CN103288747B - 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds, its preparation method and use - Google Patents
6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds, its preparation method and use Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 63
- -1 6-cyclohexyl Chemical group 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims abstract description 40
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims abstract description 20
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims abstract description 20
- 230000000694 effects Effects 0.000 claims abstract description 19
- KQJQICVXLJTWQD-UHFFFAOYSA-N N-Methylthiourea Chemical compound CNC(N)=S KQJQICVXLJTWQD-UHFFFAOYSA-N 0.000 claims abstract description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 6
- 238000007024 Blaise reaction Methods 0.000 claims abstract description 5
- 150000001412 amines Chemical class 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims abstract description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 229940124321 AIDS medicine Drugs 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 241000725303 Human immunodeficiency virus Species 0.000 abstract description 18
- 241000713772 Human immunodeficiency virus 1 Species 0.000 abstract description 5
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 206010059866 Drug resistance Diseases 0.000 abstract 1
- 238000006482 condensation reaction Methods 0.000 abstract 1
- 229940000406 drug candidate Drugs 0.000 abstract 1
- 239000000047 product Substances 0.000 description 28
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 24
- 238000004440 column chromatography Methods 0.000 description 13
- 238000000926 separation method Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 238000007405 data analysis Methods 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 9
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 9
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 125000003368 amide group Chemical group 0.000 description 7
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 0 CCC([C@@]1C)N[C@](C[C@](CCCC*C)N)*C1O Chemical compound CCC([C@@]1C)N[C@](C[C@](CCCC*C)N)*C1O 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- RCTYPNKXASFOBE-UHFFFAOYSA-M chloromercury Chemical compound [Hg]Cl RCTYPNKXASFOBE-UHFFFAOYSA-M 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds, its preparation method and use, this compound has following general structure:
, wherein: R
1for C
1-3alkyl, R
2for H or CH
3-, R
3for
or
.Take methyl-isothiourea as starting raw material; react to generate with amine or amine salt after Boc protection and protect guanidine; then will protect guanidine under the effect of tin tetrachloride; go protection to generate and replace guanidine; finally carry out condensation reaction under nitrogen protection obtain target molecule by replacing cyclohexyl methyl aceto acetate that guanidine and the alpha-alkyl prepared by Blaise reaction method replace; synthetic method is simple, and product has and significant anti HIV-1 virus is active and anti-drug resistance, can be used as HIV drug candidates.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, specifically 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds, its preparation method and use.
Background technology
At present, in the research of anti-HIV-1 RT inhibitor, the site acting on RT according to it is different with mechanism, and is divided into two large classes: efabirenz (NRTIs) and non-nucleoside reverse transcriptase inhibitor (NNRTIs).Because NNRTIs and the deformed region of enzyme act on mutually, directly can not damage the function of substrate-binding region, therefore compared with NRTIs, there is the features such as action target spot is clear and definite, the mechanism of action is clear, high-efficiency low-toxicity, significant (E.DeClercq.ChemistryBiodiversity in the research and development of antiviral, 2004, Isosorbide-5-Nitrae 4-64).But because of the variation of HIV-1RT, very easily form resistance, thus inhibit the performance of the antiviral potentiality of NNRTIs.Therefore, constantly find novel structure to have the new drug of high inhibition effect to seem to the virus with resistance to be even more important;
Along with people are to the parsing of NNRTIs/RT complex crystal structure, find that the active small molecular of these configurations and the effect of HIV-1RT all follow same pattern usually.Their molecule is incorporated into the allosteric site of the upper non-Binding Capacity of HIV-1RT in a kind of " butterfly " configuration, namely NNRTIs is by acting on the mutual adaptation of strong-hydrophobicity binding pocket in RT, indirectly changes the precise geometrical conformation of DNA polymeric area amino-acid residue and mobility thus produces inhibit activities.But NNRTIs class medicine with HIV-1RT effect after can cause RT surface portion amino acid mutation, cause the generation (RobertAD, et.al.Int.J.BiochemCellBiol.2004,36 (9): 1735-1751.) of resistance;
The research of S-DABO compounds (patent No.: CN200710066433.7) NNRTIs is found, structurally can improve this compounds, to obtain the active higher new compound of anti-HIV-1 RT.
