CN101475535A - Polysubstituted N-DACO derivative, synthesizing method and use thereof - Google Patents

Polysubstituted N-DACO derivative, synthesizing method and use thereof Download PDF

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CN101475535A
CN101475535A CNA2009100940849A CN200910094084A CN101475535A CN 101475535 A CN101475535 A CN 101475535A CN A2009100940849 A CNA2009100940849 A CN A2009100940849A CN 200910094084 A CN200910094084 A CN 200910094084A CN 101475535 A CN101475535 A CN 101475535A
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halogen
trifluoromethyl
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何严萍
赖声汉
李聪
张春生
张德华
李大雄
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Yunnan University YNU
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Abstract

The invention belongs to the technical field of medicine, and in particular discloses a polysubstituted Dihydro-Alkylamino-Cyclohexylmethyl-Oxopyrimidines,N-DACO compound, N-oxide, stereoisomer forms, stereoisomer mixtures, pharmaceutically-acceptable salts, hydrate, solvate, polycrystal and eutectic crystal thereof, as well as a precursor and derivates thereof with same biological functions. The derivates of the invention have obvious functions of inhibiting HIV activity and resisting medicine tolerance, and can be applied to medicines for treating AIDS and other relevant medicines.

Description

Polysubstituted N-DACO derivative and synthesis method and application thereof
Technical Field
The invention relates to a polysubstituted N-DACO compound, a synthetic method thereof and application thereof as an HIV non-nucleoside reverse transcriptase inhibitor, belonging to the technical field of anti-HIV medicines.
Background
Aids is a serious infectious disease caused by the Human Immunodeficiency Virus (HIV). Due to the failure of HIV vaccine research, antiviral therapy has become the key to the current suppression of the high-rate growth of aids. In 1996, "highly effective antiretroviral therapy" (HAART therapy, i.e., cocktail therapy) invented by chinese scientists became a milestone in the research progress of human aids treatment. The therapy adopts three or more drugs (commonly used combination is 1 protease inhibitor and 2 reverse transcriptase inhibitors), shows strong antiviral effect, and becomes a conventional treatment method for AIDS. However, the factors of drug resistance mutation, toxic and side effects, high price and the like caused by long-term medication promote scientists of various countries to continuously explore new targets, new drugs and new treatment schemes for treating AIDS so as to develop more effective treatment measures.
Reverse Transcriptase inhibitors are essential components of HAART therapy and can be classified into Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Non-Nucleoside Reverse Transcriptase inhibitors (NNRTIs) according to their mechanism of action, which can bind to the active site of HIV virus Reverse Transcriptase (RT) and prevent the virus from replicating to DNA by inhibiting RT enzyme. The activation process does not involve the phosphorylation process in the cell, so that the antiviral effect can be more effectively and rapidly exerted. Currently marketed NNRTIs mainly include nevirapine (nevirapine), delavirdine (delavirdine) and efavirenz (efavirens), and 2008 a new NNRTIs-TMC 125 is approved by FDA to be marketed. They are used in combination with other anti-HIV agents and have good effects in preventing the transmission of mother and infant, preventing the contact person, treating acute HIV infection, etc.
NNRTs are a series of compounds that differ in structure but have similar mechanisms of action. Thirty classes of NNRTIs that specifically inhibit HIV-1 RT have been discovered, of which dihydroalkoxybenzylpyrimidinones (Dihydro-Alkoxy-Benzyl-Oxopyrimidines, DABOs) are a novel class of NNRTIs (Bot et al), reported by Article et al 1992ta, M.et.al.Eur.J.Med.chem.1992, 27, 251-257), from the chemical structure, DABOs belongs to pyrimidinone compounds, which are characterized in that an alkoxy side chain is arranged at C-2 position of pyrimidinone, and C-6 position is substituted benzyl, the compounds have low toxicity although the activity is not very high, so people take the compounds as a lead and carry out a great deal of structural modification around improving anti-HIV activity. S-DABOs compounds obtained by substituting sulfur atom for oxygen atom in C-2 side chain of DABO (Mai, A. et. al. J. Med. chem.1995, 38, 3258-3263) can inhibit virus replication at a low μ M value; ragno, R, etc. replace the C-2 side chain sulfur atom of S-DABO with nitrogen atom to obtain N-DABOs compounds (Ragno, R.et. al.J.Med.chem.2004, 47, 928-doped 934), which have HIV-resistant activity further improved compared with S-DABO and are combined with F obtained by transforming C-6 (2, 6-difluorobenzyl)2-NH-DABOs and F2the-N, N-DABOs compounds can inhibit the replication of wild HIV virus at a lower nM value, still retain a good inhibition effect on HIV-1Y 181C mutant strains, and have broad-spectrum antiviral activity (Cancio, R.et.al.Chem.Med.Chem 2007, 2, 445. chem. 448; Mai, A.et.al.J.Med.chem.2007, 50, 5412. 5424.). Another successful example of structural modification of DABO compounds is the introduction of a methyl group on the C-6 methylene group, which restricts the conformation of the inhibitor molecule by steric hindrance of the methyl group, allowing it to stably bind to RT enzyme in a more appropriate manner, thereby increasing its anti-HIV activity (Mai, A.et.al.J.Med.Chem.2001, 44, 2544-.
