CN104876880A - Diaryl ether derivatives as well as preparation method and application thereof - Google Patents
Diaryl ether derivatives as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN104876880A CN104876880A CN201510210449.5A CN201510210449A CN104876880A CN 104876880 A CN104876880 A CN 104876880A CN 201510210449 A CN201510210449 A CN 201510210449A CN 104876880 A CN104876880 A CN 104876880A
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- acid
- dmso
- group
- pyrimidine
- thiazolinyl
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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
- C07D239/56—One oxygen atom and one sulfur atom
Abstract
The invention belongs to the technical field of medicine and particularly relates to diary ether derivatives having a general formula I, pharmaceutical salts, hydrates and solvates of the diary ether derivatives, polycrystal or eutectic crystal of the diary ether derivatives, precursors and derivatives having the same biological functions, a preparation method of the diary ether derivatives and application of compositions containing one or more of the compounds in preparation of related medicines for treating Aids. Pharmacological experiment results show that the compounds have remarkable activity of resisting HIV-1 virus, are capable of effectively inhibiting replication of MT-4 cell infected with HIV-1 virus and have relatively low cytotoxicity. The general formula I is shown in the specification.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of two aryl oxide analog derivatives and preparation method thereof and the application in the related drugs such as treatment acquired immune deficiency syndrome (AIDS).
Background technology
Acquired immune deficiency syndrome (AIDS) (AIDS) i.e. acquired immune deficiency syndrome (AIDS) (Acquired immune deficiency syndrome) is the epidemic infectious diseases caused by human immunodeficiency virus (Human immunodeficiency virus, HIV).
Reversed transcriptive enzyme (Reverse transcriptase, RT) becomes the process of DNA to play decisive role from mRNA reverse transcription at HIV, therefore becomes one of important target spot of anti-AIDS drug design.
In existing inverase research, non-nucleoside reverse transcriptase inhibitor (NNRTIs) becomes one of focus of various countries' Pharmaceutical Chemist concern because of advantages such as its high-efficiency low-toxicities.At present, the AntiHIV1 RT activity reverse transcriptase inhibitors through U.S. FDA approval listing has five kinds: how Wella puts down (Nevirapine), De Laweiding (Delavirdine), efavirenz (Efavirenz), etravirine (Etravirine), rilpivirine (Rilpivirine).In addition, RDEA806, IDX899, UK-453061 carry out clinical study.Research display, classical NNRTIs only acts on HIV-1, and invalid to HIV-2 virus.
Summary of the invention
The object of the invention is to propose a kind of reverse transcriptase inhibitors two aryl oxide analog derivative, be specifically related to two aryl oxide analog derivative and pharmaceutical salts thereof described in formula I, its hydrate and solvate, its polycrystalline and eutectic, the precursor of its same biological function and derivative.
Two aryl oxide analog derivatives provided by the present invention, have following structural formula I:
Wherein, R
1and R
2independently be selected from hydrogen, cyano group, nitro, amino, hydroxyl, halogen, the C be optionally substituted
1 ~ 6alkyl, the C be optionally substituted
2 ~ 6thiazolinyl, the C be optionally substituted
2 ~ 6alkynyl or C
1 ~ 6alkoxyl group;
R
3be selected from hydrogen, cyano group, nitro, amino, hydroxyl, halogen, sulfonic group, carboxyl, ester group, C
1 ~ 6alkyl, C
1 ~ 6alkoxyl group, C
1 ~ 6alkane sulfydryl, C
3 ~ 6cycloalkyl, C
3 ~ 6cycloalkyloxy, C
3 ~ 6naphthene amino, C
2 ~ 6thiazolinyl, C
2 ~ 6alkynyl, the C of replacement
2 ~ 6the C of thiazolinyl or replacement
2 ~ 6alkynyl;
Ar is monosubstituted or polysubstituted aromatic ring, and the substituting group on aromatic ring is selected from hydrogen, cyano group, nitro, amino, hydroxyl, halogen, sulfonic group, carboxyl, ester group, C
1 ~ 6alkyl, C
1 ~ 6alkoxyl group, C
1 ~ 6alkane sulfydryl, C
3 ~ 6cycloalkyl, C
3 ~ 6cycloalkyloxy, C
3 ~ 6naphthene amino, C
2 ~ 6thiazolinyl, C
2 ~ 6alkynyl, the C of replacement
2 ~ 6the C of thiazolinyl or replacement
2 ~ 6alkynyl.
