WO2018000450A1 - 四氢噻喃并嘧啶类衍生物及其制备方法与应用 - Google Patents

四氢噻喃并嘧啶类衍生物及其制备方法与应用 Download PDF

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WO2018000450A1
WO2018000450A1 PCT/CN2016/089710 CN2016089710W WO2018000450A1 WO 2018000450 A1 WO2018000450 A1 WO 2018000450A1 CN 2016089710 W CN2016089710 W CN 2016089710W WO 2018000450 A1 WO2018000450 A1 WO 2018000450A1
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chloride
bromide
substituted
tetrahydrothiopyranopyrimidine
formula
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PCT/CN2016/089710
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French (fr)
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刘新泳
张衡
展鹏
周忠霞
康东伟
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山东大学
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Priority to US15/735,135 priority Critical patent/US10590145B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the invention belongs to the technical field of medicine, in particular to a tetrahydrothiopyran pyrimidine derivative and a pharmaceutically acceptable salt, ester or prodrug thereof, and the invention also relates to a preparation method of the derivative and the preparation thereof Use in human immunodeficiency virus (HIV) drugs.
  • HAV human immunodeficiency virus
  • AIDS is a major infectious disease that is a serious threat to human health, killing millions of people every year.
  • anti-AIDS monomers or combination preparations are currently available, these drugs can only limit the HIV virus to a detectable range, and cannot be completely eliminated from the human body. Therefore, AIDS patients need to take medicine for life.
  • the long-term use of existing HIV drugs can lead to serious side effects and drug resistance, so there is an urgent need to develop new anti-HIV drugs.
  • reverse transcriptase plays an important role in the replication process of HIV virus.
  • Reverse transcriptase inhibitors have been reported to fall into two main categories: nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), which are highly toxic and low-toxic. extensive attention. However, due to the lack of calibration in the HIV virus replication process, HIV virus is highly susceptible to mutation and drug resistance. Therefore, the development of new anti-drug resistant NNRTIs is one of the important research directions of anti-AIDS drugs.
  • NRTIs nucleoside reverse transcriptase inhibitors
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • Diarylpyrimidine (DAPY) NNRTIs are a class of highly potent, low toxicity, anti-drug resistant HIV-1 inhibitors.
  • etravirine and rivivirin due to the poor water solubility of such compounds, their oral bioavailability is low, which greatly limits their clinical application. Therefore, the development of anti-HIV-1 drugs with better activity, stronger resistance to drug resistance, higher oral bioavailability and independent intellectual property rights is of great significance.
  • the present invention provides a tetrahydrothiopyranopyrimidine derivative and a process for the preparation thereof, and the present invention also provides the use of a tetrahydrothiopyranopyrimidine derivative as an HIV-1 inhibitor.
  • n 0, 1 or 2;
  • X is O or NH
  • R 1 , R 2 and R 3 are each independently: H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, trifluoromethyl, amino, hydroxy, cyano Vinyl, cyanoethyl or cyclopropyl;
  • Ar is: a substituted benzene ring, a substituted naphthalene ring, various substituted six-membered heterocyclic rings, various substituted five-membered heterocyclic rings, various substituted six-membered five-membered heterocyclic rings, various substituted six-membered six-membered rings.
  • Ar is a substituted benzene ring having the formula (a) or (b):
  • R 4 is H, CN, Me, COR 5 , COOR 5 , CONH 2 , CONHR 5 , SO 2 R 5 , SO 2 NH 2 , SO 2 NHR 5 , NO 2 , NH 2 , NHR 5 , NHCOR 5 or NHSO 2 R 5 ;
  • R 5 is a C1-C10 alkane, a cycloalkane, a halogenated alkane, an alkene or an aromatic hydrocarbon.
  • R 5 is Me or CH 3 CO.
  • the "pharmaceutically acceptable salt” as used in the present invention means that within the scope of reliable medical evaluation, the salt of the compound is suitable for contact with tissues of human or lower animals without undue toxicity, irritation and allergy. Reactions, etc., have a fairly reasonable yield/risk ratio, usually water or oil soluble or dispersible, and can be effectively used for their intended use.
  • a pharmaceutically acceptable acid addition salt and a pharmaceutically acceptable base addition salt are included herein for the intended use and are compatible with the chemical nature of the compound of formula I. See S. M. Birge et al, J. Pharm. Sci., 1977, 66, pp. 1-19 for a list of suitable salts.
  • a “prodrug” as used in the present invention refers to a pharmaceutically acceptable derivative such that the biotransformation product obtained from these derivatives is an active drug as defined by the compound of formula I.
  • the tetrahydrothiopyranopyrino compound is one of the compounds having the formula:
  • R 1 , R 2 , R 3 and R 4 are as shown in the formula I or II.
  • a method for preparing a tetrahydrothiopyranoline derivative which is obtained by reacting methyl thioglycolate (A) and methyl 4-chlorobutyrate (B) with sodium methoxide to obtain 4-((2-methoxy) Methyl 2-oxoethyl)sulfanylbutanoate (C)
  • Intermediate C is subjected to Dieckmann condensation under sodium methoxide to give oxotetrahydrothiopyranate (D)
  • intermediate D and methyl Isothiourea is cyclized under potassium hydroxide to give 2-methylmercaptotetrahydrothiopyrimidin-2-ol (E)
  • intermediate E is hydrolyzed under acetic acid to give tetrahydrothiopyranoline-2,4-
  • the diol (F) the intermediate F is chlorinated with N,N-dimethylaniline in the phosphorus oxychloride to obtain 2,4-dichloro
  • intermediate H is reacted with the corresponding substituted aniline to obtain the target compound; or reacted with 1-Boc-4-aminopiperidine to remove Boc protection and corresponding benzyl chloride Or bromobenzyl reaction to obtain the target compound.
  • the synthetic route is as follows:
  • Reagents and conditions (i) sodium methoxide, potassium iodide, methanol, reflux; (ii) sodium methoxide, toluene, 105 ° C; (iii) methyl isothiouron sulfate, potassium hydroxide, methanol; (iv) acetic acid / water , 110 ° C; (v) phosphorus oxychloride, N, N-dimethylaniline, 90 ° C; (vi) potassium carbonate, N, N-dimethylformamide, substituted phenol or aniline; (vii) a) 1-Boc-4-aminopiperidine, N,N-diisopropylethylamine, N-methylpyrrolidone, 120-130 ° C; b) trifluoroacetic acid / dichloromethane, room temperature; c) substituted benzyl bromide or Benzyl chloride, potassium carbonate, N,N-dimethylformamide, room temperature
  • the substituted phenol or aniline is mesitylene, 2,6-dimethyl-4-cyanophenol, (E)-2,6-dimethyl-4-cyanovinylphenol, and uniform Methylaniline, 2,6-dimethyl-4-cyanoaniline or (E)-2,6-dimethyl-4-cyanovinylaniline.
  • the substituted benzyl bromide or benzyl bromide is o-chlorobenzyl chloride, m-chlorobenzyl chloride, p-chlorobenzyl chloride, o-bromo bromide, m-bromo bromide, p-bromo bromide, o-fluorobenzyl bromide, m-chlorobenzyl chloride, P-fluorobenzyl chloride, 2,4-difluorobenzyl bromide, 3,4-difluoro bromide, o-cyanobenzyl chloride, m-cyanobenzyl chloride, p-cyanobenzyl chloride, o-nitrobenzyl chloride, m-nitro Benzyl chloride, p-nitrobenzyl chloride, o-methoxybenzyl chloride, m-methoxybenzyl chloride, p-methoxybenzyl chloride, p-methane
  • R 1 , R 2 , R 3 , A, B and X have the same meanings as defined in the above formula I or II.
  • the room temperature according to the invention is 20-30 °C.
  • the tetrahydrothiopyranoline derivatives of the invention can be used as non-nucleoside HIV-1 inhibitors. Specifically, it is used as an HIV-1 inhibitor for the preparation of an anti-AIDS drug.
  • An anti-HIV-1 pharmaceutical composition comprising a tetrahydrothiopyranin derivative of the invention and one or more pharmaceutically acceptable carriers or excipients.