Figure A200910094084D00081
For many years, the inventors of the present patent application have devoted their efforts to research on S-DABO compounds, and have succeeded in introducing a β -carbonyl side chain at C-2 position of the pyrimidine ring (He, Y.P.et. al.Bioorg.Med.chem.Lett.2004, 14, 3173-The compounds have extremely high anti-HIV activity and low cytotoxicity, and the selectivity index of some compounds is as high as 106It is an excellent anti-HIV drug precursor (He-Yan-Na et al, Chinese patent document CN 101177413A).
The successful introduction of the C-6 cyclohexylmethyl group of the pyrimidine ring guides a new research direction for the development of NNRTIs, and the invention further carries out structural modification on C-2, C-5 and C-6 substitution positions of the DACOs pyrimidine ring through a molecular simulation experiment on the basis of reserving the flexible structure of the C-6 cyclohexylmethyl group by using the research result of the structure-activity relationship of DABO compounds to develop a new NNRTIs with high efficiency and low toxicity.
Disclosure of Invention
The invention aims to provide a novel compound for preparing anti-HIV drugs, namely a polysubstituted N-DACO derivative.
The invention also relates to a method for producing said compounds.
The invention also aims to obtain the use of the above-mentioned compounds.
The invention takes S-DACO compounds which are designed and synthesized by people as a lead, and introduces various substituent groups on cyclohexyl on the basis of reserving the flexible structure of C-6 cyclohexylmethyl to increase Van der Waals force between the cyclohexyl and surrounding amino acid residues in RT enzyme combination cavities; in addition, a conformation restriction factor is introduced to a methylene bridge at the C-6 position, and the introduction of each substituent at the C-5 position of a pyrimidine ring is combined to strengthen the synergistic effect with cyclohexyl so as to interfere the catalytic effect of an amino acid residue Asp; the invention relates to a series of multi-substituted N-DACO compounds which are designed by using nitrogen atoms to replace sulfur atoms of side chains at C-2 position of S-DACOs pyrimidine ring to strengthen hydrogen bond action between an inhibitor and amino acid residue Lys103 and combining the found superior substituent of the side chains at C-2 position by taking the research result of structural modification of N-DABO compounds as reference. Finally, the interaction between the designed molecular marker and RT is analyzed by a molecular docking method, and molecules with lower binding free energy with RT are screened out from the molecular docking method, can be well adapted to the binding cavity of RT enzyme, and often have higher anti-HIV activity.
The product of the invention is a polysubstituted Dihydro-amino cyclohexyl methyl pyrimidone (N-DACO) compound shown in a general formula I, and an N-oxide, a stereoisomer form, a stereoisomer mixture and pharmaceutically acceptable salts (such as hydrochloride, sulfate, tartrate and citrate) thereof.
