CN106831605B - A kind of substituted diaryl pyridine derivatives and the preparation method and application thereof - Google Patents
A kind of substituted diaryl pyridine derivatives and the preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a kind of diaryl pyrimidine derivatives and its preparation method and application.The substituted diaryl pyrimidine derivatives or its pharmaceutically acceptable salt or prodrug, with structure shown in following general formula I or II, the composition the invention also includes the preparation method of substituted diaryl pyrimidine derivatives and containing one or more such compounds treats and prevents the application in human immunodeficiency virus (HIV) drug in preparation.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of substituted diaryl pyridine derivatives, the present invention also relate to
And the application of preparation method and its anti human immune deficiency virus (HIV) inhibitor of this analog derivative.
Background technique
AIDS (AIDS) is a kind of disease destroyed human immune system and seriously endanger human life and health, by infecting
Inhibition of HIV causes.In anti-AIDS drug, HIV-1 non-nucleoside reverse transcriptase inhibitor (Non-nucleoside
Reverse Transcriptase Inhibitors, NNRTIs) it is sent out due to the advantages that because of its strong selectivity, high activity, hypotoxicity
Wave key effect.But due to the variability of HIV-1 virus, frequently occurring antibody-resistant bacterium becomes a disaster of clinical treatment
Topic.In addition, NNRTIs occurs in clinical drug therapy, drug resistance is poor, toxic side effect is strong and pharmacokinetics is poor asks
Topic limits its clinical application to a certain extent.Therefore, the strong new and effective low toxicity of exploitation anti-drug resistance, pharmacokinetics
The good NNRTIs of matter is the hot spot and vital task of current AIDS research.
DAPY (Diarylpyrimidines) inhibitor is a kind of newfound structure with good flexible
NNRTIs has very high inhibitory activity to the HIV-1 virus of wild type and mutation.The part of compounds pair synthesized at present
The activity of mutant strain reaches nanomolar range, and there are two drugs --- etravirine etrivirine (TMC-125) and sharp Wei
Woods rilpivirine (TMC-278) has been listed.They have very high suppression as NNRTIs of new generation, to a variety of persisters
System activity, but lower water-soluble and poor permeable membrane causes that its bioavilability is low, oral dose increases, and causes malicious secondary work
With and the problems such as crossing drug resistant.For example, etravirine needs to be administered for multiple daily, and along with serious cutaneous anaphylaxis.
Rilpivirine medicine increases for property, but there are still the poison such as depression, insomnia, acute respiratory distress syndrome, headache and fash
Side effect limits its extensive use.Therefore, efficient, wide spectrum overriding resistance is researched and developed and with good pharmacokinetic property
NNRTIs is one of the key areas of preceding anti-AIDS drug research.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of substituted diaryl pyridine derivatives and preparation method thereof,
The present invention also provides the Anti-HIV-1 Active the selection result of substituted diaryl pyridine derivatives and its in antiviral field
Using.
Technical scheme is as follows:
1. substituted diaryl pyridine derivatives
A kind of substituted diaryl pyridine derivatives according to the present invention or its pharmaceutically acceptable salt, ester or preceding
Medicine has structure shown in following general formula I or II:
Wherein,
X is O or NH；
N=0 or 1；
R1Are as follows: the alkynyl or alkenyl that side is directly connect with phenyl ring, the other side are cyclopropyl, phenyl ring, substituted benzene ring, take
For naphthalene nucleus, various substituted hexa-member heterocycles, various substituted five-ring heterocycles, various substituted hexa-atomic and five-ring heterocycles, various take
The hexa-atomic and hexa-member heterocycle in generation, various substituted five yuan and five-ring heterocycles, various substituted benzo five-membered heterocycles or various substitutions
Benzo hexa-member heterocycle and various different lengths hydrocarbon chain structure；
R2, R3It is independent are as follows: H, halogen, cyano, C1-C6Alkyl, C1-C6Alkoxy, C2-C6Alkenyl, trifluoromethyl,
Amino or hydroxyl vinyl；
R4Are as follows: substituted benzene ring replaces naphthalene nucleus, various substituted hexa-member heterocycles, various substituted five-ring heterocycles, various substitutions
Hexa-atomic and five-ring heterocycles, various substituted hexa-atomic and hexa-member heterocycles, various substituted five yuan and five-ring heterocycles, various substituted
Benzo five-membered heterocycle or various substituted benzo hexa-member heterocycles.
It is preferred according to the present invention,
R1For phenyl ring, cyclopropyl, monosubstituted phenyl ring, disubstituted phenyl ring, unsubstituted phenyl ring or pyrrole with general formula III or IV
Phenazine ring, substituted pyridines ring, hydrocarbon chain；
Wherein,
R5For H2NC6H4、HOOCC6H4、C5NH4、C3H5、OH、C6H5、CONHC6H4Or F3CC6H4；
R6For C6H5Or CH3C6H4。
It is preferred according to the present invention,
R4For the substituted benzene ring with general formula V；
Wherein, R7For SO2NH2、CONH2Or CN.
Heretofore described " pharmaceutically acceptable salt " refer in reliable medicine range of value, the salt of compound
Class is suitable for being in contact with people or compared with the tissue of lower animal without unsuitable toxicity, stimulation and allergic reaction etc., has suitable
Reasonable income/risk ratio, usually water or oil are soluble or dispersible, and are effectively used for its expected purposes.
Including pharmaceutically acceptable acid-addition salts and pharmaceutically acceptable base addition salts, be herein can do expected purposes and with
Formulas I, the chemical property of II compound are compatible.The list of suitable salt referring to S.M.Birge etc., J.Pharm.Sci., 1977,
66,1-19 pages.
Heretofore described " prodrug " refers to pharmaceutically acceptable derivates, so as to the resulting biology of these derivatives
Transformation product is the active medicine as defined in Formulas I, II compound.
According to the present invention it is further preferred that substituted diaryl pyridine derivatives shown in general formula I or II are under
One of the compound of column general formula:
Wherein, R2、R3、R4、R5、R6With shown in above-mentioned general formula I or II.