In the present invention, the pharmaceutical salts of described two aryl oxide analog derivatives comprises hydrochloride, hydrobromate, vitriol, phosphoric acid salt, acetate, mesylate, tosilate, tartrate, Citrate trianion, fumarate or malate.
The present invention also proposes the preparation method of two aryl oxide analog derivatives, and its reaction expression prepared is as follows:
Concrete operation step is as follows:
With the compound shown in structure above II for raw material, in a solvent, with oxidant reaction, obtained chemical compounds I;
Described solvent is one or more in water, methylene dichloride, chloroform, ethyl acetate, methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, acetonitrile, tetrahydrofuran (THF), Nitromethane 99Min., aceticanhydride, naphthalane, DMF;
Described oxygenant is one or more in hydrogen peroxide, tertbutanol peroxide, metachloroperbenzoic acid, Peracetic Acid, trifluoro Peracetic Acid, peroxide laurostearic acid, potassium permanganate, potassium bichromate, sodium periodate, Periodic acid, clorox, hypochlorous acid, Potcrate, halogen, ammonium persulfate-sodium bisulfate, peroxy-disulfuric acid TBuA, ruthenium tetroxide, nitric acid, oxygen, N-methyl oxidation morphine, benzoyl peroxide dioctyl phthalate magnesium salts, dimethyldioxirane;
Described oxygenant and the mol ratio of compound ii are 1:1 ~ 3:1, preferred 2.1:1 ~ 2.6:1;
Temperature of reaction is 0 ~ 50 DEG C, preferably 20 ~ 40 DEG C;
Reaction times is 1 ~ 24h, preferred 5-10h.
The invention still further relates to a kind of pharmaceutical composition, said composition contains the above-claimed cpd of effective dose and relevant pharmaceutical carrier, and described compound or composition are preparing the application in prevention and therapy AIDS-treating medicine.
The present invention is based on two aryl oxide analog derivatives and reversed transcriptive enzyme binding pattern, in conjunction with Computer-Aided Drug Design, to link on son with the thiacetamides base of right flank at middle pyrimidine ring and introduce Sauerstoffatom, the Sauerstoffatom of new introducing can form hydrogen bond with high conservative amino-acid residue Tyr318, thus strengthen the bonding force of target molecule and reversed transcriptive enzyme, improve the antiviral activity of target compound further.Biological activity test shows, all compounds all have stronger anti-HIV-1 virus activity and less cytotoxicity, have higher selectivity index.
Embodiment
By following embodiment the present invention may be better understood content, but content of the present invention can not be limited.
Embodiment 1: the synthesis of end product I
At 20 ~ 40 DEG C, thioether II is joined in solvent, stirring and dissolving, then add oxygenant, stir 5-10h.TLC display reacts completely.Use saturated sodium bisulfite solution, saturated sodium carbonate solution, water, saturated common salt water washing successively, organic phase is spent the night through anhydrous sodium sulfate drying.Filter, concentrated, re crystallization from toluene, obtains required solid.
With different thioethers II aforesaid method obtained target compound respectively, partial results is as follows:
Under room temperature, by 2-{ [4-(4-cyano group-2,6-xylenol) pyrimidine-2-base] sulfenyl } Acetanilide (5.53 mmol) joins in 60 mL methylene dichloride, stirring and dissolving, then add metachloroperbenzoic acid (12.16 mmol), stir 9h.TLC display reacts completely.Use saturated sodium bisulfite solution (20 mL × 2), saturated sodium carbonate solution (20 mL × 2), water (20 mL × 2), saturated aqueous common salt (20 mL × 2) to wash successively, organic phase is spent the night through anhydrous sodium sulfate drying.Filter, concentrated, re crystallization from toluene, obtains required solid.