Figure A200910094084D00101
Wherein,
y is: -H, halogen, cyano, hydroxy, amino, trifluoromethyl, -C1-6Alkyl of-C3-6Cycloalkyl groups of (a);
z is: -H, -C1-3Alkyl, -halogen, -CN;
k is: -H, -C1-6Alkyl of-C3-6Cycloalkyl groups of (a);
r is: -H, by one or more halogen atoms, cyano, nitro, carboxyl, trifluoromethyl, -C1-4Alkyl of-C1-4Alkoxy substituted or unsubstituted-C1-12Alkyl of-C3-6Cycloalkyl of-C3-6Cycloalkenyl radical of (a) — C3-6The heterocyclic ring of (a), aryl, aralkyl, five-or six-membered aromatic heterocyclic ring; or-CH2COL (wherein L is substituted by one or more halogen atoms, cyano, nitro, carboxyl, trifluoromethyl, -C1-4Alkyl of-C1-4Alkoxy substituted or unsubstituted-C1-12Alkyl of-C3-6Cycloalkyl of-C3-6Cycloalkenyl radical of (a) — C3-12The heterocyclic ring, aryl group, five-or six-membered aromatic heterocyclic ring);
r' is: -H, halogen, cyano, nitro, hydroxy, amino, trifluoromethyl, -C1-6Alkyl groups of (a); m is 0, 1 or 2;
preferred compounds of the invention are Ia:
Figure A200910094084D0011095733QIETU
wherein,
y is: -H, -F, -Br, -C1-4Alkyl groups of (a);
z is: -H, -CH3；
K is: -H, -CH3；
R is: -C1-6Alkyl, cycloalkyl groups of (a); or mono-substituted or di-substituted benzyl (wherein, the substituent on the benzene ring is-H, -OCH3-F, -OH, -CN, the substitution being ortho and/or para); or-CH2COL (wherein L is furan ring or mono-substituted or di-substituted benzene ring, and the substituent on the benzene ring is-H, -OCH3-F, -OH, -CN, the substitution being ortho and/or para);
the compound of the general formula I can be prepared by the following two methods.
The method comprises the following steps:
substituted 6- (cyclohexylmethyl) thiouracil (3A) prepared by using substituted cyclohexyl ethyl acetoacetate (beta-ketoester for short) (4) as raw material and thiourea through condensation ring closure under catalysis of sodium alkoxide, and then iodomethane (CH)3I) Reacting to obtain substituted 2-methylthio-6- (cyclohexylmethyl) pyrimidone (2), and reacting with substituted amines
Figure A200910094084D00111
Reacting to obtain a target compound (1A), wherein the reaction formula is as follows:
Figure A200910094084D00121
wherein,
(1) beta-ketoesters (4) can be prepared by methods described in the literature (m.artico, J Med Chem, 1997, 42,619) by reacting substituted cyclohexylacetic acid (5) with CDI to produce substituted cyclohexylacetyl imidazole (6) and further with substituted monopotassium malonate (8) to produce beta-ketoesters (4) of the formula:
Figure A200910094084D00122
(2) the substituent Y is: -H, halogen, cyano, hydroxy, amino, trifluoromethyl, -C1-6Alkyl of-C3-6Cycloalkyl groups of (a); z is: -H, -C1-3Alkyl, -halogen, -CN; k is: -H, -C1-6Alkyl of-C3-6Cycloalkyl groups of (a); r is-H, substituted by one or more halogen atoms, cyano, nitro, carboxyl, trifluoromethyl, -C1-4Alkyl of-C1-4Alkoxy substituted or unsubstituted-C1-12Alkyl of-C3-6Cycloalkyl of-C3-6Cycloalkenyl radical of (a) — C3-6The heterocyclic ring of (a), aryl, aralkyl, five-or six-membered aromatic heterocyclic ring; r' is: -H, halogen, cyano, nitro, hydroxy, amino, trifluoromethyl, -C1-6Alkyl groups of (a); m is 0, 1 or 2;
(3) substituted 6-cyclohexylmethylthiouracil (3A) and iodomethane (CH)3I) The reaction molar ratio is 1: 1.5-1: 2, the reaction temperature is controlled to be 20-60 ℃, and the reaction time is 4-8 hours;
(4) the solvent 1 is one or a mixture of toluene and/or dichloromethane and/or N, N-dimethylformamide and/or acetonitrile;
(5) substituted 2-methylthio-6- (cyclohexylmethyl) pyrimidinones (2) with individually substituted amines
Figure A200910094084D0013095905QIETU
The reaction molar ratio is 1: 1.5-1: 3, the tube sealing reaction is carried out, the reaction temperature is controlled to be 60-200 ℃, and the reaction time is 12-24 hours;