Summary of the invention
For NNRTIs class medicine in prior art with HIV-1RT effect after can cause RT surface portion amino acid mutation, cause the generation of resistance, and the problem such as anti-HIV-1 RT activity is not high, the invention provides 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds, its preparation method and use.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds, this compound has following general structure:
R in described compound structure general formula
1for C
1-3alkyl; R
2for H or CH
3-; R
3for
or
;
R in described compound structure general formula
1for (CH
3)
2cH-, R
2for H, R
3for
;
R in described compound structure general formula
1for CH
3cH
2-, R
2for H, R
3for
;
R in described compound structure general formula
1for (CH
3)
2cH-, R
2for CH
3-, R
3for
.
The preparation method of 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds, comprises the following steps:
Step one: take methyl-isothiourea as starting raw material, after Boc protection, generating structure formula is
boc protection methyl-isothiourea;
The methyl-isothiourea that step 2: Boc protects and amine or amine salt react generating structure formula and are
protection guanidine;
Step 3: by protection guanidine under the effect of tin tetrachloride, go protection to generate and replace guanidine, the structural formula replacing guanidine is
;
Step 4: under nitrogen protection, to reflux replacing cyclohexyl methyl aceto acetate that guanidine and the alpha-alkyl prepared by Blaise reaction method replace 10-28h according to mol ratio 1:2, can obtain target product in EtONa/EtOH system
;
R in described structural formula
1for C
1-3alkyl; R
2for H or CH
3-; R
3for
or
.
6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds, for the preparation of anti-AIDS drug.
Based on the analysis of N-DABO compounds/RT mixture theoretical model being found to the C-2 bit substituent of N-DABO compounds is in the position of most flexibility in the active chamber of HIV-1RT equally, the NH of C-2 position also defines hydrogen bond with the carbonyl of the Lys101 amino-acid residue of RT, so the atom N introducing electronegativity stronger instead of S atom, enhance the reactive force of the carbonyl hydrogen bond of NH and Lys101 amino-acid residue, strengthen its anti-HIV-1 RT active.
Beneficial effect of the present invention: the present invention has stronger restraining effect to HIV virus, and some compounds for treating index is up to 10
6level, and good tolerance has been demonstrated to clinical strains, and raw materials is easy to get, synthetic method is simple, therefore can be used for preparing anti-AIDS drug.
Accompanying drawing explanation
Fig. 1 is 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds preparation feedback schema.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated.
6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds, this compound has following general structure:
R in described compound structure general formula
1for C
1-3alkyl; R
2for H or CH
3-; R
3for
or
;
As shown in Figure 1, be 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds preparation feedback schema, its preparation method is:
Step one, the methyl-isothiourea of Boc protection
synthesis: 350g tert-Butyl dicarbonate is dissolved in 200mlCH
2cl
2in, add 10g methyl-isothiourea and the saturated NaHCO of 200ml
3solution, vigorous stirring three days under room temperature, stopped reaction, separates organic phase, aqueous phase 70mlCH
2cl
2extract three times, merge organic phase, wash three times by the saturated NaCl solution of 100ml, then use anhydrous MgSO
4drying, obtains the methyl-isothiourea of 20gBoc protection after removal of solvent under reduced pressure, the methyl-isothiourea that yield: 80%, Boc protects is white solid, mp:122 DEG C;
Step 2, protection guanidine
synthesis: the methyl-isothiourea protected by obtained 20gBoc, 50ml triethylamine and 100mmol amine or amine salt add in 300ml dry DMF; 35g mercury chloride is added after cryosel bath is cooled to 0 DEG C; stopped reaction after stirred at ambient temperature 8h; reaction mixture 200ml diluted ethyl acetate, filter, add water separatory; collected organic layer; with 100ml extraction into ethyl acetate aqueous phase three times, merge organic phase, use the saturated NaHCO of 100ml10% citric acid, 100ml successively
3solution and the saturated NaCl solution of 100ml wash three times, then use anhydrous MgSO
4drying, removal of solvent under reduced pressure, must protect guanidine sterling through silica gel column chromatography;
Step 3, replaces guanidine
synthesis: by obtained 50mmol protect guanidine be dissolved in 150ml anhydrous ethyl acetate, drip the anhydrous SnCl of 55g at 0 DEG C
4, then under the protection of nitrogen, stirring at room temperature 4h, decompression separation, residuum is dissolved in anhydrous methanol, and the lower anhydrous diethyl ether that drips of stirring, to there being Precipitation, continues to stir 1h, filters precipitate the sterling replacing guanidine;
Step 4, target product
synthesis: in there-necked flask; 0.3g sodium is dissolved in dehydrated alcohol; add the replacement guanidine that 2mmol is obtained; under nitrogen protection; after stirring at room temperature 30min, add the cyclohexyl methyl aceto acetate of the alpha-alkyl replacement that 4mmol is prepared by Blaise reaction method, reflux 12h; removal of solvent under reduced pressure, resistates is dissolved in H
2o, with the neutralization of 3mol/LHCl solution, filter, washing, dry, column chromatography obtains target product.
