CN101475535A - Polysubstituted N-DACO derivative, synthesizing method and use thereof - Google Patents
Polysubstituted N-DACO derivative, synthesizing method and use thereof Download PDFInfo
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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
Technical field
The present invention relates to polysubstituted N-DACO compound, its synthetic method and application, belong to the inverase technical field as the HIV non-nucleoside reverse transcriptase inhibitor.
Background technology
Acquired immune deficiency syndrome (AIDS) is by body immunodeficiency virus (Human immunodeficiency virus, the serious communicable disease that HIV) causes.Because the failure of HIV vaccine research, antiviral therapy have become the key point of current inhibition acquired immune deficiency syndrome (AIDS) rapid growth.1996, " highly active antiretroviral therapy " (HAART therapy, i.e. drug cocktail therapy (treatment)) of scientist Chinese descendant in America He Dayi invention became milestone in human treatment's acquired immune deficiency syndrome (AIDS) flow of research.This therapy adopts three medicines or the above drug combination of three medicines (common combinations is that 1 proteinase inhibitor adds 2 reverse transcriptase inhibitors), has manifested powerful antivirus action, becomes the acquired immune deficiency syndrome (AIDS) conventional treatments of the current international practice.But medicament-resistant mutation, toxic side effects that long-term prescription produces, factor such as cost an arm and a leg impel the various countries scientist constantly to explore novel targets, new drug and the new treatment plan of treatment acquired immune deficiency syndrome (AIDS), to develop more effective treatment measure.
Reverse transcriptase inhibitors is the necessary component of HAART therapy, can be divided into efabirenz (Nucleoside reverse transcriptase inhibitors according to its mechanism of action, NRTIs) and non-nucleoside reverse transcriptase inhibitor (Non-nucleoside reverse transcriptase inhibitors, NNRTIs) two classes, the latter can be incorporated into HIV viral reverse transcriptase (Reverse Transcriptase, RT) avtive spot, by suppressing the RT enzyme, stop virus replication to DNA.In its reactivation process, do not relate to intracellular phosphorylation process, thereby can more effective, more promptly bring into play antivirus action.The NNRTIs that has now gone on the market mainly contains nevirapine (nevirapine), Delavirdine (delavirdine) and Wei department (efavirens) in accordance with the law, a kind of new NNRTIs-TMC125 is arranged by FDA approval listing again in 2008.The anti HIV-1 virus medicine of they and other is united use, has effect preferably at the aspects such as treatment that stop mother-to-baby transmission, contactee's prevention, acute HIV to infect.
NNRTs is that a series of structures are different but compound that mechanism of action is similar.Found at present that 30 multiclass specificitys suppress the NNRTIs of HIV-1 RT, wherein, dihydro alkoxy benzyl pyrimidinones (Dihydro-Alkoxy-Benzyl-Oxopyrimidines, DABOs) be the novel NNRTIs of a class (Botta of report such as Article in 1992, M.et.al.Eur.J.Med.Chem.1992,27,251-257), say that DABOs belongs to pyrimidinones from chemical structure, it is characterized in that one alcoxyl side chain being arranged in the C-2 position of pyrimidone, and the C-6 position is a substituted benzyl, though this compounds activity is not very high, toxicity is less, therefore people have carried out a large amount of structural modifications based on it around improving HIV (human immunodeficiency virus)-resistant activity.Mai, and the S-DABOs compounds that obtains behind the C-2 position side chain Sauerstoffatom with sulphur atom replacement DABO such as A (Mai, A.et.al.J.Med.Chem.1995,38,3258-3263), can suppress duplicating of virus in lower μ M value; Ragno obtains N-DABOs compounds (Ragno, R.et.al.J.Med.Chem.2004 behind the C-2 position side chain sulphur atom with nitrogen-atoms replacement S-DABO such as R., 47,928-934), its HIV (human immunodeficiency virus)-resistant activity further improves again than S-DABO, the F that obtains in conjunction with the transformation of C-6 position (2, the 6-difluorobenzyl)
2-NH-DABOs and F
2-N, N-DABOs compounds not only can suppress duplicating of wild-type HIV virus in lower nM value, and HIV-1 Y181C mutant strain has still been kept better restraining effect, has broad-spectrum disease resistance cytotoxic activity (Cancio, R.et.al.Chem.Med.Chem 2007,2,445-448; Mai, A.et.al.J.Med.Chem.2007,50,5412-5424.).Another successful example to DABO compounds structural modification is the introducing of methyl on the methylene radical of C-6 position, steric hindrance by methyl limits the conformation of inhibitor molecules, make it with than suitable manner and RT enzyme stable bond, thereby improve its HIV (human immunodeficiency virus)-resistant activity (Mai, A.et.al.J.Med.Chem.2001,44,2544-2554.).