According to the present invention it is further preferred that substituted diaryl pyridine derivatives shown in general formula I or II are to change as follows
Close one of object:
2. the synthetic route and preparation method of substituted diaryl pyridine derivatives
The preparation method of substituted diaryl pyridine derivatives, steps are as follows: being starting material with compound 1, with 4- ammonia
For base cyanophenyl in 180 DEG C of progress frit reactions, the intermediate 2 and phosphorus oxychloride of generation flow back under the conditions of 100 DEG C generates intermediate
3；Raw material 4 makees catalyst in cuprous iodide and bis- (triphenylphosphine) palladium chlorides, triethylamine do under conditions of alkali with alkynyl substituted
Yuan coupling reactions of intermediate Fa Sheng obtain the midbody compound 5 of alkynyl substituted, in addition, raw material 4 is under the conditions of palladium acetate
Heck reaction occurs with the intermediate that alkenyl replaces and obtains the intermediate 5 of alkenyl substitution；Intermediate 3 is made with intermediate 5 in DMF molten
Agent, the alkaline condition of potassium carbonate occur substitution reaction and obtain target product I；In addition, with intermediate 6 for starting material and intermediate
5, which are dissolved in n,N-Dimethylformamide, reacts obtain intermediate 7 at room temperature, and then intermediate 7 is in n,N-Dimethylformamide
It is reacted with N-Boc-4- amino piperidine and then takes off Boc radical protection under the conditions of trifluoroacetic acid and generate key intermediate 9；Finally
This key intermediate 9 reacts in n,N-Dimethylformamide solution and under conditions of potassium carbonate does alkali with the fragrant halogen of various substitutions
Generate target product II；
Synthetic route is as follows:
Reagent and condition: a:4- aminobenzonitrile, 180 DEG C, fusion method, 8h；B: phosphorus oxychloride, 0.5h；C: intermediate 5, carbon
Sour potassium, n,N-Dimethylformamide, 100 DEG C, 10h；D:(i) substitutedphenylethynyl, bi triphenyl phosphorus palladium chloride, cuprous iodide,
Fortified phenol, triethylamine, tetrahydrofuran, 60 DEG C, 10h；(ii) substituted phenylethylene, palladium acetate, Tol3Iodo- 2, the 6- dimethyl of P, 4-
Phenol, sodium ethoxide, n,N-dimethylacetamide, 60 DEG C, 10h；E: substitutedphenylethynyl, potassium carbonate, n,N-Dimethylformamide, room
Temperature；F:N-Boc-4- amino piperidine, potassium carbonate, n,N-Dimethylformamide, 120 DEG C, 12h；G: trifluoroacetic acid, methylene chloride,
Room temperature, 5h；H: replace fragrant halogen, potassium carbonate, n,N-Dimethylformamide, room temperature.
R1、R2、R3、R4, n is the same as shown in above-mentioned general formula I or II.
It is preferred according to the present invention, the preparation method of substituted diaryl pyridine derivatives, the specific steps are as follows:
(1) 1 p-aminophenyl nitrile of precise starting material is warming up to 180 DEG C of reaction 8h in reaction flask, nitrogen protection；Instead
After answering completely, reactant is dissolved with acetonitrile, is ultrasonically treated, filtering washs filter cake with acetonitrile, solid is dried to obtain intermediate compound
The crude product of object 2；
(2) intermediate 2 is accurately weighed, is dissolved in phosphorus oxychloride, nitrogen protection, 100 DEG C of reflux 0.5h；After reaction,
Cooling reaction solution, reaction solution is slowly added dropwise in clean ice water and phosphorus oxychloride is quenched, and after being vigorously stirred, filtering, precipitating is used
Water dissolution, sodium hydroxide tune pH are equal to 7, filter again, dry yellow solid；Acetone recrystallization, it is intermediate that solid, which is precipitated,
The sterling of body 3；
(3) precise starting material 4 is dissolved in tetrahydrofuran, sequentially adds acetylenic substituent group, bis- (triphenylphosphine) dichloros
Change palladium, cuprous iodide, triethylamine, nitrogen protection, 60 DEG C of reflux 10h；After reaction, reaction solution is filtered with diatomite, it is molten
Liquid is extracted with saturated sodium chloride solution, and filtrate mixes sample after being evaporated, and post separation obtains intermediate 5；It, will when raw material is alkenes substituent group
Itself and intermediate 4, palladium acetate, Tol3P, ethanol amine is dissolved in n,N-dimethylacetamide, is warming up to 60 DEG C of reaction 10h；Reaction knot
Shu Hou, solvent under reduced pressure are evaporated, and obtain intermediate 5 with ethyl acetate/petroleum ether system post separation；
(4) intermediate 3, intermediate 5 and potassium carbonate are accurately weighed and is dissolved in DMF, 100 DEG C of reaction 10h；After reaction, mistake
Filter, filtrate are evaporated, post separation, obtain target product I after recrystallization from ethyl acetate/petroleum ether；
(5) intermediate 6, intermediate 5 and potassium carbonate are accurately weighed and is dissolved in DMF, reacts at room temperature 10h；After reaction, mistake
Filter, evaporated under reduced pressure, post separation obtain intermediate 7；
(6) N-Boc-4- amino piperidine, potassium carbonate, heating are added into the n,N-Dimethylformamide solution of intermediate 7
To 120 DEG C of reaction 12h；After reaction is cooling, ice water is added dropwise to reaction solution, the crude product of intermediate 8 is obtained by filtration in suspension；
(7) intermediate 8 that upper step obtains is dissolved in methylene chloride, trifluoroacetic acid is slowly added dropwise, 5h, reaction knot is stirred at room temperature
Shu Houyong saturated sodium bicarbonate tune pH to 10, methylene chloride extraction, the dry isolated intermediate 9 of rear pillar；
(8) key intermediate 9 and the fragrant halogen of substitution are dissolved in n,N-Dimethylformamide, potassium carbonate is added, was stirred at room temperature
Night；Reaction terminates, and mixed liquor evaporated under reduced pressure is extracted with ethyl acetate three times, saturated common salt water washing organic layer three times, dry,
Filtering is evaporated, post separation, and target product II is obtained after recrystallization from ethyl acetate/petroleum ether.
Room temperature of the present invention refers to 20-30 DEG C.
