CN102153517B - Diaryl pyrimidone hydrazone derivatives and preparation method and application of diaryl pyrimidone hydrazone derivatives - Google Patents
Diaryl pyrimidone hydrazone derivatives and preparation method and application of diaryl pyrimidone hydrazone derivatives Download PDFInfo
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- CN102153517B CN102153517B CN201110050749.3A CN201110050749A CN102153517B CN 102153517 B CN102153517 B CN 102153517B CN 201110050749 A CN201110050749 A CN 201110050749A CN 102153517 B CN102153517 B CN 102153517B
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Abstract
The invention belongs to the technical field of medicines, particularly relates to diaryl pyrimidone hydrazone derivatives and a preparation method and application of the diaryl pyrimidone hydrazone derivatives. The diaryl pyrimidone hydrazone derivatives also contain medicine salt, a stereochemical isomer, hydrate, solvate, polycrystals or eutectic crystals and a precursor and derivatives with the same biological functions. The preparation method comprises a step that hydrazonium salt and substituted hydrazonium salt react with diaryl pyrimidine in an organic solvent under the action of alkali to prepare target products, or hydrazine, a complex compound of hydrazine and a complex compound of substituted hydrazine directly react with diaryl pyrimidine to prepare the target products. A pharmacological test result shows that most of the compounds have strong inhibitory activity for replication of a wild-type HIV-1 strains and various drug resistant HIV-1 virus strains; part of the compounds have strong inhibitory activity for HIV-2; and the compounds are expected to become HIV-resistant candidate drugs.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of diaryl pyrimidine ketone hydrazone derivative and its production and use.
Background technology
The acquired immune deficiency syndrome (AIDS) (AIDS) that human immunodeficiency virus (HIV) causes is one of scientific circles' chronic disease of being difficult to capture, presents eruption and prevalence trend, brings more and more serious threat to the mankind's survival and development.Existing medicine has certain curative effect, also exists the problems such as anti-drug resistance is poor, toxic side effect is large simultaneously.Therefore, the anti-AIDS drugs of searching high-efficiency low-toxicity remains the key subjects that Pharmaceutical Chemist faces.The research and development of anti-AIDS drugs are at present the understanding based on HIV Life Cycles process mainly, wherein, reversed transcriptive enzyme (RT) has played vital role in the reverse transcription process of geneome RNA, and be the commitment of HIV life replicative cycle, so RT becomes one of important target spot of anti-AIDS drugs research.In 20 kinds of medicines of FDA approval at present, there are 10 kinds to using HIV RT as target spot.
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 anti-hiv reverse transcriptase inhibitor through U.S. FDA approval listing has four kinds: how Wella is put down (Nevirapine), De Laweiding (Delavirdine), efavirenz (Efavirenz), etravirine (etravirine).Classical NNRTIs only acts on HIV-1 virus, and invalid to HIV-2 virus.
Summary of the invention
The object of the invention is to propose a kind of reverse transcriptase inhibitors diaryl pyrimidine ketone hydrazone derivative (
i,
hydra-dAPYs).
Another object of the present invention is to propose the preparation method of above-claimed cpd.
Still a further object of the present invention is the application that proposes above-claimed cpd.
Diaryl pyrimidine (DAPYs) derivative is the NNRTIs that the class found in recent years has higher HIV (human immunodeficiency virus)-resistant activity, through a series of structure of modification, has had been found that a series of compounds with better prospect.The present invention adopts the means of area of computer aided SARS drug design to simulate the mode of action and the structure activity relationship of such inhibitor and HIV-1 RT, with this, instructs further structure of modification.
hydra-connection chain structure between the pyrimidine ring of DAPYs derivative and right flank aromatic ring is positioned among the cavity being comprised of Glu138, Val179, Tyr181, and can form interaction of hydrogen bond with Glu138 and Tyr181, improve the avidity of whole molecule and RT, thereby improve active.In this position, add sterically hindered less hydrophilic radical, enhanced activity, if group is larger, unfavorable to activity effectively.Given this, we have entered hydrazone and have replaced the groups such as hydrazone in this position, the hydrogen bond action by reinforcement with near amino-acid residue Glu138, Val179, Tyr181, the interaction force of increase part and RT, the anti-drug resistance of raising target compound.And carried out biological activity test, and result shows that majority of compounds has stronger anti-HIV-1 virus function, higher selectivity index, and also part of compounds shows to have the effect of anti-HIV-2 ROD strain.