For many years, the contriver of present patent application is devoted to the research of S-DABO compounds, (He after β-carbonyl side chain is successfully introduced in pyrimidine ring C-2 position, Y.P.et.al.Bioorg.Med.Chem.Lett.2004,14,3173-3176), further introduce flexible bigger cyclohexyl methyl again in the C-6 position, synthesized serial dihydro sulphur alkyl cyclohexyl methyl pyrimidinones (Dihydro-Alkylsulfanyl-Cyclohexylmethyl-Oxopyrimidines, S-DACOs), the anti-HIV test of cell in vitro level and enzyme level shows that this compounds has high HIV (human immunodeficiency virus)-resistant activity, and cytotoxicity is less, and the selectivity index of some of them compound is up to 10
6, be the good inverase guide thing of a class (He Yanping etc., Chinese patent file CN101177413A).
The exploitation that the success of the C-6 position cyclohexyl methyl of pyrimidine ring is introduced as NNRTIs has guided another recent studies on direction, the present invention uses for reference the achievement in research of DABO compounds structure activity relationship, on the basis of the flexible structure that has kept C-6 position cyclohexyl methyl, further structural modification is carried out, new class NNRTIs efficient to develop, low toxicity in C-2, C-5 and each replacement position of C-6 of DACOs pyrimidine ring by the molecular simulation experiment.
Summary of the invention
The objective of the invention is to provides a class new compound for the medicine of preparation anti HIV-1 virus, and polysubstituted N-DACO derivative promptly is provided.
The present invention also aims to obtain the preparation method of above-claimed cpd.
Purpose of the present invention also is to obtain the purposes of above-claimed cpd.
The present invention has designed synthetic S-DACO compounds based on us, on the basis of the flexible structure that has kept C-6 position cyclohexyl methyl, on cyclohexyl, introduce each substituting group, with increase its with RT enzyme binding cavity cave in the Van der Waals force between amino-acid residue on every side; In addition, introduce the conformation limiting factor on the endo-methylene group of C-6 position, be combined in each the substituent introducing of pyrimidine ring C-5 position, the synergy of reinforcement and cyclohexyl is to disturb the katalysis of amino-acid residue Asp; Structure activity relationship in the past show the C-2 bit substituent to HIV (human immunodeficiency virus)-resistant activity have very must influence, the present invention uses for reference the achievement in research of N-DABO compounds structural modification, replace S-DACOs pyrimidine ring C-2 position side chain sulphur atom with nitrogen-atoms, to add potent inhibitor with the hydrogen bond action between amino-acid residue Lys103, in conjunction with the more excellent substituting group that has now found that C-2 position side chain, designed serial polysubstituted N-DACO compound.By the method for molecular docking the interaction of designed molecule and RT is analyzed at last, therefrom filter out with RT combine the lower molecule of free energy, they can adapt to the binding cavity cave of RT enzyme preferably, often have higher HIV (human immunodeficiency virus)-resistant activity.
Product of the present invention be a kind of polysubstituted dihydro amido cyclohexyl methyl Pyrimdinone shown in the general formula I (Dihydro-Alkylamino-Cyclohexylmethyl-Oxopyrimidines, N-DACO) compound, with and N-oxide compound, stereoisomer form, stereoisomer mixture and pharmacy acceptable salt (example hydrochloric acid salt, vitriol, tartrate, Citrate trianion).