3. anti-HIV-1 wild strain and the mutant strain activity of substituted diaryl pyridine derivatives and application
The anti-HIV-1 of cellular level has been carried out to the part substituted diaryl pyridine derivatives synthesized according to the method described above
(IIIB), single medicament-resistant mutation strain L100I, K103N, Y181C, Y188L and double medicament-resistant mutation strain RES056 (K103N/
Y181C), the screening active ingredients of F227L/V106A.In addition, the compound of synthesis has also carried out the test of reverse transcriptase level；Wherein
The results are shown in Table 1 for HIV-resistant activity, and substituted diaryl pyridine derivatives have significant Anti-HIV-1 Active, and all chemical combination
The EC of object50Value is all up to nanomole or sub- nanomolar range, wherein having 8 compounds (IA-1-3, IA-1-4, IA-1-5, IA-1-
6, IA-1-8) units nanomole grade is reached to wild strain activity；And compound has persister (E138K, K103N, L100I)
There is significant inhibiting effect (table 2), part of compounds reaches nanomolar range.Therefore substituted diaryl pyridine derivatives have
The value further researched and developed, the lead compound that can be used as anti-HIV-1 are used.
Substituted diaryl pyridine derivatives of the invention can be used as non-nucleoside HIV-1 inhibitor application.Specifically,
Anti-AIDS drug is used to prepare as HIV-1 inhibitor.
A kind of anti-HIV-1 medicines composition, including substituted diaryl pyridine derivatives of the invention and one or more
Pharmaceutically acceptable carrier or excipient.
The present invention provides the completely new substituted diaryl pyridine derivatives of structure, preparation method, its Anti-HIV-1 Active
The selection result and its applying in antiviral field for the first time.Test proves that substituted diaryl miazines of the invention spreads out
Biology can be used as HIV-1 inhibitor and apply and have very high application value.Specifically, as HIV-1 inhibitor for making
Standby anti-AIDS drug.
Specific embodiment
Facilitate to understand the present invention by following examples, but the contents of the present invention cannot be limited.
Synthetic route involved in embodiment is as follows:
Synthetic route one:
Synthetic route two:
Embodiment 1: the preparation of intermediate 4- ((4- chlorine pyrimidine -2-base) amino) benzonitrile
The preparation of 4- ((4- oxo -1,6- dihydro-pyrimidin -2- base) amino) benzonitrile (2)
Weigh 2- (methyl mercapto) pyrimidine -4 (3H) -one (3g, 21mmol) and 4- anthranilo nitrile (2.99g, 25mmol) in
50mL round-bottomed flask, nitrogen protection are slowly warming up to 180 DEG C, react 8h.After reaction is cooling, 20mL acetonitrile ultrasonic treatment is added,
Filtering, filter cake are washed with acetonitrile, and TLC detection is remained without 4- anthranilo nitrile, and it is 4- that dry cake, which obtains faint yellow solid,
((4- oxo -1,6- dihydro-pyrimidin -2- base) amino) benzonitrile, yield 73.6%, ESI-MS:m/z 213.3 [M+H]+,
C11H8N4O(212.12).
The preparation of intermediate 4- ((4- chlorine pyrimidine -2-base) amino) benzonitrile
4- ((4- oxo -1,6- dihydro-pyrimidin -2- base) amino) benzonitrile (0.80g, 3.8mmol) is accurately weighed, is added
5mL phosphorus oxychloride, 100 DEG C are stirred at reflux 0.5h.After reaction is cooling, mixture is slowly dropped in 50mL mixture of ice and water,
Fierce stirring, filtering, obtained filter cake are re-dissolved in water, are filtered again after adjusting pH to 7 with sodium hydroxide, are dried to obtain yellow
Solid, that is, 4- ((4- chlorine pyrimidine -2-base) amino) benzonitrile.Yield: 71.3%；1H NMR(400MHz,DMSO-d6)δ10.58
(s, 1H), 8.55 (d, J=5.2Hz, 1H, C6-pyrimidine-H), 7.87 (dd, 4H, Ph-H), 7.13 (d, J=5.2Hz,
1H,C6-pyrimidine-H)；EI-MS:231.2[M+H]+,C11H7ClN4(230.04).
Embodiment 2: the preparation of target compound
The preparation of 4- ((3- aminophenyl) acetenyl) -2,6- xylenol
Weigh 3- amino phenylacetylene (0.1g, 0.85mmol), iodo- 2, the 6- xylenol (0.254g, 1.0mmol) of 4-,
Bi triphenyl phosphorus palladium chloride (0.0359g, 0.51mmol), cuprous iodide (0.0195g, 1.0mmol), triethylamine (0.06g,
It 0.6mol) is dissolved in anhydrous tetrahydro furan, nitrogen protection, reaction solution after reaction, is used diatom by 60 DEG C of reaction 10h, TLC detections
30mL ethyl acetate is added into remaining substrate for soil filtering, evaporated under reduced pressure, and saturated common salt aqueous solution washs 3 times, each 10mL,
Divide and take organic layer, anhydrous sodium sulfate dries, filters, concentration.The isolated intermediate 4- of rapid column chromatography ((3- aminophenyl) second
Alkynyl) -2,6- xylenol.
The preparation of 4- ((4- (4- ((3- aminophenyl) acetenyl) -2,6- dimethyl phenoxy) pyrimidine -2-base) amino)
4- ((3- aminophenyl) acetenyl) -2,6- xylenol (0.05g, 0.21mmol) is weighed, ((4- chlorine is phonetic by 4-
Pyridine -2- base) amino) benzonitrile (0.049g, 0.21mmol), potassium carbonate (0.035g, 0.25mmol) is dissolved in N, N- dimethyl methyl
Amide, 100 DEG C of reaction 10h.Reaction terminates, evaporated under reduced pressure solvent, and 30mL ethyl acetate, saturation are then added into remaining substrate
Common salt aqueous solution washs 3 times, each 10mL, divides and takes organic layer, and anhydrous sodium sulfate dries, filters, concentration.Rapid column chromatography separation
Target compound is obtained, and then is recrystallized to give target compound IA-1-1 in ethyl acetate-light petrol system.
Product is yellow powder, yield: 70%, fusing point: 180-183 DEG C.