  • the invention provides a novel structure of tetrahydrothiopyranopyrimidine derivatives, a preparation method thereof, screening results thereof for anti-HIV-1 activity and their first application in the field of antiviral. It has been experimentally proved that the tetrahydrothiopyranopidine derivatives of the present invention can be applied as HIV-1 inhibitors and have high application value. Specifically, it is used as an HIV-1 inhibitor for the preparation of an anti-AIDS drug.
  • Step 8a is carried out except that the starting material is 3-(3,5-dimethyl-4-hydroxyphenyl)acrylonitrile instead of 3,5-dimethyl-4-hydroxybenzonitrile.
  • IA-1-1 (100 mg, 0.24 mmol) was dissolved in dichloromethane (10 mL). m. The reaction mixture was extracted with methylene chloride (50 mL), EtOAc (EtOAc)EtOAc. Colorless crystals (67 mg).
  • the target compounds IIA-1-1 to IIA-1-13 were obtained by substituting different bromine (chloro)benzyl and intermediate 9a-9c, and the results were as follows:
  • Iron powder (0.56 g, 10 mmol) was dissolved in 5 mL of water, 0.12 mL of acetic acid was added, and stirred at 50 ° C for 15 minutes, and compound IIA-1-12 (0.53 g, 1 mmol) of N,N-dimethylformamide was quickly added. (10 mL), reacted at 50 ° C for 1 h. The mixture was cooled, and the pH was adjusted with EtOAc (EtOAc) (EtOAc). The residue was purified by silica gel column chromatography eluting elut elut
  • Example 8 Preparation of compounds IIC-1-1, IIC-1-2 and IIC-2-1.
  • Living cells are able to absorb 3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide (MTT) and absorb it into cells.
  • MTT can be reduced in the mitochondria, from yellow to blue-violet, the absorption wavelength will change, while dead cells can not restore MTT.
  • the optical density values (OD values) at 540 nM and 690 nM were measured, and the optical density values were proportional to the number of living cells, and the corresponding survival rate was determined.
  • Cells infected with HIV can survive for up to 5-7 days, and the addition of HIV-1 inhibitors can inhibit viral replication, thereby protecting cells from disease.
  • the concentration of the compound that is free of the lesion ie, the EC 50 value).
  • the inhibitor concentration ie, CC 50 value
  • SI selectivity coefficient
  • HIV-1 (III B ), HIV-2 (ROD) strains, and various HIV-1 resistant strains provided by the Rega Institute of the University of Leuven, Belgium.
  • NTP nevirapine
  • EMR efavirenz
  • ETR etravirine
  • RV rivivirin
  • ZT zidovudine
  • Test method The sample was diluted and added to the HIV-infected MT-4 cell suspension. After a period of time, the cell viability was measured by MTT colorimetry, and the absorbance (A) value at 590 nm was recorded in a microplate reader. Calculate EC 50 , CC 50 and SI.
  • MTT colorimetry After adding a sample solution for a period of time, add 20 ⁇ L of MTT solution (5 mg/ML) to each well. After continuing to culture for several hours, discard the staining solution, and add 150 ⁇ L of DMSO to each well, and mix well. The absorbance (A) value at 590 nm was measured by a microplate reader.
  • a 96-well cell culture plate On a 96-well cell culture plate, add 50 ⁇ L of 1 ⁇ 10 4 MT-4 cell culture medium, and then add 20 ⁇ L of MT-infected with HIV-1 (III B , RES056 or other variant) or HIV-2 (ROD). 4 cell suspension (100 times CCID 50 per ml) or blank medium (toxicity determination), then add different concentrations of test compound solution or positive control drug, and design 3 replicate wells for each concentration. The cells were then cultured in a 5% CO 2 atmosphere at 37 ° C for 5 days. 20 ⁇ L (5 mg/mL) of MTT solution was added to each well, and the culture was continued for 2 hours, then DMSO was added, and the reaction solution was measured at 540 nm using a microplate reader.
  • the absorbance is calculated by calculating the cell proliferation rate P% at different concentrations of the compound.
  • a blank and a drug control group and a positive drug control group were set, thereby calculating the concentration (EC 50 ) required for the compound to protect 50% of the cells from HIV-induced cytopathic effects.
  • Select the calculation of the index: SI CC 50 /EC 50 .
  • a EC 50 concentration of compound that protects 50% of HIV-1 infected MT-4 cells from cytopathic effects
  • A represents compound EC 50 ⁇ 10 nM
  • B represents compound EC 50 value of 10-100 nM
  • C represents compound EC 50 >100nM
  • NVP, EFV, AZT, ETV, RPV represent the marketed drugs nevirapine, efavirenz, zidovudine, etravirine and rivivirin, respectively.