Wherein,
Y is :-H, halogen, cyano group, hydroxyl, amino, trifluoromethyl ,-C
1-6Alkyl ,-C
3-6Cycloalkyl;
Z is :-H ,-C
1-3Alkyl ,-halogen ,-CN;
K is :-H ,-C
1-6Alkyl ,-C
3-6Cycloalkyl;
R is :-H, by one or more halogen atoms, cyano group, nitro, carboxyl, trifluoromethyl ,-C
1-4Alkyl ,-C
1-4Alkoxyl group replace or unsubstituted-C
1-12Alkyl ,-C
3-6Cycloalkyl ,-C
3-6Cycloalkenyl group ,-C
3-6Heterocycle, aryl, aralkyl, five yuan or hexa-atomic fragrant heterocycle; Or-CH
2COL (wherein, L by one or more halogen atoms, cyano group, nitro, carboxyl, trifluoromethyl ,-C
1-4Alkyl ,-C
1-4Alkoxyl group replace or unsubstituted-C
1-12Alkyl ,-C
3-6Cycloalkyl ,-C
3-6Cycloalkenyl group ,-C
3-12Heterocycle, aryl, five yuan or hexa-atomic fragrant heterocycle);
R ' is :-H, halogen, cyano group, nitro, hydroxyl, amino, trifluoromethyl ,-C
1-6Alkyl; M is 0,1 or 2;
Preferred compound of the present invention is Ia:
Wherein,
Y is :-H ,-F ,-Br ,-C
1-4Alkyl;
Z is :-H ,-CH
3
K is :-H ,-CH
3
R is :-C
1-6Alkyl, cycloalkyl; Single replace or two substituted benzyl (wherein, the substituting group on the phenyl ring is-H-OCH
3,-F ,-OH ,-CN, replacing the position is ortho position and/or contraposition); Or-CH
2(wherein, L is furan nucleus or single the replacement or disubstituted phenyl ring to COL, and the substituting group on the phenyl ring is-H-OCH
3,-F ,-OH ,-CN, replacing the position is ortho position and/or contraposition);
The compound of general formula I of the present invention, available following two kinds of methods preparation.
Method one:
Cyclohexyl methyl aceto acetate (abbreviation 'beta '-ketoester) (4) with replacement is a raw material, closes 6-(cyclohexyl methyl) thiouracil (3A) that encircles the replacement that makes with thiocarbamide condensation under sodium alkoxide catalysis, then with methyl iodide (CH
3I) reaction makes 2-methylthio group-6-(cyclohexyl methyl) pyrimidone (2) of replacement, last and each replacement amine
React target compound (1A), its reaction formula is as follows:
Wherein,
(1) 'beta '-ketoester (4) but reference literature (M.Artico, J Med Chem, 1997,42,619) method preparation, with the cyclohexyl acetic acid (5) that replaces be raw material and the cyclohexyl acetyl imidazole (6) of CDI prepared in reaction replacement, so with propanedioic acid monopotassium salt (8) the prepared in reaction 'beta '-ketoester (4) of replacement, its reaction formula is as follows:
(2) substituting group Y is :-H, halogen, cyano group, hydroxyl, amino, trifluoromethyl ,-C
1-6Alkyl ,-C
3-6Cycloalkyl; Z is :-H ,-C
1-3Alkyl ,-halogen ,-CN; K is :-H ,-C
1-6Alkyl ,-C
3-6Cycloalkyl; R is-H, by one or more halogen atoms, cyano group, nitro, carboxyl, trifluoromethyl ,-C
1-4Alkyl ,-C
1-4Alkoxyl group replace or unsubstituted-C
1-12Alkyl ,-C
3-6Cycloalkyl ,-C
3-6Cycloalkenyl group ,-C
3-6Heterocycle, aryl, aralkyl, five yuan or hexa-atomic fragrant heterocycle; R ' is :-H, halogen, cyano group, nitro, hydroxyl, amino, trifluoromethyl ,-C
1-6Alkyl; M is 0,1 or 2;
(3) 6-cyclohexyl methyl thiouracil (3A) of Qu Daiing and methyl iodide (CH
3I) Fan Ying mol ratio is 1:1.5～1:2, and it is between 20～60 ℃ that temperature of reaction is controlled at, and the reaction times is 4-8 hour;
(4) used solvent 1 is toluene and/or methylene dichloride and/or N, a kind of in dinethylformamide and/or the acetonitrile or their mixture;
