CN106905244B - Diaryl pyrimidine-diketone acid heterozygous HIV-1 inhibitor and preparation method thereof - Google Patents
Diaryl pyrimidine-diketone acid heterozygous HIV-1 inhibitor and preparation method thereof Download PDFInfo
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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Abstract
The present invention relates to a kind of diaryl pyrimidine-diketone acid heterozygous HIV-1 inhibitor and preparation method thereof, the diaryl pyrimidine-diketone acid heterozygous HIV-1 inhibitor is formula (1) compound or pharmaceutically acceptable salt thereof:Wherein R is selected from hydrogen, C1‑5Saturated alkyl, C3‑5Naphthenic base, C2‑5Alkenyl；Two ketone acid or diketonate side chain are located at the ortho position of ehter bond oxygen atom, meta or para position.Preparation method are as follows: 1) by 2- (to cyano-aniline base) -4- chlorine pyrimidine and 4- (p-hydroxybenzene) -2,4- dioxy ethyl butyrate or 4- (hydroxy phenyl) -2,4- dioxy ethyl butyrate and alkali mixing, solvent is added, is uniformly mixing to obtain reaction solution under an inert atmosphere；2) reaction solution is heated up and carries out nucleophilic substitution, stopped heating after reaction, reaction solution is separated, purifies to obtain diaryl pyrimidine-diketone acid heterozygous HIV-1 inhibitor.
Description
Technical field
The invention belongs to pharmaceutical technology field, be related to a kind of diaryl pyrimidine-diketone acid heterozygous HIV-1 inhibitor and
Preparation method.
Background technique
AIDS, that is, acquired exempt from deficiency symptoms (AIDS) be by human immunodeficiency virus (HIV) caused by the whole world
Epidemic infectious diseases.HIV is divided to HIV-1 and HIV-2 two kinds of hypotypes, and most AIDS patients of the world and China are HIV-
1 infection.In the research of existing anti-AIDS drug, non-nucleoside reverse transcriptase inhibitor (NNRTIs) is excellent because its high-efficiency low-toxicity
Point is by as a line anti-AIDS drug.Currently, there are five types of chemical entities altogether by the NNRTIs by U.S. FDA approval listing: how
It is big to even up (nevirapine), efavirenz (efavirenz), delavirdine (delavirdine), etravirine
(etravirine) and rilpivirine (rilpivirine).Wherein, etravirine and rilpivirine all have diaryl pyrimidine knot
Structure, this kind of compound are referred to as Diarylmiazines HIV-1 inhibitor (DAPYs).DAPYs has HIV-1 persister excellent
Activity, attracted the extensive concern of various countries' Pharmaceutical Chemist.It is miscellaneous that the application designs a kind of diaryl pyrimidine-diketone acid of synthesis
Mould assembly HIV-1 inhibitor (DAPY-DKAs), expectation obtain a kind of with the active novel drugs of good HIV-1.
Summary of the invention
The technical problem to be solved by the present invention is to aiming at the above shortcomings existing in the prior art, provide a kind of two newly
Arylpyrimidines-diketone acid heterozygous HIV-1 inhibitor and preparation method thereof.
In order to solve the above technical problems, present invention provide the technical scheme that
A kind of diaryl pyrimidine-diketone acid heterozygous HIV-1 inhibitor of offer, is formula (1) compound or it can medicine
With salt:
Wherein R is selected from hydrogen, C1-5Saturated alkyl, C3-5Naphthenic base, C2-5Alkenyl, two ketone acid or diketonate side chain position
Ortho position, meta or para position in ehter bond oxygen atom；
The C1-5Saturated alkyl is methyl, ethyl, propyl, normal-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, new
One of amyl；
The C3-5Naphthenic base is one of cyclopropyl, cyclobutyl, cyclopenta；
The C2-5Alkenyl is one of vinyl, acrylic, allyl, cyclobutenyl, n-pentene base, isopentene group.
The present invention also provides above-mentioned diaryl pyrimidine-diketone acid heterozygous HIV-1 inhibitor preparation methods, special
Sign be the following steps are included:
1) by 2- (to cyano-aniline base) -4- chlorine pyrimidine, (4- is (to hydroxyl with 4- (hydroxy phenyl) -2,4- dioxy ethyl butyrate
Base phenyl) -2,4- dioxy ethyl butyrate or 4- (hydroxy phenyl) -2,4- dioxy ethyl butyrate) and alkali 2- is (right in molar ratio
Cyano-aniline base) -4- chlorine pyrimidine: 4- (hydroxy phenyl) -2,4- dioxy ethyl butyrate: solvent is added in alkali=1.1:1:3 mixing,
It is uniformly mixing to obtain reaction solution under an inert atmosphere；
2) reaction solution obtained by step 1) is warming up to 110 DEG C, carries out nucleophilic substitution, TLC monitors nucleophilic substitution
Stop heating after carrying out completely, reaction solution is separated, purifies to obtain ester type compound, is i.e. diaryl pyrimidine-diketonate
Heterozygous HIV-1 inhibitor.
According to the above scheme, the step 1) solvent be dimethyl sulfoxide (DMSO), n,N-Dimethylformamide (DMF), N,
One or more of N- dimethyl acetamide (DMA), 1,4- dioxane, tetrahydrofuran (THF).
