CN100519565C - N1, N3-disubstituted-7-methylpyrazole [4,5-e] [2,1,3] thiadiazin-2, 2, 4-triketone derivatives, their preparation method and application - Google Patents
N1, N3-disubstituted-7-methylpyrazole [4,5-e] [2,1,3] thiadiazin-2, 2, 4-triketone derivatives, their preparation method and application Download PDFInfo
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Abstract
A N1, N3-bi-substituted-7-methylpyridine(4,5-e) (2, 1, 3)thiazide-2,2,4-triketone derivative has complicated heterocyclic-ring system, excellent inhibiting activity of HCMV and can be used to prepare medicine against HCMV as precursor compound. In structural formula, CH2R1 is benzyl or ortho-chlorine-benzyl, CH2R2 is benzyl, ortho-bromine-benzyl, para-bromine-benzyl, para-nitro-benzyl, ortho-chlorine-benzyl, meta-chlorine-benzyl, para-chlorine benzyl, 2,4-dichlor-benzyl, ortho-fluoride-benzyl, para-fluoride-benzyl, ortho-cyanophoric benzyl, meta-cyanophoric benzyl, para-cyanophoric benzyl, ortho-methyl benzyl, para-methyl benzyl or cyanide methyl.
Description
Technical field
The present invention relates to N
1, N
3-two replacement-7-methylpyrazoles [4,5-e] [2,1,3] thiadiazine-2,2,4-three ketones derivative, preparation method and as the application of HCMV non-nucleoside inhibitor belong to anti-HCMV technical field of pharmaceuticals.
Background technology
(Human cytomegalovirus HCMV) belongs to simplexvirus β subfamily to human cytomegalic inclusion disease virus, infects very generally in the crowd, can propagate by multiple modes such as placenta, birth canal, lactation, blood transfusion, organ transplantations.HCMV is the pathogenic agent that intrauterine infection causes fetal anomaly, stillborn foetus, also is the major reason that the immune deficiency patient infection causes death and transplant operation is failed.Anti-HCMV medicine commonly used at present has ganciclovir, phosphine formic acid, cidofovir, Fomivirsen etc., these medicines infect the relative disease that causes to HCMV curative effect preferably, but the patient who needs the long term maintenance treatment is often produced the resistance phenomenon, bring difficulty to clinical treatment, referring to Hou Shu, Wang Yating, anti-human cytomegalic inclusion disease virus medicine and treatment progress thereof, foreign medical science paediatrics fascicle, 2004,31 (5): 234-237.
The heterogeneous ring compound that contains N, S atom has wide biological activity, occupies critical positions in medicines such as antitumor, antiviral, antibiotic, anti-inflammatory, antipsychotic, antihistamine and cardiovascular and cerebrovascular.They are widely used in drug research, and the one, as the basic structure parent nucleus that constitutes pharmacophore, being fit to the space requirement of medicine special role target spot, the 2nd, produce corresponding biological activity as the integral part of active substituent or ring system.Why medicine depends on heterocycle is because heterocycle more is difficult for the metabolism decomposition in vivo than fat or aromatic compound, and has better biocompatibility with it.
The benzothiadiazine compounds (BTD) that replaces be a class discover recently HCMV is had the active compounds of very high inhibition, contain N atom and S atom in its molecule, structure is as shown below.It is active that 1 couple of HCMV of compound has higher inhibition among the BTD, its EC
50=3 μ M, CC
50200 μ M.The BTD compounds is carried out structure activity study, find N on this compounds thiadiazine ring
1, N
3On the position hydrophobic two replace be keep active necessary, N
1Substituting group on the position is the active principal element of influence, substituent kind also has very big influence to activity, with reference to Ma Tinai appearance etc., non-nucleoside human cytomegalic inclusion disease virus inhibitor: the synthetic and antiviral activity research of benzothiadiazine analog derivative, the pharmaceutical chemistry magazine, 2000,43:3267-3273. (Martinez A, Gil C, Perez C, et al.NonnucleosideHuman Cytomegalovirus Inhibitors:Synthesis and Antiviral Evaluation of (Chlorophenylmethyl) benzothiadiazine Dioxide Derivatives[J] .J Med Chem, 2000,43:3267-3273).
Though BTD class lead compound has higher anti-HCMV activity, to compare with medicine cidofovir, the ganciclovir of clinical use, the selectivity index of lead compound is lower.Therefore be that template is significant to the research and development that it carries out composition optimizes antagonism HCMV medicine with BTD compounds structure.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, N is provided
1, N
3-two replacement-7-methylpyrazoles [4,5-e] [2,1,3] thiadiazine-2,2,4-three ketones derivative and preparation method thereof, the present invention also provides N
1, N
3-two replacement-7-methylpyrazoles [4,5-e] [2,1,3] thiadiazine-2,2, the screening active ingredients result and the application thereof of 4-three ketones derivative.