The present invention is according to the analytical results of area of computer aided SARS drug design, designed and synthesized brand new diaryl pyrimidine ketone hydrazone derivative (
hydra-dAPYs).The general structure of this compound be (
i):
Ⅰ
Wherein, R
1and R
2respectively independently selected from hydrogen, hydroxyl, halogen, optional substituted C
1-4alkyl, optional substituted C
2-6thiazolinyl, optional substituted C
2-6alkynyl, C
1-6alkoxyl group, cyano group, nitro, amino,
-nH (OH)-,-N (R
6) p-.
R
3, R
4and R
5respectively independently selected from hydrogen, hydroxyl, halogen, optionally by cyano group or-C (=O) R
6the C replacing
1-6alkyl, C
3-7cycloalkyl, optionally by the C of one or more halogen atoms or cyano group replacement
2-6thiazolinyl, optionally by the C of one or more halogen atoms or cyano group replacement
2-6alkynyl, C
1-6alkoxyl group, C
1-6carbalkoxy, carboxyl, cyano group, nitro, amino ,-NR
7-, many halogenated methyls, many halogenated methoxies, many halos methylthio group ,-S (=O)
pr
6,-NH-S (=O)
pr
6,-C (=O) R
6,-NHC (=O) H ,-C (=O) NHNH
2,-NHC (=O) R
6,-C (=NH) R
6.
X is-NR
7-,-NH-NH-,-N=N-,-O-,-C (=O)-, C
1-4alkane two bases ,-CH (OH)-,-S-,-S (=O) p-,-X
1-C
1-4alkane two bases-,-C
1-4alkane two bases-X
1-, or-CH (CN)-.
X
1for-NR
7-,-NH-NH-,-N=N-,-O-,-C (=O)-,-CH (OH)-, or-S (=O) p-.
R
6for C
1-4alkyl, amino, single or two (C
1-4alkyl) amino, or many halos C
1-4alkyl.
R
7respectively independently selected from hydrogen, aryl, formyl radical, C
1-6alkyl-carbonyl, C
1-6alkyl, C
1-6carbalkoxy, by formyl radical, C
1-6alkyl-carbonyl, C
1-6carbalkoxy or C
1-6the C that alkyl carbonyl oxy replaces
1-6alkyl, by C
1-6the C that carbalkoxy replaces
1-6alkoxyl group or C
1-6carbalkoxy.
M is 0-5, and P is 1-2.
Ar is selected from aryl, substituted aryl, naphthyl, substituted naphthyl, anthryl, replace anthryl, phenanthryl, replace phenanthryl, pyrryl, substituted azole base, pyrazolyl, substituted pyrazolecarboxylic base, imidazolyl, substituted imidazole base, triazolyl, substituted triazole base, tetrazyl, replace tetrazyl, benzimidazolyl-, substituted benzimidazole base, benzotriazole base, replace benzo triazolyl, furyl, substituted furan base, oxazolyl, substituted oxazole base, thiazolyl, substituted thiazolyl, benzothiazolyl, substituted benzene benzothiazolyl, pyridyl, substituted pyridinyl, quinolyl, substd quinolines base, isoquinolyl, substituted isoquinoline base, pyrazinyl, replace pyrazinyl, triazinyl, purine radicals, substituted purinyl, pyrimidyl, substituted pyrimidyl, other five yuan or hexa-member heterocycle base, benzo five-membered or quinary heterocyclic radical, hexa-atomic or the hexa-member heterocycle base of benzo.
The preparation method of above-claimed cpd is as follows:
Under the effect of alkali, hydrazonium salt, replacement hydrazonium salt and diaryl pyrimidine (
iI)in organic solvent, target compound is prepared in reaction, and for hydrazine, the complex compound of hydrazine, replaces hydrazine, the complex compound that replaces hydrazine directly and diaryl pyrimidine (
iI)reaction obtain target compound (
i).Its reaction formula is:
Ⅱ Ⅰ 。
Compound diaryl pyrimidine (
iI)preparation can be with reference to Chinese patent CN101723903A.