According to the above scheme, the step 1) alkali is potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, sodium hydroxide, hydroxide
One or more of potassium, sodium hydride.
According to the above scheme, the step 1) inert atmosphere is nitrogen or argon gas.
According to the above scheme, step 2) the nucleophilic substitution time is 40min.
According to the above scheme, step 2) it is described reaction solution is separated, purification step specifically: be cooled to room to reaction solution
It is poured into water after temperature, volume ratio reaction solution: water=1:3, and adjust pH value in water with dilute hydrochloric acid solution and then will to 3~4
The solid of precipitation is filtered, and gained filter cake is dissolved in ethyl acetate, with filtering again after anhydrous sodium sulfate drying, will be filtered
Liquid is spin-dried for, and obtains crude product, is further purified using column chromatography, with the mixed solvent of petroleum ether, ethyl acetate 2:1 by volume
For eluant, eluent, target compound component evaporated under reduced pressure is collected, is finally dried in vacuo.
According to the above scheme, preparation method of the present invention is further comprising the steps of:
3) ester type compound obtained by step 2) is dissolved in solvent, addition dilute alkaline soln is hydrolyzed reaction and obtains diaryl
Pyrimidin-dione acid heterozygous HIV-1 inhibitor.
According to the above scheme, the dilute alkaline soln is the water of one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide
Solution, concentration are 0.1~3mol/L.
Ester type compound issues raw hydrolysis in dilute alkaline aqueous solution effect and obtains corresponding acid compounds, reacts as follows
Shown in formula (2):
The invention also includes a kind of pharmaceutical composition, the composition includes a effective amount of above-mentioned diaryl pyrimidine-two
Mek-Tol Unit heterozygous HIV-1 inhibitor (diaryl pyrimidine-diketonate heterozygous HIV-1 inhibitor and diaryl pyrimidine-diketone
Sour heterozygous HIV-1 inhibitor).
And above-mentioned diaryl pyrimidine-diketone acid heterozygous HIV-1 inhibitor is used to having this to need in preparation
Prevent or treat HIV infection in individual or prevents, treats or postpone the purposes in the drug that AIDS breaks out.
The beneficial effects of the present invention are: 1, the present invention provide a kind of with new structural diaryl pyrimidine-two ketone acid
It is immune to can be used for preventing or treating people with preferable HIV-1 cellular level inhibitory activity for class heterozygous HIV-1 inhibitor
Defective virus (HIV) infection, and prevent, treat or postpone the breaking-out of subsequent illness such as AIDS；2, system provided by the invention
Preparation Method step is simple, and yield is higher, reproducible.
Specific embodiment
Technical solution in order to enable those skilled in the art to better understand the present invention makees the present invention below with reference to embodiment
It is described in further detail.
Embodiment 1
Weigh 2.15g 2- (to cyano-aniline base) -4- chlorine pyrimidine, two oxy butyrate of 2.00g 4- (p-hydroxybenzene) -2,4-
Ethyl ester and 8.28g cesium carbonate are added in bis- mouthfuls of flasks of 100mL, add 45mL dimethyl sulfoxide, stir.It vacuumizes, argon gas is protected
Shield.Stop heating after reaction solution is warming up to 110 DEG C of reaction 40min.After reaction solution is cooled to room temperature, it is poured into 150mL
In water, and pH value is adjusted to 3~4 with the HCl solution of 2mol/L, a large amount of solids filter after being precipitated, and filter cake is dissolved in acetic acid second
It is dry with anhydrous sodium sulfate in ester.It finally filters again, filtrate is spin-dried for, obtain crude product, column chromatographic purifying, eluant, eluent is stone
Oily ether/ethyl acetate mixed solvent (2:1, volume ratio), collects target compound component evaporated under reduced pressure, and vacuum drying obtains white
Solid A-1, yield 52%.