。
White powdery solid; Yield 72%; Fusing point: 136.9 – 137.8 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.06 (s, 6H, 2C
h 3), 4.54 (s, 2H, C
h 2), 7.09 (t,
j=7.4 Hz, 1H, Ph
' h 4), 7.32 (t,
j=7.8 Hz, 2H, Ph
' h 3,5), 7.44 (d,
j=8.0 Hz, 2H, Ph
' h 2,6), 7.55 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.64 (s, 2H, Ph
h 3,5), 9.00 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.35 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.66,57.14,109.29,110.92,118.45,119.17,124.15,128.93,132.29,132.85,138.16,152.14,159.55,161.04,164.19,168.14; IR (KBr):
ν=3347 (s;
ν(N-H)), 2223 (s;
ν(C ≡ N)), 1683 (s;
ν(C=O)), 1326 (s;
ν(S=O)), 1124 cm
-1(s;
ν(S=O)); MS (ESI+)
m/z445 (M+Na)
+; HRMS calcd for C
21h
18n
4o
4s [M+Na]
+: 445.0946, found:445.0930; HPLC:t
r=9.45 min, 97.35%.
。
Operate the same.White powdery solid; Yield 74%; Fusing point: 136.6 – 137.4 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.06 (s, 6H, 2C
h 3), 2.27 (s, 3H, C
h 3), 4.52 (s, 2H, C
h 2), 6.91 (d,
j=7.2 Hz, 1H, Ph
' h 4), 7.17-7.24 (m, 2H, Ph
' h 5,6), 7.29 (s, 1H, Ph
' h 2), 7.55 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.62 (s, 2H, Ph
h 3,5), 9.00 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.26 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.65,21.14,57.08,109.27,110.91,116.33,118.45,119.62,124.81,128.74,132.26,132.84,138.12,138.18,152.12,159.49,161.04,164.20,168.11; MS (ESI+)
m/z459 (M+Na)
+; HRMS calcd for C
22h
20n
4o
4s [M+Na]
+: 459.1103, found:459.1086; HPLC:t
r=9.98 min, 96.25%.
。
Operate the same.White powdery solid; Yield 77%; Fusing point: 138.2 – 138.9 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.06 (s, 6H, 2C
h 3), 2.25 (s, 3H, C
h 3), 4.51 (s, 2H, C
h 2), 7.10 (d,
j=8.4 Hz, 2H, Ph
' h 3,5), 7.33 (d,
j=8.0 Hz, 2H, Ph
' h 2,6), 7.55 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.65 (s, 2H, Ph
h 3,5), 8.99 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.27 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.66,20.48,57.13,109.28,110.89,118.45,119.15,129.27,132.29,132.85,133.17,135.68,152.14,159.26,161.01,164.19,168.13; MS (ESI+)
m/z459 (M+Na)
+; HRMS calcd for C
22h
20n
4o
4s [M+Na]
+: 459.1103, found:459.1099; HPLC:t
r=9.94 min, 96.77%.
。
Operate the same.White powdery solid; Yield 78%; Fusing point: 129.8 – 130.7 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.06 (s, 6H, 2C
h 3), 2.16 (s, 3H, C
h 3), 2.17 (s, 3H, C
h 3), 4.50 (s, 2H, C
h 2), 7.04 (d,
j=8.0 Hz, 1H, Ph
' h 5), 7.16 (d,
j=8.0 Hz, 1H, Ph
' h 6), 7.22 (s, 1H, Ph
' h 2), 7.55 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.63 (s, 2H, Ph
h 3,5), 8.99 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.18 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.66,18.83,19.59,57.08,109.27,110.90,116.67; 118.45,120.29,129.71,131.97,132.28,132.85,135.93; 136.58,152.14,159.21,161.03,164.22,168.12; MS (ESI+)
m/z473 (M+Na)
+; HRMS calcd for C
23h
22n
4o
4s [M+Na]
+: 473.1259, found:473.1260; HPLC:t
r=10.33 min, 97.04%.
。
Operate the same.White powdery solid; Yield 79%; Fusing point: 144.3 – 145.0 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.06 (s, 6H, 2C
h 3), 3.72 (s, 3H, C
h 3), 4.49 (s, 2H, C
h 2), 6.87 (d,
j=8.8 Hz, 2H, Ph
' h 3,5), 7.35 (d,
j=8.8 Hz, 2H, Ph
' h 2,6), 7.55 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.66 (s, 2H, Ph
h 3,5), 8.99 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.23 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.65,55.22,57.09,109.27,110.87,114.01,118.45,120.71,131.30,132.31,132.85,152.15,155.77,158.96,161.00,164.20,168.13; MS (ESI+)
m/z475 (M+Na)
+; HRMS calcd for C
22h
20n
4o
5s [M+Na]
+: 475.1052, found:475.1057; HPLC:t
r=9.24 min, 97.49%.
