CN102382062B - Naphthenic base aryl pyrimidines derivative, preparation method and application thereof - Google Patents
Naphthenic base aryl pyrimidines derivative, preparation method and application thereof Download PDFInfo
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- CN102382062B CN102382062B CN201110218038.2A CN201110218038A CN102382062B CN 102382062 B CN102382062 B CN 102382062B CN 201110218038 A CN201110218038 A CN 201110218038A CN 102382062 B CN102382062 B CN 102382062B
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a naphthenic base aryl pyrimidines derivative, a preparation method and application thereof. The structural formula of the compound is shown in formula (I), the compound comprises stereochemical isomer, hydrate, solvate and polycrystal or eutectic of the compound, and precursor and derivatives with the same biological functions of the compound. Pharmacological tests show that: the compound has obvious anti-human immunodeficiency virus (HIV)-1 activity, can effectively restrain the MT-4 cells infected by the HIV-1 from replication, and has lower cytotoxicity. Consequently, the composite which contains one or a plurality of the compound(s) can be used for preparing related medicines for curing aids and the like.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of cycloalkyl Arylpyrimidines analog derivative and its production and use.
Background technology
Acquired immune deficiency syndrome (AIDS) (AIDS) is that acquired immune deficiency syndrome (AIDS) (Acquired immune deficiency syndrome) is the epidemic infectious diseases being caused by human immunodeficiency virus (Human immunodeficiency virus, HIV).
Studies show that, reversed transcriptive enzyme (RT) plays irreplaceable effect in the HIV-1 virus replication cycle, becomes one of important target spot of anti-AIDS drug design.In the research of existing inverase, non-nucleoside reverse transcriptase inhibitor (NNRTIs) is called one of focus that various countries' Pharmaceutical Chemist gives more sustained attention because of advantages such as its high-efficiency low-toxicities.At present, anti-NNRTIs through U.S. FDA approval listing has four kinds, nevirapine (Nevirapine), delavirdine (Delavirdine), efavirenz (Efavirenz) and etravirine (Etravirine, TMC-125), also have multiple drug candidate to enter clinical trial.
Diarylmiazines derivatives (DAPYs, general structure is as above formula) is the NNRTIs that the class of being shown great attention in recent years has higher Anti-HIV-1 Active, through a series of structure of modification, has developed a series of compounds with better prospect.Wherein, the Diarylmiazines inverase etravirine (Etravirine of U.S. Tibotec company exploitation, TMC-125) in 2008, obtained FDA approval listing, another diaryl pyrimidine compounds rilpivirine (Rilpivirine of the said firm, TMC-125) phase iii clinical trial data also made us inspiring very much, and Tibotec company has submitted the application for quotation of this medicine to FDA in 2010.
Document (
journal of Medicinal Chemistry 2010, 53(10), 4295-4299) report keeps good molecular flexibility extremely important to the activity of diaryl pyrimidine compounds.Therefore, we attempt left wing's aromatic ring of diaryl pyrimidine compounds to replace with saturated alkyl ring, better have the compound of HIV activity to obtaining molecular flexibility.
Summary of the invention
The object of the invention is to propose a kind of reverse transcriptase inhibitors cycloalkyl Arylpyrimidines analog derivative.
Another object of the present invention is to propose the preparation method of above-claimed cpd.
A further object of the present invention is the application that proposes above-claimed cpd.
Cycloalkyl Arylpyrimidines analog derivative provided by the invention (CAPYs), has one of following structural formula:
。
R wherein
1be selected from hydrogen, hydroxyl, halogen atom, cyano group, amino, sulfoamido, carboxyl, ester group, nitro, C
1 ~ 6alkyl, C
1 ~ 6alkoxyl group, C
1 ~ 6alkane sulfydryl, C
1 ~ 6hydroxyalkyl, C
3 ~ 7cycloalkyl, C
3 ~ 7cycloalkyloxy, C
3 ~ 7naphthene amino, the C of replacement
2 ~ 6thiazolinyl, the C of replacement
2 ~ 6alkene oxygen base, the C of replacement
2 ~ 6alkynyl.M represents monosubstituted or polysubstituted, the integer that its numerical value is 1-5.
