CN106905244A - Inhibitor of diaryl pyrimidine diketone acid heterozygous HIV 1 and preparation method thereof - Google Patents
Inhibitor of diaryl pyrimidine diketone acid heterozygous HIV 1 and preparation method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
Abstract
The present invention relates to a kind of inhibitor of diaryl pyrimidine diketone acid heterozygous HIV 1 and preparation method thereof, the inhibitor of diaryl pyrimidine diketone acid heterozygous HIV 1 is formula (1) compound or pharmaceutically acceptable salt thereof：Wherein R is selected from hydrogen, C1‑5Saturated alkyl, C3‑5Cycloalkyl, C2‑5Alkenyl；Two ketone acid or diketonate side chain are located at ortho position, the meta or para position of ehter bond oxygen atom.Its preparation method is：1) by 2 (to cyano-aniline base) 4 chlorine pyrimidine and 4 (p-hydroxybenzenes) 2,4 dioxy ethyl butyrates or 4 (hydroxy phenyl) 2,4 dioxy ethyl butyrates and alkali mix, and add solvent, and reaction solution is uniformly mixing to obtain under an inert atmosphere；2) reaction solution heats up carries out nucleophilic substitution, and reaction stops heating after terminating, and reaction solution is separated, is purified and is obtained the inhibitor of diaryl pyrimidine diketone acid heterozygous HIV 1.
Description
Technical field
The invention belongs to pharmaceutical technology field, be related to a class diaryl pyrimidine-diketone acid heterozygous HIV-1 inhibitor and
Its preparation method.
Background technology
AIDS is that acquired deficiency symptoms (AIDS) of exempting from are the whole world caused by HIV (HIV)
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.At present, five kinds of chemical entities are had by the NNRTIs of U.S. FDA approval listing：How
It is big to even up (nevirapine), efavirenz (efavirenz), delavirdine (delavirdine), etravirine
And rilpivirine (rilpivirine) (etravirine).Wherein, etravirine and rilpivirine are respectively provided with diaryl pyrimidine knot
Structure, this kind of compound is referred to as Diarylmiazines HIV-1 inhibitor (DAPYs).DAPYs has excellent to HIV-1 persisters
Activity, attracted the extensive concern of various countries' Pharmaceutical Chemist.The application design synthesis one class diaryl pyrimidine-diketone acid is miscellaneous
Mould assembly HIV-1 inhibitor (DAPY-DKAs), expectation obtains a class has the novel drugs of good HIV-1 activity.
The content of the invention
The technical problems to be solved by the invention are directed to above shortcomings in the prior art, there is provided a kind of new two
Arylpyrimidines-diketone acid heterozygous HIV-1 inhibitor and preparation method thereof.
In order to solve the above technical problems, the technical scheme that the present invention is provided is：
One class diaryl pyrimidine-diketone acid heterozygous HIV-1 inhibitor is provided, its be formula (1) compound or its can medicine
Use salt：
Wherein R is selected from hydrogen, C1-5Saturated alkyl, C3-5Cycloalkyl, C2-5Alkenyl, two ketone acid or diketonate side chain position
In the ortho position of ehter bond oxygen atom, meta or para position；
The C1-5Saturated alkyl is methyl, ethyl, propyl group, normal-butyl, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, new
One kind in amyl group；
The C3-5Cycloalkyl is the one kind in cyclopropyl, cyclobutyl, cyclopenta；
The C2-5Alkenyl is the one kind in vinyl, acrylic, pi-allyl, cyclobutenyl, n-pentene base, isopentene group.
The present invention also provides the preparation method of above-mentioned diaryl pyrimidine-diketone acid heterozygous HIV-1 inhibitor, and it is special
Levy is to comprise the following steps：
1) by 2- (to cyano-aniline base) -4- chlorine pyrimidines, (4- is (to hydroxyl with 4- (hydroxy phenyl) -2,4- dioxies ethyl butyrate
Base phenyl) -2,4- dioxies ethyl butyrate or 4- (hydroxy phenyl) -2,4- dioxies ethyl butyrate) and alkali 2- is (right in molar ratio
Cyano-aniline base) -4- chlorine pyrimidines：4- (hydroxy phenyl) -2,4- dioxy ethyl butyrates：Alkali=1.1:1:3 mixing, add solvent,
Reaction solution is uniformly mixing to obtain under an inert atmosphere；
2) by step 1) gained reaction solution is warming up to 110 DEG C, carries out nucleophilic substitution, TLC monitoring nucleophilic substitutions
Stop heating after carrying out completely, reaction solution is separated, is purified and is obtained ester type compound, be i.e. diaryl pyrimidine-diketonate
Heterozygous HIV-1 inhibitor.