Technical scheme of the present invention is as follows:
1.N
1, N
3-two replacement-7-methylpyrazoles [4,5-e] [2,1,3] thiadiazine-2,2,4-three ketones derivative
The present invention is a lead compound with the BTD compounds, according to bioisostere medicinal design principle, with the thiphene ring in the N-methylpyrazole ring replacement BTD molecule, simultaneously at N
3Bit substituent is under the situation of benzyl and o-chlorobenzyl, with the different substituting groups that contains the πDian Zi system at N
1Last replacement is with examination N
1Different substituents is to the inhibition activity of HCMV on the position, and a series of novel N have been synthesized in design thus
1, N
3-two replacement-7-methylpyrazoles [4,5-e] [2,1,3] thiadiazine-2,2,4-three ketones derivative, general structure is as follows:
CH wherein
2R
1Be benzyl or o-chlorobenzyl, CH
2R
2For benzyl, adjacent bromobenzyl, to bromobenzyl, to nitrobenzyl, o-chlorobenzyl, m-chloro benzyl, p-chlorobenzyl, 2,4-dichloro benzyl, adjacent luorobenzyl, to luorobenzyl, o-cyanobenzyl, a cyano group benzyl, to cyano group benzyl, adjacent methyl-benzyl, to methyl-benzyl or cyanogen methyl.
2.N
1, N
3-two replacement-7-methylpyrazoles [4,5-e] [2,1,3] thiadiazine-2,2, the synthetic route of 4-three ketones derivative is as follows:
In the above-mentioned reaction formula, CH
2R
2For benzyl, adjacent bromobenzyl, to bromobenzyl, to nitrobenzyl, o-chlorobenzyl, m-chloro benzyl, p-chlorobenzyl, 2,4-dichloro benzyl, adjacent luorobenzyl, to luorobenzyl, o-cyanobenzyl, a cyano group benzyl, to cyano group benzyl, adjacent methyl-benzyl, to methyl-benzyl or cyanogen methyl.
Reagent: (i) ClSO
3H/CH
2Cl
2(ii) PCl
5/ toluene; (iii) toluene; (iv) a:H
2O/5%KOH, b:H
2O/2mol/L NaOH; (v) H
2O/HCl; (vi) DMF/NaH/R
2CH
2X.
3. intermediate N
3-substituting group-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2, the preparation method of 4-triketone (6)
With benzylamine (1) is starting raw material, and methylene dichloride is a solvent, dropwise adds chlorsulfonic acid under the ice bath, filter white solid, be N-benzyl amine sulfonic acid (2) crude product.N-benzyl amine sulfonic acid (2) is dissolved in toluene, add phosphorus pentachloride, refluxed 1 hour, cold filtration, filtrate decompression concentrate yellow oily liquid, be N-benzyl amine SULPHURYL CHLORIDE (3) crude product, N-benzyl amine SULPHURYL CHLORIDE (3) is joined immediately in the toluene solution of 1-methyl-5-amino-4-pyrazole carboxylic acid ethyl ester (4), 60 ℃ were reacted 4 hours, with KOH or the cyclization of the NaOH aqueous solution, add dilute hydrochloric acid and separate out white crystal, be intermediate N
3-substituting group-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2,4-triketone (6).
4.N
1, N
3-two replacement-7-methylpyrazoles [4,5-e] [2,1,3] thiadiazine-2,2, the preparation method of 4-three ketones derivative (7)
Utilize above-mentioned intermediate N
3-substituting group-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2,4-triketone (6) by deprotonation, the alkylation reaction to the thiadiazine ring, obtains N through separation, purifying then
1, N
3-disubstituted pyrazole [4,5-e] [2,1,3]-triketone derivative.Concrete steps are as follows:
With intermediate N
3-substituting group-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2,4-triketone (6) is dissolved in anhydrous N, dinethylformamide (DMF), ice bath add 1.5 normal sodium hydrides (containing 40% mineral oil) down, add halocarbon after 30 minutes, reacting by heating, the TLC monitoring reaction is complete, removes solvent under reduced pressure, and residue is washed with distillation, dichloromethane extraction, anhydrous sodium sulfate drying filters, and steams to desolventize methylene dichloride, oily matter, dehydrated alcohol recrystallization or rapid column chromatography separate product (7).
