellow color.
The MTT powder is bought the company in Sigma, during use, with phosphoric acid buffer (PBS), is mixed with the solution that concentration is 5mg/ml, with 0.22 μ m membrane filtration, to remove the bacterium in solution, then under 4 ℃, keeps in Dark Place.
MTT colorimetric method for determining cytoactive comprises following several step (annotate: the testing method of K562 cell of take is example, and the testing method of KG1a, MCF-7, HCC-1954 cell is consistent with the method for K562 cell):
Step 1): choose in the K562 of logarithmic phase cell (purchased from Beijing gold amethyst bio tech ltd), by every hole 3 * 10
3be inoculated in 96 orifice plates, 5%CO
2, hatch overnight incubation for 37 ℃.(cell culture medium used in this experiment is modified form RPMI-1640 (Hyclone) basic medium, adds 10% foetal calf serum (Hyclone)).
Step 2): cultivate after 24 hours and add medicine.Be provided with 9 concentration gradients in this experiment, system Chinese traditional medicine final concentration gradient is: 30 μ M, 15 μ M, 7.5 μ M, 3.7 μ M, 1.8 μ M, 0.9 μ M, 0.5 μ M, 0.2 μ M, 0.1 μ M.5 multiple holes of each concentration arrange control group (not dosing is inoculating cell only) and blank well (inoculating cell does not only add substratum), 5%CO simultaneously
2, 37 ℃ of incubators are hatched 48 hours.
Step 3): after 48 hours, every hole adds 20 μ L MTT solution (5mg/ml, MTT) again, continues to cultivate 4 hours.If medicine can react with MTT, discard nutrient solution after can be first centrifugal, carefully with PBS rinse 2-3 all over after, then add the nutrient solution containing MTT.
Step 4): stop after 4 hours cultivating, carefully suck liquid in hole.Every hole adds 150 μ L dimethyl sulfoxide (DMSO).Adopt enzyme-linked immunosorbent assay instrument MULTISKAN FC (Thermo scientific) to measure the absorbance in 490nm place and each hole of 570nm, using blank well during measurement as the zeroing hole.
Step 5): processing data.At first adopt following formula to calculate inhibiting rate:
Inhibiting rate=1-dosing group OD value/control group OD value
Then take drug level as X-coordinate, cell is ordinate zou, carries out probit weighted regression method (Bliss method) with data processing software SPSS software (IBM Corporation) and carries out data processing, and mapping, obtain IC
50and IC
90value.
According to above-mentioned testing method, record positive standard specimen imatinib and each embodiment compound at 48 hours IC of the inhibition to the K562 cell
50(μ mol/L) and IC
90(μ mol/L) value is (for increasing solvability, embodiment 1 compound carries out biological activity determination by its mesylate form) as shown in Table 1.
In table one: embodiment 1 to 7, the compound of preparation was at 48 hours IC of the inhibition to the K562 cell
50and IC
90value
On foundation, table has been chosen active best compound (embodiment 2) and is continued the clones such as KG1a, MCF-7, HCC-1954 have been carried out to the cytoactive test, the IC at 48 hours
50(μ mol/L) and IC
90(μ mol/L) value as shown in Table 2.
Table two: the IC that the compound of choosing records three kinds of different clones in 48 hours
50and IC
90value
According to foregoing, embodiment 2 compounds all have restraining effect preferably to the growth of KG1a, MCF-7, HCC-1954 cell, especially can significantly suppress growth and the survival of KG1a cell, stem cell is had to good restraining effect, thereby this compounds can be mixed with for preventing or treat the medicine of leukemia, mammary cancer.
For clear and understandable purpose, explanation and embodiment have described foregoing invention in detail by way of example.Can be changed in the scope of subsidiary claim and revise, this be clearly to one skilled in the art.Therefore, be appreciated that top specification sheets is intended to for explanation rather than for restriction.Therefore, scope of the present invention should not determine with reference to above-mentioned specification sheets, and the determined four corner of doctrine of equivalents that should enjoy with reference to following claims and these claims is determined.
Claims (6)
1.4-two replace-1,2,3-triazole compound, and this compounds has following general formula (I) structure:
Wherein, R
1be selected from
R
2be selected from H, F, Cl, Br, I, CH
3o, CF
3; And
R
3be selected from
cH
3o.