1HNMR(400MHz,DMSO-d6) δ 10.15 (s, 1H, NH), 8.48 (d, J=5.7Hz, 1H, C6-pyrimidine-
), H 7.63 (d, J=8.5Hz, 2H, Ph-H), 7.51 (d, J=8.8Hz, 2H, Ph-H), 7.42 (s, 2H, Ph-H), 7.07 (t, J
=7.8Hz, Ph-H), 6.76 (t, J=1.9Hz, 1H, Ph-H), 6.70 (dt, J=7.5,1.2Hz, 1H, Ph-H), 6.60-
6.67 (m, 2H, C5-pyrimidine-H, Ph-H), 5.26 (s, 2H, NH2), 2.09 (s, 6H, 2CH3)；13C NMR(100MHz,
DMSO)δ168.83,160.85,159.64,150.19,149.30,145.05,133.05,132.14,131.68,129.69,
122.96,120.50,119.85,119.32,118.75,116.63,115.09,102.99,99.37,90.37,87.83,
16.30；ESI-MS:432.5[M+H]+.C27H21N5O(431.50).
Operation is same as above, except that using 4- ((4- hydroxyl -3,5- 3,5-dimethylphenyl) acetenyl) benzoic acid.
Product is pale yellow powder, yield: 67%, fusing point: 273-281 DEG C.
1H NMR(400MHz,DMSO-d6)δ13.10(s,1H,carbonyl-H),10.16(s,1H,NH),8.49(d,J
=5.7Hz, 1H, C6-pyrimidine-H), 7.99 (d, 2H, Ph-H), 7.69 (d, 2H, Ph-H), 7.62 (d, J=8.5Hz,
2H, Ph-H), 7.51 (m, 4H, Ph-H), 6.66 (d, J=5.6Hz, 1H, C5-pyrimidine-H), 2.10 (s, 6H, 2CH3)
；13C NMR(100MHz,DMSO)δ168.77,167.15,160.90,159.62,150.76,145.02,133.04,132.44,
131.94,131.06,130.06,127.09,119.84,119.68,118.74,103.01,99.37,91.96,88.73,
16.31；ESI-MS:459.4[M-H]﹣.C28H20N4O3(460.49).
Operation is same as above, except that using 2,6- dimethyl -4- (pyridin-3-yl acetenyl) phenol.
Product is white crystal, yield: 89%, fusing point: 220-223 DEG C.
1H NMR(400MHz,DMSO-d6) δ 10.16 (s, 1H, NH), 8.78 (dd, J=2.2,0.9Hz, 1H,
), pyridine-H 8.61 (dd, J=4.9,1.7Hz, 1H, pyridine-H), 8.49 (d, J=5.6Hz, 1H, C6-
), pyrimidine-H 8.00 (dt, J=7.9,1.9Hz, 1H, pyridine-H), 7.61 (d, J=8.6Hz, 2H, Ph-H),
7.46-7.54 (m, 5H, Ph-H, pyridine-H), 6.67 (d, J=5.6Hz, 1H, C5-pyrimidine-H), 2.10 (s,
6H, 2CH3)；13C NMR(100MHz,DMSO)δ168.76,160.92,159.62,152.04,150.76,149.48,
145.01,138.96,133.05,132.40,131.91,124.13,119.90,119.84,119.59,118.75,103.01,
99.37,92.28,86.25,16.31；ESI-MS:418.5[M+H]+.C26H19N5O(417.47).
Operation is same as above, except that using 2,6- dimethyl -4- (pyridine -2- ethyl-acetylene base) phenol.
Product is white crystal, yield: 86%, fusing point: 213-216 DEG C.
1H NMR(400MHz,DMSO-d6) δ 10.15 (s, 1H, NH), 8.63 (dd, J=4.9,1.8,1.0Hz, 1H,
), pyridine-H 8.49 (d, J=5.7Hz, 1H, C6-pyrimidine-H), 7.87 (td, J=7.8,1.8Hz, 1H,
), pyridine-H 7.66 (dt, J=7.8,1.1Hz, 1H, pyridine-H), 7.62 (d, J=8.6Hz, 2H, Ph-H), 7.51
(m, 4H, Ph-H), 7.43 (m, 1H, pyridine-H), 6.67 (d, J=5.6Hz, 1H, C5-pyrimidine-H), 2.11 (s,
6H,2CH3)；13C NMR(100MHz,DMSO)δ168.76,160.91,159.62,150.91,150.66,145.02,
142.80,137.28,133.05,132.58,131.96,127.75,123.98,119.83,119.30,118.73,103.01,
99.40,89.13,88.34,16.32；ESI-MS:418.6[M+H]+.C26H19N5O(417.47).
Operation is same as above, except that using (cyclopropyl acethlene base) -2,6- xylenol
Product is white crystal, yield: 79%, fusing point: 227-229 DEG C.
1H NMR(400MHz,DMSO-d6) δ 10.14 (s, 1H, NH), 8.46 (d, J=5.6Hz, 1H, C6-
), pyrimidine-H 7.62 (s, 2H, Ph-H), 7.53 (m, 4H, Ph-H), 6.65 (d, J=5.6Hz, 1H, C5-
pyrimidine-H),2.03(s,6H,2CH3)；0.92(m,1H,CH),0.85(m,2H,CH2),0.75(m,2H,CH2)；13C
NMR(100MHz,DMSO)δ168.63,160.89,159.56,150.09,145.03,137.63,133.79,133.02,
119.85,118.73,102.97,99.38,91.06,16.00,13.41,0.52；ESI-MS:381.5[M+H]+.C24H20N4O
(380.45).
Operation is same as above, except that using 4- (4- hydroxyl butyl- 1- alkynes -1- base) -2,6- xylenol
Product is yellow crystals, yield: 49%, fusing point: 181-183 DEG C.
1H NMR(400MHz,DMSO-d6) δ 10.13 (s, 1H, NH), 8.46 (d, J=5.6Hz, 1H, C6-
), pyrimidine-H 7.60 (d, J=8.6Hz, 2H, Ph-H), 7.49 (d, J=8.8Hz, 2H, Ph-H), 7.27 (s, 2H, Ph-
), H 6.62 (d, J=5.6Hz, 1H, C6-pyrimidine-H), 4.91 (t, J=5.6Hz, 1H ,-OH), 3.62 (q, J=
6.7Hz,2H,CH2), 2.58 (t, J=6.9Hz, 2H, CH2),2.04(s,6H,2CH3)；13C NMR(100MHz,DMSO)δ
168.83,160.82,159.62,149.72,145.03,133.03,132.14,131.38,121.12,119.84,118.71,
102.96,99.32,88.49,80.99,60.35,23.76,16.26；ESI-MS:385.5[M+1]+,402.5[M+NH3]+
.C23H20N4O2(384.22).