R
2and R
3be selected from hydrogen, hydroxyl, halogen atom, cyano group, amino, sulfoamido, carboxyl, ester group, nitro, C
1 ~ 3alkyl, C
1 ~ 3alkoxyl group, C
1 ~ 3alkane sulfydryl, C
1 ~ 3hydroxyalkyl, cyclopropyl, ring propoxy-, cyclopropylamino, the C of replacement
2 ~ 4thiazolinyl, the C of replacement
2 ~ 4alkene oxygen base, the C of replacement
2 ~ 4alkynyl.
Cycloalkyl is monosubstituted or polysubstituted cycloalkyl.Cycloalkyl is monosubstituted or polysubstituted cyclohexyl, cyclopentyl or cyclopropyl.Substituting group in cycloalkyl is selected from hydrogen, hydroxyl, halogen atom, cyano group, amino, sulfoamido, carboxyl, ester group, nitro, C
1 ~ 6alkyl, C
1 ~ 6alkoxyl group, C
1 ~ 6alkane sulfydryl, C
1 ~ 6hydroxyalkyl, C
3 ~ 7cycloalkyl, C
3 ~ 7cycloalkyloxy, C
3 ~ 7naphthene amino, the C of replacement
2 ~ 6thiazolinyl, the C of replacement
2 ~ 6alkene oxygen base, the C of replacement
2 ~ 6alkynyl.
X is-O-,-S-, and-NH ,-CH (OH) ,-C (=O)-,-S (=O)-,-SO
2-,-NH-NH-or-NR
5-(R
5for hydroxyl, ester group or C
1 ~ 6alkyl, C
3 ~ 7cycloalkyl, the C of replacement
2 ~ 6thiazolinyl, the C of replacement
2 ~ 6alkynyl) a kind of connection base.
Y is-O-,-S-and-NH-in a kind of connection base.
The reaction expression of preparing this compounds is as follows:
。
Target compound CAPYs(
i)preparation be under the protection of inert nitrogen gas or argon gas, take structural formula as (
iI)compound and cycloalkyl-YH be raw material, under the effect of alkali, obtain through nucleophilic substitution reaction.Cycloalkyl-YH refers to monosubstituted or polysubstituted hexalin, cyclopentanol, and cyclohexylmercaptan, cyclopentyl mercaptan, hexahydroaniline, in cyclopentamine and cyclopropylamine.Described alkali (base) comprises sodium hydrogen, salt of wormwood, sodium carbonate, sodium methylate, one or more in sodium ethylate or potassium tert.-butoxide.
Embodiment
By following part example the present invention may be better understood content, but can not limit content of the present invention.
embodiment 1: I-A's is synthetic
。
3 mmol raw material mix formulas are dissolved in to 20 mL DMF for (II-1) compound and 7 mmol hexalin, under room temperature, add 8 mmol sodium hydrogen, nitrogen protection, be warming up to 100 ℃ of reaction 8h, question response liquid cooling is but imported in 100 mL water afterwards, separates out solid, filter, silica gel column chromatography (ethyl acetate/petroleum ether wash-out) obtains the finished product (I-A), white solid, yield 62%; Mp 190.1-191.2 ℃; H
1nMR (400MHz, DMSO-
d 6) δ (ppm) 1.24-2.00 (m, 10H, cyclohexyl
h 2-11 ), 5.02-5.05 (m, 1H, cyclohexyl
h 1 ), 6.33 (d,
j=6.0 Hz, 1H, pyrimidine
h 5 ), 7.70 (d,
j=8.4 Hz, 2H, Ar
h 2,6), 7.94 (d,
j=8.4Hz, 2H, Ar
h 3,5), 8.24 (d,
j=6.0 Hz, 1H, pyrimidine
h 6 ), 10.02 (s, 1H, NH); C
13nMR (100MHz, DMSO-
d 6) δ (ppm) 23.51,24.98,31.20,73.86,100.49,102.33,118.32,119.54,132.91,144.96,158.51,159.08,168.61; MS (EI) m/z 294 (M
+); Anal. calcd for C
17h
18n
4o.