Above-mentioned halocarbon is: bromobenzyl, adjacent bromine bromobenzyl, to the bromine bromobenzyl, to nitro bromobenzyl, adjacent chlorobenzyl chloride, a chlorobenzyl chloride, 4-chlorobenzyl chloride, 2,4-dichlorobenzyl chloride, adjacent fluorobenzyl chloride, to fluorobenzyl chloride, adjacent cyano group benzyl chloride, a cyano group benzyl chloride, to the cyano group benzyl chloride, to methoxyl group benzyl chloride, adjacent methyl benzyl chloride, to methyl benzyl chloride or chloromethyl cyanide.
Table 1 compound 6a, 6b, 7a1-15, the structure of 7b1-15 and the activity of anti-HCMV and toxicity
αEC
50: protect the cell of 50% HCMV infection to avoid cytopathic compound concentration;
bCC
50: make 50% concentration of the cell generation pathology of HCMV infection not.
5. the anti-HIV-1 activity and the toxicity test of target compound
30 compounds of above-mentioned synthetic and intermediate 6a and 6b have been carried out anti-HCMV (Davis) screening active ingredients, and the active and toxicity data of their anti-HCMV is listed in the table 1, and is contrast with ganciclovir and cidofovir.As can be seen from Table 1, part target compound such as 7a1,7a3,7a8,7b1,7b4,7b7,7b12 show certain inhibition activity to HCMV, and wherein compound 7a8 is the highest to the inhibition activity of HCMV, its EC
50And CC
50Be respectively 4 μ M and 41.7 μ M, SI=10, active close with BTDs.
N
1, N
3-two replacement-7-methylpyrazoles [4,5-e] [2,1,3] thiadiazine-2,2,4-three ketones derivative are the HCMV inhibitor of a series of novel structures, the 7a8 activity is the highest in this compounds, have and the lead compound similar activity, illustrate that this compounds has further research and development and is worth, the lead compound that can be used as anti-HCMV is used.
N of the present invention
1, N
3-two replacement-7-methylpyrazoles [4,5-e] [2,1,3] thiadiazine-2,2,4-three ketones derivative can be used as HCMV non-nucleoside inhibitor and use.Specifically, be used to prepare the medicine of anti-HCMV as the HCMV inhibitor.
A kind of anti-HCMV pharmaceutical composition comprises N of the present invention
1, N
3-two replacement-7-methylpyrazoles [4,5-e] [2,1,3] thiadiazine-2,2,4-three ketones derivative.
Embodiment
The present invention will be further described below in conjunction with embodiment, and the numbering of all compounds is identical with table 1.
Embodiment 1. intermediate N
3-benzyl-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2, the preparation of 4-triketone (6a)
Add benzylamine (1a) 10.7g (0.1mol) in the 250ml flask, methylene dichloride 100ml dropwise adds chlorsulfonic acid 3.49g (0.03mol) under 0 ℃, and 30 minutes after-filtration of stirring at room get white solid, are N-benzyl amine sulfonic acid (2a) crude product.The white solid (2a) that reaction is obtained is dissolved in 50ml toluene, add phosphorus pentachloride 6.24g (0.03mol), after stirring at room treated that thermopositive reaction was slowed down in 30 minutes, heated solvent refluxed 1 hour, stopped reaction, cooling, elimination solid, remove solvent under reduced pressure and get the yellow oily residue, be N-benzyl amine SULPHURYL CHLORIDE (3a) crude product.(3a) must not separate; join immediately in the 50ml toluene solution of 1-methyl-5-amino-4-pyrazole carboxylic acid ethyl ester (4) 2.5g (0.015mol); the following 60 ℃ of reactions of nitrogen protection 4 hours; potassium hydroxide aqueous solution to the pH value of solution value of cooling back adding 5% is 11, and after stirring at room 16-20 hour, dividing water-yielding stratum to add dilute hydrochloric acid to pH value of solution value is 1; the white solid that filtration is separated out; get intermediate (6a) 1.2g, productive rate 27.3%, mp186-188 ℃.
The product spectral analysis data:
1H-NMR(DMSO-d
6)δ?ppm：7.76(s，1H，pyrazole)，7.32-7.17(m，5H，benzene)，6.04(m，1H，NH)，4.80(s，2H，CH
2)，3.51(s，3H，CH
3)；
13C-NMR(DMSO-d
6)δ?ppm：159.42(C＝O)，151.14，138.95，135.28，128.39，128.18，127.99(2C)，127.10，98.41，43.45(CH
2-N
3)，33.03(CH
2-N
7)；
IR(KBr，cm
-1)：3450(N
1-H)，3030(Ar-H)，1658(C＝O)，1536(Ar，C＝C)，1385，1148(SO
2).
EI-MS：m/z?293.3(M+).