After tested, 173~175 DEG C of the present embodiment products therefrom A-1 fusing point；1H NMR spectra peak value (400MHz, DMSO-
d6): δ 10.16 (s, 1H), 8.51-8.50 (d, J=4.8Hz, 1H), 8.24-8.22 (d, J=7.6Hz, 2H), 7.71-7.69
(d, J=8.0Hz, 2H), 7.54-7.47 (q, 4H), 7.16 (s, 1H), 6.70-6.89 (d, J=4.4Hz, 1H), 4.35-4.30
(q, J=6.8Hz, 2H), 1.34-1.30 (t, J=6.8Hz, 3H；MS (ESI): 431.95 (M+1)+.The present embodiment products therefrom
Shown in the structural formula of A-1 such as following formula (3):
Embodiment 2
Weigh 2.15g 2- (to cyano-aniline base) -4- chlorine pyrimidine, two oxy butyrate of 2.00g 4- (p-hydroxybenzene) -2,4-
Ethyl ester and 2.69g sodium carbonate are added in bis- mouthfuls of flasks of 100ml, add 45mL n,N-Dimethylformamide, stir.It vacuumizes,
Nitrogen protection.Stop heating after reaction solution is warming up to 110 DEG C of reaction 40min.After reaction solution is cooled to room temperature, it is poured into
In 150mL water, and pH to 3~4 is adjusted with the HCl of 2mol/L, a large amount of solids are precipitated.It filters, filter cake is dissolved in ethyl acetate
In, it is dry with anhydrous sodium sulfate.Finally, filtering again, filtrate is spin-dried for, obtains crude product.Column chromatographic purifying, eluant, eluent are petroleum
Ether/ethyl acetate mixed solvent (2:1, volume ratio), collects target compound component evaporated under reduced pressure, and vacuum drying obtains white solid
Body A-1, yield 44%.173~175 DEG C of fusing point；1H NMR (400MHz, DMSO-d6): δ 10.16 (s, 1H), 8.51-8.50 (d,
J=4.8Hz, 1H), 8.24-8.22 (d, J=7.6Hz, 2H), 7.71-7.69 (d, J=8.0Hz, 2H), 7.54-7.47 (q,
4H), 7.16 (s, 1H), 6.70-6.89 (d, J=4.4Hz, 1H), 4.35-4.30 (q, J=6.8Hz, 2H), 1.34-1.30 (t,
J=6.8Hz, 3H；MS (ESI): 431.95 (M+1)+。
Embodiment 3
Weigh 2.15g 2- (to cyano-aniline base) -4- chlorine pyrimidine, two oxy butyrate of 2.00g 4- (p-hydroxybenzene) -2,4-
Ethyl ester and 3.51g potassium carbonate are added in bis- mouthfuls of flasks of 100ml, add 45mL n,N-dimethylacetamide, stir.It vacuumizes,
Nitrogen protection.Stop heating after reaction solution is warming up to 110 DEG C of reaction 40min.After reaction solution is cooled to room temperature, it is poured into
In 150mL water, and pH to 3~4 is adjusted with the HCl of 2mol/L, a large amount of solids are precipitated.It filters, filter cake is dissolved in ethyl acetate
In, it is dry with anhydrous sodium sulfate.Finally, filtering again, filtrate is spin-dried for, obtains crude product.Column chromatographic purifying, eluant, eluent are petroleum
Ether/ethyl acetate mixed solvent (2:1, volume ratio), collects target compound component evaporated under reduced pressure, and vacuum drying obtains white solid
Body A-1, yield 42%.173~175 DEG C of fusing point；1H NMR (400MHz, DMSO-d6): δ 10.16 (s, 1H), 8.51-8.50 (d,
J=4.8Hz, 1H), 8.24-8.22 (d, J=7.6Hz, 2H), 7.71-7.69 (d, J=8.0Hz, 2H), 7.54-7.47 (q,
4H), 7.16 (s, 1H), 6.70-6.89 (d, J=4.4Hz, 1H), 4.35-4.30 (q, J=6.8Hz, 2H), 1.34-1.30 (t,
J=6.8Hz, 3H；MS (ESI): 431.95 (M+1)+。
Embodiment 4
Weigh 2.15g 2- (to cyano-aniline base) -4- chlorine pyrimidine, two oxy butyrate of 2.00g 4- (p-hydroxybenzene) -2,4-
Ethyl ester and 1.88g lithium carbonate are added in bis- mouthfuls of flasks of 100ml, add 45mL Isosorbide-5-Nitrae-dioxane, stir.It vacuumizes, nitrogen
Protection.Stop heating after reaction solution is warming up to 110 DEG C of reaction 40min.After reaction solution is cooled to room temperature, it is poured into
In 150mL water, and pH to 3~4 is adjusted with the HCl of 2mol/L, a large amount of solids are precipitated.It filters, filter cake is dissolved in ethyl acetate
In, it is dry with anhydrous sodium sulfate.Finally, filtering again, filtrate is spin-dried for, obtains crude product.Column chromatographic purifying, eluant, eluent are petroleum
Ether/ethyl acetate mixed solvent (2:1, volume ratio), collects target compound component evaporated under reduced pressure, and vacuum drying obtains white solid
Body A-1, yield 38%.173~175 DEG C of fusing point；1H NMR (400MHz, DMSO-d6): δ 10.16 (s, 1H), 8.51-8.50 (d,
J=4.8Hz, 1H), 8.24-8.22 (d, J=7.6Hz, 2H), 7.71-7.69 (d, J=8.0Hz, 2H), 7.54-7.47 (q,
4H), 7.16 (s, 1H), 6.70-6.89 (d, J=4.4Hz, 1H), 4.35-4.30 (q, J=6.8Hz, 2H), 1.34-1.30 (t,
J=6.8Hz, 3H；MS (ESI): 431.95 (M+1)+。
Embodiment 5
Weigh 2.15g 2- (to cyano-aniline base) -4- chlorine pyrimidine, two oxy butyrate of 2.00g 4- (p-hydroxybenzene) -2,4-
Ethyl ester and 1.02g sodium hydroxide are added in bis- mouthfuls of flasks of 100ml, add 45mL Isosorbide-5-Nitrae-dioxane, stir.It vacuumizes, nitrogen
Gas shielded.Stop heating after reaction solution is warming up to 110 DEG C of reaction 40min.After reaction solution is cooled to room temperature, it is poured into
In 150mL water, and pH to 3~4 is adjusted with the HCl of 2mol/L, a large amount of solids are precipitated.It filters, filter cake is dissolved in ethyl acetate