Concrete operation step is as follows: by hydrazine derivative and compound
iIbe placed in solvent, then heat up (for hydrazonium salt, need add alkali), react complete and afterwards reaction solution is poured in frozen water, be extracted with ethyl acetate, by ethyl acetate with 2 M salt pickling once, saturated common salt is washed once, anhydrous sodium sulfate drying, column chromatography for separation obtains target product.Wherein:
(1) compound
iI, hydrazine derivative, alkali three mol ratio be 1:(1.5~10): (3~50), preferably 1:5:15.
(2) solvent is water, methyl alcohol, ethanol, Virahol, the trimethyl carbinol, and propyl carbinol, acetonitrile, tetrahydrofuran (THF),
n,N-dimethyl formamide,
n, N-n,N-DIMETHYLACETAMIDE, toluene, or dimethylbenzene; Preferred alcohol.
(3) alkali used is salt of wormwood, sodium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, pyridine, triethylamine, Isopropylamine, or n-Butyl Amine 99; Preferred pyridine.
Compound of the present invention is a kind of synthetic simple brand-new anti HIV-1 virus reagent, can be used as the drug candidates of anti-HIV.The biological activity test of cell levels shows:
1) this compounds generally has good anti-HIV-1 virus activity, and wherein part of compounds not only demonstrates other biological activity of nmole level, and demonstrates higher selectivity index;
2), in the compound of synthesized, part of compounds demonstrates good anti-HIV-2 virus function.
Therefore, the invention still further relates to a kind of pharmaceutical composition.This pharmaceutical composition contains the foregoing arbitrary compound of effective dose and pharmaceutical carrier.
The present invention also comprises the pharmaceutical salts of described compound, its three-dimensional chemical isomer, its hydrate and solvate, its polycrystalline or eutectic, the precursor of its same biological function and derivative; Especially comprise hydrochloride, vitriol, tartrate, Citrate trianion, fumarate, malate and pharmaceutically acceptable prodrug and derivative.
The invention still further relates to the application of described compound in preparation prevention and treatment AIDS-treating medicine.
The invention still further relates to the application of described compound in preparation prevention and medicine for treating tumor thing, described tumour comprises carcinoma of the pancreas, colorectal cancer, bladder cancer, mammary cancer, ovarian cancer, squamous cell carcinoma, incidence cancer, or non-small cell carcinoma.
The pharmacological results shows, in this compounds, major part copies with several drug resistance HIV-1 virus strain (K103N+ Y181C) and all has very strong inhibition active (nmole level) wild-type HIV-1 strain (IIIB), and it is active that part of compounds also has stronger inhibition to HIV-2, be expected to become the drug candidate of anti-HIV.
The compounds of this invention novel structure, has good anti-HIV biological activity, and cytotoxicity is less; Compounds process for production thereof is simple, can further be developed as anti-AIDS drugs and antitumor drug.
Embodiment
By following embodiment, will contribute to understand the present invention, but not limit content of the present invention.
Embodiment 1: diaryl pyrimidine ketone hydrazone derivative synthetic
By hydrazine derivative and the different pyrimidone derivatives replacing
iIbe placed in solvent, then heat up (for hydrazonium salt, need add alkali), react complete and afterwards reaction solution is poured in frozen water, be extracted with ethyl acetate, by ethyl acetate with 2 M salt pickling once, saturated common salt is washed once, anhydrous sodium sulfate drying, column chromatography for separation obtains target product.Following instance describes preparation process method in detail with different instances:
By substituted pyrimidines ketone derivatives
iI(6 mmol) and hydrazine dihydrochloride (3.15 g, 30 mmol) be dissolved in EtOH (30 mL), add again pyridine (6.5 mL g, 80 mmol), then temperature rising reflux reacts 2 h, after completion of the reaction, cooling, reaction solution is poured into water to (100 ml), be extracted with ethyl acetate (3 * 100 ml), combined ethyl acetate layer, with 2 M salt pickling once, saturated common salt is washed once, anhydrous sodium sulfate drying, remove solvent under reduced pressure, solid residue uses column chromatography to obtain light yellow solid.