Embodiment 2. intermediate N
3-o-chlorobenzyl-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2, the preparation of 4-triketone (6b)
As embodiment 1 described method, different is that raw material is o-chlorine benzylamine (1b), and cyclization reagent is the aqueous sodium hydroxide solution of 2mol/L, gets intermediate (6b) 1.5g, white solid, productive rate 30.6%, mp144-146 ℃.
The product spectral analysis data:
1H-NMR(DMSO-d
6)δ?ppm：7.64(s，1H，pyrazole)，7.42-7.09(m，4H，benzene)，4.85(s，2H，CH
2)，4.08(m，1H，NH)，3.51(s，3H，CH
3)；
13C-NMR(DMSO-d
6)δ?ppm：159.29(C＝O)，151.26，135.59，135.33，130.94，128.59，127.94，127.62，126.82，96.89，40.54(CH
2-N
3)，32.62(CH
2-N
7)；
IR(KBr，cm
-1)：3451(N
1-H)，3042(Ar-H)，1659(C＝O)，1528(Ar，C＝C)，1373，1149(SO
2).
EI-MS：m/z?327.6(M+).
Embodiment 3.N
1-benzyl-N
3-benzyl-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2,4-triketone (7a1)
The intermediate 6a 1.17g (4mmol) of embodiment 1 preparation is dissolved in the anhydrous N of 15ml; dinethylformamide (DMF); under the nitrogen protection, 0 ℃ of sodium hydride (containing 40% mineral oil) that adds 0.24g (6mmol) stirs 30 minutes recession deicings and bathes; add bromobenzyl 1.0g (6mmol) under the room temperature; 80 ℃ of reaction 24h, the TLC monitoring reaction is complete, removes solvent under reduced pressure; residue is washed with distillation; 10ml dichloromethane extraction twice is told organic phase, anhydrous sodium sulfate drying; remove methylene dichloride under reduced pressure; get oily matter, the dehydrated alcohol recrystallization gets yellow solid 0.3g; productive rate 19.6%, mp120-122 ℃.
The product spectral analysis data:
1H-NMR(DMSO-d
6)δ?ppm：8.04(s，1H，pyrazole)，7.37-7.09(m，10H，benzene)，4.90(s，2H，CH
2)，4.75(s，2H，CH
2)，3.82(s，3H，CH
3)；
13C-NMR(DMSO-d
6)δ?ppm：157.43(C＝O)，141.14(C-5’)，137.86(C-5)，136.27，132.30(C-4’)，129.31(2C)，129.06，128.69(2C)，128.66(2C)，128.23(2C)，127.95，107.78，56.79(CH
2-N
1)，45.88(CH
2-N
3)，36.37(CH
3-N
7)；IR(KBr，cm
-1)：3054(Ar-H)，1703(C＝O)，1497(Ar，C＝C)，1382，1158(SO
2).
EI-MS：m/z?383.5(M+).
Embodiment 4.N
1-o-chlorobenzyl-N
3-benzyl-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2,4-triketone (7a5)
As embodiment 3 described methods, that different is intermediate reagent 6a and 84 ℃ of reactions of the adjacent chlorobenzyl chloride of the 0.97g 24h that embodiment 1 is prepared.Rapid column chromatography separates, eluent: ethyl acetate/hexanaphthene (1:4) gets white solid 0.2g, productive rate 12.0%, mp98-100 ℃.
As embodiment 3 described methods, different is with the intermediate reagent 6a of embodiment 1 preparation with
1H-NMR (DMSO-d
6) δ ppm:8.10 (s, IH, pyrazole), 7.54 (d, 1H, J=7.8Hz, benzene), 7.47 (d, 1H, J=7.8Hz, benzene), 7.43-7.30 (m, 7H, benzene), 4.93 (s, 2H, CH
2), 4.85 (s, 2H, CH
2), 3.57 (s, 3H, CH
3);
The product spectral analysis data:
13C-NMR(DMSO-d
6)δ?ppm：157.57(C＝O)，141.45(C-5’)，138.10(C-5)，136.30，133.45，131.90，131.06，130.63，129.85，128.73(2C)，128.12(2C)，127.97，127.81，107.67，54.48(CH
2-N
1)，45.91(CH
2-N
3)，35.83(CH
3-N
7)；
IR(KBr，cm
-1)：3066(Ar-H)，1694(C＝O)，1523(Ar，C＝C)，1388，1169(SO
2).
EI-MS：m/z?417.4(M+).
Embodiment 5.N
1-(2, the 4-dichloro benzyl)-N
3-benzyl-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2,4-triketone (7a8)
As embodiment 3 described methods, that different is intermediate reagent 6a and the 1.17g 2 that embodiment 1 is prepared, 80 ℃ of reactions of 4-dichlorobenzyl chloride 24h.Rapid column chromatography separates, eluent: ethyl acetate/hexanaphthene (1:3) gets white solid 0.2g, productive rate 11.1%, mp126-128 ℃.