(5) 2-methylthio group-6-(cyclohexyl methyl) pyrimidone (2) of Qu Daiing replaces amine with each
The reaction mol ratio is 1:1.5～1:3, tube sealing reaction, and it is between 60～200 ℃ that temperature of reaction is controlled at, the reaction times is 12-24 hour;
Method two:
With 'beta '-ketoester (4) is raw material, closes 2-amino-6-(cyclohexyl methyl) pyrimidone (3B) that encircles the replacement that makes with Guanidinium hydrochloride condensation under sodium alkoxide catalysis, then under The suitable solvent and alkaline condition, respectively with various halides (XCH
2COL) reaction generates the target compound (1B) shown in the formula I of the present invention, and its reaction formula is as follows:
Wherein:
(1) substituting group Y is :-H, halogen, cyano group, hydroxyl, amino, trifluoromethyl ,-C
1-6Alkyl ,-C
3-6Cycloalkyl; Z is :-H ,-C
1-3Alkyl ,-halogen ,-CN; L by one or more halogen atoms, cyano group, nitro, carboxyl, trifluoromethyl ,-C
1-4Alkyl ,-C
1-4Alkoxyl group replace or unsubstituted-C
1-12Alkyl ,-C
3-6Cycloalkyl ,-C
3-6Cycloalkenyl group ,-C
3-12Heterocycle, aryl, five yuan or hexa-atomic fragrant heterocycle; R ' is :-H, halogen, cyano group, nitro, hydroxyl, amino, trifluoromethyl ,-C
1-6Alkyl; M is 0,1 or 2;
(2) 'beta '-ketoester (4) is 1:1～1:1.5 with the mol ratio of Guanidinium hydrochloride reaction, and temperature of reaction is controlled between 20～120 ℃, and the reaction times is 8-12 hour.Used solvent 2 is a kind of in methyl alcohol and/or ethanol and/or the Virahol or their mixture;
(3) the 2-amino of Qu Daiing-6-cyclohexyl methyl pyrimidone (3B) and various halides (XCH
2COL) Fan Ying mol ratio is 1:1～1:1.5, and it is between 120～180 ℃ that temperature of reaction is controlled at, and the reaction times is 8-24 hour;
(4) used solvent 3 is toluene, methylene dichloride, N, a kind of in the dinethylformamide or their mixture.Alkali is sodium alkoxide, salt of wormwood or triethylamine;
The purposes of invention product is as the anti-AIDS drug material standed for.
Through Johns Hopkin university pathology is that external HIV (human immunodeficiency virus)-resistant activity experiment showed, the compound that the chemical structural formula I that proposed by the present invention is comprised, and generally has stronger anti-HIV-1 virus activity and lower cytotoxicity and higher selectivity index.Wherein preferred compound can suppress duplicating of HIV in lower nM scope, and clinical mutant strain Y181C and K103N are had tangible antimutagenic effect.
Embodiment
To help to understand the present invention by following embodiment, but can not limit the scope of the invention.
Synthesizing of embodiment one 5-sec.-propyl-2-(methylthio group)-6-cyclohexyl methyl-4 (3H) pyrimidone (2a)
With 5-sec.-propyl-6-cyclohexyl methyl-2-thiouracil (3mmol) and K
2CO
3Place flask, add the dry DMF of 15ml, stirring at room is reacted half an hour, add methyl iodide (3.6mmol), continue stirring reaction under optimal temperature, TLC follows the tracks of raw material point disappearance stopped reaction, reaction solution is poured in the 30mL frozen water, precipitation is separated out in stirring, filters, and washes precipitation with water, the suction filtration oven dry, crude product, can get the white crystal of 5-sec.-propyl-2-(methylthio group)-6-(cyclohexyl methyl)-4 (3H) pyrimidone (2a), productive rate 85% with the appropriate solvent recrystallization.