In, it is dry with anhydrous sodium sulfate.Finally, filtering again, filtrate is spin-dried for, obtains crude product.Column chromatographic purifying, eluant, eluent are petroleum
Ether/ethyl acetate mixed solvent (2:1, volume ratio), collects target compound component evaporated under reduced pressure, and vacuum drying obtains white solid
Body A-1, yield 40%.173~175 DEG C of fusing point；1H NMR (400MHz, DMSO-d6): δ 10.16 (s, 1H), 8.51-8.50 (d,
J=4.8Hz, 1H), 8.24-8.22 (d, J=7.6Hz, 2H), 7.71-7.69 (d, J=8.0Hz, 2H), 7.54-7.47 (q,
4H), 7.16 (s, 1H), 6.70-6.89 (d, J=4.4Hz, 1H), 4.35-4.30 (q, J=6.8Hz, 2H), 1.34-1.30 (t,
J=6.8Hz, 3H；MS (ESI): 431.95 (M+1)+。
Embodiment 6
Weigh 2.15g 2- (to cyano-aniline base) -4- chlorine pyrimidine, two oxy butyrate of 2.00g 4- (p-hydroxybenzene) -2,4-
Ethyl ester and 1.42g potassium hydroxide are added in bis- mouthfuls of flasks of 100ml, add 45mL tetrahydrofuran, stir.It vacuumizes, argon gas is protected
Shield.Stop heating after reaction solution is warming up to 110 DEG C of reaction 40min.After reaction solution is cooled to room temperature, it is poured into 150mL
In water, and pH to 3~4 is adjusted with the HCl of 2mol/L, a large amount of solids are precipitated.It filters, filter cake is dissolved in ethyl acetate, use
Anhydrous sodium sulfate is dry.Finally, filtering again, filtrate is spin-dried for, obtains crude product.Column chromatographic purifying, eluant, eluent are petroleum ether/second
Acetoacetic ester mixed solvent (2:1, volume ratio) collects target compound component evaporated under reduced pressure, and vacuum drying obtains white solid A-1,
Yield 42%.173~175 DEG C of fusing point；1H NMR (400MHz, DMSO-d6): δ 10.16 (s, 1H), 8.51-8.50 (d, J=
4.8Hz, 1H), 8.24-8.22 (d, J=7.6Hz, 2H), 7.71-7.69 (d, J=8.0Hz, 2H), 7.54-7.47 (q, 4H),
7.16 (s, 1H), 6.70-6.89 (d, J=4.4Hz, 1H), 4.35-4.30 (q, J=6.8Hz, 2H), 1.34-1.30 (t, J=
6.8Hz,3H；MS (ESI): 431.95 (M+1)+。
Embodiment 7
Weigh 2.15g 2- (to cyano-aniline base) -4- chlorine pyrimidine, two oxy butyrate of 2.00g 4- (p-hydroxybenzene) -2,4-
Ethyl ester and 0.61g sodium hydrogen are added in bis- mouthfuls of flasks of 100ml, add 40mL tetrahydrofuran, stir.It vacuumizes, nitrogen protection.It will
Reaction solution stops heating after being warming up to 110 DEG C of reaction 40min.After reaction solution is cooled to room temperature, it is poured into 150mL water,
And pH to 3~4 is adjusted with the HCl of 2mol/L, a large amount of solids are precipitated.It filters, filter cake is dissolved in ethyl acetate, with anhydrous sulphur
Sour sodium is dry.Finally, filtering again, filtrate is spin-dried for, obtains crude product.Column chromatographic purifying, eluant, eluent are petrol ether/ethyl acetate
Mixed solvent (2:1, volume ratio), collects target compound component evaporated under reduced pressure, and vacuum drying obtains white solid A-1, yield
45%.173~175 DEG C of fusing point；1H NMR (400MHz, DMSO-d6): δ 10.16 (s, 1H), 8.51-8.50 (d, J=4.8Hz,
1H), 8.24-8.22 (d, J=7.6Hz, 2H), 7.71-7.69 (d, J=8.0Hz, 2H), 7.54-7.47 (q, 4H), 7.16 (s,
1H), 6.70-6.89 (d, J=4.4Hz, 1H), 4.35-4.30 (q, J=6.8Hz, 2H), 1.34-1.30 (t, J=6.8Hz,
3H；MS (ESI): 431.95 (M+1)+。
Embodiment 8
Weigh 2.15g 2- (to cyano-aniline base) -4- chlorine pyrimidine, two oxy butyrate of 2.00g 4- (hydroxy phenyl) -2,4-
Ethyl ester and 8.28g cesium carbonate are added in bis- mouthfuls of flasks of 100ml, add 45mL dimethyl sulfoxide, stir.It vacuumizes, nitrogen is protected
Shield.Stop heating after reaction solution is warming up to 110 DEG C of reaction 40min.After reaction solution is cooled to room temperature, it is poured into 150mL
In water, and pH to 3~4 is adjusted with the HCl of 2mol/L, a large amount of solids are precipitated.It filters, filter cake is dissolved in ethyl acetate, use
Anhydrous sodium sulfate is dry.Finally, filtering again, filtrate is spin-dried for, obtains crude product.Column chromatographic purifying, eluant, eluent are petroleum ether/second
Acetoacetic ester mixed solvent (2:1, volume ratio) collects target compound component evaporated under reduced pressure, and vacuum drying obtains white solid A-2,
Yield 47%.170~172 DEG C of fusing point；1H NMR (400MHz, DMSO-d6): δ 10.14 (s, 1H), 8.48-8.47 (d, J=
5.2Hz, 1H), 8.08-8.06 (d, J=7.2Hz, 1H), 7.98 (s, 1H), 7.74-7.70 (t, J=7.6Hz, 1H), 7.64-
7.42 (d, J=7.6Hz, 3H), 7.48-7.46 (d, J=8.0Hz, 2H), 7.16 (s, 1H), 6.68-6.66 (d, J=5.2Hz,
1H), 4.32-4.27 (m, J=6.8Hz, 2H), 1.31-1.27 (t, J=6.8Hz, 3H)；MS (ESI): 431.86 (M+1)+.This
Shown in the structural formula such as following formula (4) of embodiment products therefrom A-2:
Embodiment 9
Weigh 2.15g 2- (to cyano-aniline base) -4- chlorine pyrimidine, two oxy butyrate of 2.00g 4- (hydroxy phenyl) -2,4-
Ethyl ester and 8.28g cesium carbonate are added in bis- mouthfuls of flasks of 100ml, add 45mL tetrahydrofuran, stir.It vacuumizes, nitrogen protection.