the second method comprises the following steps:
beta-ketoester (4) is used as a raw material, condensed with guanidine hydrochloride under the catalysis of sodium alkoxide to prepare substituted 2-amino-6- (cyclohexylmethyl) pyrimidone (3B), and then respectively mixed with various halides (XCH) under the conditions of proper solvent and alkali2COL) to give the target compound (1B) of the present invention represented by formula I, which is represented by the following formula:
Figure A200910094084D00131
wherein:
(1) the substituent Y is: -H, halogen, cyano, hydroxy, amino, trifluoromethyl, -C1-6Alkyl of-C3-6Cycloalkyl groups of (a); z is: -H, -C1-3Alkyl, -halogen, -CN; l is substituted by one or more halogen atoms, cyano, nitro, carboxyl, trifluoromethyl, -C1-4Alkyl of-C1-4Alkoxy substituted or unsubstituted-C1-12Alkyl of-C3-6Cycloalkyl of-C3-6Cycloalkenyl radical of (a) — C3-12The heterocyclic ring of (1), an aryl group, a five-or six-membered aromatic heterocyclic ring; r' is: -H, halogen, cyano, nitro, hydroxy, amino, trifluoromethyl, -C1-6Alkyl groups of (a); m is 0, 1 or 2;
(2) the molar ratio of the beta-ketoester (4) to the guanidine hydrochloride is 1: 1-1: 1.5, the reaction temperature is controlled between 20 and 120 ℃, and the reaction time is 8 to 12 hours. The solvent 2 is one or a mixture of methanol and/or ethanol and/or isopropanol;
(3) substituted 2-amino-6-cyclohexylmethylpyrimidinone (3B) and various halides (XCH)2COL) at a molar ratio of 1: 1-1: 1.5 and at a reaction temperature of 120-180 deg.CThe time is 8-24 hours;
(4) the solvent 3 is one of toluene, dichloromethane and N, N-dimethylformamide or their mixture. The base is sodium alkoxide, potassium carbonate or triethylamine;
the product of the invention is used as a candidate of anti-AIDS drugs.
The experiment of anti-HIV activity in vitro of the pathological system of Johns Hopkin university proves that the compound contained in the chemical structural formula I provided by the invention generally has stronger anti-HIV-1 virus activity, lower cytotoxicity and higher selection index. The preferred compounds can inhibit HIV replication in a lower nM range and have significant antimutagenic effects on clinical mutants Y181C and K103N.
Detailed Description
The following examples will aid understanding of the present invention, but are not intended to limit the scope of the present invention.
EXAMPLE-Synthesis of 5-isopropyl-2- (methylthio) -6-cyclohexylmethyl-4 (3H) pyrimidinone (2a)
5-isopropyl-6-cyclohexylmethyl-2-thiouracil (3mmol) and K2CO3Placing the mixture into a flask, adding 15mL of dry DMF, stirring the mixture at room temperature for reaction for half an hour, adding methyl iodide (3.6mmol), continuing to stir the mixture at a proper temperature for reaction, tracking the disappearance of a raw material point by TLC to stop the reaction, pouring the reaction solution into 30mL of ice water, stirring the mixture to separate out a precipitate, filtering the precipitate, washing the precipitate with water, performing suction filtration and drying to obtain a crude product, and recrystallizing the crude product with a proper solvent to obtain a white crystal of 5-isopropyl-2- (methylthio) -6- (cyclohexylmethyl) -4(3H) pyrimidinone (2a), wherein the yield is 85%.
Figure A200910094084D00151
1HNMR，(CDCl3，500MHz)：δ(ppm)＝0.92-0.99(m，4H，cyclohexyl)，1.13-1.26(m，5H，cyclohexyl)，1.30-1.32(d，6H，2CH3)，1.67(m，2H，cyclohexyl)，2.44-2.46(d，2H，CH 2 cyclohexyl)，2.53(s，3H，CH 3 S)，2.96-2.98(m，1H，CHMe2)，12.42(s，brs，1H，NH)；
EXAMPLES Synthesis of disubstituted 2-amino-6- (cyclohexylmethyl) -pyrimidin-4 (3H) -one (3B)
Dissolving metal sodium (0.40mol) in 200mL of absolute ethanol, adding guanidine hydrochloride (0.38mol), stirring for 0.5h, and filtering for later use.