1HNMR，(CDCl
3，500MHz)：δ(ppm)＝0.92-0.99(m，4H，cyclohexyl)，1.13-1.26(m，5H，cyclohexyl)，1.30-1.32(d，6H，2CH
3)，1.67(m，2H，cyclohexyl)，2.44-2.46(d，2H，C
H 2 cyclohexyl)，2.53(s，3H，C
H 3 S)，2.96-2.98(m，1H，C
HMe
2)，12.42(s，brs，1H，NH)；
Embodiment two replaces the synthetic of 2-amino-6-(cyclohexyl methyl)-pyrimidine-4 (3H)-ketone (3B)
Sodium Metal 99.5 (0.40mol) is dissolved in the dehydrated alcohol of 200mL the back and adds Guanidinium hydrochloride (0.38mol) and stir 0.5h, filter, stand-by.
Get the 0.52mol sodium Metal 99.5, be dissolved in the dehydrated alcohol of 250mL, add above-mentioned filtrate, stir a moment; Slowly drip 'beta '-ketoester (0.32mol) subsequently, backflow 2h.Ethanol is removed in decompression, use the 300mL water dissolution, filter, filtrate is transferred pH to 6 with HCl, separates out white precipitate, filters, be washed to neutrality, vacuum-drying must replace 2-amino-6-cyclohexyl methyl pyrimidone (3B) crude product, can get white crystal with the appropriate solvent recrystallization, and this product can not purifiedly be directly used in next step reaction.
Embodiment three 2-(substituted amido)-6-replaces the synthetic of cyclohexyl methyl-5-alkyl-4 (3H)-pyrimidin-4-one (1A)
2-methylthio group-5-alkyl-6-is replaced cyclohexyl methyl-4-pyrimidone (0.75mmol) and replace fully mixing of amine (3.75mmol), place tube sealing, reacted 12-24 hour in 140-180 ℃ under the nitrogen protection.Reaction is finished, and cooling is poured in the 30mL water, and the adding ethyl acetate (3 * 50mL) extractions merge organic phase, the saturated common salt water washing, and dry back removal of solvent under reduced pressure, column chromatography for separation can get target product.
Operate as above, column chromatography for separation gets white powder 1A-1, productive rate: 61%; Fusing point: 176-177 ℃;
1HNMR (CDCl
3, 500MHz): δ (ppm)=1.04-1.75 (m, 11H, cyclohexyl), 1.23-1.26 (t, 3H, CH
2C
H 3 ), 2.30-2.50 (q, 2H, C
H 2 CH
3), 2.49-2.50 (d, 2H, C
H 2 Cyclohexyl), and 7.60-7.85 (m, 4H, Ph-H), 9.09 (s, brs, 1H, N
H-Ph), 12.00 (s, brs, 1H, NH).
Operate as above, column chromatography for separation gets pale yellow powder 1A-2, productive rate: 52%; Fusing point: 228-230 ℃;
1HNMR (CDCl
3, 500MHz): δ (ppm)=1.05-1.85 (m, 11H, cyclohexyl), 2.04 (s, 3H, CH
3), 2.49-2.50 (d, 2H, C
H 2 Cyclohexyl), and 7.61-7.87 (m, 4H, Ph-H), 9.09 (s, brs, 1H, N
H-Ph-CN), 12.15 (s, brs, 1H, NH).
Operate as above, column chromatography for separation gets white powder 1A-3; Productive rate: 57%; Fusing point: 236-238 ℃;
1HNMR (CDCl
3, 500MHz): δ (ppm)=1.02-1.82 (m, 11H, cyclohexyl), 1.3l-1.37 (d, 6H, 2CH
3), 2.53-2.54 (d, 2H, C
H 2 Cyclohexyl), 3.05 (m, 1H, C
HMe
2), 7.60-7.92 (m, 4H, Ph-H), 9.35 (s, brs, 1H, N
H-Ph), 12.99 (s, brs, 1H, NH);
Operate as above, column chromatography for separation gets white powder 1A-4, productive rate: 47%; Fusing point: 173-174 ℃;
1HNMR (CDCl
3, 500MHz): 0.97-1.72 (m, 22H, 2 cyclohexyl), 2.01 (s, 3H, CH
3), 2.34-2.49 (d, 2H, C
H 2 Cyclohexyl), 11.48 (s, brs, 1H, NH);
Operate as above, column chromatography for separation gets pale yellow powder 1A-5, productive rate: 57%; Fusing point: 192-193 ℃;
1HNMR (CDCl
3, 500MHz): δ (ppm)=1.03-1.72 (m, 11H, cyclohexyl), 1.21-1.24 (t, 3H, CH
2C
H 3 ), 2.38 (q, 2H, C
H 2 CH
3), 2.41-2.44 (d, 2H, C
H 2 Cyclohexyl), 6.57-6.68 (s, 2H, Ph-N
H 2 ), 7.04-7.44 (m, 4H, Ph-H), 9.11 (s, brs, 1H, N
H-Ph), 11.90 (s, brs, 1H, NH).