The product spectral analysis data:
1H-NMR(DMSO-d
6)δ?ppm：8.12(s，1H，pyrazole)，7.65(d，1H，benzene，7.57(d，1H，benzene)，7.47-7.31(m，7H，benzene)，4.93(s，2H，CH
2)，4.86(s，2H，CH
2)，3.67(s，3H，CH
3)；
13C-NMR(DMSO-d
6)δ?ppm：157.53(C＝O)，141.33(C-5’)，138.11(C-5)，136.23，134.61，134.26，132.96，130.05(C-4’)，129.33，128.72(2C)，128.15(2C)，127.98，127.94，107.62，53.71(CH
2-N
1)，45.85(CH
2-N
3)，36.02(CH
3-N
7)；
IR(KBr，cm
-1)：3032(Ar-H)，1689(C＝O)，1538(Ar，C＝C)，1389，1164(SO
2).
EI-MS：m/z?451.3(M).
Embodiment 6.N
1-to luorobenzyl-N
3-benzyl-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2,4-triketone (7a10)
As embodiment 3 described methods, different is that intermediate reagent 6a and 0.87g that embodiment 1 prepares are reacted 24h for 80 ℃ to fluorobenzyl chloride.Rapid column chromatography separates, eluent: ethyl acetate/hexanaphthene (1:3) gets white solid 0.31g, productive rate 19.4%, mp150-152 ℃.
The product spectral analysis data:
1H-NMR(DMSO-d
6)δ?ppm：8.04(s，1H，pyrazole)，7.43-7.16(m，9H，benzene)，4.99(s，2H，CH
2)，4.74(s，2H，CH
2)，3.83(s，3H，CH
3)；
13C-NMR(DMSO-d
6)δ?ppm：163.16，161.53，157.37(C＝O)，140.89(C-5’)，137.88(C-5)，136.20，131.68(C-4’)，128.69(2C)，128.54，128.24(2C)，127.97，115.59，115.45，107.79，55.92(CH
2-N
1)，45.82(CH
2-N
3)，36.40(CH
3-N
7)；
IR(KBr，cm
-1)：3066(Ar-H)，1702(C＝O)，1511(Ar，C＝C)，1381，1159(SO
2).
EI-MS：m/z?401.4(M+).
Embodiment 7.N
1-cyano group benzyl-N
3-benzyl-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2,4-triketone (7a12)
As embodiment 3 described methods, different is with 80 ℃ of reactions of cyano group benzyl chloride 24h between the intermediate reagent 6a of embodiment 1 preparation and 0.91g.Rapid column chromatography separates, eluent: ethyl acetate/hexanaphthene (1:2) gets white solid 0.51g, productive rate 31.3%, mp152-154 ℃.
The product spectral analysis data:
1H-NMR(DMSO-d
6)δ?ppm：8.11(s，1H，pyrazole)，7.84(dt，1H，benzene)，7.60-7.29(m，8H，benzene)，4.95(s，2H，CH
2)，4.75(s，2H，CH
2)，3.88(s，3H，CH
3)；
13C-NMR(DMSO-d
6)δ?ppm：157.34(C＝O)，141.05(C-5’)，137.90(C-5)，136.12，134.54，133.94，132.74，132.49，129.98，128.73(2C)，128.18(2C)，128.02，118.45，111.58(CN)，107.59，55.66(CH
2-N
1)，45.81(CH
2-N
3)，36.45(CH
3-N
7)；
IR(KBr，cm
-1)：3034(Ar-H)，2230(CN)，1686(C＝O)，1534(Ar，C＝C)，1389，1180(SO
2).
EI-MS：m/z?408.6(M+).
Embodiment 8.N
1-cyanogen methyl-N
3-benzyl-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2,4-triketone (7a15)
As embodiment 3 described methods, that different is intermediate reagent 6a and 80 ℃ of reactions of the 0.45g chloromethyl cyanide 28h that embodiment 1 is prepared.The dehydrated alcohol recrystallization gets yellow solid 0.19g, productive rate 14.3%, mp176-180 ℃.
The product spectral analysis data:
1H-NMR(DMSO-d
6)δ?ppm：8.24(s，1H，pyrazole)，7.41-7.32(m，5H，benzene)，5.07(s，2H，CH
2)，5.01(s，2H，CH
2)，3.92(s，3H，CH
3)；
13C-NMR(DMSO-d
6)δ?ppm：157.36(C＝O)，139.84，138.21，136.01，128.74(2C)，128.17(2C)，128.09，114.01(CN)，107.47，46.86(CH
2-N
3)，40.73(CH
2-N
1)，30.88(CH
3-N
7)；
IR(KBr，cm
-1)：3035(Ar-H)，1689(C＝O)，1536(Ar，C-C)，1385，1168(SO
2).