Operation is same as above, except that using 2,6- dimethyl -4- (phenylene-ethynylene) phenol.
Product is pale yellow powder, yield: 53% fusing point: 198-201 DEG C.
1H NMR(400MHz,DMSO-d6) δ 10.16 (s, 1H, NH), 8.48 (d, J=5.6Hz, 1H, C6-
), pyrimidine-H 7.55-7.66 (m, 4H, Ph-H), 7.51 (d, J=8.7Hz, 2H, Ph-H), 7.45 (d, J=5.9Hz,
5H, Ph-H), 6.66 (d, J=5.6Hz, 1H, C5-pyrimidine-H), 2.09 (s, 6H, 2CH3)；13C NMR(100MHz,
DMSO)δ168.80,160.89,159.63,150.42,145.03,137.64,133.79,133.04,132.25,131.78,
129.26,122.74,120.17,119.84,118.75,103.00,99.36,89.41,89.26,16.30；ESI-MS:
417.5[M+1]+.C27H20N4O(416.48).
Operation is same as above, except that using N- (3- ((4- hydroxyl -3,5- 3,5-dimethylphenyl) acetenyl) phenyl) acetyl
Amine.
Product is pale yellow powder, yield: 41%, fusing point: 251-252 DEG C.
1H NMR(400MHz,DMSO-d6) δ 10.14 (s, 1H, NH), 10.06 (s, 1H, NH), 8.48 (d, J=5.6Hz,
1H, C6-pyrimidine-H), 7.91 (t, J=1.8Hz, 1H, Ph-H), 7.63 (d, J=8.6Hz, 2H, Ph-H), 7.47-
7.57 (m, 5H, Ph-H), 7.36 (t, J=7.9Hz, 1H, Ph-H), 7.23 (dt, J=7.6,1.3Hz, 1H, Ph-H), 6.65
(d, J=5.6Hz, 1H, C5-pyrimidine-H), 2.09 (s, 6H, 2CH3),2.07(s,3H,CH3)；13C NMR(100MHz,
DMSO)δ169.03,168.81,160.86,159.64,150.42,145.03,140.07,133.06,132.28,131.77,
129.69,126.45,123.00,121.84,120.09,119.84,118.75,103.00,99.38,89.40,88.99,
24.52,16.30；ESI-MS:474.4[M+H]+,496.5[M+Na]+.C29H23N5O2(473.54).
Operation is same as above, except that using 4- ((4- aminophenyl) acetenyl) -2,6- xylenol.
Product is brown ceramic powder, yield: 63% fusing point: 195-198 DEG C.
H NMR(400MHz,DMSO-d6) δ 10.15 (s, 1H, NH), 8.47 (d, J=5.6Hz, 1H, C6-
), pyrimidine-H 7.62 (d, J=8.6Hz, 2H, Ph-H), 7.51 (d, J=8.9Hz, 2H, Ph-H), 7.35 (s, 2H, Ph-
), H 7.22 (d, J=8.5Hz, 2H, Ph-H), 6.58 (d, J=8.5Hz, 2H, Ph-H), 6.63 (d, J=5.7Hz, 1H, C5-
pyrimidine-H),5.59(s,2H,NH2),2.07(s,6H,2CH3)；13C NMR(100MHz,DMSO)δ168.89,
160.82,159.64,149.92,149.63,145.05,133.04,133.00,131.71,131.49,121.37,119.85,
118.74,114.16,108.67,102.97,99.33,91.34,86.35,16.30；ESI-MS:432.6[M+H]+
.C27H21N5O(431.50).
Embodiment 3: the preparation of target compound
The preparation of 2,6- dimethyl -4- styrylphenol
It weighs styrene (0.177g, 1.5mmol), iodo- 2, the 6- xylenol (0.248g, 1.0mmol) of 4-, palladium acetate
(0.0224g, 0.1mmol), Tol3P (0.091g, 0.3mmol), sodium ethoxide (0.184g, 2.3mmol) is in two-neck bottle, nitrogen
N,N-dimethylacetamide is added dropwise with constant pressure funnel under guard mode, is warming up to 60 DEG C, reacts 10h, after reaction, steams
Dry solvent, quick post separation obtain the crude product of intermediate 5.
(E) -4- ((4- (2,6- dimethyl -4- styryl phenoxy group) pyrimidine -2-base) amino) benzonitrile
The preparation with IB-1-1 is operated, except that using 2,6- dimethyl -4- styrylphenol.
Product is white crystal, yield: 38%, fusing point；222-224℃.
1H NMR(400MHz,DMSO-d6) δ 10.15 (s, 1H, NH), 8.47 (d, J=5.6Hz, 1H, C6-
), pyrimidine-H 7.69-7.59 (m, 4H, Ph-H), 7.47 (d, J=8.4Hz, 4H, Ph-H), 7.40 (m, 2H, J=
16Hz,tran-CH2=CH2), 7.32-7.25 (m, 3H, Ph-H), 6.63 (d, J=5.6Hz, 1H, C5-pyrimidine-H),
2.10 (s, 6H, 2CH3)；13C NMR(100MHz,DMSO)δ169.08,160.71,159.69,149.45,149.33,
145.09,138.24,137.47,135.32,135.22,134.81,133.03,131.06,131.02,129.79,129.08,
128.96,128.81,127.99,127.40,127.30,127.20,127.16,126.84,124.21,119.83,118.73,
102.90,99.34,21.50,21.31,16.60,15.99；ESI-MS:419.3[M+H]+.C27H22N4O(418.50).
Operation is same as above, except that using 2,6- dimethyl -4- (4- methyl styrene base) phenol.
Product is light yellow crystal, yield: 43% fusing point: 212-214 DEG C.
1H NMR (400MHz, DMSO-d6) δ 10.15 (s, 1H, NH), 8.46 (d, J=5.6Hz, 1H, C6-
), pyrimidine-H 7.71-7.58 (m, 5H, Ph-H), 7.47 (d, J=7.7Hz, 5H), 7.40 (m, 2H, J=16Hz,
tran-CH2=CH2), 7.33-7.23 (m, 3H), 6.63 (d, J=5.7Hz, 1H, C5-pyrimidine-H), 2.11 (s, 6H,
2CH3)；13C NMR(100MHz,DMSO)δ169.07,160.73,159.69,149.49,145.09,137.58,135.16,
133.79,133.04,131.07,129.20,128.88,128.18,128.07,127.35,126.90,119.82,118.74,
102.90,99.36,16.60,15.99；ESI-MS:433.5[M+H]+.C28H24N4O(432.53).