By such scheme, step 1) solvent be dimethyl sulfoxide (DMSO) (DMSO), DMF (DMF), N,
One or more in N- dimethylacetylamides (DMA), 1,4- dioxane, tetrahydrofuran (THF).
By such scheme, step 1) alkali be potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, NaOH, hydroxide
One or more in potassium, sodium hydride.
By such scheme, step 1) inert atmosphere be nitrogen or argon gas.
By such scheme, step 2) the nucleophilic substitution time be 40min.
By such scheme, step 2) it is described reaction solution is separated, purification step is specially：Question response liquid is cooled to room
It is poured into water after temperature, volume ratio reaction solution：Water=1:3, and, to 3~4, then will with pH value in dilute hydrochloric acid solution regulation water
The solid of precipitation carries out suction filtration, and gained filter cake is dissolved in ethyl acetate, with suction filtration again after anhydrous sodium sulfate drying, will filter
Liquid is spin-dried for, and obtains crude product, is further purified using column chromatography, with petroleum ether, ethyl acetate by volume 2:1 mixed solvent
It is eluant, eluent, collects target compound component evaporated under reduced pressure, is finally vacuum dried.
By such scheme, preparation method of the present invention is further comprising the steps of：
3) by step 2) gained ester type compound is dissolved in solvent, adds the dilute alkaline soln reaction that is hydrolyzed to obtain diaryl
Pyrimidin-dione acid heterozygous HIV-1 inhibitor.
By such scheme, the dilute alkaline soln is the water of one or more in NaOH, potassium hydroxide, lithium hydroxide
Solution, concentration is 0.1~3mol/L.
Ester type compound issues raw hydrolysis and obtains corresponding acid compounds in dilute alkaline aqueous solution effect, reacts as follows
Shown in formula (2)：
Present invention additionally comprises a kind of pharmaceutical composition, above-mentioned diaryl pyrimidine-two of the composition comprising effective dose
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 being prepared for having what this needed
Prevent or treat HIV or prevention, treatment in individuality or postpone the purposes in the medicine of AIDS breaking-outs.
The beneficial effects of the present invention are：1st, the present invention provides a kind of ketone acid of diaryl pyrimidine-two with new structure
Class heterozygous HIV-1 inhibitor, it has preferable HIV-1 cellular levels inhibitory activity, can be used to preventing or treat people and is immunized
Defective virus (HIV) infects, and prevention, treats or postpone the breaking-out of subsequent illness such as AIDS；2nd, the system that the present invention is provided
Preparation Method step is simple, and yield is higher, reproducible.
Specific embodiment
To make those skilled in the art more fully understand technical scheme, the present invention is made with reference to embodiment
Describe in further detail.
Embodiment 1
Weigh 2.15g 2- (to cyano-aniline base) -4- chlorine pyrimidine, the oxy butyrates of 2.00g 4- (p-hydroxybenzene) -2,4- two
Ethyl ester and 8.28g cesium carbonates are added in bis- mouthfuls of flasks of 100mL, add 45mL dimethyl sulfoxide (DMSO)s, are stirred.Vacuumize, argon gas is protected
Shield.Stop heating after reaction solution is warmed up into 110 DEG C of reaction 40min.After question response liquid is cooled to room temperature, 150mL is poured into
In water, and pH value is adjusted to 3~4 with the HCl solution of 2mol/L, filter cake is dissolved in acetic acid second by suction filtration after a large amount of solids precipitations
In ester, anhydrous sodium sulfate drying is used.Last suction filtration again, filtrate is spin-dried for, and obtains crude product, and column chromatography is purified, and eluant, eluent is stone
Oily ether/ethyl acetate mixed solvent (2:1, volume ratio), target compound component evaporated under reduced pressure is collected, vacuum drying obtains white
Solid A-1, yield 52%.