embodiment 2: I-B's is synthetic
。
3 mmol raw material mix formulas are dissolved in to 20 mL DMF for (II-2) compound and 7 mmol hexalin, under room temperature, add 8 mmol sodium hydrogen, nitrogen protection, be warming up to 100 ℃ of reaction 8h, question response liquid cooling is but imported in 100 mL water afterwards, separates out solid, filter, silica gel column chromatography (ethyl acetate/petroleum ether wash-out) obtains the finished product (I-B), white solid, yield 59%; Mp 141.8-142.5 ℃; H
1nMR (400MHz, DMSO-
d 6) δ (ppm) 1.23-1.99 (m, 10H, cyclohexyl
h 2-11 ), 2.27 (s, 3H, Me), 4.96-5.01 (m, 1H, cyclohexyl
h 1 ), 6.20 (s, 1H, pyrimidine
h 5 ), 7.68 (d,
j=8.8 Hz, 2H, Ar
h 2,6), 7.94 (d,
j=8.8 Hz, 2H, Ar
h 3,5), 9.99 (s, 1H, NH); C
13nMR (100MHz, DMSO-
d 6) δ (ppm) 23.37,23.54,25.02,31.30,73.79,98.76,102.12,118.18,119.60,132.89,145.14,158.73,168.22,169.12; MS (EI) m/z 308 (M
+); Anal. calcd for C
18h
20n
4o.
embodiment 3: I-C's is synthetic
。
3 mmol raw material mix formulas are dissolved in to 20 mL DMF for (II-1) compound and 8 mmol cyclopentamine, under room temperature, add 6 mmol salt of wormwood, be warming up to 100 ℃ of reaction 8h, question response liquid cooling is but imported in 100 mL water afterwards, separate out solid, filter, silica gel column chromatography (ethyl acetate/petroleum ether wash-out) obtains the finished product (I-C): white solid, yield 54%; Mp 203.6-204.9 ℃; H
1nMR (400MHz, DMSO-
d 6) δ (ppm) 1.45-1.97 (m, 8H, cyclopentyl
h 2-9 ), 4.25 (brs, 1H, cyclopentyl
h 1 ), 6.01 (d,
j=6.0 Hz, 1H, pyrimidine
h 5 ), 7.24 (brs, 1H, NH, deuterium-exchanged), 7.64 (d,
j=8.4 Hz, 2H, Ar
h 2,6), 7.83 (s, 1H, pyrimidine
h 6 ), 8.01 (d,
j=8.8 Hz, 2H, Ar
h 3,5), 9.53 (s, 1H, NH, deuterium-exchanged); C
13nMR (100MHz, DMSO-
d 6) δ (ppm) 23.48,32.37,51.67,99.19,101.19,117.96,119.86,132.78,145.90,154.30,159.22,162.15; MS (ESI+) m/z 280 (M+H)
+; Anal. calcd for C
16h
17n
5.
embodiment 4: I-D's is synthetic
。
3 mmol raw material mix formulas are dissolved in to 20 mL DMF for (II-1) compound and 5 mmol cyclohexylmercaptans, under room temperature, add 8 mmol sodium hydrogen, nitrogen protection, be warming up to 100 ℃ of reaction 8h, question response liquid cooling is but imported in 100 mL water afterwards, separates out solid, filters, silica gel column chromatography (ethyl acetate/petroleum ether wash-out) obtains the finished product (I-D): light yellow solid, yield 66%; Mp 207.1-207.8 ℃; H
1nMR (400MHz, DMSO-
d 6) δ (ppm) 1.26-2.05 (m, 10H, cyclohexyl
h 2-11 ), 3.83 (s, 1H, cyclohexyl
h 1 ), 6.81 (d,
j=5.6 Hz, 1H, pyrimidine
h 5 ), 7.72 (d,
j=8.4 Hz, 2H, Ar
h 2,6), 7.93 (d,
j=8.8 Hz, 2H, Ar
h 3,5), 8.20 (d,
j=5.2 Hz, 1H, pyrimidine
h 6 ), 10.12 (s, 1H, NH); C
13nMR (100MHz, DMSO-
d 6) δ (ppm) 25.13,25.51,32.58,41.54,102.54,110.97,118.43,119.54,132.95,144.76,156.20,158.74,169.85; MS (EI) m/z 310 (M
+); Anal. calcd for C
17h
18n
4s.