  • the tetrahydrothiopyranoline derivatives of the present invention are a series of non-nucleoside HIV-1 inhibitors having novel skeletons, exhibiting strong anti-HIV-1 wild strain and mutant activity. . Most of the compounds inhibited the wild-type and mutant strains with EC 50 values below 1 ⁇ M. Among them, the activity of compound IA-1-3 was particularly prominent, and its EC 50 value for HIV-1 wild-type strain was the first generation anti-AIDS drug nevirapine. More than 30 times (NVP), comparable to the latest generation of drug etravirine (ETV). Compound IA-1-3 also showed high safety with a selectivity index for HIV-1 wild strains greater than 1000.
  • compound IA-1-2 showed inhibitory activity comparable to etravirine, and inhibitory activity against single mutant strains L100I, Y181C and double mutants (F227L/V106A and Y181C/K103N) More than twice the amount of etravirine. Therefore, tetrahydrothiopyranopyrimines have further development value and can be utilized as a lead compound against HIV-1.

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Abstract

一种四氢噻喃并嘧啶类化合物及其制备方法和应用，所述四氢噻喃并嘧啶类化合物或其药学上可接受的盐或前药，具有如下通式（I）或（II）所示的结构。还包括四氢噻喃并嘧啶类化合物的制备方法以及含有一个或多个此类化合物的组合物在制备治疗和预防人免疫缺陷病毒（HIV）药物中的应用。

Description

四氢噻喃并嘧啶类衍生物及其制备方法与应用 技术领域
本发明属于医药技术领域，具体涉及一种四氢噻喃并嘧啶类衍生物及其药学上可接受的盐、酯或前药，本发明还涉及这类衍生物的制备方法及其在制备抗人免疫缺陷病毒(HIV)药物中的用途。
背景技术
艾滋病(AIDS)是一种严重危害人类健康的重大传染性疾病，每年造成上百万人的死亡。虽然目前已有多种抗艾滋病单体或者复方制剂上市，但是这些药物只能将HIV病毒限制在可检测范围以下，而不能彻底的从人体内清除，因此AIDS感染者需要终生服药。但是，现有HIV药物的长期服用会导致严重的毒副作用和耐药性的出现，因此急需开发新型抗HIV药物。逆转录酶作为HIV病毒生命周期中的关键酶，在HIV病毒复制过程中发挥着重要的作用。已报道的逆转录酶抑制剂主要分为两类：核苷类逆转录酶抑制剂(NRTIs)和非核苷类逆转录酶抑制剂(NNRTIs)，NNRTIs由于具有高效低毒的特点而受到人们的广泛关注。但是由于HIV病毒复制过程中缺乏校正的特点，HIV病毒极易发生突变而产生耐药，因此开发新型抗耐药的NNRTIs是目前抗艾滋病药物研究的重要方向之一。
二芳基嘧啶类(DAPY)NNRTIs是一类高效、低毒、抗耐药的HIV-1抑制剂，目前已有依曲韦林和利匹韦林两种药物上市。但是由于该类化合物水溶性较差，导致其口服生物利用度低，大大限制了其临床应用。因此开发活性更好、抗耐药性更强、口服生物利用度更高并且具有自主知识产权的抗HIV-1药物具有重要的意义。
Figure PCTCN2016089710-appb-000001
发明内容
针对现有技术的不足，本发明提供了一种四氢噻喃并嘧啶类衍生物及其制备方法，本发明还提供了四氢噻喃并嘧啶类衍生物作为HIV-1抑制剂的应用。
本发明的技术方案如下：
1.四氢噻喃并嘧啶类衍生物
一种四氢噻喃并嘧啶类衍生物，或其药学上可接受的盐或前药，具有通式I或II所示的结构：
Figure PCTCN2016089710-appb-000002
其中A为S(＝O)n或CH2；B为S(＝O)n或CH2，并且A和B不能同时为S(＝O)n；n＝0,1或2；
X为O或NH；
R1、R2、R3各自独立的为：H、卤素、氰基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、三氟甲基、氨基、羟基、氰基乙烯基、氰基乙基或环丙基；
Ar为：取代苯环、取代萘环、各种取代的六元杂环、各种取代的五元杂环、各种取代的六元并五元杂环、各种取代的六元并六元杂环、各种取代的五元并五元杂环、各种取代的苯并五元杂环或各种取代的苯并六元杂环。
根据本发明优选的，
R1、R3为甲基，R2为CN、Me或CH＝CHCN；Ar为具有通式(a)或者通式(b)的取代苯环：
Figure PCTCN2016089710-appb-000003
其中，R4为H、CN、Me、COR5、COOR5、CONH2、CONHR5、SO2R5、SO2NH2、SO2NHR5、NO2、NH2、NHR5、NHCOR5或NHSO2R5；R5为C1-C10烷烃、环烷烃、卤代烷烃、烯烃或芳香烃。优选的，R5为Me或CH3CO。
本发明中所述的“药学上可接受的盐”是指在可靠的医药评价范围内，化合物的盐类适于与人或较低等动物的组织相接触而无不适当的毒性、刺激及过敏反应等，具有相当合理的收益/风险比例，通常是水或油可溶的或可分散的，并可有效地用于其预期的用途。包括药学上可接受的酸加成盐和药学上可接受的碱加成盐，在这里是可做预期的用途并与式I化合物的化学性质相容的。适宜的盐的列表参见S.M.Birge等，J.Pharm.Sci.,1977,66,1-19页。
本发明中所述的“前药”是指药学上可接受的衍生物，以便这些衍生物所得的生物转换产物是如式I化合物所定义的活性药物。
根据本发明进一步优选的，四氢噻喃并嘧啶类化合物为具有下列结构式的化合物之一：
Figure PCTCN2016089710-appb-000004
其中，R1、R2、R3、R4如通式I或II所示。
更进一步优选的，四氢噻喃并嘧啶类衍生物为如下具体化合物之一：
Figure PCTCN2016089710-appb-000005
Figure PCTCN2016089710-appb-000006
2.四氢噻喃并嘧啶类衍生物的制备方法
四氢噻喃并嘧啶衍生物的制备方法，以巯基乙酸甲酯(A)和4-氯丁酸甲酯(B)为原料，在甲醇钠的条件下反应得到4-((2-甲氧基-2-氧代乙基)硫)丁酸甲酯(C)，中间体C在甲醇钠条件下经Dieckmann缩合得到氧代四氢噻喃甲酸酯(D)，中间体D与甲基异硫脲在氢氧化钾条件下环合得到2-甲巯基四氢噻喃并嘧啶-2-醇(E)，中间体E在醋酸条件下水解得到四氢噻喃并嘧啶-2,4-二醇(F)，中间体F在三氯氧磷中以N,N-二甲基苯胺为碱氯化得到2,4-二氯四氢噻喃并嘧啶(G)，中间体G在碱性条件下与取代苯酚或苯胺反应得到中间体H，中间体H与相应的取代苯胺反应得到目标化合物；或与1-Boc-4-氨基哌啶反应，脱去Boc保护之后与相应的氯苄或溴苄反应得到目标化合物。
合成路线如下：
Figure PCTCN2016089710-appb-000007
试剂和条件：(i)甲醇钠，碘化钾，甲醇，回流；(ii)甲醇钠，甲苯，105℃；(iii)甲基异硫脲硫酸盐，氢氧化钾，甲醇；(iv)醋酸/水，110℃；(v)三氯氧磷，N,N-二甲基苯胺，90℃；(vi)碳酸钾，N,N-二甲基甲酰胺，取代苯酚或苯胺；(vii)a)1-Boc-4-氨基哌啶，N,N-二异丙基乙胺，N-甲基吡咯烷酮，120-130℃；b)三氟乙酸/二氯甲烷，室温；c)取代溴苄或氯苄，碳酸钾，N,N-二甲基甲酰胺，室温；(viii)1-取代-4-氨基哌啶，N,N-二异丙基乙胺，N-甲基吡咯烷酮，120-130℃；(ix)4-氨基苯甲腈，2,2'-双-(二苯膦基)-1,1'-联萘，三(二亚苄基丙酮)二钯，1,4-二氧六环。
所述的取代苯酚或苯胺为均三甲基苯酚、2,6-二甲基-4-氰基苯酚、(E)-2,6-二甲基-4-氰基乙烯基苯酚、均三甲基苯胺、2,6-二甲基-4-氰基苯胺或(E)-2,6-二甲基-4-氰基乙烯基苯胺。
所述的取代溴苄或氯苄为邻氯氯苄、间氯氯苄、对氯氯苄、邻溴溴苄、间溴溴苄、对溴溴苄、邻氟氯苄、间氟氯苄、对氟氯苄、2,4-二氟溴苄、3,4-二氟溴苄、邻氰基氯苄、间氰基氯苄、对氰基氯苄、邻硝基氯苄、间硝基氯苄、对硝基氯苄、邻甲氧基氯苄、间甲氧基氯苄、对甲氧基氯苄、对甲磺酰基溴苄、对磺酰胺基溴苄、间磺酰胺基溴苄、对甲酰胺基溴苄、4-溴甲基苯甲酸乙酯、4-溴甲基苯甲酸酰胺、3-溴甲基苯甲酸酰胺、N-(4-溴甲基苯基)甲磺酰胺。
其中，R1、R2、R3、A、B、X的定义同上通式I或II所述。
本发明所述的室温为20-30℃。
3.四氢噻喃并嘧啶类衍生物的抗HIV-1野生株及突变株活性及应用
对按照上述方法合成的部分四氢噻喃并嘧啶类衍生物进行了细胞水平的抗HIV-1(IIIB)， 单耐药突变株L100I、K103N、Y181C、Y188L以及双耐药突变株RES056(K103N/Y181C)、F227L/V106A的活性筛选。经过实验得出：本发明的四氢噻喃并嘧啶衍生物是一系列具有新颖骨架的非核苷类HIV-1抑制剂，表现出了极强的抗HIV-1野生株和突变株活性。因此，四氢噻喃并嘧啶类化合物具有进一步研发的价值，可作为抗HIV-1的先导化合物加以利用。
本发明的四氢噻喃并嘧啶衍生物可作为非核苷类HIV-1抑制剂应用。具体地说，作为HIV-1抑制剂用于制备抗艾滋病药物。
一种抗HIV-1药物组合物，包括本发明的四氢噻喃并嘧啶衍生物和一种或多种药学上可接受载体或赋形剂。
本发明提供了结构全新的四氢噻喃并嘧啶类衍生物、其制备方法、其抗HIV-1活性筛选结果及其在抗病毒领域中的首次应用。经实验证明，本发明的四氢噻喃并嘧啶类衍生物可作为HIV-1抑制剂应用，并具有很高的应用价值。具体地说，作为HIV-1抑制剂用于制备抗艾滋病药物。
具体实施方式
通过下述实例有助于理解本发明，但不能限制本发明的内容。
实施例中所涉及的合成路线如下：
合成路线一：
Figure PCTCN2016089710-appb-000008
实施例1:母环2,6-二氯-7,8-二氢-6H-噻喃[3,2-d]嘧啶(7)的制备
4-((2-甲氧基-2-氧代乙基)硫)丁酸甲酯(3)的制备。
巯基乙酸甲酯(3.93mL,44mmol)溶于甲醇钠(2.75g,51mmol)的甲醇(30mL)溶液，搅拌0.5h，加入碘化钾(50mg)和4-氯丁酸甲酯(6.2mL,51mmol)升温至65℃，反应20h。反应液冷却，过滤后浓缩，加二氯甲烷(100mL)后用水洗(20mL×3)，饱和食盐水洗，无水硫酸钠干燥，过滤浓缩得浅黄色液体2-甲氧基2-氧代乙硫基丁酸甲酯(8.24g)。中间体无需纯化直接进行下一步。
1H NMR(600MHz,CDCl3)δ:3.75(s,3H),3.66(s,3H),3.21(s,2H),2.77(t,J＝7.2Hz,2H),2.66(t,J＝7.2Hz,2H),1.93(p,J＝7.2Hz,2H).ESI-MS:m/z 207.3(M+1)+,224.4(M+18)+.C8H14O4S(206.06).