。
Operate the same.White powdery solid; Yield 81%; Fusing point: 126.5 – 127.4 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.06 (s, 6H, 2C
h 3), 4.69 (s, 2H, C
h 2), 7.13-7.20 (m, 2H, Ph
' h 4,6), 7.25-7.30 (m, 1H, Ph
' h 5), 7.55 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.66 (s, 2H, Ph
h 3,5), 7.80 (m, 1H, Ph
' h 2), 8.99 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.18 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.66,56.68,109.29,110.93,115.71 (d,
j c-C-F=19.1 Hz), 118.44,123.20 (d,
j c-C-F=22.0 Hz), 124.53 (d,
j c4-F=3.5 Hz), 125.37 (d,
j c3-F=11.3 Hz), 125.89 (d,
j c3-F=7.5 Hz), 132.31,132.87,152.14,154.29 (d,
j c-F=244.0 Hz), 160.23,161.03,164.20,168.16; MS (ESI+)
m/z463 (M+Na)
+; HRMS calcd for C
21h
17fN
4o
4s [M+Na]
+: 463.0852, found:463.0850; HPLC:t
r=9.53 min, 96.76%.
。
Operate the same.White powdery solid; Yield 77%; Fusing point: 128.9 – 129.5 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.05 (s, 6H, 2C
h 3), 4.56 (s, 2H, C
h 2), 6.94 (t,
j=8.4 Hz, 1H, Ph
' h 4), 7.17 (d,
j=8.0 Hz, 1H, Ph
' h 6), 7.34-7.42 (m, 2H, Ph
' h 2,5), 7.56 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.63 (s, 2H, Ph
h 3,5), 9.00 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.57 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.66,57.11,106.16 (d,
j c-C-F=26.2 Hz), 109.32,110.81 (d,
j c-C-F=20.8 Hz), 111.00,115.01 (d,
j c4-F=2.6 Hz), 118.44,130.74 (d,
j c3-F=9.4 Hz), 132.28,132.86,139.85 (d,
j c3-F=11.1 Hz), 152.13,160.02,161.11,163.30 (d,
j c-F=240.6 Hz), 164.14,168.15; MS (ESI+)
m/z463 (M+Na)
+; HRMS calcd for C
21h
17fN
4o
4s [M+Na]
+: 463.0852, found:463.0834; HPLC:t
r=9.65 min, 97.98%.
。
Operate the same.White powdery solid; Yield 75%; Fusing point: 124.1 – 125.0 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.06 (s, 6H, 2C
h 3), 4.52 (s, 2H, C
h 2), 7.15 (t,
j=8.8 Hz, 2H, Ph
' h 3,5), 7.45-7.49 (m, 2H, Ph
' h 2,6), 7.55 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.65 (s, 2H, Ph
h 3,5), 8.99 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.43 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.67,57.09,109.32,110.97,115.70 (d,
j c-C-F=22.2 Hz), 118.48,121.09 (d,
j c3-F=7.9 Hz), 132.33,132.88,134.58 (d,
j c4-F=2.4 Hz), 152.17,159.51,159.66 (d,
j c-F=239.4 Hz), 161.07,164.17,168.17; MS (ESI+)
m/z463 (M+Na)
+; HRMS calcd for C
21h
17fN
4o
4s [M+Na]
+: 463.0852, found:463.0855; HPLC:t
r=9.52 min, 97.53%.
。
Operate the same.White powdery solid; Yield 76%; Fusing point: 130.1 – 130.9 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.06 (s, 6H, 2C
h 3), 4.73 (s, 2H, C
h 2), 7.20 (t,
j=7.6 Hz, 1H, Ph
' h 4), 7.32 (t,
j=7.6 Hz, 1H, Ph
' h 5), 7.49 (d,
j=8.0 Hz, 1H, Ph
' h 3), 7.54 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.63 (d,
j=8.0 Hz, 1H, Ph
' h 6), 7.69 (s, 2H, Ph
h 3,5), 8.99 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 9.93 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.69,56.61,109.30,110.95,118.45,125.18,125.68,126.80,127.57,129.68,132.35,132.90,133.93,152.16,160.24,161.02,164.19,168.21; MS (ESI+)
m/z479 (M+Na)
+; HRMS calcd for C
21h
17clN
4o
4s [M+Na]
+: 479.0557, found:479.0546; HPLC:t
r=9.89 min, 97.92%.