Dissolving 0.52mol of metal sodium in 250mL of absolute ethyl alcohol, adding the filtrate, and stirring for a moment; beta-ketoester (0.32mol) was then slowly added dropwise and refluxed for 2 h. Removing ethanol under reduced pressure, dissolving with 300mL of water, filtering, adjusting pH of the filtrate to 6 with HCl, precipitating white precipitate, filtering, washing with water to neutrality, vacuum drying to obtain crude product of substituted 2-amino-6-cyclohexylmethylpyrimidinone (3B), and recrystallizing with appropriate solvent to obtain white crystal which can be directly used in the next reaction without purification.
EXAMPLE Synthesis of tris 2- (substituted amino) -6-substituted cyclohexylmethyl-5-alkyl-4 (3H) -pyrimidin-4-one (1A)
The 2-methylthio-5-alkyl-6-substituted cyclohexylmethyl-4-pyrimidone (0.75mmol) and the substituted amine (3.75mmol) are fully mixed and put in a sealed tube to react for 12 to 24 hours at the temperature of 140 ℃ and 180 ℃ under the protection of nitrogen. After the reaction is finished, cooling, pouring into 30mL of water, adding ethyl acetate (3X 50mL) for extraction, combining organic phases, washing with saturated saline solution, drying, removing the solvent under reduced pressure, and carrying out column chromatography separation to obtain the target product.
Figure A200910094084D00161
As above, column chromatography gave white powder 1A-1, yield: 61%; melting point: 176-177 ℃;1HNMR(CDCl3，500MHz)：δ(ppm)＝1.04-1.75(m，11H，cyclohexyl)，1.23-1.26(t，3H，CH2CH 3 )，2.30-2.50(q，2H，CH 2 CH3)，2.49-2.50(d，2H，CH 2 cyclohexyl)，7.60-7.85(m，4H，Ph-H)，9.09(s，brs，1H，NH-Ph)，12.00(s，brs，1H，NH).
Figure A200910094084D00162
as above, column chromatography gave a pale yellow powder 1A-2, yield: 52 percent; melting point: 228 ℃ and 230 ℃;1HNMR(CDCl3，500MHz)：δ(ppm)＝1.05-1.85(m，11H，cyclohexyl)，2.04(s，3H，CH3)，2.49-2.50(d，2H，CH 2 cyclohexyl)，7.61-7.87(m，4H，Ph-H)，9.09(s，brs，1H，NH-Ph-CN)，12.15(s，brs，1H，NH).
Figure A200910094084D00163
performing column chromatography to obtain white powder 1A-3; yield: 57 percent; melting point: 236-238 ℃;1HNMR(CDCl3，500MHz)：δ(ppm)＝1.02-1.82(m，11H，cyclohexyl)，1.3l-1.37(d，6H，2CH3)，2.53-2.54(d，2H，CH 2 cyclohexyl)，3.05(m，1H，CHMe2)，7.60-7.92(m，4H，Ph-H)，9.35(s，brs，1H，NH-Ph)，12.99(s，brs，1H，NH)；
Figure A200910094084D00171
as above, column chromatography gave white powder 1A-4, yield: 47%; melting point: 173-174 ℃;1HNMR(CDCl3，500MHz)：0.97-1.72(m，22H，2 cyclohexyl)，2.01(s，3H，CH3)，2.34-2.49(d，2H，CH 2 cyclohexyl)，11.48(s，brs，1H，NH)；
Figure A200910094084D00172
as above, column chromatography gave light yellow powder 1A-5, yield: 57 percent; melting point: 192 ℃ to 193 ℃;1HNMR(CDCl3，500MHz)：δ(ppm)＝1.03-1.72(m，11H，cyclohexyl)，1.21-1.24(t，3H，CH2CH 3 )，2.38(q，2H，CH 2 CH3)，2.41-2.44(d，2H，CH 2 cyclohexyl)，6.57-6.68(s，2H，Ph-NH 2 )，7.04-7.44(m，4H，Ph-H)，9.11(s，brs，1H，NH-Ph)，11.90(s，brs，1H，NH).