After tested, 173~175 DEG C of the present embodiment products therefrom A-1 fusing points；1H NMR spectra peak values (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, the oxy butyrates of 2.00g 4- (p-hydroxybenzene) -2,4- two
Ethyl ester and 2.69g sodium carbonate are added in bis- mouthfuls of flasks of 100ml, add 45mL DMFs, are stirred.Vacuumize,
Nitrogen is protected.Stop heating after reaction solution is warmed up into 110 DEG C of reaction 40min.After question response liquid is cooled to room temperature, it is poured into
In 150mL water, and pH is adjusted to 3~4 with the HCl of 2mol/L, a large amount of solids are separated out.Suction filtration, ethyl acetate is dissolved in by filter cake
In, use anhydrous sodium sulfate drying.Finally, suction filtration again, filtrate is spin-dried for, and obtains crude product.Column chromatography is purified, and eluant, eluent is oil
Ether/ethyl acetate mixed solvent (2:1, volume ratio), target compound component evaporated under reduced pressure is collected, 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, the oxy butyrates of 2.00g 4- (p-hydroxybenzene) -2,4- two
Ethyl ester and 3.51g potassium carbonate are added in bis- mouthfuls of flasks of 100ml, add 45mL DMAs, are stirred.Vacuumize,
Nitrogen is protected.Stop heating after reaction solution is warmed up into 110 DEG C of reaction 40min.After question response liquid is cooled to room temperature, it is poured into
In 150mL water, and pH is adjusted to 3~4 with the HCl of 2mol/L, a large amount of solids are separated out.Suction filtration, ethyl acetate is dissolved in by filter cake
In, use anhydrous sodium sulfate drying.Finally, suction filtration again, filtrate is spin-dried for, and obtains crude product.Column chromatography is purified, and eluant, eluent is oil
Ether/ethyl acetate mixed solvent (2:1, volume ratio), target compound component evaporated under reduced pressure is collected, 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, the oxy butyrates of 2.00g 4- (p-hydroxybenzene) -2,4- two
Ethyl ester and 1.88g lithium carbonates are added in bis- mouthfuls of flasks of 100ml, add 45mL Isosorbide-5-Nitraes-dioxane, are stirred.Vacuumize, nitrogen
Protection.Stop heating after reaction solution is warmed up into 110 DEG C of reaction 40min.After question response liquid is cooled to room temperature, it is poured into
In 150mL water, and pH is adjusted to 3~4 with the HCl of 2mol/L, a large amount of solids are separated out.Suction filtration, ethyl acetate is dissolved in by filter cake
In, use anhydrous sodium sulfate drying.Finally, suction filtration again, filtrate is spin-dried for, and obtains crude product.Column chromatography is purified, and eluant, eluent is oil
Ether/ethyl acetate mixed solvent (2:1, volume ratio), target compound component evaporated under reduced pressure is collected, 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, the oxy butyrates of 2.00g 4- (p-hydroxybenzene) -2,4- two
Ethyl ester and 1.02g NaOH are added in bis- mouthfuls of flasks of 100ml, add 45mL Isosorbide-5-Nitraes-dioxane, are stirred.Vacuumize, nitrogen
Gas shielded.Stop heating after reaction solution is warmed up into 110 DEG C of reaction 40min.After question response liquid is cooled to room temperature, it is poured into
In 150mL water, and pH is adjusted to 3~4 with the HCl of 2mol/L, a large amount of solids are separated out.Suction filtration, ethyl acetate is dissolved in by filter cake
In, use anhydrous sodium sulfate drying.Finally, suction filtration again, filtrate is spin-dried for, and obtains crude product.Column chromatography is purified, and eluant, eluent is oil
Ether/ethyl acetate mixed solvent (2:1, volume ratio), target compound component evaporated under reduced pressure is collected, 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, the oxy butyrates of 2.00g 4- (p-hydroxybenzene) -2,4- two
Ethyl ester and 1.42g potassium hydroxide are added in bis- mouthfuls of flasks of 100ml, add 45mL tetrahydrofurans, are stirred.Vacuumize, argon gas is protected
Shield.Stop heating after reaction solution is warmed up into 110 DEG C of reaction 40min.After question response liquid is cooled to room temperature, 150mL is poured into
In water, and pH is adjusted to 3~4 with the HCl of 2mol/L, a large amount of solids are separated out.Suction filtration, filter cake is dissolved in ethyl acetate, is used
Anhydrous sodium sulfate drying.Finally, suction filtration again, filtrate is spin-dried for, and obtains crude product.Column chromatography is purified, and eluant, eluent is petroleum ether/second
Acetoacetic ester mixed solvent (2:1, volume ratio), target compound component evaporated under reduced pressure is collected, 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, the oxy butyrates of 2.00g 4- (p-hydroxybenzene) -2,4- two