Stop heating after reaction solution is warming up to 110 DEG C of reaction 40min.After reaction solution is cooled to room temperature, it is poured into 150mL water
In, and pH to 3~4 is adjusted with the HCl of 2mol/L, a large amount of solids are precipitated.It filters, filter cake is dissolved in ethyl acetate, with nothing
Aqueous sodium persulfate is dry.Finally, filtering again, filtrate is spin-dried for, obtains crude product.Column chromatographic purifying, eluant, eluent are petroleum ether/acetic acid
Acetate mixed solvent (2:1, volume ratio) collects target compound component evaporated under reduced pressure, and vacuum drying obtains white solid A-2, receives
Rate 43%.170~172 DEG C of fusing point；1H NMR (400MHz, DMSO-d6): δ 10.14 (s, 1H), 8.48-8.47 (d, J=
5.2Hz, 1H), 8.08-8.06 (d, J=7.2Hz, 1H), 7.98 (s, 1H), 7.74-7.70 (t, J=7.6Hz, 1H), 7.64-
7.42 (d, J=7.6Hz, 3H), 7.48-7.46 (d, J=8.0Hz, 2H), 7.16 (s, 1H), 6.68-6.66 (d, J=5.2Hz,
1H), 4.32-4.27 (m, J=6.8Hz, 2H), 1.31-1.27 (t, J=6.8Hz, 3H)；MS (ESI): 431.86 (M+1)+。
Embodiment 10
It weighs 1.00g ester A-1 to be added in the single-necked flask of 50mL, adds 12mL tetrahydrofuran, finally add
The lithium hydroxide of 13mL 1mol/L.2.5h is stirred at room temperature, and TLC monitoring display ester A-1 disappears, and stops stirring.Then, it uses
The HCl of 2mol/L adjusts the pH to 2~3 of reaction solution, and a large amount of solids are precipitated.It filters, filter cake is with respectively with methanol and ethyl acetate
It washes 2~3 times, is dried in vacuo, obtains white solid A-3, yield 51%.198~200 DEG C of fusing point；1H NMR (400MHz, DMSO-
d6): δ 10.14 (s, 1H), 8.51-8.50 (d, J=5.6Hz, 1H), 8.23-8.20 (d, J=8.4Hz, 2H), 7.73-7.70
(d, J=8.8Hz, 2H), 7.54-7.52 (d, J=8.8Hz, 2H), 7.48-7.46 (d, J=8.4Hz, 2H), 7.15 (s, 1H),
(6.70-6.68 d, J=5.6Hz, 1H)；MS (ESI): 403.65 (M+1)+.The structural formula such as formula of the present embodiment products therefrom A-3
(5) shown in:
Embodiment 11
It weighs 1.00g ester A-1 to be added in the single-necked flask of 50mL, adds 12mL methanol, finally add 13mL
The potassium hydroxide of 1mol/L.2.5h is stirred at room temperature, and TLC monitoring display ester A-1 disappears, and stops stirring.Then, with 2mol/L's
HCl adjusts the pH to 2~3 of reaction solution, and a large amount of solids are precipitated.Filter, filter cake with being washed 2~3 times with methanol and ethyl acetate respectively,
Vacuum drying, obtains white solid A-3, yield 44%.198~200 DEG C of fusing point；1H NMR (400MHz, DMSO-d6): δ 10.14
(s, 1H), 8.51-8.50 (d, J=5.6Hz, 1H), 8.23-8.20 (d, J=8.4Hz, 2H), 7.73-7.70 (d, J=
8.8Hz, 2H), 7.54-7.52 (d, J=8.8Hz, 2H), 7.48-7.46 (d, J=8.4Hz, 2H), 7.15 (s, 1H), 6.70-
6.68 (d, J=5.6Hz, 1H)；MS (ESI): 403.65 (M+1)+。
Embodiment 12
It weighs 1.00g ester A-1 to be added in the single-necked flask of 50mL, adds 12mL tetrahydrofuran/methanol (1:1, volume
Than), finally add the sodium hydroxide solution of 13mL 1mol/L.2.5h is stirred at room temperature, TLC monitoring display ester A-1 disappears,
Stop stirring.Then, the pH to 2~3 of reaction solution is adjusted with the HCl of 2mol/L, a large amount of solids are precipitated.It filters, filter cake difference
It is washed 2~3 times with methanol and ethyl acetate, is dried in vacuo, obtains white solid I -3, yield 77%.198~200 DEG C of fusing point；1H
NMR (400MHz, DMSO-d6): δ 10.14 (s, 1H), 8.51-8.50 (d, J=5.6Hz, 1H), 8.23-8.20 (d, J=
8.4Hz, 2H), 7.73-7.70 (d, J=8.8Hz, 2H), 7.54-7.52 (d, J=8.8Hz, 2H), 7.48-7.46 (d, J=
8.4Hz, 2H), 7.15 (s, 1H), 6.70-6.68 (d, J=5.6Hz, 1H)；MS (ESI): 403.65 (M+1)+。
Embodiment 13
It weighs 1.00g ester A-2 to be added in the single-necked flask of 50mL, adds 12mL tetrahydrofuran/methanol (1:1, volume
Than), finally add the KOH of 13mL 1mol/L.2.5h is stirred at room temperature, and TLC monitoring display ester I -2 disappears, and stops stirring.