Figure A200910094084D00173
as above, column chromatography gave a pale yellow powder 1A-2, yield: 49 percent;1HNMR(CDCl3，500MHz)：δ(ppm)＝1.08(d，3H，CH3)，1.35-1.87(m，10H，cyclohexyl)，1.98(s，3H，CH3)，2.47-2.48(d，2H，CH 2 cyclohexyl)，7.60-7.84(m，4H，Ph-H)，9.12(s，brs，1H，NH-Ph-CN)，12.05(s，brs，1H，NH)；
as above, column chromatography gave light yellow powder 1A-7, yield: 51 percent;1HNMR(CDCl3，500MHz)：δ(ppm)＝1.18(d，3H，CHCH 3 )，1.45-1.67(m，11H，cyclohexyl)，1.98(s，3H，CH3)，2.47(m，1H，CHCH3)，7.62-7.78(m，4H，Ar-H)，9.08(s，brs，1H，NH-Ph-CN)，12.05(s，brs，1H，NH)；
EXAMPLE Synthesis of tetrakis 6- (cyclohexylmethyl) -5-ethyl-2- (2-oxo-2-phenylethylamino) pyrimidin-4 (3H) -one (1B-1)
2-amino-6-cyclohexylmethyl-5-ethyl-pyrimidone (2.1mmol), alpha-bromoacetophenone (2.1mmol) and DMF (15mL) are put in a reaction bottle and stirred for reaction for 4 hours at the temperature of 140 ℃ and 160 ℃ under the protection of nitrogen. And cooling to room temperature, pouring the reaction solution into 70mL of ice water, stirring, separating out a yellow precipitate, filtering, drying to obtain a crude product, and performing column chromatography separation to obtain a pure product of the target compound 1B-1 with the yield of 48%.
Figure A200910094084D00182
1H NMR(CDCl3)δ(ppm)：0.86-1.64(m，11H，cyclohexyl)，1.07(t，3H，CH2CH 3 )，2.0(s，1H，NH)，2.38(d，2H，-CH 2 cyclohexyl)，2.54-2.59(q，2H，CH 2 CH3)，5.37(d，2H，CH 2 -NH)，7.41-7.88(m，5H，Ph-H)，12.35(s，brs，1H，NH)；
Example five anti-HIV Activity assays
anti-HIV viral activity at the cellular level in vitro was determined by the university of Johns Hopkin pathology line. Including the inhibition activity and cytotoxicity to the MT-4 and C8166 cells infected by HIV.
The material and the method are as follows:
the anti-HIV activity of each compound was monitored by the efficiency of the drug's inhibition of cell-induced cytopathic effects in the cells. MT-4 and C8166 cells were used for cell culture. The viral strains used were: HIV-1 IIIBViral strains, HIV-2 viral strain ROD and typical NNRTIs Selective variants RES056 (variant sites and variant types: K103N and Y181)C) In that respect The specific operation is as follows:
the test compound was dissolved in DMSO and diluted with a phosphate buffered saline solution to different concentrations. Because the MT-4 and C8166 cells infected by HIV often have pathological changes within 5-7 days, the solution of the compound to be tested with different concentrations is added into the suspension of the HIV-1 infected cells, and the suspension is added with 5% CO2After a period of culture (5-7 days) at 37 ℃ in an atmosphere, the number of viable cells was determined using the MTT method to obtain the drug concentration (EC) that protects 50% of the cells from cytopathic effects50) The anti-HIV activity of the compound can be obtained. Toxicity assays were performed in parallel with anti-HIV activity assays, and the concentration of compound that caused 50% of uninfected cells to develop cytopathic effects (CC) was also determined by MTT in MT-4 or C8166 cell cultures50) And calculating the selection index SI ═ CC50/EC50。
According to the invention, AZT and NVP are used as controls, and anti-HIV-1 activity screening is carried out on the synthesized 35 multi-substituted N-DACO compounds through the pathology system of Johns Hopkin university. The experimental result shows that the tested compound generally has obvious inhibitory activity on wild type HIV-1, wherein the preferable compound can inhibit the replication of HIV in a lower nM range, the cytotoxicity is lower, the inhibitory activity of some compounds on selective variant RES056 is higher than that of the currently marketed anti-HIV drugs AZT and NVP, and more activity evaluation and pharmacological experiments are ongoing.