Yield 44.6%; yellow solid, mp 199.2-200.5 °C;
1H NMR (DMSO-
d 6)
δ (ppm): 7.28-7.70 (m, 11H, Ph
H, N
H 2, C
H), 8.40 (d, 1H,
J = 5.2 Hz, C
H), 9.94 (s, 1H, N
H);
13C NMR (DMSO-
d 6 )
δ: 102.6, 109.9, 118.3 (2C), 120.0, 122.9, 130.0, 131.6, 132.2, 132.9, 133.0 (2C), 133.4, 145.2, 145.5, 159.2, 159.4, 162.2; MS (ESI)
m/z 394 ((M
++1), calcd for C
18H
13 BrN
6 393, Anal. (C
18H
13 BrN
6) C, H, N, Br。
By substituted pyrimidines ketone derivatives
iI(6 mmol) and thiosemicarbazide (6.76 g, 30 mmol) be dissolved in EtOH (30 mL), then temperature rising reflux reacts 2 h, after completion of the reaction, cooling, reaction solution is poured into water to (100 ml), is extracted with ethyl acetate (3 * 100 ml), combined ethyl acetate layer, saturated common salt washing once, anhydrous sodium sulfate drying, removes solvent under reduced pressure, and solid residue uses column chromatography to obtain light yellow solid.
Yield 26.4%; yellow solid, mp 259.3-260.5 °C;
1H NMR (DMSO-
d 6)
δ (ppm): 3.73 (s, 3H, OC
H 3 ), 7.30-7.83 (m, 9H, Ph
H, N
H 2, C
H), 8.60 (d, 1H,
J = 5.2 Hz, C
H), 10.19 (s, 1H, N
H), 10.80 (s, 1H, N
H);
13C NMR (DMSO-
d 6 )
δ: 52.5, 102.0, 108.6, 117.9 (2C), 119.5, 122.8, 128.1, 131.0, 131.2, 132.5 (2C), 132.6, 133.5, 144.7, 154.0, 158.8, 159.0, 162.3; MS (ESI)
m/z 452 ((M
++1), calcd for C
20H
15BrN
6O
2 451, Anal. (C
20H
15BrN
6O
2) C, H, N, Br, O。
By substituted pyrimidines ketone derivatives
iI(6 mmol) and methyl carbazate (2.70 g, 30 mmol) be dissolved in EtOH (30 mL), then temperature rising reflux reacts 2 h, after completion of the reaction, cooling, reaction solution is poured into water to (100 ml), is extracted with ethyl acetate (3 * 100 ml), combined ethyl acetate layer, saturated common salt washing once, anhydrous sodium sulfate drying, removes solvent under reduced pressure, and solid residue uses column chromatography to obtain light yellow solid.
Yield 26.4%; yellow solid, mp 259.3-260.5 °C;
1H NMR (DMSO-
d 6)
δ (ppm): 7.37-8.13 (m, 7H, Ph
H), 7.39 (d, 1H,
J = 5.2 Hz, C
H), 8.62 (d, 1H,
J = 5.2 Hz, C
H),
8.86 (s, 1H, N
H 2 ), 8.88 (s, 1H, N
H 2 ), 9.57 (s, 1H, N
H), 10.16 (s, 1H, N
H);
13C NMR (DMSO-
d 6 )
δ: 102.0, 109.4, 117.8 (2C), 119.5, 122.4, 128.5, 131.1, 131.7, 132.4 (2C), 132.5, 132.9, 144.7, 145.0, 158.7, 158.9, 161.7, 178.9; MS (ESI)
m/z 453 ((M
++1), calcd for C
19H
14BrN
7S452, Anal. (C
19H
14BrN
7S) C, H, N, Br。
The anti-HIV biological activity test of embodiment 2
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: inhibition activity and cytotoxicity two aspects of the MT-4 cell that HIV is infected.Method is described below: make compound in the MT-4 cell of HIV infection; in infected by HIV different time; with mtt assay, measure the cytopathic provide protection of medicine to HIV mutagenesis, calculate the required concentration medium effective concentration IC of cytopathy that makes 50% cell avoid HIV induction
50, parallel the carrying out of toxicity test and HIV (human immunodeficiency virus)-resistant activity experiment, is also in MT-4 cell cultures, with mtt assay, measures and makes 50% non-infected cells that cytopathic concentration (CC occur
50), and calculate selectivity index SI=CC
50/ IC
50.
Materials and methods:
The cytopathic restraining effect efficiency that the HIV (human immunodeficiency virus)-resistant activity of each compound is caused HIV by medicine in cell is monitored.Adopt MT-4 cell to carry out cell cultures.The virus strain adopting has: HIV-1 virus strain III B and HIV-2 virus strain ROD.