Ethyl ester and 0.61g sodium hydrogen are added in bis- mouthfuls of flasks of 100ml, add 40mL tetrahydrofurans, are stirred.Vacuumize, nitrogen protection.Will
Reaction solution stops heating after being warmed up to 110 DEG C of reaction 40min.After question response liquid is cooled to room temperature, it is poured into 150mL water,
And pH is adjusted to 3~4 with the HCl of 2mol/L, a large amount of solids are separated out.Suction filtration, filter cake is dissolved in ethyl acetate, uses anhydrous sulphur
Sour sodium is dried.Finally, suction filtration again, filtrate is spin-dried for, and obtains crude product.Column chromatography is purified, and eluant, eluent is petrol ether/ethyl acetate
Mixed solvent (2:1, volume ratio), target compound component evaporated under reduced pressure is collected, 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, 2.00g 4- (hydroxy phenyl) oxy butyrates of -2,4- two
Ethyl ester and 8.28g cesium carbonates are added in bis- mouthfuls of flasks of 100ml, add 45mL dimethyl sulfoxide (DMSO)s, are stirred.Vacuumize, nitrogen is protected
Shield.Stop heating after reaction solution is warmed up into 110 DEG C of reaction 40min.After question response liquid is cooled to room temperature, 150mL is poured into
In water, and pH is adjusted to 3~4 with the HCl of 2mol/L, a large amount of solids are separated out.Suction filtration, filter cake is dissolved in ethyl acetate, is used
Anhydrous sodium sulfate drying.Finally, suction filtration again, filtrate is spin-dried for, and obtains crude product.Column chromatography is purified, and eluant, eluent is petroleum ether/second
Acetoacetic ester mixed solvent (2:1, volume ratio), target compound component evaporated under reduced pressure is collected, 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, 2.00g 4- (hydroxy phenyl) oxy butyrates of -2,4- two
Ethyl ester and 8.28g cesium carbonates are added in bis- mouthfuls of flasks of 100ml, add 45mL tetrahydrofurans, are stirred.Vacuumize, nitrogen protection.
Stop heating after reaction solution is warmed up into 110 DEG C of reaction 40min.After question response liquid is cooled to room temperature, 150mL water is poured into
In, and pH is adjusted to 3~4 with the HCl of 2mol/L, a large amount of solids are separated out.Suction filtration, filter cake is dissolved in ethyl acetate, with nothing
Aqueous sodium persulfate is dried.Finally, suction filtration again, filtrate is spin-dried for, and obtains crude product.Column chromatography is purified, and eluant, eluent is petroleum ether/acetic acid
Acetate mixed solvent (2:1, volume ratio), target compound component evaporated under reduced pressure is collected, 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
Weigh 1.00g esters A-1 to be added in the single-necked flask of 50mL, add 12mL tetrahydrofurans, finally add
The lithium hydroxide of 13mL 1mol/L.2.5h is stirred at room temperature, and TLC monitoring display esters A-1 disappears, and stops stirring.Then, use
To 2~3, a large amount of solids are separated out the pH of the HCl regulation reaction solutions of 2mol/L.Suction filtration, filter cake is with respectively with methyl alcohol and ethyl acetate
Wash 2~3 times, be vacuum dried, obtain 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
Weigh 1.00g esters A-1 to be added in the single-necked flask of 50mL, add 12mL methyl alcohol, finally add 13mL
The potassium hydroxide of 1mol/L.2.5h is stirred at room temperature, and TLC monitoring display esters A-1 disappears, and stops stirring.Then, with 2mol/L's
To 2~3, a large amount of solids are separated out the pH of HCl regulation reaction solutions.Suction filtration, filter cake with being washed 2~3 times with methyl alcohol 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)：δ10.14
(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
Weigh 1.00g esters A-1 to be added in the single-necked flask of 50mL, add 12mL tetrahydrofurans/methyl alcohol (1:1, volume
Than), finally add the sodium hydroxide solution of 13mL 1mol/L.2.5h is stirred at room temperature, and TLC monitoring display esters A-1 disappears,
Stop stirring.Then, the pH of reaction solution is adjusted to 2~3 with the HCl of 2mol/L, a large amount of solids are separated out.Suction filtration, filter cake difference
Washed 2~3 times with methyl alcohol and ethyl acetate, be vacuum dried, obtain 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
Weigh 1.00g esters A-2 to be added in the single-necked flask of 50mL, add 12mL tetrahydrofurans/methyl alcohol (1:1, volume
Than), finally add the KOH of 13mL 1mol/L.2.5h is stirred at room temperature, and TLC monitoring display esters I -2 disappear, and stop stirring.