Described Boc represents " tertbutyloxycarbonyl ", is amido protecting group conventional in organic synthesis;
Described Blaise reaction is the organic zinc reagent that formed by alpha-halogen ester and zinc of a class and nitrile addition, then generates the reaction of the cyclohexyl methyl aceto acetate that alpha-alkyl replaces with enamine ester.
Below to R
1, R
2and R
3when getting different group, obtained 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds carries out HIV (human immunodeficiency virus)-resistant activity test respectively, and is analyzed with existing S-DABO compounds.Testing method is: the C8166 cell adopting HIV-1 to infect carries out the test of cell levels HIV (human immunodeficiency virus)-resistant activity, and concrete testing method is as follows:
Cell toxicity test: compound
mTT colorimetric method for determining is adopted to the toxicity of C8166 cell.In 96 porocyte culture plates, this compound is carried out 5 times of doubling dilutions, every hole adds 4 × 10
5the C8166 cell suspension of/ml, add the liquid of 100uL different concns substratum dilution respectively, each extent of dilution repeats 3 holes, establishes without pharmaceutically-active cell controls group and AZT drug control group simultaneously, puts 37 DEG C, 5%CO simultaneously
2cultivate 4 days in saturated humidity incubator, every hole adds 50%DMF-10%SDS100uL, and 37
oc, 5%CO
2overnight incubation, mixes rear BIO-TEKEL × 800ELISA instrument and measures OD value (wavelength: 595nm; Reference wavelength: 630nm), experimentally result draws Dose-Response Curve, calculates the poisonous concentration (CC of medicine half
50);
Synplasm inhibition test: by 4 × 10
5/ mlC8166 cell suspension inoculation is to containing compound
in 96 porocyte culture plates of 5 times of doubling dilutions, add HIV-1
iII Bdilution supernatant (MOI=0.04), each extent of dilution repeats 3 holes, establishes not containing the HIV-1 of this compound simultaneously
iII Bthe negative control hole infected and the Positive control wells of AZT medicine, put 37 DEG C, 5%CO
2cultivate 4 days in saturated humidity incubator, under inverted microscope (100 ×), choose 5 nonoverlapping visuals field, calculate synplasm number, calculate medicine half-inhibition concentration (EC by Reed & Muench method
50).
Embodiment 1
As previously mentioned, column chromatography for separation (P:E=2:3) obtains white powder to target product 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds preparation method, productive rate: 41%; Fusing point: 186-187 DEG C, molecular formula is C
20h
25n
3o
2, molecular weight is 339.43, wherein C70.77%, H7.42%, N12.38%, O9.43%;
1HNMR(CDCl
3，500MHz)：d(ppm)=0.76-0.79(m，3H，cyclohexyl)，1.18-1.86(m，8H，cyclohexyl)，2.44-2.46(d，2H，CH
2-cyclohexyl)，2.44(s，3H，CH
3)，2.1(s，1H，N-H)，3.85-3.89(s，2H，N-CH
2)，7.26-7.61(m，5H，Ar-H)，12.75(s，brs，1H，NH)；
Learnt by above-mentioned data analysis: embodiment 1 products therefrom is 6-(cyclohexyl methyl)-5-methyl 2-(2-oxygen-2-styroyl amido) pyrimidine-4 (3H)-one, and its structural formula is:
As previously mentioned, result of study shows (experimental data is in table 1) to this compound HIV (human immunodeficiency virus)-resistant activity test method: this compound and 6-cyclohexyl methyl replace in S-DABO compounds (patent No.: CN200710066433.7)
compare, change S wherein into NH, its selectivity index increases to 4950 by 2150.