embodiment 5: anti-HIV biological activity test
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 * 105MT-4 cell with 100 μ 1 each these solution of compound different concns at 37 ℃ of preculture 1h, then in this compound, add the suitable viral dilution liquid of 100 μ l, 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 in 5%CO2 atmosphere, at 37 ℃, cultivate again 7 days, and the 3rd day after infecting replaces and supplement 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.
Biological activity and the cytotoxicity of table 1 compound anti-HIV-1
Note: in table, dotted portion represents not test.
Four compounds testing all have other activity of micromole's level, wherein with compound
i-Dactivity is the strongest.The cycloalkyl moiety of the compound of synthesized is all without any substituting group, and therefore activity still has very large room for promotion.
Claims (7)
1. a cycloalkyl Arylpyrimidines analog derivative, is characterized in that having one of following structural formula:
Wherein, R
1for cyano group, m is 1; R
2and R
3represent hydrogen or methyl; X represents NH; Y represents O, NH or S; Cycloalkyl representative ring hexyl, cyclopentyl.
2. a preparation method for cycloalkyl Arylpyrimidines analog derivative as claimed in claim 1, its reaction expression is as follows:
it is characterized in that under the protection of inert nitrogen gas or argon gas, compound and cycloalkyl-YH that the structural formula of take is (II) are raw material, under the effect of alkali, through nucleophilic substitution reaction, obtain target compound;
Wherein, R
1for cyano group, m is 1; R
2and R
3represent hydrogen or methyl; X represents NH; Y represents O, NH or S; Cycloalkyl representative ring hexyl, cyclopentyl.
3. preparation method as claimed in claim 2, is characterized in that raw material cycloalkyl-YH is hexalin, cyclopentanol, cyclohexylmercaptan, cyclopentyl mercaptan, hexahydroaniline or cyclopentamine.
4. preparation method as claimed in claim 2, is characterized in that described alkali is sodium hydrogen, salt of wormwood, sodium carbonate, sodium methylate, a kind of in sodium ethylate or potassium tert.-butoxide, or wherein several.
5. a pharmaceutical composition, is characterized in that containing effective dose arbitrary compound as claimed in claim 1 and pharmaceutical carrier.
6. the application of cycloalkyl Arylpyrimidines analog derivative in preparation prevention and treatment AIDS-treating medicine as claimed in claim 1.
7. the application of pharmaceutical composition in preparation prevention and treatment AIDS-treating medicine as claimed in claim 5.
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US5264621A (en) * | 1991-10-25 | 1993-11-23 | Sanyo-Kokusaku Pulp Co., Ltd. | Anti-virus agent |
CN101553483A (en) * | 2006-12-13 | 2009-10-07 | 弗·哈夫曼-拉罗切有限公司 | 2-(piperidin-4-yl)-4-phenoxy-or phenylamino-pyrimidine derivatives as non-nucleoside reverse transcriptase inhibitors |
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JP2589120B2 (en) * | 1988-02-16 | 1997-03-12 | 株式会社日本抗体研究所 | Anti-HIV agent |
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US5264621A (en) * | 1991-10-25 | 1993-11-23 | Sanyo-Kokusaku Pulp Co., Ltd. | Anti-virus agent |
CN101553483A (en) * | 2006-12-13 | 2009-10-07 | 弗·哈夫曼-拉罗切有限公司 | 2-(piperidin-4-yl)-4-phenoxy-or phenylamino-pyrimidine derivatives as non-nucleoside reverse transcriptase inhibitors |
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