2. Isosorbide-5-Nitrae according to claim 1-bis-replaces-1,2,3-triazole compound, wherein R
1be selected from
r
2be selected from H, Cl, CF
3, R
3be selected from
cH
3o.
3. prepare Isosorbide-5-Nitrae claimed in claim 1-bis-and replace-1, the method for 2,3-triazole compound, comprise the following steps:
Step a: make formula (II) compound
Through acid amide condensation reaction production (III) compound
Step b: make formula (III) compound under 0 ℃ in aprotic solvent with reductive agent generation reduction reaction production (IV) compound
Step c: formula (IV) compound is reacted in solvent with catalyzer under 20～25 ℃, alkaline environment and generate the formula V compound
Steps d: make formula (VI) compound
At 80～85 ℃, with DPPA, in the trimethyl carbinol, react the scheduled time, then the product of gained reacts production (VII) compound under acidic conditions in solvent
Step e: make formula (VII) compound react the scheduled time with Sodium Nitrite under sour existence in polar solvent under preset temperature, and then with reaction of sodium azide production (VIII) compound
Step f: make formula (V) compound react production (I) compound with 20～25 ℃ with formula (VIII) compound in polar solvent in the presence of catalyzer,
Wherein, formula (I) has identical implication to the R1 in formula (V), is selected from
Formula (I), (VI), (VII) and (VIII) in R
2there is identical implication, be selected from H, F, Cl, Br, I, CH
3o, CF
3; And
Formula (I), (VI), (VII) and (VIII) in R
3there is identical implication, be selected from
cH
3o.
4. Isosorbide-5-Nitrae claimed in claim 2-bis-replaces-1, and the preparation method of 2,3-triazole compound, comprise the steps:
Step a: make formula (II) compound
Through acid amide condensation reaction production (III) compound
Step b: make formula (III) compound under 0 ℃ in aprotic solvent with reductive agent generation reduction reaction production (IV) compound
Step c: formula (IV) compound is reacted in solvent with catalyzer under 20～25 ℃, alkaline environment and generate the formula V compound
Steps d: make (VI) compound
At 80～85 ℃, with DPPA, in the trimethyl carbinol, react the scheduled time, then products therefrom reacts production (VII) compound under acidic conditions in solvent
Step e: make formula (VII) compound react the scheduled time with Sodium Nitrite under sour existence in polar solvent under preset temperature, and then with reaction of sodium azide production (VIII) compound
Step f: make formula (V) compound react production (I) compound with 20～25 ℃ with formula (VIII) compound in polar solvent in the presence of catalyzer,
Wherein, formula (I) is to the R in formula (V)
1there is identical implication, for
formula (I), (VI), (VII) and (VIII) in R
2having identical implication, is H, CF
3, and formula (I), (VI), (VII) and (VIII) in R
3there is identical implication, for
cH
3o.
5. Isosorbide-5-Nitrae claimed in claim 1-bis-replaces-1, the application of 2,3-triazole compound in the medicine of preparation inhibition K562, KG1a, HCC-1954, MCF-7 cytoactive.
6. a pharmaceutical composition, this pharmaceutical composition comprises at least one Isosorbide-5-Nitrae according to claim 1-bis-as activeconstituents and replaces-1,2,3-triazole compound.
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|---|---|---|---|---|
| CN106188006A (en) * | 2015-05-05 | 2016-12-07 | 天津国际生物医药联合研究院 | Containing 1,2,3 triazole heterocycle compounds and its preparation method and application |
| CN106188028A (en) * | 2015-05-05 | 2016-12-07 | 天津国际生物医药联合研究院 | Containing oxadiazoles heterocycle compound and its preparation method and application |
| CN111253455A (en) * | 2019-09-04 | 2020-06-09 | 大连民族大学 | Synthesis and application of adenosine derivative |
-
2012
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106188006A (en) * | 2015-05-05 | 2016-12-07 | 天津国际生物医药联合研究院 | Containing 1,2,3 triazole heterocycle compounds and its preparation method and application |
| CN106188028A (en) * | 2015-05-05 | 2016-12-07 | 天津国际生物医药联合研究院 | Containing oxadiazoles heterocycle compound and its preparation method and application |
| CN111253455A (en) * | 2019-09-04 | 2020-06-09 | 大连民族大学 | Synthesis and application of adenosine derivative |
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