Embodiment 4: the preparation of target compound
The system of (4- ((3- aminophenyl) acetenyl) -2,6- dimethyl phenoxy)-N- (piperidin-4-yl) pyrimidine -2- amine
It is standby
Weigh Compound 2,4- dichloro pyrimidine (50.0mmol), 4- ((3- aminophenyl) acetenyl) -2,6- dimethyl benzene
Phenol (50.0mmol) is in 10mL DMF, Anhydrous potassium carbonate (60.0mmol), and stirring 10h under room temperature, (TLC detection has been reacted
Finish).The isolated target compound of rapid column chromatography, and then crude product is recrystallized to obtain in ethyl acetate-light petrol system.It obtains
Crude product (0.3g, 0.86mmol), N-Boc-4- amino piperidine (0.21g, 1.0mmol) and potassium carbonate (0.15g, 1.7mmol)
In the n,N-Dimethylformamide of 10mL, then it is heated to reflux 12 hours.It, at leisure will be anti-after reacting and being cooled to room temperature
It answers drop to be added in 20mL aqueous solution, stirs, there are a large amount of solids to generate.Filtering, dry crude product 4- ((4- (4- ((3- aminobenzene
Base) acetenyl) -2,6- dimethyl phenoxy) pyrimidine -2-base) amino) piperidines -1- t-butyl formate.Weigh the crude product
(0.60g, 1.5mmol) is dissolved in 5mL methylene chloride, and trifluoroacetic acid (0.74mL, 10mmol) then is added thereto at leisure,
It stirs under room temperature 5 hours (TLC detects end of reaction).10mL water is added into reaction solution, with the sodium bicarbonate water of saturation
Solution tune PH is 10, and methylene chloride extracts (3 × 5mL), and saturated salt solution washing divides and takes organic layer, and anhydrous sodium sulfate is dry.So
Carrying out the isolated white solid of rapid column chromatography afterwards is compound (4- ((3- aminophenyl) acetenyl) -2,6- dimethyl
Phenoxy group)-N- (piperidin-4-yl) pyrimidine -2- amine.
3- (4- ((4- (4- ((3- aminophenyl) acetenyl) -2,6- dimethyl phenoxy) pyrimidine -2-base) amino) piperazine
Pyridine -1- base) preparation
Weigh Compound 4- ((3- aminophenyl) acetenyl) -2,6- dimethyl phenoxy)-N- (piperidin-4-yl) pyrimidine -
Anhydrous potassium carbonate (0.13g, 0.96mmol) is added after stirring and dissolving under room temperature in 10mL DMF in 2- amine (0.48mmol)
With substituted benzyl chloride or bromobenzyl (0.58mmol), stir 12h under room temperature (TLC detects end of reaction).Evaporated under reduced pressure solvent
30mL ethyl acetate is added in backward remaining substrate, saturated common salt aqueous solution washs 3 times, each 10mL, divides and takes organic layer, anhydrous
Sodium sulphate dries, filters, concentration.The isolated target compound of rapid column chromatography, and then in ethyl acetate-light petrol system
It is recrystallized to give target compound IA-1-1.
Product is light yellow crystal, yield: 43% fusing point: 113-115 DEG C.
1H NMR(400MHz,DMSO-d6)δ8.18(s,1H,-NH2),7.89(s,1H,-NH2),7.48-6.94(m,8H,
C6-pyrimidine-H,Ph-H),6.79-6.51(m,3H,Ph-H,C5-pyrimidine-H),6.15(s,1H,NH),5.24
(s,2H,NH2),3.53-3.92(m,4H,piperidine-H),2.86-2.63(m,1H,piperidine-H),2.07(s,
6H,2CH3),1.23(s,4H,piperidine-H),0.93-0.74(m,1H,piperidine-H).13C NMR(100MHz,
DMSO)δ168.71,151.23,149.27,135.39,131.62,129.66,129.22,122.98,120.07,119.25,
117.98,116.56,60.22,48.22,29.48,22.56,21.23,16.37,14.56；ESI-MS:533.5[M+H]+
.C32H32N6O2(532.65).
Operation is same as above, except that using 4- methylsulfonyl bromobenzyl.
Product is light yellow crystal, yield: 43% fusing point: 159-161 DEG C.
1H NMR (400MHz, DMSO-d6) δ 8.15 (d, J=5.5Hz, 1H, C6-pyrimidine-H), 7.75 (s, 2H,
Ph-H),7.43(s,2H,Ph-H),7.30(s,2H,Ph-H),7.29(s,2H,-SO2NH2), 7.06 (t, J=7.8Hz, 1H,
), Ph-H 6.72 (s, 1H, NH), 6.70-6.56 (m, 2H, Ph-H), 6.13 (d, J=5.5Hz, 1H, C5-pyrimidine-H),
5.25(s,2H,NH2),3.69(s,1H,piperidine-H),3.37-3.59(m,2H,piperidine-H),2.55-2.87
(m,2H,piperidine-H),2.04(s,6H,2CH3),1.2-1.8(m,6H,piperidine-H)；13C NMR(100MHz,
DMSO)δ168.78,149.30,131.61,129.69,129.40,126.04,123.04,120.06,119.24,116.57,
115.01,95.61,94.00,90.11,61.98,52.66,31.50,22.57,16.34；ESI-MS:583.4[M+H]+
.C32H34N6O3S(582.72).
Embodiment 5: the external HIV-resistant activity test experiments of target compound
Test philosophy:
The screening of Compound ira vitro HIV-resistant activity uses mtt assay.MTT full name is bromination -3- (4,5- dimethyl -2- thiazole
Base) -2,5- diphenyltetrazoliumbromide nitrogen (trade name: thiazolyl blue), it can be used for detecting the survival and growth of cell.Testing principle are as follows: MTT
The bluish violet crystallization first a ceremonial jade-ladle, used in libation that water-insoluble can be reduced in conjunction with intracellular succinate dehydrogenase living is deposited in cell, and
Dead cell has no this function.Dimethyl sulfoxide can dissolve the first a ceremonial jade-ladle, used in libation in cell, detect its extinction at 590 nm with microplate reader
Degree (A) value can indirectly reflect the quantity of living cells.Within the scope of certain cell number, MTT crystallizes the amount to be formed and cell
Number is directly proportional.