。
Operate the same.White powdery solid; Yield 79%; Fusing point: 126.2 – 127.1 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.05 (s, 6H, 2C
h 3), 4.55 (s, 2H, C
h 2), 7.15 (d,
j=7.6 Hz, 1H, Ph
' h 4), 7.29 (d,
j=8.0 Hz, 1H, Ph
' h 6), 7.36 (t,
j=8.0 Hz, 1H, Ph
' h 5), 7.56 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.62 (s, 2H, Ph
h 3,5), 7.65 (s, 1H, Ph
' h 2), 9.00 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.56 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.68,57.13,109.34,110.04,117.66,118.46,118.67,123.96,130.73,132.30,132.87,133.27,139.55,152.14,160.08,161.13,164.14,168.16; MS (ESI+)
m/z479 (M+Na)
+; HRMS calcd for C
21h
17clN
4o
4s [M+Na]
+: 479.0557, found:479.0553; HPLC:t
r=10.13 min, 98.60%.
。
Operate the same.White powdery solid; Yield 82%; Fusing point: 132.8 – 133.6 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.05 (s, 6H, 2C
h 3), 4.54 (s, 2H, C
h 2), 7.36 (d,
j=8.8 Hz, 2H, Ph
' h 3,5), 7.47 (d,
j=8.8 Hz, 2H, Ph
' h 2,6), 7.55 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.65 (s, 2H, Ph
h 3,5), 8.99 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.51 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.66,57.11,109.31,110.97,118.45,120.76,127.77,128.87,132.29,132.86,137.09,152.13,159.74,161.06,164.13,168.15; MS (ESI+)
m/z479 (M+Na)
+; HRMS calcd for C
21h
17clN
4o
4s [M+Na]
+: 479.0557, found:479.0555; HPLC:t
r=10.11 min, 96.28%.
。
Operate the same.White powdery solid; Yield 84%; Fusing point: 135.1 – 135.8 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.06 (s, 6H, 2C
h 3), 4.74 (s, 2H, C
h 2), 7.40 (d,
j=8.8 Hz, 1H, Ph
' h 5), 7.54 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.66-7.69 (m, 4H, Ph
h 3,5+ Ph
' h 3,6), 8.99 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.01 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.70,56.60,109.31,110.00,118.45,126.08,127.73,129.14,129.88,132.24,132.35,132.91,133.14,152.16,160.42,161.04,164.16,168.22; MS (ESI+)
m/z513 (M+Na)
+; HRMS calcd for C
21h
16cl
2n
4o
4s [M+Na]
+: 513.0167, found:513.0169; HPLC:t
r=10.69 min, 97.67%.
。
Operate the same.White powdery solid; Yield 79%; Fusing point: 126.2 – 127.0 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.05 (s, 6H, 2C
h 3), 4.55 (s, 2H, C
h 2), 7.33-7.36 (m, 1H, Ph
' h 5), 7.56-7.59 (m, 2H, pyrimidine
h 5+ Ph
' h 6), 7.63 (s, 2H, Ph
h 3,5), 7.81 (d,
j=2.4 Hz, 1H, Ph
' h 2), 9.00 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.68 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.64,57.07,109.31,111.02,118.40,119.27,120.37,125.73,130.93,131.21,132.24,132.83,138.13,152.10,160.17,161.11,164.08,168.12; MS (ESI+)
m/z513 (M+Na)
+; HRMS calcd for C
21h
16cl
2n
4o
4s [M+Na]
+: 513.0167, found:513.0162; HPLC:t
r=10.73 min, 97.34%.