EI-MS：m/z?332.3(M+).
Embodiment 9.N
1-to nitrobenzyl-N
3-o-chlorobenzyl-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2,4-triketone (7b2)
The intermediate 6b 1.31g (4mmol) of embodiment 2 preparations is dissolved in the anhydrous N of 15ml; dinethylformamide (DMF); under the nitrogen protection, 0 ℃ of sodium hydride (containing 40% mineral oil) that adds 0.24g (6mmol) stirs 30 minutes recession deicings and bathes; add under the room temperature nitro bromobenzyl 1.3g (6mmol); 80 ℃ of reaction 24h, the TLC monitoring reaction is complete, removes solvent under reduced pressure; residue is washed with distillation; 10ml dichloromethane extraction twice is told organic phase, anhydrous sodium sulfate drying; remove methylene dichloride under reduced pressure; get oily matter, the dehydrated alcohol recrystallization gets white solid 0.2g; productive rate 13.5%, mp186-188 ℃.
The product spectral analysis data:
1H-NMR(DMSO-d
6)δ?ppm：8.24(m，2H，benzene)，8.16(s，1H，pyrazole)，7.54-7.21(m，6H，benzene)，5.60(s，2H，CH
2)，4.86(s，2H，CH
2)，3.86(s，3H，CH
3)；
13C-NMR(DMSO-d
6)δ?ppm：157.20(C＝O)，147.35，141.29，140.91(C-5’)，137.81(C-5)，132.95，131.40(C-4’)，129.71(2C)，129.37，129.26，128.26，128.29，123.58(2C)，107.03，55.41(CH
2-N
1)，43.73(CH
2-N
3)，36.25(CH
3-N
7)；
IR(KBr，cm
-1)：3076(Ar-H)，1693(C＝O)，1528(Ar，C-C)，1348，1183(SO
2).
EI-MS：m/z?462.7(M+).
Embodiment 10.N
1-p-chlorobenzyl-N
3-o-chlorobenzyl-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2,4-triketone (7b7)
As embodiment 9 described methods, that different is intermediate reagent 6b and 80 ℃ of reactions of the 1.0g 4-chlorobenzyl chloride 24h that embodiment 2 is prepared.Rapid column chromatography separates, eluent: ethyl acetate/hexanaphthene (1:3) gets white solid 0.2g, productive rate 11.1%, mp148-151 ℃.
The product spectral analysis data:
1H-NMR(DMSO-d
6)δ?ppm：8.13(s，1H，pyrazole)，7.49(dd，1H，benzene)，7.44-7.14(m，7H，benzene)，4.95(s，2H，CH
2)，4.75(s，2H，CH
2)，3.87(s，3H，CH
3)；
13C-NMR(DMSO-d
6)δ?ppm：157.46(C＝O)，141.25(C-5’)，138.05(C-5)，133.81，133.19，131.72，131.60(C-4’)，131.16(2C)，129.62，129.49，128.74(2C)，128.32，127.56，107.62，55.99(CH
2-N
1)，43.95(CH
2-N
3)，36.47(CH
3-N
7)；
IR(KBr，cm
-1)：3072(Ar-H)，1698(C＝O)，1534(Ar，C-C)，1357，1179(SO
2).
EI-MS：m/z?451.4(M).
Embodiment 11.N
1-to luorobenzyl-N
3-o-chlorobenzyl-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2,4-triketone (7b10)
As embodiment 9 described methods, different is that intermediate reagent 6b and 0.87g that embodiment 2 prepares are reacted 24h for 80 ℃ to fluorobenzyl chloride.Rapid column chromatography separates, eluent: ethyl acetate/hexanaphthene (1:3) gets white solid 0.45g, productive rate 25.9%, mp144-146 ℃.
The product spectral analysis data:
1H-NMR(DMSO-d
6)δ?ppm：8.12(s，1H，pyrazole)，7.49(dd，1H，benzene)，7.34-7.15(m，7H，benzene)，4.93(s，2H，CH
2)，4.74(s，2H，CH
2)，3.87(s，3H，CH
3)；
13C-NMR(DMSO-d
6)δ?ppm：163.38，161.75，157.56(C＝O)，141.26(C-5’)，138.14(C-5)，133.30，131.87，131.72(C-4’)，129.74，129.61，128.85，128.46，127.68，115.80，115.65，107.86，56.20(CH
2-N
1)，44.05(CH
2-N
3)，36.53(CH
3-N
7)；
IR(KBr，cm
-1)：3067(Ar-H)，1692(C＝O)，1512(Ar，C-C)，1356，1159(SO
2).