Operate as above, column chromatography for separation gets pale yellow powder 1A-2, productive rate: 49%;
1HNMR (CDCl
3, 500MHz): δ (ppm)=1.08 (d, 3H, CH
3), 1.35-1.87 (m, 10H, cyclohexyl), 1.98 (s, 3H, CH
3), 2.47-2.48 (d, 2H, C
H 2 Cyclohexyl), and 7.60-7.84 (m, 4H, Ph-H), 9.12 (s, brs, 1H, N
H-Ph-CN), 12.05 (s, brs, 1H, NH);
Operate as above, column chromatography for separation gets pale yellow powder 1A-7, productive rate: 51%;
1HNMR (CDCl
3, 500MHz): δ (ppm)=1.18 (d, 3H, CHC
H 3 ), 1.45-1.67 (m, 11H, cyclohexyl), 1.98 (s, 3H, CH
3), 2.47 (m, 1H, C
HCH
3), 7.62-7.78 (m, 4H, Ar-H), 9.08 (s, brs, 1H, N
H-Ph-CN), 12.05 (s, brs, 1H, NH);
Synthesizing of embodiment four 6-(cyclohexyl methyl)-5-ethyl-2-(2-oxo-2-phenyl-ethyl amine base) pyrimidine-4 (3H)-ketone (1B-1)
Get 2-amido-6-cyclohexyl methyl-5-ethyl-pyrimidone (2.1mmol), alpha-brominated methyl phenyl ketone (2.1mmol), DMF (15mL) and place in the reaction flask, under the nitrogen protection, in 140-160 ℃ of stirring reaction 4h.Be cooled to room temperature, reaction solution poured in the 70mL frozen water stirred, separate out yellow mercury oxide, filter, the dry crude product that gets can get the pure product of target compound 1B-1, productive rate 48% through column chromatography for separation.
1H?NMR(CDCl
3)δ(ppm)：0.86-1.64(m，11H，cyclohexyl)，1.07(t，3H，CH
2C
H 3 )，2.0(s，1H，NH)，2.38(d，2H，-C
H 2 cyclohexyl)，2.54-2.59(q，2H，C
H 2 CH
3)，5.37(d，2H，C
H 2 -NH)，7.41-7.88(m，5H，Ph-H)，12.35(s，brs，1H，NH)；
The test of embodiment five HIV (human immunodeficiency virus)-resistant activity
The anti HIV-1 virus activity of cell in vitro level is measured by pathology system of Johns Hopkin university.Comprise MT-4 and C8166 cell inhibitory activity that HIV is infected, cytotoxicity two aspects.
Materials and methods:
The HIV (human immunodeficiency virus)-resistant activity of each compound is monitored by the cytopathic restraining effect efficient that causes in the medicine pair cell.Adopt MT-4 and C8166 cell to carry out cell cultures.The virus strain that adopts has: HIV-1 III
BVirus strain, HIV-2 virus strain ROD and typical NNRTIs selective variant RES056 (variation position and variation type are: K103N and Y181C).Concrete operations are as follows:
Testing compound is diluted to different concns solution with DMSO dissolving back with the phosphate buffered common salt aqueous solution.Because MT-4 and C8166 cell that HIV infects often in 5-7 days pathology take place, therefore in HIV-1 cells infected suspension liquid, add the testing compound solution of different concns, at 5% CO
2Atmosphere after the cultivation of (5-7 days), uses mtt assay to measure the survivaling cell number through after a while in 37 ℃, must protect 50% cell to avoid cytopathic drug level (EC
50), get final product the activity of anti-HIV of compound.Toxicity test and HIV (human immunodeficiency virus)-resistant activity experiment parallel running also in MT-4 or C8166 cell cultures, are measured compound with mtt assay and are made 50% non-infected cells that cytopathic concentration (CC take place
50), and calculate selectivity index SI=CC
50/ EC
50
The present invention is contrast with AZT, NVP, through pathology system of Johns Hopkin university 35 polysubstituted N-DACO compounds of synthetic has been carried out the anti-HIV-1 screening active ingredients.Experimental result shows, the compound of surveying generally has obvious inhibiting activity to wild-type HIV-1, preferred compound wherein can suppress duplicating of HIV in lower nM scope, and cytotoxicity is less, some compound is higher than inverase AZT and the NVP that has now gone on the market to the inhibition activity of selecting property variant RES056, and is in progress to more activity rating and pharmacological evaluation.