3-氧代四氢-2H-噻喃-2-甲酸甲酯(4)的制备
中间体3(5g,24.3mmol)溶于甲苯(40mL)中，室温搅拌下加入甲醇钠(1.43g,26.5mmol)，升温至105℃反应3h。冷却，反应液倒入冷却的12N HCl(5mL)中，乙酸乙酯萃取(30mL×3)，合并有机层，饱和食盐水洗，无水硫酸钠干燥，过滤浓缩后硅胶柱色谱分离得浅黄色液体(1.93g)。
产率45.8％，1H NMR(CDCl3)δ:12.18(1H,s),2.79-2.83(2H,m),2.42(2H,t,J＝6.6Hz),2.10-2.17(2H,m).ESI-MS:m/z 175.3(M+1)+,192.5(M+18)+.C7H10O3S(174.04).
2-甲巯基-7,8-二氢-6H-噻喃[3,2-d]嘧啶-2-醇(5)的制备
氢氧化钾(0.57g,10.76mmol)溶于甲醇(30mL)中，加入中间体4a(1.25g,7.17mmol)和甲基异硫脲硫酸盐(1g,3.58mmol)，室温搅拌16h。反应完成后将反应液倒入冰水中(40mL)，加醋酸2mL后过滤，收集沉淀，干燥后得白色固体，反应无需纯化继续进行下一步。
熔点：234-236℃，1H NMR(400MHz,DMSO-d6)δ:12.70(s,1H),2.94-2.84(m,2H),2.61(t,J＝6.3Hz,2H),2.45(s,3H),2.08-1.95(m,2H).ESI-MS:m/z 215.4(M+1)+,237.3(M+23)+.C8H10N2OS2(214.02).
7,8-二氢-6H-噻喃[3,2-d]嘧啶-2,4-二醇(6)的制备
中间体5(1.05g)悬浮于10mL水中，加醋酸20mL后反应液在110℃回流反应3天。反应液冷却，过滤，水洗得无色晶体(0.5g)。
两步产率37.7％，熔点：>300℃，1H NMR(400MHz,DMSO-d6)δ:11.17(s,1H),10.82(s,1H),2.84(d,J＝6.0Hz,2H),2.43(t,J＝6.3Hz,2H),2.04-1.91(m,2H).ESI-MS:m/z 185.0(M+1)+,207.2(M+23)+.C7H8N2O2S(184.03).
2,4-二氯-7,8-二氢-6H-噻喃[3,2-d]嘧啶(7)的制备
中间体6(0.42g,2.3mmol)溶于三氯氧磷(2mL)中，加入N,N-二甲基苯胺(70μL)后升温至90℃反应18小时。冷却至室温后倒入50mL冰水中，二氯甲烷萃取(30mL×3)，合并有机层，饱和食盐水洗，无水硫酸钠干燥，过滤后浓缩，硅胶柱色谱分离，得浅灰色固体(0.35g)。
产率69.4％，熔点：105-108℃，1H NMR(CDCl3)δ:3.09-3.13(2H,m),2.99(2H,t,J＝6.3Hz),2.21-2.28(2H,m).ESI-MS:m/z 221.3(M+1)+.C7H6Cl2N2S(219.96).
合成路线二：
Figure PCTCN2016089710-appb-000009
实施例2:4-((2-氯-7,8-二氢-6H-噻喃[3,2-d]嘧啶-4-基)氧)-3,5-二甲基苯甲腈(8a)的制备
中间体7(0.5g,2.26mmol)溶于N,N-二甲基甲酰胺中，加入碳酸钾(0.38g,2.71mmol)和3,5-二甲基-4-羟基苯甲腈(0.40g,2.71mmol)，室温搅拌过夜。过滤，蒸干后加二氯甲烷溶解，水洗三次，饱和食盐水洗，无水硫酸钠干燥，过滤后蒸干乙酸乙酯/石油醚重结晶得浅灰色粉末(0.54g)。
产率72.5％，熔点：176-179℃，1H NMR(400MHz,DMSO-d6)δ:7.73(s,2H),3.16(d,J＝5.6Hz,2H),2.92(t,J＝6.2Hz,2H),2.23-2.13(m,2H),2.07(s,6H).ESI-MS:m/z 332.4(M+1)+.C16H14ClN3OS(331.05).
2-氯-4-(2,4,6-三甲基苯基)-7,8-二氢-6H-噻喃[3,2-d]嘧啶(8b)的制备
操作步骤同8a，所不同的是起始原料用的是2,4,6-三甲基苯酚代替3,5-二甲基-4-羟基苯甲腈。
浅灰色粉末(0.48g)，产率66.6％，熔点：254-255℃，1H NMR(400MHz,DMSO-d6)δ:7.05(s,2H),3.04-2.93(m,2H),2.66(t,J＝6.1Hz,2H),2.24(s,3H),2.09(dt,J＝12.1,6.1Hz,2H),1.98(s,6H).ESI-MS:m/z 321.4(M+1)+.C16H17ClN2OS(320.08).
E-3-(4-((2-氯-7,8-二氢-6H-噻喃[3,2-d]嘧啶-4-基)氧)-3,5-二甲基苯基)丙烯酰胺(8c)的制备
操作步骤8a，所不同的是起始原料用的是3-(3,5-二甲基-4-羟基苯基)丙烯腈代替3,5-二甲基-4-羟基苯甲腈。
浅灰色粉末(0.7g)，产率86.1％，熔点：240-242℃，1H NMR(400MHz,CDCl3)δ:7.34(d,J＝16.7Hz,1H),7.19(s,2H),5.82(d,J＝16.6Hz,1H),3.17-3.05(m,2H),2.97(t,J＝6.3Hz,2H),2.30(p,J＝6.2Hz,2H),2.13(s,6H).ESI-MS:m/z 358.3(M+1)+.C18H16ClN3OS(357.07).
实施例3：化合物的制备
中间体8a(0.5g,1.5mmol)和对氨基苯甲腈(0.36g,3mmol)溶于二氧六环(20mL)中，加入2,2'-双-(二苯膦基)-1,1'-联萘(93mg,0.15mmol)和三(二亚苄基丙酮)二钯(140mg,0.15mmol)室温搅拌溶解后加入碳酸铯(0.98g,3mmol)，氮气保护下升温至100℃反应3h。冷却过滤后浓缩，乙酸乙酯(100mL)溶解后水洗(20mL×3)，饱和食盐水洗，无水硫酸钠干燥，过滤后硅胶柱色谱分离得白色固体(0.48g)。
Figure PCTCN2016089710-appb-000010
产率77.0％，熔点：253-254℃，1H NMR(400MHz,DMSO-d6)δ:9.98(s,2H),7.78(s,2H),7.45(s,4H),3.19-3.05(m,2H),2.88(t,J＝6.2Hz,2H),2.26-2.16(m,2H),2.11(s,6H).13C NMR(100MHz,DMSO-d6)δ:163.63,163.07,154.68,154.12,145.20,133.10,133.02,132.98,119.92,119.00,118.05,109.09,104.50,102.39,31.74,26.34,22.96,16.12.ESI-MS:m/z 414.5(M+1)+,431.5(M+18)+.C23H19N5OS(413.13).
Figure PCTCN2016089710-appb-000011
操作步骤同IA-1-1，所不同的是使用中间体8c(0.2g)代替中间体8a。
白色粉末(100mg)，产率40.6％。熔点：278-280℃，1H NMR(400MHz,DMSO-d6)δ:9.95(s,1H),7.68(d,J＝16.7Hz,1H),7.54(s,2H),7.48(d,J＝8.6Hz,2H),7.39(d,J＝8.8Hz,2H),6.48(d,J＝16.7Hz,1H),3.19-3.06(m,2H),2.87(t,J＝6.2Hz,2H),2.20(p,J＝6.0Hz,2H),2.08(s,6H).13C NMR(100MHz,DMSO-d6)δ:163.47,163.30,154.76,152.47,150.45,145.29,132.97,131.93,131.63,128.64,119.95,119.33,118.06,104.49,102.26,96.93,31.71,26.33,22.98,16.40.ESI-MS:m/z 440.6(M+1)+,457.6(M+18)+.C25H21N5OS(439.15).