。
Operate the same.White powdery solid; Yield 77%; Fusing point: 123.2 – 124.1 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.05 (s, 6H, 2C
h 3), 4.56 (s, 2H, C
h 2), 7.33 (s, 1H, Ph
' h 4), 7.48 (s, 2H, Ph
' h 2,6), 7.56 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.61 (s, 2H, Ph
h 3,5), 9.00 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.71 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.71,57.10,109.39,111.15,117.42,118.45,123.58,132.31,132.88,134.41,140.39,152.16,160.55,161.22,164.13,168.17; MS (ESI-)
m/z489 (M-H)
-; HRMS calcd for C
21h
16cl
2n
4o
4s [M+Na]
+: 513.0167, found:513.0162; HPLC:t
r=11.00 min, 97.36%.
。
Operate the same.White powdery solid; Yield 76%; Fusing point: 136.3 – 137.1 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.05 (s, 6H, 2C
h 3), 4.53 (s, 2H, C
h 2), 7.41 (d,
j=8.8 Hz, 2H, Ph
' h 3,5), 7.49 (d,
j=8.8 Hz, 2H, Ph
' h 2,6), 7.55 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.65 (s, 2H, Ph
h 3,5), 9.00 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.51 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.70,57.16,109.34,111.02,115.88,118.50,121.17,131.83,132.34,132.90,137.53,152.17,159.81,161.10,164.15,168.19; MS (ESI+)
m/z523 (M+Na)
+; HRMS calcd for C
21h
17brN
4o
4s [M+Na]
+: 523.0052, found:523.0056; HPLC:t
r=10.27 min, 98.48%.
。
Operate the same.White powdery solid; Yield 78%; Fusing point: 222.4 – 223.1 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.04 (s, 6H, 2C
h 3), 4.59 (s, 2H, C
h 2), 7.55 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.61-7.63 (m, 4H, Ph
h 3,5+ Ph
' h 3,5), 7.78 (d,
j=8.8 Hz, 2H, Ph
' h 2,6), 8.99 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.79 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.69,57.17,106.07,109.35,111.10,118.49,118.91,119.36,132.30,132.89,133.53,142.26,152.15,160.52,161.16,164.11,168.18; MS (ESI+)
m/z470 (M+Na)
+; HRMS calcd for C
22h
17n
5o
4s [M+Na]
+: 470.0899, found:470.0890; HPLC:t
r=9.06 min, 98.87%.
。
Operate the same.White powdery solid; Yield 79%; Fusing point: 197.6 – 198.4 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.04 (s, 6H, 2C
h 3), 4.59 (s, 2H, C
h 2), 7.20 (d,
j=8.8 Hz, 1H, Ph
' h 3), 7.41 (d,
j=8.4 Hz, 1H, Ph
' h 5), 7.55 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.65 (s, 2H, Ph
h 3,5), 7.99 (d,
j=8.4 Hz, 1H, Ph
' h 6), 8.99 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.79 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.69,57.17,106.07,110.25 (d,
j c3-F=9.5 Hz), 111.10,118.49,118.91,120.12 (d,
j c-C-F=22.0 Hz), 124.11 (d,
j c3-F=11.0 Hz), 126.26 (d,
j c-C-F=23.2 Hz), 128.14 (d,
j c4-F=2.9 Hz), 132.30,133.53,152.15,160.52,161.16,162.23 (d,
j c-F=246.0 Hz), 164.11,168.18; MS (ESI+)
m/z488 (M+Na)
+; HRMS calcd for C
22h
16fN
5o
4s [M+Na]
+: 488.0805, found:488.0799; HPLC:t
r=9.27 min, 96.67%.
。
Operate the same.White powdery solid; Yield 79%; Fusing point: 123.7 – 124.6 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.05 (s, 6H, 2C
h 3), 4.59 (s, 2H, C
h 2), 7.57 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.60 (s, 2H, Ph
h 3,5), 7.63 (d,
j=8.0 Hz, 1H, Ph
' h 5), 7.74 (d,
j=8.4 Hz, 1H, Ph
' h 6), 7.96 (d,
j=8.4 Hz, 1H, Ph
' h 4), 8.46 (s, 1H, Ph
' h 2), 9.01 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.87 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.68,57.08,109.33,111.13,113.30,118.46,118.81,125.20,130.56,132.31,132.87,139.21,148.03,152.16,160.52,161.19,164.15,168.18; MS (ESI+)
m/z490 (M+Na)
+; HRMS calcd for C
21h
17n
5o
6s [M+Na]
+: 490.0797, found:490.0803; HPLC:t
r=9.39 min, 97.04%.