Then, the pH of reaction solution is adjusted to 2~3 with the HCl of 1mol/L, a large amount of solids are separated out.Suction filtration, filter cake is with respectively with methyl alcohol 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
Weigh 1.00g esters A-1 to be added in the single-necked flask of 50mL, add 12mL tetrahydrofurans/methyl alcohol (1:1, volume
Than), finally add the NaOH of 130mL 0.1mol/L.2.5h is stirred at room temperature, and TLC monitoring display esters A-1 disappears, stops stirring
Mix.Then, the pH of reaction solution is adjusted to 2~3 with the HCl of 1mol/L, a large amount of solids are separated out.Suction filtration, filter cake with using methyl alcohol respectively
Washed 2~3 times with ethyl acetate, be vacuum dried, obtain white solid A-3, yield 48%.198~200 DEG C of fusing point,1H NMR and
MS (ESI) is consistent with the data of embodiment 10.
Embodiment 15
Weigh 1.00g esters A-1 to be added in the single-necked flask of 50mL, add 12mL tetrahydrofurans/methyl alcohol (1:1, volume
Than), finally add the NaOH of 5mL 3mol/L.2.5h is stirred at room temperature, and TLC monitoring display esters A-1 disappears, and stops stirring.
Then, the pH of reaction solution is adjusted to 2~3 with the HCl of 1mol/L, a large amount of solids are separated out.Suction filtration, filter cake is with respectively with methyl alcohol and second
Acetoacetic ester is washed 2~3 times, vacuum drying, obtains white solid A-3, yield 45%.197~200 DEG C of fusing point；1H NMR and MS
(ESI) it is consistent with the data of embodiment 10.
Embodiment 16
Weigh 1.00g esters A-2 to be added in the single-necked flask of 50mL, add 12mL tetrahydrofurans/methyl alcohol (1:1, volume
Than), finally add the KOH of 130mL 0.1%.2.5h is stirred at room temperature, and TLC monitoring display esters A-2 disappears, and stops stirring.
Then, the pH of reaction solution is adjusted to 2~3 with the HCl of 1mol/L, a large amount of solids are separated out.Suction filtration, filter cake is with respectively with methyl alcohol 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) it is consistent with the data of embodiment 13.
Embodiment 17
Weigh 1.00g esters A-2 to be added in the single-necked flask of 50mL, add 12mL tetrahydrofurans/methyl alcohol (1:1, volume
Than), finally add the KOH of 5mL 3mol/L.2.5h is stirred at room temperature, and TLC monitoring display esters A-2 disappears, and stops stirring.With
Afterwards, the pH of reaction solution is adjusted to 2~3 with the HCl of 1mol/L, a large amount of solids are separated out.Suction filtration, filter cake is with respectively with methyl alcohol 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 the data of embodiment 13.
Embodiment 18
AntiHIV1 RT activity biological activity test is carried out to the product obtained by the embodiment of the present invention：
The anti HIV-1 virus determination of activity of cell in vitro level, the main inhibitory activity included to the MT-4 cells of HIV
And the aspect of cytotoxicity two.Method is described as follows：Make compound in the MT-4 cells of HIV, when infected by HIV is different
Between, determining protective effect of the medicine to the cytopathy of HIV mutagenesis with mtt assay, calculating makes what 50% cell was induced from HIV
Concentration medium effective concentration EC needed for cytopathy50, toxicity test is parallel with HIV-resistant activity experiment to be carried out, and is also in MT-4
In cell culture, being determined with mtt assay makes 50% non-infected cells that the concentration (CC of cytopathy to occur50)。
Materials and methods：The suppression of the cytopathy that the HIV-resistant activity of each compound is caused to HIV by medicine in cell
Functioning efficiency is monitored.Cell culture is carried out using MT-4 cells.The Strain for using is HIV-1 Strain IIIB.