Embodiment 2
As previously mentioned, column chromatography for separation (P:E=2:3) obtains white powder to target product 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds preparation method, productive rate: 45%; Fusing point: 187-188 DEG C, molecular formula is C
21h
27n
3o
2, molecular weight is 353.21, wherein C71.36%, H7.70%, N11.89%, O9.05%;
1HNMR(CDCl
3，500MHz)：d(ppm)=0.76-0.79(m，3H，cyclohexyl)，1.06(t，3H，C
5-CH
2CH
3)，1.18-1.86(m，8H，cyclohexyl)，2.44-2.46(d，2H，CH
2-cyclohexyl)，2.44(q，2H，CH
2)，2.1(s，1H，N-H)，3.85-3.89(s，2H，N-CH
2)，7.26-7.61(m，5H，Ar-H)，12.75(s，brs，1H，NH)；
Learnt by above-mentioned data analysis: embodiment 2 products therefrom is 6-(cyclohexyl methyl)-5-ethyl-2-(2-oxygen-2-styroyl amido) pyrimidine-4 (3H)-one, and its structural formula is:
As previously mentioned, result of study shows (experimental data is in table 1) to this compound HIV (human immunodeficiency virus)-resistant activity test method: this compound and 6-cyclohexyl methyl replace in S-DABO compounds (patent No.: CN200710066433.7)
compare, change S wherein into NH, its selectivity index increases to 8548000 by 6460000.
Embodiment 3
As previously mentioned, column chromatography for separation (P:E=2:3) obtains white powder to target product 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds preparation method, productive rate: 33%; Fusing point: 187-189 DEG C, molecular formula is C
22h
29n
3o
2, molecular weight is 367.48, wherein C71.90%, H7.95%, N11.43%, O8.71%;
1HNMR(CDCl
3，500MHz)：d(ppm)=0.76-0.79(m，3H，cyclohexyl)，1.06(t，6HC
5-CH(CH
3)
2)，1.18-1.86(m，8H，cyclohexyl)，2.44-2.46(d，2H，CH
2-cyclohexyl)，2.50(q，1H，CH)，2.1(s，1H，N-H)，3.85-3.89(s，2H，N-CH
2)，7.26-7.61(m，5H，Ar-H)，12.75(s，brs，1H，NH)；
Learnt by above-mentioned data analysis: embodiment 3 products therefrom is 6-(cyclohexyl methyl)-5-sec.-propyl 2-(2-oxygen-2-styroyl amido) pyrimidine-4 (3H)-one, and its structural formula is:
As previously mentioned, result of study shows (experimental data is in table 1) to this compound HIV (human immunodeficiency virus)-resistant activity test method: this compound and 6-cyclohexyl methyl replace in S-DABO compounds (patent No.: CN200710066433.7)
compare, change S wherein into NH, its selectivity index increases to 4180000 by 3620000.