。
Operate the same.White powdery solid; Yield 76%; Fusing point: 187.1 – 187.7 DEG C;
1h NMR (400 MHz, DMSO-
d 6) δ=2.04 (s, 6H, 2C
h 3), 4.62 (s, 2H, C
h 2), 7.57 (d,
j=5.6 Hz, 1H, pyrimidine
h 5), 7.62 (s, 2H, Ph
h 3,5), 7.68 (d,
j=8.8 Hz, 2H, Ph
' h 2,6), 8.22 (d,
j=8.8 Hz, 2H, Ph
' h 3,5), 9.00 (d,
j=5.6 Hz, 1H, pyrimidine
h 6), 10.95 (s, 1H, N
h);
13c NMR (100 MHz, DMSO-
d 6) δ=15.70,57.15,109.36,111.14,118.49,119.12,125.16,132.30,132.90,142.96,144.13,152.15,160.71,161.18,164.12,168.19; MS (ESI+)
m/z490 (M+Na)
+; HRMS calcd for C
21h
17n
5o
6s [M+Na]
+: 490.0797, found:490.0792; HPLC:t
r=9.39 min, 97.53%.
Embodiment 2: AntiHIV1 RT activity biological activity test
The anti HIV-1 virus activity of cell in vitro level is measured by the Rega institute of materia medica of Belgian Katholleke university, mainly comprises: to inhibit activities and cytotoxicity two aspect of the MT-4 cell of HIV.Method is as follows: make compound in the MT-4 cell of HIV; in infected by HIV different time; measure medicine to the cytopathic provide protection of HIV mutagenesis with mtt assay, calculate the concentration medium effective concentration EC needed for cytopathy making the cell of 50% avoid HIV induction
50, toxicity test and HIV (human immunodeficiency virus)-resistant activity test parallel carrying out, and are also in MT-4 cell cultures, measure make the non-infected cells of 50% that cytopathic concentration (CC occur with mtt assay
50), and calculate selectivity index SI=CC
50/ EC
50.
Materials and methods:
The HIV (human immunodeficiency virus)-resistant activity of each compound is monitored the cytopathic restraining effect efficiency that HIV causes in cell by medicine.MT-4 cell is adopted to carry out cell cultures.The virus strain adopted has: HIV-1 virus strain III B and HIV-2 virus strain ROD.
Concrete operations are as follows: by after compound DMSO or water dissolution at phosphate buffer saline solution dilution, by 3 × 10
5mT-4 cell at 37 DEG C of preculture 1h, then adds the suitable viral dilution liquid of 100 μ L with each this solution of compound different concns of 100 μ L in this compound, and cell is cultivated 1h in 37 DEG C.After washing three times, cell be suspended in again respectively containing or do not contain in the developing medium of compound.Then by cell at 5% CO
2in atmosphere, at 37 DEG C, cultivate 7 days again, and the 3rd day after infecting supplements nutrient solution with the developing medium replacement containing or do not contain compound.Often kind of nutrient solution condition repetitive operation twice.Reverse optical microscope is all used to monitor every day to the cytopathic effect of virus.Typical case, viral dilution liquid used in this experiment usually can cause cytopathy in the 5th day after virus infection.Drug inhibition concentration produces 50% restraining effect with drug on viral cytopathic effect and simultaneously to the concentration (CC of cell without direct toxicity
50) represent.It is emphasized that when compound water soluble is poor, when needing DMSO to dissolve, DMSO specific concentration, relative to water, is generally less than 2% lower than 10%(DMSO ultimate density in MT-4 cell culture medium).Because DMSO can affect the antiviral activity of test compounds, also should parallelly carry out containing same concentrations DMSO solution antiviral activity contrast blank assay.In addition, DMSO ultimate density (1/1000) copies required concentration well below HIV-1 in T cell.
The present invention uses marketed drug, and how Wella puts down (Nevirapine, NVP), efavirenz (Efavirenz, and etravirine (Etravirine EFV), ETV) compare product, the inhibit activities of partial target compound to HIV the results are shown in Table 1 (Anti-HIV activity and cytotoxicity of compounds 1-19 in MT-4 cells).