EI-MS：m/z?435.6(M+).
Embodiment 12.N
1-cyano group benzyl-N
3-o-chlorobenzyl-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2,4-triketone (7b12)
As embodiment 9 described methods, different is with 80 ℃ of reactions of cyano group benzyl chloride 24h between the intermediate reagent 6b of embodiment 2 preparations and 0.91g.Rapid column chromatography separates, eluent: ethyl acetate/hexanaphthene (1:1) gets white solid 0.40g, productive rate 22.6%, mp165-167 ℃.
The product spectral analysis data:
1H-NMR(DMSO-d
6)δ?ppm：8.16(s，1H，pyrazole)，7.88-7.16(m，8H，benzene)，4.99(s，2H，CH
2)，4.73(s，2H，CH
2)，3.90(s，3H，CH
3)；
13C-NMR(DMSO-d
6)δ?ppm：157.47(C＝O)，141.28(C-5’)，138.12(C-5)，134.64，134.02，133.20，132.87，132.78，131.63(C-4’)，130.09，129.72，129.61，128.28，127.72，118.49，111.74(CN)，107.68，55.84(CH
2-N
1)，44.07(CH
2-N
3)，36.56(CH
3-N
7)；
IR(KBr，cm
-1)：3061(Ar-H)，2230(CN)，1710(C＝O)，1530(Ar，C-C)，1364，1181(SO
2).
EI-MS：m/z?442.5(M+).
Embodiment 13.N
1-to methyl-benzyl-N
3-o-chlorobenzyl-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2,4-triketone (7b14)
As embodiment 9 described methods, different is that intermediate reagent 6b and 0.84g that embodiment 2 prepares are reacted 24h for 80 ℃ to the methyl benzyl chloride.Rapid column chromatography separates, eluent: ethyl acetate/hexanaphthene (1:3) gets white solid 0.45g, productive rate 26.1%, mp146-148 ℃.
The product spectral analysis data:
1H-NMR(DMSO-d
6)δ?ppm：8.10(s，1H，pyrazole)，7.49(dd，1H，benzene，J＝7.6Hz)，7.35-7.14(m，5H，benzene)，7.08(d，1H，J＝7.7Hz，benzene)，6.98(s，1H，benzene)，4.89(s，2H，CH
2)，4.71(s，2H，CH
2)，3.87(s，3H，CH
3)，2.28(s，3H，CH
3)；
13C-NMR(DMSO-d
6)δ?ppm：157.28(C＝O)，141.07(C-5’)，138.37(C-5)，137.75，133.04，131.28(C-4’)，129.33，129.18，129.14(2C)，129.04，128.96(2C)，128.00，127.31，107.48，56.50(CH
2-N
1)，44.75(CH
2-N
3)，36.14(CH
3-N
7)，20.67(CH
3)；
IR(KBr，cm
-1)：2998(Ar-H)，1690(C＝O)，1514(Ar，C-C)，1354，1158(SO
2).
EI-MS：m/z?431.4(M+).
Embodiment 14.N
1-cyanogen methyl-N
3-o-chlorobenzyl-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2,4-triketone (7b15)
As embodiment 9 described methods, that different is intermediate reagent 6b and 80 ℃ of reactions of the 0.45g chloromethyl cyanide 28h that embodiment 2 is prepared.Rapid column chromatography separates, eluent: ethyl acetate/hexanaphthene (1:1) gets yellow solid 0.23g, productive rate 15.8%, mp158-160 ℃.
The product spectral analysis data:
1H-NMR(DMSO-d
6)δ?ppm：8.27(s，1H，pyrazole)，7.52-7.36(m，4H，benzene)，5.10(s，4H，2CH
2)，3.94(s，3H，CH
3)；
13C-NMR(DMSO-d
6)δ?ppm：157.11(C＝O)，139.65，138.06，132.77，131.42，128.74，129.45，128.23，127.44，113.97(CN)，107.10，44.67(CH
2-N
3)，40.61(CH
2-N
1)，36.12(CH
3-N
7)；
IR(KBr，cm
-1)：3010(Ar-H)，1705(C＝O)，1528(Ar，C-C)，1363，1134(SO
2).
EI-MS：m/z?366.2(M+).