Embodiment 4
As previously mentioned, column chromatography for separation (P:E=2:4) obtains white powder to target product 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds preparation method, productive rate: 27%; Fusing point: 171-172 DEG C, molecular formula is C
18h
23n
3o
3, molecular weight is 329.17, wherein C65.63%, H7.04%, N12.76%, O14.57%;
1HNMR(CDCl
3，500MHz)：d(ppm)=0.76-0.79(m，3H，cyclohexyl)，1.18-1.86(m，8H，cyclohexyl)，1.86(d，2H，CH
2-cyclohexyl)，2.50(s，3H，CH
3)，2.1(s，1H，N-H)4.20(s，2H，N-CH
2)，7.26-7.61(m，3H，furan)，12.55(s，brs，1H，NH)；
Learnt by above-mentioned data analysis: embodiment 4 products therefrom is 6-(cyclohexyl methyl)-2-(-2-furyl-2-carbonvlmethyl amido)-5-methylpyrimidine-4-(3H)-one, and its structural formula is:
Embodiment 5
As previously mentioned, column chromatography for separation (P:E=2:4) obtains white powder to target product 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds preparation method, productive rate: 28%; Fusing point: 174-175 DEG C, molecular formula is C
19h
25n
3o
3, molecular weight is 343.19, wherein C66.44%, H7.34%, N12.24%, O13.98%;
1HNMR(CDCl
3，500MHz)：d(ppm)=0.76-0.79(m，3H，cyclohexyl)，1.18-1.86(m，8H，cyclohexyl)，1.86(d，2H，CH
2-cyclohexyl)，1.6(t，3H，CH
2CH
3)，2.50(q，2H，CH
2CH
3)，2.1(s，1H，NH)，4.20(s，2H，N-CH
2)，7.26-7.61(m，3H，furan)，12.55(s，brs，1H，NH)；
Learnt by above-mentioned data analysis: embodiment 5 products therefrom is 6-(cyclohexyl methyl)-5-ethyl-2-(-2-furyl-2-carbonvlmethyl amido) pyrimidine-4-(3H)-one, and its structural formula is:
Embodiment 6
As previously mentioned, column chromatography for separation (P:E=2:4) obtains white powder to target product 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds preparation method, productive rate: 25%; Fusing point: 175-176 DEG C, molecular formula is C
20h
27n
3o
3, molecular weight is 357.21, wherein C67.20%, H7.61%, N11.76%, O13.43%;
1HNMR(CDCl
3，500MHz)：d(ppm)=0.76-0.79(m，3H，cyclohexyl)，1.18-1.86(m，8H，cyclohexyl)，1.86(d，2H，CH
2-cyclohexyl)，1.06(d，6H，CH(CH
3)
2)，2.50(m，1H，CH(CH
3)
2)，2.1(s，1H，N-H)，4.20(s，2H，N-CH
2)，7.26-7.61(m，3H，furan)，12.55(s，brs，1H，NH)；
Learnt by above-mentioned data analysis: embodiment 6 products therefrom is 6-(cyclohexyl methyl)-2-(-2-furyl-2-carbonvlmethyl amido)-5-isopropylpyrimidin-4-(3H)-one, and its structural formula is:
Embodiment 7
As previously mentioned, column chromatography for separation (P:E=2:4) obtains white powder to target product 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds preparation method, productive rate: 21%; Fusing point: 169-170 DEG C, molecular formula is C
19h
25n
3o
33, molecular weight is 343.19, wherein C66.44%, H7.34%, N12.24%, O13.98%;
1HNMR(CDCl
3，500MHz)：d(ppm)=0.76-0.79(m，3H，cyclohexyl)，1.18-1.86(m，8H，cyclohexyl)，1.86(d，2H，CH
2-cyclohexyl)，2.50(s，3H，CH
3)，3.04(s，3H，N-CH
3)，4.20(s，2H，N-CH
2)，7.26-7.61(m，3H，furan)，12.40(s，brs，1H，NH)；
Learnt by above-mentioned data analysis: embodiment 7 products therefrom is 6-(cyclohexyl methyl)-2-(-2-furyl-2-carbonylethyl methyl amido)-5-methylpyrimidine-4-(3H)-one, and its structural formula is:
Embodiment 8
As previously mentioned, column chromatography for separation (P:E=2:4) obtains white powder to target product 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds preparation method, productive rate: 25%; Fusing point: 174-176 DEG C, molecular formula is C
20h
27n
3o
3, molecular weight is 357.45, wherein C67.20%, H7.61%, N11.76%, O13.43%;
1HNMR(CDCl
3，500MHz)：d(ppm)=0.76-0.79(m，3H，cyclohexyl)，1.18-1.86(m，8H，cyclohexyl)，1.86(d，2H，CH
2-cyclohexyl)，1.6(t，3H，CH
2CH
3)，2.50(q，2H，CH
2CH
3)，29.8(s，3H，N-CH
3)，4.20(s，2H，N-CH
2)，7.26-7.61(m，3H，furan)，12.55(s，brs，1H，NH)；