Concrete operations are as follows：Compound is diluted with after DMSO or water dissolves with phosphate buffer saline solution, by 3 ×
105Then MT-4 cells each this solution of compound various concentrations of 100 μ L add in 37 DEG C of preculture lh in the compound
100 μ L appropriate viral dilution liquid, lh is cultivated by cell in 37 DEG C.Washing three times after, cell is suspended in respectively again containing
Or in not containing the culture medium of compound.Then by cell in 5% carbon dioxide atmosphere, in being further cultured at 37 DEG C 7 days, and
In the 3rd day after infection supplement nutrient solution was replaced with the culture medium for containing or not contain compound.Every kind of nutrient solution condition is all weighed
Multiple operation is twice.Cytopathic effect to virus is all monitored with reverse optical microscope daily.For typical case, institute in this experiment
Viral dilution liquid usually can cause cytopathy on the 5th day after virus infection.Drug inhibition concentration is thin with drug on viral
Born of the same parents' lesion effect produce 50% inhibitory action and simultaneously to concentration (CC of the cell without direct toxicity50) represent.It is emphasized that
When compound water soluble is poor, it is necessary to when could be dissolved with DMSO, DMSO specific concentrations for water, generally below 10%
(DMSO ultimate densities in MT-4 cell culture mediums are less than 2%).Because DMSO can influence the antiviral work of test compound
Property, to parallel should also be carried out containing same concentrations DMSO solution antiviral activity contrast blank assay.In addition, DMSO is finally dense
Degree (1/1000) replicates required concentration well below influence HIV-1 in T cell.
HIV-1RT inhibitory activity tests are carried out to the target product obtained by 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') annealing is formed.VU5BR/VU5 is pressed
1：1.2 are mixed in TEN buffer solutions (10mM Tris-HCI pH 8.0,1mM EDTA pH 8.0 and 0.1M NaCl), 80 DEG C
Heating 3min, is slowly down to room temperature, is stored in 4 DEG C of refrigerators.The 96 orifice plates distillation washing that will be coated with three times, 2.5%BSA
37 DEG C are closed 3h, and 0.1%PBST is washed three times.Add target molecule 20mM HEPES pH 7.5,10mM MnCl per hole2、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 for adding 100 μ L streptavidins to mark per hole
Thing enzyme 1：3000,0.1%BSA+0.025%PBST dilute solutions, 37 DEG C of incubation 1h.0.1%PBST is washed three times, plus the μ L of TMB 1,
37 DEG C of 20~30min of placement, plus 50 μ L/ holes 2M H2SO4, absorbance is detected under 450nm wavelength.
The EC that target compound suppresses HIV-1IIIB is listed in table 150、CC50.Marketed drug NVP
(Nevirapine) also it is tested concurrently as reference.Additionally, we are also tested for target compound to HIV1-RT
(HIV-1RT) inhibitory activity IC50(IC50Refer to the compound concentration needed for suppressing 50%HIV-1RT), it is shown in Table 1.
The Anti-HIV-1 Active and cytotoxicity of the target compound of table 1
As shown in Table 1,4 compounds tested are respectively provided with good HIV-1 cellular level inhibitory activity, less thin
Cellular toxicity, with the potentiality for being further developed as anti-AIDS drug.It is true that the active testing of enzyme level indicates such compound
It is real that there is HIV1-RT inhibitory activity, belong to HIV1-RT inhibitor.
Claims (10)
1. a class diaryl pyrimidine-diketone acid heterozygous HIV-1 inhibitor, it is characterised in that its be formula (1) compound or its
Officinal salt：
Wherein R is selected from hydrogen, C1-5Saturated alkyl, C3-5Cycloalkyl, C2-5Alkenyl, two ketone acid or diketonate side chain are located at ether
The ortho position of key oxygen atom, meta or para position；
The C1-5Saturated alkyl is methyl, ethyl, propyl group, normal-butyl, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl
In one kind；
The C3-5Cycloalkyl is the one kind in cyclopropyl, cyclobutyl, cyclopenta；
The C2-5Alkenyl is the one kind in vinyl, acrylic, pi-allyl, cyclobutenyl, n-pentene base, isopentene group.