Claims (6)
1, a kind of polysubstituted dihydro amido cyclohexyl methyl Pyrimdinone (Dihydro-Alkylamino-Cyclohexylmethyl-Oxopyrimidines, N-DACO) compound, its general structure are I, with and N-oxide compound, stereoisomer form, stereoisomer mixture or pharmacy acceptable salt:
Wherein,
Y is :-H, halogen, cyano group, hydroxyl, amino, trifluoromethyl ,-C
1-6Alkyl ,-C
3-6Cycloalkyl;
Z is :-H ,-C
1-3Alkyl ,-halogen ,-CN;
K is :-H ,-C
1-6Alkyl ,-C
3-6Cycloalkyl;
R is :-H, by one or more halogen atoms, cyano group, nitro, carboxyl, trifluoromethyl ,-C
1-4Alkyl ,-C
1-4Alkoxyl group replace or unsubstituted-C
1-12Alkyl ,-C
3-6Cycloalkyl ,-C
3-6Cycloalkenyl group ,-C
3-6Heterocycle, aryl, aralkyl, five yuan or hexa-atomic fragrant heterocycle; Or-CH
2COL (wherein, L by one or more halogen atoms, cyano group, nitro, carboxyl, trifluoromethyl ,-C
1-4Alkyl ,-C
1-4Alkoxyl group replace or unsubstituted-C
1-12Alkyl ,-C
3-6Cycloalkyl ,-C
3-6Cycloalkenyl group ,-C
3-12Heterocycle, aryl, five yuan or hexa-atomic fragrant heterocycle);
R ' is :-H, halogen, cyano group, nitro, hydroxyl, amino, trifluoromethyl ,-C
1-6Alkyl;
M is 0,1 or 2.
2, compound as claimed in claim 1 is characterized in that general structure is Ia:
Wherein,
Y is :-H ,-F ,-Br ,-C
1-4Alkyl;
Z is :-H ,-CH
3
K is :-H ,-CH
3
R is :-C
1-6Alkyl, cycloalkyl; Single replace or two substituted benzyl (wherein, the substituting group on the phenyl ring is-H-OCH
3,-F ,-OH ,-CN, replacing the position is ortho position and/or contraposition); Or-CH
2(wherein, L is furan nucleus or single the replacement or disubstituted phenyl ring to COL, and the substituting group on the phenyl ring is-H-OCH
3,-F ,-OH ,-CN, replacing the position is ortho position and/or contraposition).