Learnt by above-mentioned data analysis: embodiment 8 products therefrom is 6-(cyclohexyl methyl)-5-ethyl-2-(-2-furyl-2-carbonylethyl methyl amido) pyrimidine-4-(3H)-one, and its structural formula is:
Embodiment 9
As previously mentioned, column chromatography for separation (P:E=2:4) obtains white powder to target product 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds preparation method, productive rate: 20%; Fusing point: 177-178 DEG C, molecular formula is C
21h
29n
3o
3, molecular weight is 371.47, wherein C67.90%, H7.87%, N11.31%, O12.92%;
1HNMR(CDCl
3，500MHz)：d(ppm)=0.76-0.79(m，3H，cyclohexyl)，1.18-1.86(m，8H，cyclohexyl)，1.86(d，2H，CH
2-cyclohexyl)，1.06(d，6H，CH(CH
3)
2)，2.50(m，1H，CH(CH
3)
2)，2.8(s，3H，N-CH
3)，4.20(s，2H，N-CH
2)，7.26-7.61(m，3H，furan)，12.55(s，brs，1H，NH)；
Learnt by above-mentioned data analysis: embodiment 9 products therefrom is 6-(cyclohexyl methyl)-2-(-2-furyl-2-carbonylethyl methyl amido)-5-isopropylpyrimidin-4-(3H)-one, and its structural formula is:
Embodiment 10
As previously mentioned, column chromatography for separation (P:E=2:3) obtains white powder to target product 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds preparation method, productive rate: 26%; Fusing point: 188-189 DEG C, molecular formula is C
21h
27n
3o
2, molecular weight is 353.21, wherein C71.36%, H7.70%, N11.89%, O9.05%;
1HNMR(CDCl
3，500MHz)：d(ppm)=0.76-0.79(m，3H，cyclohexyl)，1.18-1.86(m，8H，cyclohexyl)，2.44-2.46(d，2H，CH
2-cyclohexyl)，2.44(s，3H，CH
3)，2.89(s，3H，N-CH
3)，3.85-3.89(s，2H，N-CH
2)，7.26-7.61(m，5H，Ar-H)，12.04(s，brs，1H，NH)；
Learnt by above-mentioned data analysis: embodiment 10 products therefrom is 6-(cyclohexyl methyl)-5-methyl 2-(2-(methyl) 2-oxygen-2-styroyl) amine pyrimidine-4 (3H)-one, and its structural formula is:
Embodiment 11
As previously mentioned, column chromatography for separation (P:E=2:3) obtains white powder to target product 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds preparation method, productive rate: 27%; Fusing point: 190-191 DEG C, molecular formula is C
22h
29n
3o
2, molecular weight is 367.23, wherein C71.91%, H7.95%, N11.43%, O8.71%;
1HNMR(CDCl
3，500MHz)：d(ppm)=0.76-0.79(m，3H，cyclohexyl)，1.06(t，3H，C
5-CH
2CH
3)，1.18-1.86(m，8H，cyclohexyl)，2.44-2.46(d，2H，CH
2-cyclohexyl)，2.44(q，2H，CH
2)，3.04(s，3H，N-CH
3)，3.85-3.89(s，2H，N-CH
2)，7.26-7.61(m，5H，Ar-H)，12.75(s，brs，1H，NH)；
Learnt by above-mentioned data analysis: embodiment 11 products therefrom is 6-(cyclohexyl methyl)-5-ethyl-2-(methyl (2-oxygen-2-styroyl) amido) pyrimidine-4 (3H)-one, and its structural formula is:
Embodiment 12
As previously mentioned, column chromatography for separation (P:E=2:3) obtains white powder to target product 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds preparation method
,productive rate: 23%; Fusing point: 191-192 DEG C, molecular formula is C
23h
31n
3o
2, molecular weight is 381.51), wherein C72.41%, H8.19%, N11.01%, O8.39%;
1HNMR(CDCl
3，500MHz)：d(ppm)=0.76-0.79(m，3H，cyclohexyl)，1.06(t，6H，C
5-CH(CH
3)
2)，1.18-1.86(m，8H，cyclohexyl)，2.44-2.46(d，2H，CH
2-cyclohexyl)，2.50(q，1H，CH)，3.04(s，3H，N-CH
3)，3.85-3.89(s，2H，N-CH
2)，7.26-7.61(m，5H，Ar-H)，12.75(s，brs，1H，NH)；
Learnt by above-mentioned data analysis: embodiment 12 products therefrom be 6-(cyclohexyl methyl)-5-sec.-propyl 2-(methyl (2-oxygen-2-styroyl amido) pyrimidine-4 (3H)-one, its structural formula is:
As previously mentioned, the present invention AZT and NVP compares product to HIV (human immunodeficiency virus)-resistant activity test method, and 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds is to HIV-1
iII Binhibit activities the results are shown in Table 1.