Claims (6)
1.N
1, N
3-two replacement-7-methylpyrazoles [4,5-e] [2,1,3] thiadiazine-2,2,4-three ketones derivative, its general structure is as follows:
CH wherein
2R
1Be benzyl or o-chlorobenzyl, CH
2R
2For benzyl, adjacent bromobenzyl, to bromobenzyl, to nitrobenzyl, o-chlorobenzyl, m-chloro benzyl, p-chlorobenzyl, 2,4-dichloro benzyl, adjacent luorobenzyl, to luorobenzyl, o-cyanobenzyl, a cyano group benzyl, to cyano group benzyl, adjacent methyl-benzyl, to methyl-benzyl or cyanogen methyl.
2. the described N of claim 1
1, N
3-two replacement-7-methylpyrazoles [4,5-e] [2,1,3] thiadiazine-2,2, the preparation method of 4-three ketones derivative, step is as follows:
With intermediate N
3-substituting group-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2, the 4-triketone is dissolved in anhydrous N, and dinethylformamide, ice bath add 1.5 normal sodium hydrides down, contain 40%wt mineral oil in the sodium hydride, add halocarbon after 30 minutes, reacting by heating, the TLC monitoring reaction is complete, removes solvent under reduced pressure, and residue is washed with distillation, dichloromethane extraction, anhydrous sodium sulfate drying filters, steaming desolventizes methylene dichloride, oily matter, dehydrated alcohol recrystallization or rapid column chromatography separate product;
Above-mentioned halocarbon is: bromobenzyl, adjacent bromine bromobenzyl, to the bromine bromobenzyl, to nitro bromobenzyl, adjacent chlorobenzyl chloride, a chlorobenzyl chloride, 4-chlorobenzyl chloride, 2,4-dichlorobenzyl chloride, adjacent fluorobenzyl chloride, to fluorobenzyl chloride, adjacent cyano group benzyl chloride, a cyano group benzyl chloride, to the cyano group benzyl chloride, to methoxyl group benzyl chloride, adjacent methyl benzyl chloride, to methyl benzyl chloride or chloromethyl cyanide.
3. the described N of claim 2
1, N
3-two replacement-7-methylpyrazoles [4,5-e] [2,1,3] thiadiazine-2,2, the preparation method of 4-three ketones derivative, wherein, intermediate N
3-substituting group-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2, the preparation process of 4-triketone is as follows:
With the benzylamine is starting raw material, methylene dichloride is a solvent, dropwise add chlorsulfonic acid under the ice bath, filter white solid, be N-benzyl amine sulfonic acid crude product, N-benzyl amine sulfonic acid is dissolved in toluene, adds phosphorus pentachloride, refluxed 1 hour, cold filtration, filtrate decompression concentrate yellow oily liquid, be N-benzyl amine SULPHURYL CHLORIDE crude product, N-benzyl amine SULPHURYL CHLORIDE is joined immediately in the toluene solution of 1-methyl-5-amino-4-pyrazole carboxylic acid ethyl ester, 60 ℃ were reacted 4 hours, with KOH or the cyclization of the NaOH aqueous solution, add dilute hydrochloric acid and separate out white crystal, be intermediate N
3-substituting group-7-methylpyrazole [4,5-e] [2,1,3] thiadiazine-2,2, the 4-triketone.
4. the described N of claim 1
1, N
3-two replacement-7-methylpyrazoles [4,5-e] [2,1,3] thiadiazine-2,2,4-three ketones derivative is in the application of preparation HCMV inhibitor.
5. the described N of claim 1
1, N
3-two replacement-7-methylpyrazoles [4,5-e] [2,1,3] thiadiazine-2,2,4-three ketones derivative is used to prepare the medicine of anti-HCMV.
6. anti-HCMV pharmaceutical composition comprises the N of claim 1
1, N
3-two replacement-7-methylpyrazoles [4,5-e] [2,1,3] thiadiazine-2,2,4-three ketones derivative.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2136013A1 (en) * | 1997-04-15 | 1999-11-01 | Consejo Superior Investigacion | Pharmacologically active derivatives of thiene and pyrazol(1,2,4)thiadiazine-1,1-dioxide |
| CN1740179A (en) * | 2005-08-25 | 2006-03-01 | 山东大学 | N4-substituent pyrazolyl [4,5-e][1,2,4] thiadiazine derivative and its prepn process and medicine composition |
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2007
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|---|---|---|---|---|
| ES2136013A1 (en) * | 1997-04-15 | 1999-11-01 | Consejo Superior Investigacion | Pharmacologically active derivatives of thiene and pyrazol(1,2,4)thiadiazine-1,1-dioxide |
| CN1740179A (en) * | 2005-08-25 | 2006-03-01 | 山东大学 | N4-substituent pyrazolyl [4,5-e][1,2,4] thiadiazine derivative and its prepn process and medicine composition |
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