Since within a certain period of time (5-7 days) lesion can occur for the MT-4 cell of HIV infection, to the MT- of HIV infection
The compound solution to be detected that debita spissitudo is added in 4 cell suspensions uses MTT through after a period of time after the culture of (5-7 days)
Assay MT-4 cell viability obtains 50% cell of protection from the drug concentration (EC of cytopathy50) you can get it mesh
Mark the activity of the AntiHIV1 RT activity of compound.The concentration that target compound makes 50% cell for being uninfected by HIV that lesion occur is obtained simultaneously
(CC50), calculate selection coefficient (selectivity index, SI=CC50/EC50)。
Test material and method:
(1)HIV-1(IIIB), HIV-2 (ROD) strain, various HIV-1 persisters: by Belgian medical college, Univ Louvain
Rega research institute provides.
(2) it MT-4 cell: is provided by Belgian Rega research institute, medical college, Univ Louvain.
(3) MTT: it is purchased from Sigma Co., USA.
(4) sample treatment: sample is dissolved in DMSO before use and is made into debita spissitudo, and makees 5 times with distilled water and dilute, and each 5
Dilution.
(5) positive control drug: nevirapine (NVP), efavirenz (EFV), etravirine (TMC125), Zidovudine
(AZT), Delavirdine (DLV), rilpivirine (TMC278).
(6) it test method: is added in HIV infection MT-4 cell suspension after sample dilution, uses after a period of time
MTT colorimetric method for determining cell viability calculates EC with absorbance (A) value recorded in microplate reader at 590 nm50、CC50And
SI。
(7) after sample solution culture for a period of time is added, MTT solution (5mg/mL) 20 μ MTT colorimetric method: is added to every hole
L continues after cultivating several hours, abandons dyeing liquor, and 150 μ L DMSO are added to every hole, is sufficiently mixed, is measured in microplate reader
Absorbance (A) value under 590nm.
Experimental method:
In 96 porocyte culture plates, 50 μ L are added and contain 1 × 104MT-4 cell culture fluid, then it is separately added into 20 μ L infection
HIV-1(IIIBOr RES056) or HIV-2 (ROD) MT-4 cell suspension (every milliliter contain 100 times of CCID50) or blank
Culture medium (toxicity test), is then added the testing compound solution or positive control medicine of various concentration, and each concentration is set
Count 3 multiple holes.Then cell is in 5%CO2Atmosphere cultivates 5 days at 37 DEG C, it is molten that 20 μ L (5mg/mL) MTT is added into each hole
Liquid continues culture 2 hours, DMSO is then added, and uses trap of the microplate reader measurement reaction solution at 540nm, calculatingization
Close the cell proliferation rate P% under object various concentration.Blank and drug control group and positive drug control group are set simultaneously, is thus calculated
Concentration (EC needed for the cytopathy that the cell of compound protection 50% is induced from HIV50).Select the calculating of index: SI=
CC50/EC50。
The anti-of cellular level has been carried out according to part substituted diaryl pyridine derivatives of the above-mentioned experimental method to synthesis
HIV-1(IIIB), the activity sieve of single mutation strain K103N, Y181C, Y188L and double-mutant strain RES056 (K103N/Y181C)
Choosing, Activity Results are as shown in Table 1 and Table 2.
The inhibitory activity and cytotoxicity (MT-4 of the anti-HIV-1 (IIIB) of 1 part substituted diaryl pyridine derivatives of table
Cell)
Note:aEC50: compound concentration of the MT-4 cell of 50% infected by HIV -1 of protection from cytopathy；bCC50: make
The compound concentration of lesion occurs for 50% cell for being uninfected by HIV-1；cSelectivity factor: CC50/EC50Ratio；TMC278,
NVP, EFV, ETV, DLV respectively represent marketed drug rilpivirine, nevirapine, Sustiva, etravirine and Delavirdine.
Inhibitory activity (MT-4 cell) of 2 part of compounds of table to HIV drug resistance strain
Note:aEC50: compound concentration of the MT-4 cell of 50% infected by HIV -1 of protection from cytopathy；TMC278,
NVP, EFV, ETV, DLV respectively represent marketed drug rilpivirine, nevirapine, Sustiva, etravirine and Delavirdine.
Conclusion:
Substituted diaryl pyrimidine derivatives of the invention are a series of left wings containing alkynyl and bone it can be seen from Tables 1 and 2
The novel non-nucleoside HIV-1 inhibitor of frame shows preferable anti-HIV-1 wild strain and mutant strain activity.Exhausted big portion
The EC for dividing compound to inhibit wild strain and mutant strain50Value is reaching nanomole rank, wherein the activity of compound IA-1-3 is especially
It is prominent, to the EC of HIV-1 wild strain50Value for 0.003 μM with latest generation drug etravirine (ETV) quite, cell toxicant
Property (CC50=3.476 μM) it is lower, it is 1.58 times of etravirine, the selectivity index to HIV-1 wild strain is 1010, is higher than
Etravirine.In addition, compound IIA-1-3 also shows preferable inhibitory activity to mutant strain, therefore, substituted diaryl is phonetic
Piperidine derivatives have the value further researched and developed, and the lead compound that can be used as anti-HIV-1 is used.
Claims (7)
1. a kind of substituted diaryl pyridine derivatives or its pharmaceutically acceptable salt have shown in following general formula I or II
Structure:
Wherein,
X is O or NH；
N=0 or 1；
R1For the substituent group with general formula III or IV；
Wherein, R5For H2NC6H4、HOOCC6H4、C5NH4、C3H5、C6H5、CONHC6H4Or F3CC6H4；R6For C6H5Or CH3C6H4；
R2, R3It is independent are as follows: H, halogen, cyano, C1-C6Alkyl, C1-C6Alkoxy, C2-C6Alkenyl, trifluoromethyl, amino
Or hydroxyl vinyl；
R4For the substituted benzene ring with general formula V；
Wherein, R7For SO2NH2、CONH2Or CN.
2. a kind of substituted diaryl pyridine derivatives, which is characterized in that be one of the compound with general formula:
Wherein, R2、R3、R4、R5、R6With described in claim 1.