。
table 1
[a]
[a] All data represent mean values of at least three separate experiments. [b] EC
50: effective concentration required to protect 50% of cells against viral cytopathicity in MT-4 cells. [c] CC
50: cytotoxic concentration of the compound that reduces the normal uninfected MT-4 cell viability by 50%. [d] SI: selectivity index, ratio CC
50/EC
50(WT)。
Experimental result shows, the compound comprised in chemical general formula generally has stronger anti-HIV-1 virus activity, less cytotoxicity and higher selectivity index.
The invention is not restricted to above-mentioned example.
Claims (5)
1. two aryl oxide analog derivatives, is characterized in that structural formula is as follows:
Wherein, R
1and R
2independently be selected from hydrogen, cyano group, nitro, amino, hydroxyl, halogen, the C be optionally substituted
1 ~ 6alkyl, the C be optionally substituted
2 ~ 6thiazolinyl, the C be optionally substituted
2 ~ 6alkynyl or C
1 ~ 6alkoxyl group;
R
3be selected from hydrogen, cyano group, nitro, amino, hydroxyl, halogen, sulfonic group, carboxyl, ester group, C
1 ~ 6alkyl, C
1 ~ 6alkoxyl group, C
1 ~ 6alkane sulfydryl, C
3 ~ 6cycloalkyl, C
3 ~ 6cycloalkyloxy, C
3 ~ 6naphthene amino, C
2 ~ 6thiazolinyl, C
2 ~ 6alkynyl, the C of replacement
2 ~ 6the C of thiazolinyl or replacement
2 ~ 6alkynyl;
Ar is monosubstituted or polysubstituted aromatic ring, and the substituting group on aromatic ring is selected from hydrogen, cyano group, nitro, amino, hydroxyl, halogen, sulfonic group, carboxyl, ester group, C
1 ~ 6alkyl, C
1 ~ 6alkoxyl group, C
1 ~ 6alkane sulfydryl, C
3 ~ 6cycloalkyl, C
3 ~ 6cycloalkyloxy, C
3 ~ 6naphthene amino, C
2 ~ 6thiazolinyl, C
2 ~ 6alkynyl, the C of replacement
2 ~ 6the C of thiazolinyl or replacement
2 ~ 6alkynyl.
2. the preparation method of two aryl oxide analog derivatives as claimed in claim 1, is characterized in that concrete operation step is as follows:
With the compound shown in following structural formula II for raw material, in a solvent, with oxidant reaction, obtained chemical compounds I; Its reaction expression is as follows:
Described solvent is one or more in water, methylene dichloride, chloroform, ethyl acetate, methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, acetonitrile, tetrahydrofuran (THF), Nitromethane 99Min., aceticanhydride, naphthalane, toluene, DMF, N-Methyl pyrrolidone;
Described oxygenant is one or more in hydrogen peroxide, tertbutanol peroxide, metachloroperbenzoic acid, Peracetic Acid, trifluoro Peracetic Acid, peroxide laurostearic acid, potassium permanganate, potassium bichromate, sodium periodate, Periodic acid, clorox, hypochlorous acid, Potcrate, halogen, ammonium persulfate-sodium bisulfate, peroxy-disulfuric acid TBuA, ruthenium tetroxide, nitric acid, oxygen, N-methyl oxidation morphine, benzoyl peroxide dioctyl phthalate magnesium salts, dimethyldioxirane;
Described oxygenant and the mol ratio of compound ii are 1:1 ~ 3:1;
Temperature of reaction is 0 ~ 50 DEG C;
Reaction times is 1 ~ 24h.
3. a pharmaceutical composition, is characterized in that containing effective dose arbitrary compound as claimed in claim 1 and pharmaceutical carrier.
4. the pharmaceutical salts of two aryl oxide analog derivatives as claimed in claim 1, it is characterized in that comprising hydrochloride, hydrobromate, vitriol, phosphoric acid salt, acetate, mesylate, tosilate, tartrate, Citrate trianion, fumarate or malate, and pharmaceutically acceptable prodrug and derivative.
5. two application of aryl oxide analog derivative in the medicine preparing prevention and therapy acquired immune deficiency syndrome (AIDS) as claimed in claim 1.
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