Claims (6)

1. A polysubstituted Dihydro-aminocyclohexyl-pyrimides (N-DACO) compound, the general structural formula is I, and the N-oxide, the stereoisomer form, the stereoisomer mixture or the pharmaceutically acceptable salt thereof:
Figure A200910094084C00021
wherein,
y is: -H, halogen, cyano, hydroxyRadical, amino, trifluoromethyl, -C1-6Alkyl of-C3-6Cycloalkyl groups of (a);
z is: -H, -C1-3Alkyl, -halogen, -CN;
k is: -H, -C1-6Alkyl of-C3-6Cycloalkyl groups of (a);
r is: -H, by one or more halogen atoms, cyano, nitro, carboxyl, trifluoromethyl, -C1-4Alkyl of-C1-4Alkoxy substituted or unsubstituted-C1-12Alkyl of-C3-6Cycloalkyl of-C3-6Cycloalkenyl radical of (a) — C3-6The heterocyclic ring of (a), aryl, aralkyl, five-or six-membered aromatic heterocyclic ring; or-CH2COL (wherein L is substituted by one or more halogen atoms, cyano, nitro, carboxyl, trifluoromethyl, -C1-4Alkyl of-C1-4Alkoxy substituted or unsubstituted-C1-12Alkyl of-C3-6Cycloalkyl of-C3-6Cycloalkenyl radical of (a) — C3-12The heterocyclic ring, aryl group, five-or six-membered aromatic heterocyclic ring);
r' is: -H, halogen, cyano, nitro, hydroxy, amino, trifluoromethyl, -C1-6Alkyl groups of (a);
m is 0, 1 or 2.
2. The compound of claim 1, having the general structural formula Ia:
wherein,
y is: -H, -F, -Br, -C1-4Alkyl groups of (a);
z is: -H, -CH3；
K is: -H, -CH3；
R is: -C1-6Alkyl, cycloalkyl groups of (a); or mono-substituted or di-substituted benzyl (wherein, the substituent on the benzene ring is-H, -OCH3-F, -OH, -CN, the substitution being ortho and/or para); or-CH2COL (wherein L is furan ring or mono-or di-substitutedSubstituted benzene ring, the substituents on the benzene ring being-H, -OCH3-F, -OH, -CN, the substitution being ortho and/or para).
3. A process for the preparation of a compound of formula I according to claim 1, characterized in that:
substituted 6- (cyclohexylmethyl) thiouracil (3A) prepared by using substituted cyclohexyl ethyl acetoacetate (beta-ketoester for short) (4) as raw material and thiourea through condensation ring closure under catalysis of sodium alkoxide, and then iodomethane (CH)3I) Reacting to obtain substituted 2-methylthio-6- (cyclohexylmethyl) pyrimidone (2), and reacting with substituted amines
Figure A200910094084C0003171455QIETU
Reacting to obtain a target compound (1A), wherein the reaction formula is as follows:
Figure A200910094084C00041
wherein,
(1) beta-ketoesters (4) can be prepared by methods described in the literature (m.artico, J Med Chem, 1997, 42,619) by reacting substituted cyclohexylacetic acid (5) with CDI to produce substituted cyclohexylacetyl imidazole (6) and further with substituted monopotassium malonate (8) to produce beta-ketoesters (4) of the formula:
Figure A200910094084C00042
(2) the substituent Y is: -H, halogen, cyano, hydroxy, amino, trifluoromethyl, -C1-6Alkyl of-C3-6Cycloalkyl groups of (a); z is: -H, -C1-3Alkyl, -halogen, -CN; k is: -H, -C1-6Alkyl of-C3-6Cycloalkyl groups of (a); r is-H, substituted by one or more halogen atoms, cyano, nitro, carboxyl, trifluoromethyl, -C1-4Alkyl of-C1-4Alkoxy substituted or unsubstituted-C1-12Alkyl of-C3-6Cycloalkyl of-C3-6Cycloalkenyl radical of (a) — C3-6Of (2)A ring, aryl, aralkyl, five-or six-membered aromatic heterocycle; r' is: -H, halogen, cyano, nitro, hydroxy, amino, trifluoromethyl, -C1-6Alkyl groups of (a); m is 0, 1 or 2;
(3) substituted 6-cyclohexylmethylthiouracil (3A) and iodomethane (CH)3I) The reaction molar ratio is 1: 1.5-1: 2, the reaction temperature is controlled to be 20-60 ℃, and the reaction time is 4-8 hours;
(4) the solvent 1 is one or a mixture of toluene and/or dichloromethane and/or N, N-dimethylformamide and/or acetonitrile;