Then, the pH to 2~3 of reaction solution is adjusted with the HCl of 1mol/L, a large amount of solids are precipitated.It filters, filter cake is with respectively with methanol and second
Acetoacetic ester is washed 2~3 times, vacuum drying.Obtain white solid A-4, yield 66%.194~196 DEG C of fusing point；1H NMR
(400MHz, DMSO-d6): δ 10.14 (s, 1H), 8.48-8.47 (d, J=5.6Hz, 1H), 8.07-8.05 (d, J=7.6Hz,
1H), 7.98 (s, 1H), 7.74-7.70 (t, 1H), 7.65-7.61 (m, 3H), 7.49-7.47 (d, J=8.8Hz, 2H), 7.15
(s, 1H), 6.68-6.66 (d, J=5.6Hz, 1H)；MS (ESI): 403.58 (M+1)+。
Shown in the structural formula such as formula (6) of the present embodiment products therefrom A-4:
Embodiment 14
It weighs 1.00g ester A-1 to be added in the single-necked flask of 50mL, adds 12mL tetrahydrofuran/methanol (1:1, volume
Than), finally add the NaOH of 130mL 0.1mol/L.2.5h is stirred at room temperature, and TLC monitoring display ester A-1 disappears, stops stirring
It mixes.Then, the pH to 2~3 of reaction solution is adjusted with the HCl of 1mol/L, a large amount of solids are precipitated.It filters, filter cake with using methanol respectively
It is washed 2~3 times with ethyl acetate, is dried in vacuo, obtains white solid A-3, yield 48%.198~200 DEG C of fusing point,1H NMR and
MS (ESI) is consistent with 10 data of embodiment.
Embodiment 15
It weighs 1.00g ester A-1 to be added in the single-necked flask of 50mL, adds 12mL tetrahydrofuran/methanol (1:1, volume
Than), finally add the NaOH of 5mL 3mol/L.2.5h is stirred at room temperature, and TLC monitoring display ester A-1 disappears, and stops stirring.
Then, the pH to 2~3 of reaction solution is adjusted with the HCl of 1mol/L, a large amount of solids are precipitated.It filters, filter cake is with respectively with methanol and second
Acetoacetic ester is washed 2~3 times, and vacuum drying obtains white solid A-3, yield 45%.197~200 DEG C of fusing point；1H NMR and MS
(ESI) consistent with 10 data of embodiment.
Embodiment 16
It weighs 1.00g ester A-2 to be added in the single-necked flask of 50mL, adds 12mL tetrahydrofuran/methanol (1:1, volume
Than), finally add the KOH of 130mL 0.1%.2.5h is stirred at room temperature, and TLC monitoring display ester A-2 disappears, and stops stirring.
Then, the pH to 2~3 of reaction solution is adjusted with the HCl of 1mol/L, a large amount of solids are precipitated.It filters, filter cake is with respectively with methanol and second
Acetoacetic ester is washed 2~3 times, vacuum drying.Obtain white solid A-4, yield 52%.194~196 DEG C of fusing point；1H NMR and MS
(ESI) consistent with 13 data of embodiment.
Embodiment 17
It weighs 1.00g ester A-2 to be added in the single-necked flask of 50mL, adds 12mL tetrahydrofuran/methanol (1:1, volume
Than), finally add the KOH of 5mL 3mol/L.2.5h is stirred at room temperature, and TLC monitoring display ester A-2 disappears, and stops stirring.With
Afterwards, the pH to 2~3 of reaction solution is adjusted with the HCl of 1mol/L, a large amount of solids are precipitated.It filters, filter cake is with respectively with methanol and acetic acid
Ethyl ester is washed 2~3 times, vacuum drying.Obtain white solid A-4, yield 43%.195~196 DEG C of fusing point；1H NMR and MS (ESI)
It is consistent with 13 data of embodiment.