2. the preparation method of the diaryl pyrimidine described in a kind of claim 1-diketone acid heterozygous HIV-1 inhibitor, it is special
Levy is to comprise the following steps：
1) by 2- (to cyano-aniline base) -4- chlorine pyrimidines and 4- (hydroxy phenyl) -2,4- dioxies ethyl butyrate and alkali by mole
Than 2- (to cyano-aniline base) -4- chlorine pyrimidines：4- (hydroxy phenyl) -2,4- dioxy ethyl butyrates：Alkali=1.1:1:3 mixing, plus
Enter solvent, reaction solution is uniformly mixing to obtain under an inert atmosphere；
2) by step 1) gained reaction solution is warming up to 110 DEG C, carries out nucleophilic substitution, and TLC monitoring nucleophilic substitutions are carried out
Stop heating after completely, reaction solution is separated, is purified and is obtained ester type compound, be i.e. diaryl pyrimidine-diketonate heterozygosis
Type HIV-1 inhibitor.
3. preparation method according to claim 2, it is characterised in that step 1) solvent is dimethyl sulfoxide (DMSO), N, N- bis-
One or more in NMF, DMAC N,N' dimethyl acetamide, 1,4- dioxane, tetrahydrofuran.
4. preparation method according to claim 2, it is characterised in that step 1) alkali is potassium carbonate, sodium carbonate, carbonic acid
One or more in caesium, lithium carbonate, NaOH, potassium hydroxide, sodium hydride.
5. preparation method according to claim 2, it is characterised in that step 1) inert atmosphere is nitrogen or argon gas.
6. preparation method according to claim 2, it is characterised in that step 2) described reaction solution is separated, step is purified
It is rapid to be specially：Question response liquid is poured into water after being cooled to room temperature, volume ratio reaction solution：Water=1:3, and use dilute hydrochloric acid solution
The solid of precipitation is then carried out suction filtration by pH value to 3~4 in regulation water, gained filter cake is dissolved in ethyl acetate, with anhydrous
Sodium sulphate dry after suction filtration again, filtrate is spin-dried for, obtain crude product, be further purified using column chromatography, with petroleum ether, acetic acid
Ethyl ester by volume 2:1 mixed solvent is eluant, eluent, collects target compound component evaporated under reduced pressure, is finally vacuum dried.
7. preparation method according to claim 2, it is characterised in that further comprising the steps of：
3) by step 2) gained ester type compound is dissolved in solvent, and to obtain diaryl phonetic for reaction to add dilute alkaline soln to be hydrolyzed
The ketone acid heterozygous HIV-1 inhibitor of pyridine-two.
8. preparation method according to claim 7, it is characterised in that the dilute alkaline soln be NaOH, potassium hydroxide,
The aqueous solution of one or more in lithium hydroxide, concentration is 0.1~3mol/L.
9. a kind of pharmaceutical composition, the diaryl pyrimidine-diketone acid described in claim 1 of the composition comprising effective dose
Heterozygous HIV-1 inhibitor.
10. the diaryl pyrimidine described in claim 1-diketone acid heterozygous HIV-1 inhibitor is being prepared for there is this need
Purposes in the individuality wanted in prevention or treatment HIV or prevention, the medicine treated or postpone AIDS breaking-outs.
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| WO1999062520A1 (en) * | 1998-06-03 | 1999-12-09 | Merck & Co., Inc. | Hiv integrase inhibitors |
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| WO2003049695A2 (en) * | 2001-12-07 | 2003-06-19 | The Government Of The United States Of America As Represented By The Secretary, Department Of Healthand Human Services | Compounds to treat hiv infection and aids |
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| 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 |
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2017
- 2017-02-27 CN CN201710108100.XA patent/CN106905244B/en not_active Expired - Fee Related
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| WO1999062520A1 (en) * | 1998-06-03 | 1999-12-09 | Merck & Co., Inc. | Hiv integrase inhibitors |
| 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 |
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| WO2003049695A2 (en) * | 2001-12-07 | 2003-06-19 | The Government Of The United States Of America As Represented By The Secretary, Department Of Healthand Human Services | Compounds to treat hiv infection and aids |
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