Figure PCTCN2016089710-appb-000012
IA-1-1(200mg,0.48mmol)溶于二氯甲烷(5mL)中，冷却至-78℃，氮气保护下滴加间氯过氧苯甲酸(107mg,0.57mmol)的二氯甲烷溶液(3mL)，反应1h。反应液升至室温，加饱和亚硫酸氢钠(30mL)，乙酸乙酯萃取(20mL×3)，饱和食盐水洗，无水硫酸钠干燥，过滤后硅胶柱色谱分离得白色粉末(150mg)。
产率72.2％，熔点：247-249℃，1H NMR(400MHz,DMSO-d6)δ:10.52(s,1H),7.80(d,J＝4.6Hz,2H),7.50(s,4H),3.32-3.19(m,1H),3.09-2.79(m,3H),2.61-2.51(m,2H),2.15(d,J＝14.7Hz,6H).13C NMR(100MHz,DMSO-d6)δ:169.09,167.61,158.94,153.63,144.12,133.16,133.08,119.60,119.31,118.95,111.11,109.44,104.19,60.21,45.19,32.08,16.22,12.89.ESI-MS:m/z 447.5(M+18)+,452.3(M+23)+.C23H19N5O2S(429.13).
Figure PCTCN2016089710-appb-000013
IA-1-1(100mg,0.24mmol)溶于二氯甲烷(10mL)中，加入间氯过氧苯甲酸(125mg,0.73mmol)，室温搅拌过夜。反应液加二氯甲烷萃取(50mL)，饱和亚硫酸氢钠洗(30mL)，水洗(20mL×2)，饱和食盐水洗，无水硫酸钠干燥，过滤蒸干后乙酸乙酯/氯仿重结晶得无色晶体(67mg)。
产率62.2％，熔点：263-265℃，1H NMR(400MHz,DMSO-d6)δ:10.62(s,1H),7.81(s,2H),7.64-7.18(m,4H),3.69-3.55(m,2H),3.02(t,J＝6.0Hz,2H),2.34(d,J＝5.1Hz,2H),2.16(s,6H).13C NMR(100MHz,DMSO-d6)δ:169.89,164.70,158.49,153.31,143.82,133.19,133.08,132.92,119.52,119.44,118.92,112.61,109.52,104.48,52.49,32.08,18.98,16.08.ESI-MS:m/z463.5(M+18)+,468.4(M+23)+.C23H19N5O3S(445.12).
合成路线四：
Figure PCTCN2016089710-appb-000014
实施例4:3,5-二甲基-4-((2-(哌啶-4-氨基)-7,8-二氢-6H-噻喃[3,2-d]嘧啶-4-基)氧)苯甲腈(9a)的制备
中间体8a(2g,6.03mmol)和1-Boc-4-氨基哌啶(1.45g,7.23mmol)溶于N-甲基吡咯烷酮(10mL)中，加入N,N-二异丙基乙胺(1.2mL)后升温至100-120℃反应4-6h。冷却，乙酸乙酯溶解后水洗(30mL×3)，饱和食盐水洗，无水硫酸钠干燥，过滤蒸干后溶于三氟乙酸和二氯甲烷溶液中，室温反应4h，加饱和碳酸氢钾调节pH显中性后用乙酸乙酯萃取(30mL×3)，合并有机层，饱和食盐水洗，无水硫酸钠干燥，过滤蒸干后硅胶柱色谱分离得白色粉末(1.5g)。
产率62.9％，熔点：250℃分解，1H NMR(400MHz,DMSO-d6)δ:9.00(s,2H),7.67(s,2H),7.02(s,1H),3.14(d,J＝12.5Hz,2H),3.07-2.99(m,2H),2.71(t,J＝6.3Hz,4H),2.18-2.09(m,2H),2.07(s,6H),1.81(s,2H),1.54(s,2H).13C NMR(100MHz,DMSO-d6)δ:163.27,157.76,154.08,132.96,132.77,119.08,108.60,46.02,41.99,31.86,28.05,26.31,23.39,16.18.ESI-MS:m/z 396.4(M+1)+.C21H25N5OS(395.18).
4-(2,4,6-三甲基苯基)-N-(哌啶-4-基)-7,8-二氢-6H-噻喃[3,2-d]嘧啶-2-氨(9b)的制备
操作步骤同9a，所不同的是使用中间体8b(1g)代替中间体8a。
白色粉末(0.34g)，产率28.7％，熔点：290℃分解，1H NMR(400MHz,DMSO-d6)δ:8.91(s,2H),6.90(s,3H),3.15(d,J＝12.6Hz,2H),3.07-2.96(m,2H),2.69(t,J＝6.3Hz,4H),2.24(s,3H),2.12(p,J＝5.9Hz,2H),1.98(s,6H),1.82(s,2H),1.54(s,2H).13C NMR(100MHz,DMSO-d6)δ:164.00,157.90,147.95,134.59,130.15,129.29,46.06,42.15,31.84,28.14,26.30,23.45,20.81,16.44.ESI-MS:m/z 385.5(M+1)+.C21H28N4OS(384.20).
E-3-(3,5-二甲基-4-((2-(哌啶-4-氨基)-7,8-二氢-6H-噻喃[3,2-d]嘧啶-4-基)氧)苯基)丙烯酰胺(9c)的制备
操作步骤同9a，所不同的是使用中间体8c(0.5g)代替中间体8a。
白色粉末(0.32g)，产率54.2％，熔点：280℃分解，1H NMR(400MHz,DMSO-d6)δ:8.85(s,2H),7.59(d,J＝16.7Hz,1H),7.43(s,2H),7.30(s,2H),6.66(s,1H),6.40(d,J＝16.7Hz,1H),3.43(s,2H),3.08-2.95(m,2H),2.68(t,J＝6.2Hz,4H),2.15-2.09(m,2H),2.06(s,1H),2.03(s, 6H),1.61(s,4H),1.32(s,2H).13C NMR(100MHz,DMSO-d6)δ:163.65,158.05,152.59,150.58,131.62,131.45,126.05,119.42,96.51,62.02,52.67,49.07,31.89,26.34,23.50,16.46.ESI-MS:m/z 422.5(M+1)+.C23H27N5OS(421.19).
实施例5：化合物的制备
中间体9a(0.2g,0.51mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入对溴甲基苯磺酰胺(0.19g,0.76mmol)和碳酸钾(0.11g,0.76mmol)室温下搅拌过夜，反应液过滤，真空泵下浓缩，乙酸乙酯溶解(50mL)后水洗(20mL×3)，饱和食盐水洗，无水硫酸钠干燥，过滤后浓缩，硅胶柱色谱分离，产物用甲醇冲洗涤即得产物(0.24g)。
以不同的取代溴(氯)苄和中间体9a-9c得到目标化合物IIA-1-1～IIA-1-13，结果如下：
Figure PCTCN2016089710-appb-000015
白色粉末，产率84.1％，熔点：193-195℃，1H NMR(400MHz,DMSO-d6)δ:7.77(d,J＝8.3Hz,2H),7.66(s,2H),7.45(d,J＝8.0Hz,2H),7.30(s,2H),6.88(s,1H),3.45(s,2H),3.13-2.95(m,2H),2.91-2.57(m,4H),2.16-2.08(m,2H),2.06(s,6H),1.99-0.81(m,6H).13C NMR(100MHz,DMSO-d6))δ:163.25,157.97,154.22,143.35,143.13,133.02,132.66,129.41,126.04,119.10,108.56,61.97,52.61,49.07,31.86,31.65,26.34,23.48,16.15.ESI-MS:m/z 565.5(M+1)+.C28H32N6O3S2(564.20).
Figure PCTCN2016089710-appb-000016
操作步骤同IIA-1-1，所不同的是使用中间体9b(0.2g)代替中间体9a。
白色粉末(157mg)，产率43.6％，熔点：218-220℃，1；H NMR(400MHz,DMSO-d6)δ:7.77(d,J＝8.3Hz,2H),7.44(d,J＝8.0Hz,2H),7.30(s,2H),6.88(s,2H),6.60(s,1H),3.45(s,2H),3.08-2.91(m,2H),2.79-2.57(m,4H),2.23(s,3H),2.10(dt,J＝11.8,5.4Hz,2H),1.97(s,6H), 1.72-1.47(m,2H),1.46-1.10(m,2H).13C NMR(100MHz,DMSO-d6))δ:163.97,162.36,158.15,148.02,143.36,143.13,134.49,130.15,129.42,129.22,126.03,61.99,52.65,49.07,31.86,31.74,26.33,23.54,20.80,16.43.ESI-MS:m/z 554.5(M+1)+.C28H35N5O3S2(553.22).