Concrete operations are as follows: by use phosphate buffered common salt aqueous solution dilution after DMSO or water dissolution for compound, by 3 * 10
5mT-4 cell at 37 ℃ of preculture 1h, then adds the suitable viral dilution liquid of 100 μ l with 100 μ 1 each these solution of compound different concns in this compound, and cell is cultivated to 1h in 37 ℃.Wash after three times, cell is again suspended in respectively and contains or do not contain in the developing medium of compound.Follow cell at 5%CO
2in atmosphere, at 37 ℃, cultivate again 7 days, and the 3rd day after infecting replaces and supplements nutrient solution with the developing medium that contains or do not contain compound.All twice of the repetitive operations of every kind of nutrient solution condition.To viral cytopathic effect, all use reverse opticmicroscope to monitor every day.Typical case, viral dilution liquid used in this experiment usually can cause cytopathy for the 5th day after virus infection.Medicine inhibition concentration with medicine to virocyte pathology effect produce 50% restraining effect and simultaneously to cell without the direct concentration (CC of toxicity
50) represent.It is emphasized that when compound water soluble poor, need to be with DMSO could dissolve time, DMSO specific concentration is with respect to water, generally lower than 10%, (DMSO ultimate density in MT-4 cell culture medium is less than 2%).Because DMSO can affect the antiviral activity of test compounds, to containing same concentrations DMSO solution antiviral activity contrast blank assay, also should parallelly carry out.In addition, DMSO ultimate density (1/1000) copies required concentration well below affecting HIV-1 in T cell.
Part target compound of the present invention the results are shown in Table 1 to the inhibition activity of HIV.
Anti-HIV-1 Activity and Cytotoxicity of Compounds
9a-9t in MT-4 Cells
aEC
50: effective concentration of compound required to protect the cell against viral bytopathogenicity by 50% in MT-4 cells.
bRES056: HIV-1 mutated strain bearing both K103N andY181C mutations.
cCC
50: cytotoxic concentration of compound that reduces the normal uninfected MT-4 cell viability by 50%.
dSI: selectivity index: ratio CC
50/EC
50。
Experimental result shows, the compound comprising in chemical structure of general formula generally has stronger anti-HIV-1 virus activity, less cytotoxicity and higher selectivity index; Wherein part of compounds also shows to have anti-HIV-2 effect, and this is different with classical NNRTIs.
The invention is not restricted to above-mentioned example.
Claims (7)
1. a diaryl pyrimidine ketone hydrazone derivative, have following structural formula (
i):
Ⅰ
Wherein, R
1, R
2, R
4, R
5for hydrogen, R
3for contraposition cyano group, m is 1, Y is-NH-, Ar is o-tolyl, a tolyl, p-methylphenyl, adjacent fluorophenyl, a fluorophenyl, to fluorophenyl, Chloro-O-Phenyl, a chloro-phenyl-, rubigan, o-bromophenyl, to bromophenyl, p-methoxyphenyl, to trimethylphenylmethane base, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 2-naphthyl.
3. preparation method as claimed in claim 2, is characterized in that described hydrazonium salt is hydrochloride, hydrobromate or vitriol.
4. preparation method as claimed in claim 2, is characterized in that organic solvent used is methyl alcohol, ethanol, Virahol, the trimethyl carbinol, propyl carbinol, and acetonitrile, tetrahydrofuran (THF),
n,N-dimethyl formamide,
n, N-n,N-DIMETHYLACETAMIDE, toluene, or dimethylbenzene.
5. preparation method as claimed in claim 2, is characterized in that alkali used is salt of wormwood, sodium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, pyridine, triethylamine, Isopropylamine, or n-Butyl Amine 99.
6. a pharmaceutical composition, is characterized in that containing effective dose arbitrary compound as claimed in claim 1 and pharmaceutical carrier.
7. the application of compound in preparation prevention and treatment AIDS-treating medicine as claimed in claim 1.
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CN101723903A (en) * | 2009-11-26 | 2010-06-09 | 复旦大学 | 4-carbonyl diaryl pyridine derivatives as well as preparation methods and applications thereof |
CN101723904A (en) * | 2009-11-26 | 2010-06-09 | 复旦大学 | 4-cyano-diaryl pyridine derivatives as well as preparation methods and applications thereof |
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CN101723903A (en) * | 2009-11-26 | 2010-06-09 | 复旦大学 | 4-carbonyl diaryl pyridine derivatives as well as preparation methods and applications thereof |
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