Embodiment 18
AntiHIV1 RT activity biological activity test is carried out to the resulting product of the embodiment of the present invention:
The anti HIV-1 virus determination of activity of cell in vitro level mainly includes the inhibitory activity to the MT-4 cell of HIV infection
And two aspect of cytotoxicity.Method is described as follows: making compound in the MT-4 cell of HIV infection, when infected by HIV difference
Between, with protective effect of the mtt assay measurement drug to the cytopathy of HIV mutagenesis, calculating induces 50% cell from HIV
Concentration medium effective concentration EC needed for cytopathy50, toxicity test is parallel with HIV-resistant activity experiment to be carried out, and in MT-4
In cell culture, the concentration (CC of 50% non-infected cells generation cytopathy is made with mtt assay measurement50)。
Materials and methods: inhibition of the HIV-resistant activity of each compound by drug to HIV caused cytopathy in cell
Functioning efficiency monitors.Cell culture is carried out using MT-4 cell.The Strain used is HIV-1 Strain IIIB.
Concrete operations are as follows: compound diluted with after DMSO or water dissolution with phosphate buffer saline solution, by 3 ×
105MT-4 cell, in 37 DEG C of preculture lh, is then added into the compound with each this solution of compound various concentration of 100 μ L
100 μ L viral dilutions appropriate, by cell in 37 DEG C of culture lh.Washing three times after, cell is suspended in respectively again containing
Or in the culture medium without containing compound.Then it by cell in 5% carbon dioxide atmosphere, is further cultured at 37 DEG C 7 days, and
The third day culture medium replacement supplement culture solution for containing or not contain compound after infection.Every kind of culture solution condition is all heavy
Multiple operation is twice.The cytopathic effect of virus is all monitored with reverse optical microscope daily.For typical case, institute in this experiment
Viral dilution usually can lead to cytopathy on the 5th day after the virus infection.Drug inhibition concentration is thin to virus with drug
The effect of born of the same parents' lesion generates 50% inhibiting effect and the simultaneously concentration (CC to cell without direct toxicity50) indicate.It is emphasized that
When compound water soluble is poor, needs to be dissolved with DMSO, DMSO specific concentration is for water, and generally below 10%
(DMSO in MT-4 cell culture medium ultimate density less than 2%).Because DMSO can influence to test the antiviral work of compound
Property, it should also be carried out in parallel to containing same concentrations DMSO solution antiviral activity comparison blank assay.In addition, DMSO is finally dense
Degree (1/1000) replicates required concentration well below HIV-1 is influenced in T cell.
The test of HIV-1RT inhibitory activity is carried out to the resulting target product of embodiment: using a kind of the similar of on-radiation
In the method for ELISA: donor dna is by two artificial synthesized single-stranded oligonucleotide chain (VU5BR:5'-Biotin-
GTGTGGAAAATCTCTAGCAGT-3', VU5:5'-ACTGCTAGAGATTTTCCACAC-3') it anneals.VU5BR/VU5 is pressed
1:1.2 is mixed in TEN buffer (10mM Tris-HCI pH 8.0,1mM EDTA pH 8.0 and 0.1M NaCl), and 80 DEG C
3min is heated, room temperature is slowly down to, is stored in 4 DEG C of refrigerators.Three times by 96 orifice plates being coated with distillation washing, 2.5%BSA
37 DEG C of closing 3h, 0.1%PBST are washed three times.Every hole adds target molecule 20mM HEPES pH 7.5,10mM MnCl2、10mM
MgCl2, 30mM NaCl, 10mM DTT, 0.05%NP-40,100 μ g/mL BSA, 5nM VU5/VU5BR, 2.5-80nM it is different
RT 100 the μ L, 37 DEG C of incubation 1h of concentration.0.1%PBST is washed three times, the horseradish peroxidating that every hole adds 100 μ L streptavidins to mark
Object enzyme 1:3000,0.1%BSA+0.025%PBST dilute solution, 37 DEG C of incubation 1h.0.1%PBST is washed three times, adds 1 μ L of TMB,
37 DEG C of 20~30min of placement add 50 hole μ L/ 2M H2SO4, absorbance is detected under 450nm wavelength.
The EC that target compound inhibits HIV-1IIIB is listed in table 150、CC50.Marketed drug nevirapine
(Nevirapine) it is also tested concurrently as reference.In addition, we are also tested for target compound to HIV-1 reverse transcriptase
(HIV-1RT) inhibitory activity IC50(IC50Refer to compound concentration needed for inhibiting 50%HIV-1RT), it is shown in Table 1.
The Anti-HIV-1 Active and cytotoxicity of 1 target compound of table
As shown in Table 1,4 compounds tested all have good HIV-1 cellular level inhibitory activity, lesser thin
Cellular toxicity has the potentiality for being further developed as anti-AIDS drug.It is true that the active testing of enzyme level shows such compound
It is real that there is HIV-1 reverse transcriptase inhibitory activity, belong to HIV-1 reverse transcriptase inhibitor.
Claims (10)
1. a kind of diaryl pyrimidine-diketone acid heterozygous HIV-1 inhibitor, which is characterized in that its for formula (1) compound or its
Officinal salt:
(1)；
Wherein R is selected from hydrogen, C1-5Saturated alkyl, C3-5Naphthenic base, C2-5Alkenyl, two ketone acids or diketonate side chain are located at ehter bond oxygen
The ortho position of atom, meta or para position；
The C1-5Saturated alkyl is methyl, ethyl, propyl, normal-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl
One of；
The C3-5Naphthenic base is one of cyclopropyl, cyclobutyl, cyclopenta；
The C2-5Alkenyl is one of vinyl, acrylic, allyl, cyclobutenyl, n-pentene base, isopentene group.