Figure PCTCN2016089710-appb-000017
操作步骤同IIA-1-1，所不同的是使用中间体9c(0.2g)代替中间体9a。
白色粉末(0.18g)，产率64.2％，熔点：237-239℃，1H NMR(400MHz,DMSO-d6)δ:7.77(d,J＝8.3Hz,2H),7.59(d,J＝16.7Hz,1H),7.43(s,4H),7.30(s,2H),6.66(s,1H),6.40(d,J＝16.7Hz,1H),3.43(s,2H),3.08-2.95(m,2H),2.68(t,J＝6.2Hz,4H),2.15-2.09(m,2H),2.06(s,1H),2.03(s,6H),1.61(s,4H),1.32(s,2H).13C NMR(100MHz,DMSO-d6))δ:163.65,158.05,152.59,150.58,143.41,143.14,131.62,131.45,129.43,128.33,126.05,119.42,96.51,62.02,52.67,49.07,31.89,31.68,26.34,23.50,16.46.ESI-HRMS:m/z 591.2257(M+1)+.C30H34N6O3S2(590.2134).
Figure PCTCN2016089710-appb-000018
操作步骤同IIA-1-1，所不同的是使用3-溴甲基苯磺酰胺(152mg)代替4-溴甲基苯磺酰胺。
白色粉末(0.21g)，产率73.5％，熔点：170-172℃，1H NMR(400MHz,DMSO-d6)δ:7.74(s,1H),7.71(d,J＝7.4Hz,1H),7.67(s,2H),7.51(t,J＝7.5Hz,1H),7.47(d,J＝7.5Hz,1H),7.36(s,2H),6.80(s,1H),3.46(s,2H),3.02(dd,J＝6.7,4.1Hz,2H),2.69(t,J＝6.1Hz,4H),2.19-2.09(m,2H),2.08(s,1H),2.06(s,6H),1.66(s,4H),1.32(s,2H).13C NMR(100MHz,DMSO-d6)δ:163.25,157.84,154.22,144.59,144.09,140.31,133.01,132.74,132.47,129.26,125.92,124.68,119.13,108.55,62.05,52.62,49.07,31.82,31.65,26.30,23.45,16.18.ESI-HRMS:m/z 565.2045(M+1)+.C28H32N6O3S2(564.1977).
Figure PCTCN2016089710-appb-000019
操作步骤同IIA-1-1，所不同的是使用4-氯甲基苯甲腈(92mg)代替4-溴甲基苯磺酰胺。
白色粉末(0.21g)，产率81.3％，熔点：184-186℃，1H NMR(400MHz,DMSO-d6)δ:7.77(d,J＝8.2Hz,2H),7.66(s,2H),7.47(d,J＝8.1Hz,2H),6.89(br,1H),3.48(s,2H),3.12-2.95(m,2H),2.69(t,J＝6.3Hz,5H),2.19-2.02(m,8H),1.63(s,4H),1.32(s,2H).13C NMR(100MHz,DMSO-d6)δ:163.26,158.00,154.22,145.26,133.01,132.66,132.58,129.87,119.38,119.10,110.08,108.56,61.93,52.59,48.66,31.84,31.66,26.33,23.47,16.16.ESI-MS:m/z 511.6(M+1)+.C29H30N6OS(510.22).
Figure PCTCN2016089710-appb-000020
操作步骤同IIA-1-1，所不同的是使用3-溴甲基苯甲腈(119mg)代替4-溴甲基苯磺酰胺。
白色粉末(0.21g)，产率81.3％，熔点：164-166℃，1H NMR(400MHz,DMSO-d6)δ:7.72(d,J＝7.6Hz,1H),7.68(s,1H),7.65(s,2H),7.62(d,J＝7.8Hz,1H),7.53(t,J＝7.7Hz,1H),6.87(s,1H),3.45(s,2H),3.09-2.94(m,2H),2.69(t,J＝6.3Hz,4H),2.19-2.09(m,2H),2.09(s,1H),2.06(s,6H),1.63(s,4H),1.31(s,2H).13C NMR(100MHz,DMSO-d6)δ:163.26,157.96,154.22,140.90,134.02,133.02,132.68,132.44,131.22,129.89,119.34,119.10,111.65,108.56,61.46,55.38,52.49,31.86,31.64,31.15,26.33,23.47,21.52,16.16.ESI-HRMS:m/z 511.2335(M+1)+.C29H30N6OS(510.2202).
Figure PCTCN2016089710-appb-000021
操作步骤同IIA-1-1，所不同的是使用2-溴甲基苯甲腈(92mg)代替4-溴甲基苯磺酰胺。
白色粉末(0.2mg)，产率77.5％，熔点：206-208℃，1H NMR(400MHz,DMSO-d6)δ:7.79(d,J＝7.6Hz,1H),7.70-7.61(m,3H),7.52(d,J＝7.7Hz,1H),7.46(t,J＝7.6Hz,1H),6.86(s,1H),3.56(s,2H),3.10-2.94(m,2H),2.69(t,J＝6.2Hz,4H),2.17-2.09(m,2H),2.09(s,1H),2.06(s,6H),1.59(s,4H),1.30(s,2H).13C NMR(100MHz,DMSO-d6)δ:163.26,158.00,154.22,142.82,133.42,133.41,133.02,132.69,130.48,128.36,119.08,118.11,112.53,108.57,60.36,60.22,52.54,31.88,31.58,31.19,26.33,23.47,16.17,14.56.ESI-MS:m/z 511.3(M+1)+.C29H30N6OS(510.22).
Figure PCTCN2016089710-appb-000022
操作步骤同IIA-1-1，所不同的是使用4-氯甲基苯甲酰胺(103mg)代替4-溴甲基苯磺酰胺。
白色粉末(0.2g)，产率74.8％，熔点：261-263℃，1H NMR(400MHz,DMSO-d6)δ:7.91(s,1H),7.81(d,J＝8.1Hz,2H),7.66(s,2H),7.33(d,J＝7.9Hz,2H),7.30(s,1H),6.86(br,1H),3.43(s,2H),3.08-2.94(m,2H),2.69(t,J＝6.2Hz,4H),2.17-2.10(m,2H),2.09(s,1H),2.06(s,6H),1.60(s,4H),1.31(s,2H).13C NMR(100MHz,DMSO-d6)δ:168.25,163.26,158.04,154.23,142.60,142.52,133.45,133.02,132.69,128.88,127.88,119.11,108.56,79.65,62.19,52.63,31.84,31.65,31.16,26.33,23.47,16.16.ESI-MS:m/z 529.5(M+1)+,551.6(M+23)+.C29H32N6O2S(528.23).
Figure PCTCN2016089710-appb-000023
操作步骤同IIA-1-1，所不同的是使用3-氯甲基苯甲酰胺(103mg)代替4-溴甲基苯磺酰胺。
白色粉末(0.19g)，产率71.1％，熔点：245-247℃，1H NMR(400MHz,DMSO-d6)δ:7.95(s,1H),7.76(d,J＝11.6Hz,2H),7.66(s,2H),7.39(d,J＝7.3Hz,2H),7.33(s,1H),6.86(s,1H),3.43(s,2H),3.02(s,2H),2.77-2.58(m,4H),2.19-2.09(m,2H),2.09(s,1H),2.06(s,6H),1.63(s,4H),1.32(s,2H).13C NMR(100MHz,DMSO-d6)δ:168.43,163.26,157.96,154.22,139.22,134.68,133.02,132.68,132.03,128.45,126.44,119.10,108.56,62.44,52.60,48.81,31.87,31.65,31.15,26.33,23.47,16.16.ESI-MS:m/z 529.4(M+1)+,551.6(M+23)+.C29H32N6O2S(528.23).