3, the preparation method of the compound of general formula I according to claim 1 is characterized in that:
Cyclohexyl methyl aceto acetate (abbreviation 'beta '-ketoester) (4) with replacement is a raw material, closes 6-(cyclohexyl methyl) thiouracil (3A) that encircles the replacement that makes with thiocarbamide condensation under sodium alkoxide catalysis, then with methyl iodide (CH
3I) reaction makes 2-methylthio group-6-(cyclohexyl methyl) pyrimidone (2) of replacement, last and each replacement amine
React target compound (1A), its reaction formula is as follows:
Wherein,
(1) 'beta '-ketoester (4) but reference literature (M.Artico, J Med Chem, 1997,42,619) method preparation, with the cyclohexyl acetic acid (5) that replaces be raw material and the cyclohexyl acetyl imidazole (6) of CDI prepared in reaction replacement, so with propanedioic acid monopotassium salt (8) the prepared in reaction 'beta '-ketoester (4) of replacement, its reaction formula is as follows:
(2) substituting group Y is :-H, halogen, cyano group, hydroxyl, amino, trifluoromethyl ,-C
1-6Alkyl ,-C
3-6Cycloalkyl; Z is :-H ,-C
1-3Alkyl ,-halogen ,-CN; K is :-H ,-C
1-6Alkyl ,-C
3-6Cycloalkyl; R is-H, by one or more halogen atoms, cyano group, nitro, carboxyl, trifluoromethyl ,-C
1-4Alkyl ,-C
1-4Alkoxyl group replace or unsubstituted-C
1-12Alkyl ,-C
3-6Cycloalkyl ,-C
3-6Cycloalkenyl group ,-C
3-6Heterocycle, aryl, aralkyl, five yuan or hexa-atomic fragrant heterocycle; R ' is :-H, halogen, cyano group, nitro, hydroxyl, amino, trifluoromethyl ,-C
1-6Alkyl; M is 0,1 or 2;
(3) 6-cyclohexyl methyl thiouracil (3A) of Qu Daiing and methyl iodide (CH
3I) Fan Ying mol ratio is 1:1.5～1:2, and it is between 20～60 ℃ that temperature of reaction is controlled at, and the reaction times is 4-8 hour;
(4) used solvent 1 is toluene and/or methylene dichloride and/or N, a kind of in dinethylformamide and/or the acetonitrile or their mixture;
(5) 2-methylthio group-6-(cyclohexyl methyl) pyrimidone (2) of Qu Daiing replaces amine with each
The reaction mol ratio is 1:1.5～1:3, tube sealing reaction, and it is between 60～200 ℃ that temperature of reaction is controlled at, the reaction times is 12-24 hour;
4, the preparation method of the compound of general formula I according to claim 1 is characterized in that:
With 'beta '-ketoester (4) is raw material, closes 2-amino-6-(cyclohexyl methyl) pyrimidone (3B) that encircles the replacement that makes with Guanidinium hydrochloride condensation under sodium alkoxide catalysis, then under The suitable solvent and alkaline condition, respectively with various halides (XCH
2COL) reaction generates the target compound (1B) shown in the formula I of the present invention, and its reaction formula is as follows:
Wherein,
(1) substituting group Y is :-H, halogen, cyano group, hydroxyl, amino, trifluoromethyl ,-C
1-6Alkyl ,-C
3-6Cycloalkyl; Z is :-H ,-C
1-3Alkyl ,-halogen ,-CN; L by one or more halogen atoms, cyano group, nitro, carboxyl, trifluoromethyl ,-C
1-4Alkyl ,-C
1-4Alkoxyl group replace or unsubstituted-C
1-12Alkyl ,-C
3-6Cycloalkyl ,-C
3-6Cycloalkenyl group ,-C
3-12Heterocycle, aryl, five yuan or hexa-atomic fragrant heterocycle; R ' is :-H, halogen, cyano group, nitro, hydroxyl, amino, trifluoromethyl ,-C
1-6Alkyl; M is 0,1 or 2;
(2) 'beta '-ketoester (4) is 1:1～1:1.5 with the mol ratio of Guanidinium hydrochloride reaction, and temperature of reaction is controlled between 20～120 ℃, and the reaction times is 8-12 hour.Used solvent 2 is a kind of in methyl alcohol and/or ethanol and/or the Virahol or their mixture;
(3) the 2-amino of Qu Daiing-6-cyclohexyl methyl pyrimidone (3B) and various halides (XCH
2COL) Fan Ying mol ratio is 1:1～1:1.5, and it is between 120～180 ℃ that temperature of reaction is controlled at, and the reaction times is 8-24 hour;
(4) used solvent 3 is toluene, methylene dichloride, N, a kind of in the dinethylformamide or their mixture.Alkali is sodium alkoxide, salt of wormwood or triethylamine.
5, the pharmacy acceptable salt of compound according to claim 1 is characterized in that being hydrochloride, vitriol, tartrate, Citrate trianion.
6, be used for the treatment of the catch purposes of shape or the relevant medicine of disease as claim 1,2,5 described arbitrary compounds in preparation with HIV.
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Cited By (2)
| 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 |
-
2009
- 2009-02-05 CN CNA2009100940849A patent/CN101475535A/en active Pending
Cited By (4)
| 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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