2. a kind of diaryl pyrimidine described in claim 1-diketone acid heterozygous HIV-1 inhibitor preparation method, special
Sign be the following steps are included:
1) by 2- (to cyano-aniline base) -4- chlorine pyrimidine and 4- (hydroxy phenyl) -2,4- dioxy ethyl butyrate and alkali by mole
Than 2- (to cyano-aniline base) -4- chlorine pyrimidine: 4- (hydroxy phenyl) -2,4- dioxy ethyl butyrate: alkali=1.1:1:3 mixing is added
Solvent is uniformly mixing to obtain reaction solution under an inert atmosphere；
2) reaction solution obtained by step 1) is warming up to 110 DEG C, carries out nucleophilic substitution, TLC monitors nucleophilic substitution and carries out
Stop heating after completely, reaction solution is separated, purifies to obtain ester type compound, is i.e. diaryl pyrimidine-diketonate heterozygosis
Type HIV-1 inhibitor.
3. preparation method according to claim 2, it is characterised in that solvent described in step 1) be dimethyl sulfoxide,N,N- two
Methylformamide,N,NOne or more of dimethyl acetamide, 1,4- dioxane, tetrahydrofuran.
4. preparation method according to claim 2, it is characterised in that alkali described in step 1) is potassium carbonate, sodium carbonate, carbonic acid
One or more of caesium, lithium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride.
5. preparation method according to claim 2, it is characterised in that inert atmosphere described in step 1) is nitrogen or argon gas.
6. preparation method according to claim 2, it is characterised in that separated described in step 2 to reaction solution, purify step
Suddenly specifically: be poured into water after reaction solution is cooled to room temperature, volume ratio reaction solution: water=1:3, and use dilute hydrochloric acid solution
PH value in water is adjusted then to filter the solid of precipitation to 3 ~ 4, gained filter cake is dissolved in ethyl acetate, use is anhydrous
It is filtered again after sodium sulphate is dry, filtrate is spin-dried for, crude product is obtained, be further purified using column chromatography, with petroleum ether, acetic acid
Ethyl ester by volume 2:1 mixed solvent be eluant, eluent, collect target compound component evaporated under reduced pressure, be finally dried in vacuo.
7. preparation method according to claim 2, it is characterised in that further comprising the steps of:
3) ester type compound obtained by step 2 is dissolved in solvent, dilute alkaline soln is added and reaction is hydrolyzed to obtain diaryl phonetic
- two ketone acid heterozygous HIV-1 inhibitor of pyridine.
8. preparation method according to claim 7, it is characterised in that the dilute alkaline soln be sodium hydroxide, potassium hydroxide,
The aqueous solution of one or more of lithium hydroxide, concentration are 0.1 ~ 3mol/L.
9. a kind of pharmaceutical composition, the composition includes a effective amount of diaryl pyrimidine-diketone acid described in claim 1
Heterozygous HIV-1 inhibitor.
10. diaryl pyrimidine described in claim 1-diketone acid heterozygous HIV-1 inhibitor is used to having this to need in preparation
Prevent or treat HIV-1 infection in the individual wanted or prevents, treats or postpone the purposes in the drug that AIDS breaks out.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1335834A (en) * | 1998-12-25 | 2002-02-13 | 盐野义制药株式会社 | Aromatic heterocycle compounds having HIV integrase inhibiting activities |
| CN1541215A (en) * | 2001-08-13 | 2004-10-27 | ղɭҩҵ����˾ | HIV inhibiting pyrimidines derivatives |
| CN1747937A (en) * | 2003-02-07 | 2006-03-15 | 詹森药业有限公司 | Pyrimidine derivatives for the prevention of HIV infection |
| CN105085410A (en) * | 2015-08-21 | 2015-11-25 | 武汉工程大学 | Diarylpyrimidine HIV-1 (human immunodeficiency virus-1) inhibitor and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2333707A1 (en) * | 1998-06-03 | 1999-12-09 | Melissa Egbertson | Hiv integrase inhibitors |
| AU2002360523A1 (en) * | 2001-12-07 | 2003-06-23 | The Government Of The United States Of America As Represented By The Secretary, Department Of Health | Compounds to treat hiv infection and aids |
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- 2017-02-27 CN CN201710108100.XA patent/CN106905244B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1335834A (en) * | 1998-12-25 | 2002-02-13 | 盐野义制药株式会社 | Aromatic heterocycle compounds having HIV integrase inhibiting activities |
| CN1541215A (en) * | 2001-08-13 | 2004-10-27 | ղɭҩҵ����˾ | HIV inhibiting pyrimidines derivatives |
| CN1747937A (en) * | 2003-02-07 | 2006-03-15 | 詹森药业有限公司 | Pyrimidine derivatives for the prevention of HIV infection |
| CN105085410A (en) * | 2015-08-21 | 2015-11-25 | 武汉工程大学 | Diarylpyrimidine HIV-1 (human immunodeficiency virus-1) inhibitor and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| From Ligand to Complexes: Inhibition of Human Immunodeficiency Virus Type 1 Integrase by β-Diketo Acid Metal Complexes;Mario Sechi et al.;《J. Med. Chem.》;20060620;第49卷;4248-4260 |
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