Figure PCTCN2016089710-appb-000024
操作步骤同IIA-1-1，所不同的是使用4-氯甲基苯甲酸乙酯(148mg)代替4-溴甲基苯磺酰胺。
白色粉末(0.16g)，产率56.7％，熔点：181-183℃，1H NMR(400MHz,DMSO-d6)δ:7.91(d,J＝8.1Hz,2H),7.65(s,2H),7.41(d,J＝8.1Hz,2H),6.87(br,1H),4.30(q,J＝7.1Hz,2H),3.46(s,2H),3.09-2.97(m,2H),2.69(t,J＝6.2Hz,4H),2.16-2.09(m,2H),2.09(s,1H),2.06(s,6H),1.60(s,4H),1.31(t,J＝7.1Hz,5H).13C NMR(100MHz,DMSO-d6)δ:166.11,163.26,157.99,154.24,144.87,141.04,133.02,132.74,129.52,129.29,128.98,119.10,108.56,62.16,61.04,56.50,52.62,31.88,31.65,31.16,26.33,23.47,16.15,14.66.ESI-MS:m/z 558.6(M+1)+.C31H35N5O3S(557.25).
Figure PCTCN2016089710-appb-000025
操作步骤同IIA-1-1，所不同的是使用4-溴甲基硝基苯(131mg)代替4-溴甲基苯磺酰胺。
浅黄色粉末(140mg)，产率52.2％，熔点：190-192℃，1H NMR(400MHz,DMSO-d6)δ:8.18(d,J＝8.7Hz,2H),7.66(s,2H),7.55(d,J＝8.6Hz,2H),6.88(s,1H),3.53(s,2H),3.11-2.92(m,2H),2.69(t,J＝6.2Hz,4H),2.19-2.10(m,2H),2.09(s,1H),2.06(s,6H),1.59(s,4H),1.33(s,2H).13C NMR(100MHz,DMSO-d6)δ:163.26,157.99,154.23,147.51,146.97,133.02,132.67,130.03,123.80,119.10,108.56,61.63,52.61,31.84,31.66,31.15,26.33,23.47,19.03,16.15.ESI-MS:m/z 531.5(M+1)+.C28H30N6O3S(530.21).
Figure PCTCN2016089710-appb-000026
操作步骤同IIA-1-1，所不同的是使用1-氯甲基-4-甲砜基苯(151mg)代替4-溴甲基苯磺酰胺。
白色粉末(0.19g)，产率66.7％，熔点：265-267℃，1H NMR(400MHz,DMSO-d6)δ:7.87(d,J＝8.3Hz,2H),7.66(s,2H),7.54(d,J＝8.2Hz,2H),6.89(br,1H),3.50(s,2H),3.20(s,3H),3.10-2.95(m,2H),2.69(t,J＝6.2Hz,4H),2.11(m,2H),2.09(s,1H),2.06(s,6H),1.64(s,4H),1.32(s,2H).13C NMR(100MHz,DMSO-d6)δ:163.26,158.00,157.98,154.22,145.46,139.81,133.02,132.69,129.77,127.39,119.12,108.56,61.89,52.65,48.68,44.07,31.86,31.66,26.33,23.47,16.16.ESI-MS:m/z 564.5(M+1)+,586.5(M+23)+.C29H33N5O3S2(563.20).
合成路线五：
Figure PCTCN2016089710-appb-000027
实施例6：化合物IIA-1-13的制备
铁粉(0.56g,10mmol)溶于5mL水中，加0.12mL醋酸，50℃条件下搅拌15分钟，快速加入化合物IIA-1-12(0.53g,1mmol)的N,N-二甲基甲酰胺(10mL)，50℃反应1h。冷却，用碳酸氢钠溶液调节pH>9，硅藻土过滤，固体用乙酸乙酯洗涤，液体用乙酸乙酯萃取(15mL×3)，合并有机层，饱和食盐水洗，无水硫酸钠干燥，硅胶柱色谱分离，甲醇洗涤产物得淡黄色粉末(0.31g)。
Figure PCTCN2016089710-appb-000028
产率63.6％，熔点：169-171℃，1H NMR(400MHz,DMSO-d6)δ:7.66(s,2H),6.87(d,J＝8.1Hz,2H),6.49(d,J＝8.2Hz,2H),4.94(s,2H),3.17(s,2H),3.08-2.95(m,2H),2.68(t,J＝6.1Hz,4H),2.12(d,J＝5.3Hz,2H),2.09(s,1H),2.05(s,6H),1.48(s,4H),1.23(s,2H).13C NMR(100MHz,DMSO-d6)δ:163.24,158.03,154.22,147.95,133.01,132.65,130.16,125.66,123.82,119.11,114.01,108.55,62.55,52.39,31.65,26.31,23.46,21.24,19.03,16.16,14.56.ESI-MS:m/z501.5(M+1)+.C28H32N6OS(500.24).
实施例7：化合物IIA-1-14的制备。
Figure PCTCN2016089710-appb-000029
化合物IIA-1-13(0.2g,0.4mmol)和三乙胺(32μL,0.4mmol)溶于二氯甲烷中，冰浴条件下滴加甲磺酰氯(100μL,1.2mmol)，反应2h后升至室温搅拌过夜。加水15mL后用饱和碳酸氢钠调节pH>7后用乙酸乙酯萃取(15mL×3)，合并有机层，饱和食盐水洗，无水硫酸钠干燥，甲醇/氯仿重结晶得白色粉末(40mg)。
产率17.3％，熔点：153-157℃，1H NMR(400MHz,DMSO-d6)δ:9.68(s,1H),7.66(s,2H),7.21(d,J＝8.3Hz,2H),7.14(d,J＝8.4Hz,2H),6.70(br,1H),3.32(s,2H),3.07-2.99(m,2H),2.96(s,3H),2.69(t,J＝6.3Hz,4H),2.11(t,J＝5.7Hz,2H),2.09(s,1H),2.06(s,6H),1.55(s,4H),1.23(s,2H).13C NMR(100MHz,DMSO-d6)δ:163.25,137.49,134.60,133.01,132.90,132.77,132.70,130.12,120.24,119.13,108.54,100.98,62.08,52.56,39.62,36.25,31.81,31.63,31.17,26.30,23.45,16.16.ESI-HRMS:m/z 579.2250(M+1)+.C29H34N6O3S2(578.2134).
合成路线六：
Figure PCTCN2016089710-appb-000030
实施例8：化合物IIC-1-1，IIC-1-2及IIC-2-1的制备。
中间体8a(0.2g,0.6mmol)和3-(4-氨基哌啶-1-基)苯甲腈(145mg,0.72mmol)溶于N-甲基吡咯烷酮(5mL)中，加N,N-二异丙基乙胺(120μL)后升温至100-120℃，反应过夜。反应液冷却，加水析出固体，过滤后甲醇/氯仿重结晶即得白色粉末(129mg)。
Figure PCTCN2016089710-appb-000031
产率43.1％，熔点：186-187℃，1H NMR(400MHz,DMSO-d6)δ:7.65(s,2H),7.34(dd,J＝8.5,7.4,1H),7.26(s,1H),7.21(d,J＝8.5Hz,1H),7.09(d,J＝7.4Hz,1H),6.82(br,1H),3.67(s,3H),3.02(p,2H),2.70(t,J＝6.0Hz,3H),2.12(t,J＝5.7Hz,2H),2.08(s,1H),2.07(s,6H),1.69(s,2H),1.35(s,2H).13C NMR(100MHz,DMSO-d6)δ:163.26,157.91,154.17,151.25,133.01,132.73,130.64,121.53,120.26,119.84,119.12,118.11,112.37,108.58,56.52,47.19,31.85,31.16,30.82,26.31,23.42,18.98,16.18.ESI-HRMS:m/z 497.2133(M+1)+.C28H28N6OS(496.2045).
Figure PCTCN2016089710-appb-000032
操作步骤同IIC-1-1，所不同的是使用3-(4-氨基哌啶-1-基)苯甲酰胺(0.16g)代替3-(4-氨基哌啶-1-基)苯甲腈。
白色粉末(109mg)，产率35.1％，熔点：232-234℃，1H NMR(400MHz,DMSO-d6)δ:7.91(s,1H),7.68(s,2H),7.38(s,1H),7.29(s,1H),7.25(s,1H),7.23(s,1H),7.03(d,J＝4.1Hz,2H),6.73(s,1H),3.65(s,2H),3.03(d,J＝5.4Hz,2H),2.72(t,J＝6.3Hz,3H),2.13(t,J＝5.7Hz,2H),2.09(s,1H),2.09(s,6H),1.72(s,2H),1.42(s,2H).13C NMR(100MHz,DMSO-d6)δ:168.71,163.27,157.95,154.18,151.18,135.40,133.01,132.75,129.25,119.11,118.66,117.98,115.09,108.58,56.50,48.06,31.88,31.16,26.32,23.46,19.04,16.21.ESI-HRMS:m/z 515.2226(M+1)+.C28H30N6O2S(514.2151).