(5) substituted 2-methylthio-6- (cyclohexylmethyl) pyrimidinones (2) with individually substituted amines
Figure A200910094084C00051
The reaction molar ratio is 1: 1.5-1: 3, the tube sealing reaction is carried out, the reaction temperature is controlled to be 60-200 ℃, and the reaction time is 12-24 hours;
4. a process for the preparation of a compound of formula I according to claim 1, characterized in that:
beta-ketoester (4) is used as a raw material, condensed with guanidine hydrochloride under the catalysis of sodium alkoxide to prepare substituted 2-amino-6- (cyclohexylmethyl) pyrimidone (3B), and then respectively mixed with various halides (XCH) under the conditions of proper solvent and alkali2COL) to give the target compound (1B) of the present invention represented by formula I, which is represented by the following formula:
Figure A200910094084C00061
wherein,
(1) the substituent Y is: -H, halogen, cyano, hydroxy, amino, trifluoromethyl, -C1-6Alkyl of-C3-6Cycloalkyl groups of (a); z is: -H, -C1-3Alkyl, -halogen, -CN; l is substituted by one or more halogen atoms, cyano, nitro, carboxyl, trifluoromethyl, -C1-4Alkyl of-C1-4Alkoxy substituted or unsubstituted-C1-12Alkyl of-C3-6Cycloalkyl of-C3-6Cycloalkenyl radical of (a) — C3-12The heterocyclic ring of (1), an aryl group, a five-or six-membered aromatic heterocyclic ring; r' is: -H, halogen, cyano, nitro, hydroxy, amino, trifluoromethyl, -C1-6Alkyl groups of (a); m is 0, 1 or 2;
(2) the molar ratio of the beta-ketoester (4) to the guanidine hydrochloride is 1: 1-1: 1.5, the reaction temperature is controlled between 20 and 120 ℃, and the reaction time is 8 to 12 hours. The solvent 2 is one or a mixture of methanol and/or ethanol and/or isopropanol;
(3) substituted 2-amino-6-cyclohexylmethylpyrimidinone (3B) and various halides (XCH)2COL) at a molar ratio of 1: 1-1: 1.5, at a reaction temperature of 120-180 ℃ for 8-24 hours;
(4) the solvent 3 is one of toluene, dichloromethane and N, N-dimethylformamide or their mixture. The base is sodium alkoxide, potassium carbonate or triethylamine.
5. The pharmaceutically acceptable salt of the compound of claim 1, which is a hydrochloride, sulfate, tartrate, citrate.
6. Use of a compound according to any one of claims 1, 2, 5 for the manufacture of a medicament for the treatment of a condition or disease associated with HIV infection.
CNA2009100940849A 2009-02-05 2009-02-05 Polysubstituted N-DACO derivative, synthesizing method and use thereof Pending CN101475535A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102295609A (en) * 2011-06-17 2011-12-28 云南大学 2-[(substituted phenylamino)carbonyl methylthio]-6-cyclohexylmethyl-3H-pyrimidine-4-ketone compounds, synthetic method thereof and purpose thereof
CN103288747A (en) * 2013-06-14 2013-09-11 张虽栓 6-Cyclohexylmethyl-2-aromatic ring carbonyl substituted N-DABO compounds, and synthetic method and use thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102295609A (en) * 2011-06-17 2011-12-28 云南大学 2-[(substituted phenylamino)carbonyl methylthio]-6-cyclohexylmethyl-3H-pyrimidine-4-ketone compounds, synthetic method thereof and purpose thereof
CN102295609B (en) * 2011-06-17 2013-06-19 云南大学 2-[(substituted phenylamino)carbonyl methylthio]-6-cyclohexylmethyl-3H-pyrimidine-4-ketone compounds, synthetic method thereof and purpose thereof
CN103288747A (en) * 2013-06-14 2013-09-11 张虽栓 6-Cyclohexylmethyl-2-aromatic ring carbonyl substituted N-DABO compounds, and synthetic method and use thereof
CN103288747B (en) * 2013-06-14 2016-03-30 张虽栓 6-cyclohexyl methyl-2-aromatic ring carbonyl substituted N-DABO compounds, its preparation method and use

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