Table 1. anti-HIV-1
iII Bactivity Results
Note: SI
a(selectivity index)=CC
50/ EC
50.
HIV (human immunodeficiency virus)-resistant activity result of study shows:
After six introducing cyclohexyl methyls of N-pyrimidine ring, the activity of compound improves significantly, and wherein the selectivity index of the compound that embodiment 2, embodiment 3 and embodiment 12 is obtained is than the medicine AZT gone on the market now and NVP height 1-2 order of magnitude;
Contrast through above-described embodiment is known, and compared with the compound that the present invention obtains replaces S-DABO compounds with 6-cyclohexyl methyl, after the atom N that introduction electronegativity is stronger instead of S atom, selectivity index obviously uprises, and has better HIV (human immunodeficiency virus)-resistant activity.
Claims (2)
1.6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds, it is characterized in that, this compound has following general structure:
R in described compound structure general formula
1for (CH
3)
2cH-; R
2for H; R
3for
, the preparation method of this compound comprises the following steps:
Step one: take methyl-isothiourea as starting raw material, after Boc protection, generating structure formula is
boc protection methyl-isothiourea;
The methyl-isothiourea that step 2: Boc protects and amine or amine salt react generating structure formula and are
protection guanidine;
Step 3: by protection guanidine under the effect of tin tetrachloride, go protection to generate and replace guanidine, the structural formula replacing guanidine is
;
Step 4: under nitrogen protection, to reflux replacing cyclohexyl methyl aceto acetate that guanidine and the alpha-alkyl prepared by Blaise reaction method replace 10-28h according to mol ratio 1:2, can obtain target product in EtONa/EtOH system
.
2. the purposes of 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds as claimed in claim 1, is characterized in that: this compounds is for the preparation of anti-AIDS drug.
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| CN101177413A (en) * | 2007-12-11 | 2008-05-14 | 云南大学 | 6-cyclohexyl methyl substituted S-DABO compound, method for synthesizing same and uses thereof |
| CN101475535A (en) * | 2009-02-05 | 2009-07-08 | 云南大学 | Polysubstituted N-DACO derivative, synthesizing method and use thereof |
| CN103086926A (en) * | 2011-10-27 | 2013-05-08 | 复旦大学 | Preparation method for leonurine and derivatives thereof |
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2013
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| CN101177413A (en) * | 2007-12-11 | 2008-05-14 | 云南大学 | 6-cyclohexyl methyl substituted S-DABO compound, method for synthesizing same and uses thereof |
| CN101475535A (en) * | 2009-02-05 | 2009-07-08 | 云南大学 | Polysubstituted N-DACO derivative, synthesizing method and use thereof |
| CN103086926A (en) * | 2011-10-27 | 2013-05-08 | 复旦大学 | Preparation method for leonurine and derivatives thereof |
Non-Patent Citations (1)
| Title |
|---|
| 非核苷类HIV-1逆转录酶抑制剂2，5，6-三取代S-DABO及6-萘甲基取代N-DABO类似物的分子设计、合成及构效关系研究;王月平;《复旦大学博士学位论文》;20071020;Scheme 10，正文第81页3.5.1 * |
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