3. a kind of substituted diaryl pyridine derivatives, which is characterized in that be one of the compound with general formula:
4. the preparation method of substituted diaryl pyridine derivatives as described in claim 1, which is characterized in that with compound 1
For starting material, with 4- aminobenzonitrile in 180 DEG C of progress frit reactions, the intermediate 2 and phosphorus oxychloride of generation are in 100 DEG C of conditions
Lower reflux generates intermediate 3；Raw material 4 makees catalyst in cuprous iodide and bis- (triphenylphosphine) palladium chlorides, and triethylamine does alkali
Under the conditions of with Yuan coupling reactions of intermediate Fa Sheng of alkynyl substituted obtain the midbody compound 5 of alkynyl substituted, in addition, raw material
4 intermediates replaced under the conditions of palladium acetate with alkenyl occur Heck reaction and obtain the intermediate 5 of alkenyl substitution；Intermediate 3 with
Intermediate 5 makees solvent in DMF, and the alkaline condition of potassium carbonate occurs substitution reaction and obtains target product I；In addition, being with intermediate 6
Starting material is dissolved in n,N-Dimethylformamide with intermediate 5 and reacts to obtain intermediate 7 at room temperature, and then intermediate 7 is in N,
It is reacted in dinethylformamide with N-Boc-4- amino piperidine and then takes off Boc radical protection under the conditions of trifluoroacetic acid and generated
Key intermediate 9；Under conditions of this last key intermediate 9 does alkali with potassium carbonate in n,N-Dimethylformamide solution, with
The fragrant halogen reaction of various substitutions generates target product II；
Synthetic route is as follows:
Reagent and condition: a:4- aminobenzonitrile, 180 DEG C, fusion method, 8h；B: phosphorus oxychloride, 0.5h；C: intermediate 5, potassium carbonate,
N,N-Dimethylformamide, 100 DEG C, 10h；D:(i) substitutedphenylethynyl, bi triphenyl phosphorus palladium chloride, cuprous iodide, substituted benzene
Phenol, triethylamine, tetrahydrofuran, 60 DEG C, 10h；(ii) substituted phenylethylene, palladium acetate, Tol3Iodo- 2, the 6- xylenol of P, 4-,
Sodium ethoxide, n,N-dimethylacetamide, 60 DEG C, 10h；E: substitutedphenylethynyl, potassium carbonate, n,N-Dimethylformamide, room temperature；F:
N-Boc-4- amino piperidine, potassium carbonate, n,N-Dimethylformamide, 120 DEG C, 12h；G: trifluoroacetic acid, methylene chloride, room temperature,
5h；H: replace fragrant halogen, potassium carbonate, n,N-Dimethylformamide, room temperature；
R1、R2、R3、R4, n with shown in claim 1 general formula I or II, X O.
5. the preparation method of substituted diaryl pyridine derivatives as claimed in claim 4, which is characterized in that steps are as follows:
(1) 1 p-aminophenyl nitrile of precise starting material, in reaction flask, nitrogen protection is warming up to 180 DEG C of reaction 8h；It has reacted
Quan Hou, dissolves reactant with acetonitrile, is ultrasonically treated, and filtering washs filter cake with acetonitrile, solid is dried to obtain midbody compound 2
Crude product；
(2) intermediate 2 is accurately weighed, is dissolved in phosphorus oxychloride, nitrogen protection, 100 DEG C of reflux 0.5h；After reaction, cooling
Reaction solution is slowly added dropwise in clean ice water and phosphorus oxychloride is quenched by reaction solution, and after being vigorously stirred, filtering is precipitated with water-soluble
Solution, sodium hydroxide tune pH are equal to 7, filter again, dry yellow solid；Acetone recrystallization, it is intermediate 3 that solid, which is precipitated,
Sterling；
(3) precise starting material 4 is dissolved in tetrahydrofuran, sequentially adds replaced acetylene, bis- (triphenylphosphine) palladium chlorides, iodine
Change cuprous, triethylamine, nitrogen protection, 60 DEG C of reflux 10h；After reaction, reaction solution is filtered with diatomite, solution saturation
Sodium chloride solution, filtrate mix sample after being evaporated, post separation obtains intermediate 5；When raw material is substituted ethylene, by itself and intermediate
4, palladium acetate, Tol3P, ethanol amine is dissolved in n,N-dimethylacetamide, is warming up to 60 DEG C of reaction 10h；After reaction, solvent subtracts
Pressure is evaporated, and obtains intermediate 5 with ethyl acetate/petroleum ether system post separation；
(4) intermediate 3, intermediate 5 and potassium carbonate are accurately weighed and is dissolved in DMF, 100 DEG C of reaction 10h；After reaction, it filters, filter
Liquid is evaporated, post separation, and target product I is obtained after recrystallization from ethyl acetate/petroleum ether；
(5) intermediate 6, intermediate 5 and potassium carbonate are accurately weighed and is dissolved in DMF, reacts at room temperature 10h；After reaction, it filters, subtracts
Pressure is evaporated, and post separation obtains intermediate 7；
(6) N-Boc-4- amino piperidine, potassium carbonate are added into the n,N-Dimethylformamide solution of intermediate 7, is warming up to 120
DEG C reaction 12h；After reaction is cooling, ice water is added dropwise to reaction solution, the crude product of intermediate 8 is obtained by filtration in suspension；
(7) intermediate 8 that upper step obtains is dissolved in methylene chloride, trifluoroacetic acid is slowly added dropwise, 5h is stirred at room temperature, after reaction
With saturated sodium bicarbonate tune pH to 10, methylene chloride extraction, the dry isolated intermediate 9 of rear pillar；
(8) key intermediate 9 and the fragrant halogen of substitution are dissolved in n,N-Dimethylformamide, potassium carbonate is added, is stirred overnight at room temperature；Instead
It should terminate, mixed liquor evaporated under reduced pressure is extracted with ethyl acetate three times, and saturated common salt water washing organic layer three times dries, filters steaming
It does, post separation, obtains target product II after recrystallization from ethyl acetate/petroleum ether.
6. a kind of compound as described in claim any one of 1-3 treats and prevents in human immunodeficiency virus's drug in preparation
Using.
7. a kind of pharmaceutical composition for treating and preventing human immunodeficiency virus includes any one of the claim 1-3 chemical combination
Object and one or more pharmaceutically acceptable carriers or excipient.
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