实施例9：目标化合物的体外抗HIV活性测试实验
测试原理
活细胞能够吸收3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT)，吸收进入细胞内的 MTT可以在线粒体内被还原，由黄色变成蓝紫色，吸收波长会发生变化，而死细胞则不能还原MTT。测定540nM和690nM处的光密度值(OD值)，光密度值与活细胞的数量成正比，即可求出相应的存活率。
感染了HIV病毒的细胞最多能够存活5-7天，而加入HIV-1抑制剂之后能够抑制病毒的复制，从而保护细胞免于病变。向感染HIV病毒的MT-4细胞内加入梯度稀释的抑制剂，培养5-7天以后，用MTT法测定细胞存活率，利用抑制剂浓度与细胞存活率做标准曲线即可得到保护50％细胞免于病变的化合物浓度(即EC50值)。
同理，向正常MT-4细胞内加入梯度稀释的抑制剂，可以计算出使50％正常细胞发生病变的抑制剂浓度(即CC50值)，然后得出选择性系数SI(SI＝CC50/EC50)。
1.测试材料和方法
(1)HIV-1(IIIB)、HIV-2(ROD)毒株、各种HIV-1耐药株：由比利时鲁汶大学医学院Rega研究所提供。
(2)MT-4细胞：由比利时鲁汶大学医学院Rega研究院提供。
(3)MTT：购自美国Sigma公司。
(4)样品处理：样品临用前溶于DMSO配成适当浓度，并用双蒸水作5倍稀释，各5个稀释度。
(5)阳性对照药：奈韦拉平(NVP)、依法韦仑(EFV)、依曲韦林(ETR)、利匹韦林(RPV)和齐多夫定(AZT)。
(6)测试方法：样品稀释后加入到HIV感染MT-4细胞悬浊液中，经过一段时间后用MTT比色法测定细胞活力，用酶标仪中记录在590nm下的吸光度(A)值,计算出EC50，CC50以及SI。
(7)MTT比色法：加入样品溶液培养一段时间后，向每孔加入MTT溶液(5mg/ML)20μL，继续培养若干小时后，弃染色液，并向每孔加入150μL DMSO，充分混合，用酶标仪中测定590nm下的吸光度(A)值。
2.实验方法
在96孔细胞培养板上，加入50μL含1×104MT-4细胞培养液，再分别加入20μL感染HIV-1(IIIB、RES056或其它变异株)或HIV-2(ROD)的MT-4细胞混悬液(每毫升含100倍CCID50)或者空白培养基(毒性测定)，然后加入不同浓度的待测化合物溶液或者阳性对照药物，每个浓度设计3个复孔。接着细胞在5％CO2氛围，37℃下培养5天，向每个孔中加入20μL(5mg/mL)MTT溶液，继续培养2小时，然后加入DMSO，使用酶标仪测定反应溶液在540nm处的吸收度，计算化合物不同浓度下的细胞增值率P％。同时设空白和药物对照组和阳性药物对照组，由此计算化合物保护50％的细胞免于HIV诱导的细胞病变所需浓度(EC50)。选择指数的计算： SI＝CC50/EC50。
3.四氢噻喃并嘧啶类衍生物的抗HIV-1野生株及突变株活性及应用
对按照上述方法合成的部分四氢噻喃并嘧啶类衍生物进行了细胞水平的抗HIV-1(IIIB)，单耐药突变株L100I、K103N、Y181C、Y188L以及双耐药突变株RES056(K103N/Y181C)、F227L/V106A的活性筛选，以奈韦拉平(NVP)、依法韦伦(EFV)、依曲韦林(ETV)、利匹韦林(RPV)和齐多夫定(AZT)为阳性对照。它们的抗HIV-1活性数据列于表1中。
表1 部分化合物和参考药物的结构及其抗HIV-1活性(MT-4细胞)
Figure PCTCN2016089710-appb-000033
Figure PCTCN2016089710-appb-000034
注：aEC50:保护50％感染HIV-1的MT-4细胞免于细胞病变的化合物浓度；A代表化合物EC50<10nM，B代表化合物EC50值为10-100nM，C代表化合物EC50>100nM；NVP、EFV、AZT、ETV、RPV分别代表上市药物奈韦拉平、依法韦伦、齐多夫定、依曲韦林和利匹韦林。
4.结论：
由表1可以看出，本发明的四氢噻喃并嘧啶衍生物是一系列具有新颖骨架的非核苷类HIV-1抑制剂，表现出了极强的抗HIV-1野生株和突变株活性。绝大部分化合物抑制野生株和突变株的EC50值在1μM以下，其中，化合物IA-1-3的活性尤为突出，其对HIV-1野生株的EC50值是第一代抗艾滋病药物奈韦拉平(NVP)的30倍以上，与最新一代药物依曲韦林(ETV)相当。化合物IA-1-3亦表现出了高的安全性，其对HIV-1野生株的选择性指数大于1000。对单突变株K103N和Y188L，化合物IA-1-2表现出了与依曲韦林相当的抑制活性，对于单突变株L100I，Y181C和双突变株(F227L/V106A和Y181C/K103N)的抑制活性为依曲韦林的2倍以上。因此，四氢噻喃并嘧啶类化合物具有进一步研发的价值，可作为抗HIV-1的先导化合物加以利用。

Claims (9)

  1. 一种四氢噻喃并嘧啶类衍生物，或其药学上可接受的盐或前药，其特征在于具有通式I或II所示的结构：
    Figure PCTCN2016089710-appb-100001
    其中A为S(＝O)n或CH2；B为S(＝O)n或CH2，并且A和B不能同时为S(＝O)n；n＝0,1或2；
    X为O或NH；
    R1、R2、R3各自独立的为：H、卤素、氰基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、三氟甲基、氨基、羟基、氰基乙烯基、氰基乙基或环丙基；
    Ar为：取代苯环、取代萘环、各种取代的六元杂环、各种取代的五元杂环、各种取代的六元并五元杂环、各种取代的六元并六元杂环、各种取代的五元并五元杂环、各种取代的苯并五元杂环或各种取代的苯并六元杂环。
  2. 如权利要求1所述的四氢噻喃并嘧啶类衍生物，其特征在于所述通式I或II中R1、R3为甲基，R2为CN、Me或CH＝CHCN。
  3. 如权利要求1所述的四氢噻喃并嘧啶类衍生物，其特征在于所述通式II中Ar为具有通式(a)或者通式(b)的取代苯环：
    Figure PCTCN2016089710-appb-100002
    其中，R4为H、CN、Me、COR5、COOR5、CONH2、CONHR5、SO2R5、SO2NH2、SO2NHR5、NO2、NH2、NHR5、NHCOR5或NHSO2R5；R5为C1-C10烷烃、环烷烃、卤代烷烃、烯烃或芳香烃。
  4. 如权利要求3所述的四氢噻喃并嘧啶类衍生物，其特征在于，R5为Me或CH3CO。
  5. 如权利要求1所述的四氢噻喃并嘧啶类衍生物，其特征在于为具有下列结构式的化合物之一：
    Figure PCTCN2016089710-appb-100003
    其中，R1、R2、R3、R4如通式I或II中所示。
  6. 如权利要求5所述的四氢噻喃并嘧啶类衍生物，其特征在于为具有下列结构式的化合物之一：
    Figure PCTCN2016089710-appb-100004
    Figure PCTCN2016089710-appb-100005
  7. 如权利要求1所述的四氢噻喃并嘧啶类衍生物的制备方法，以巯基乙酸甲酯(A)和4-氯丁酸甲酯(B)为原料，在甲醇钠的条件下反应得到4-((2-甲氧基-2-氧代乙基)硫)丁酸甲酯(C)，中间体C在甲醇钠条件下经Dieckmann缩合得到氧代四氢噻喃甲酸酯(D)，中间体D与甲基异硫脲在氢氧化钾条件下环合得到2-甲巯基四氢噻喃并嘧啶-2-醇(E)，中间体E在醋酸 条件下水解得到四氢噻喃并嘧啶-2,4-二醇(F)，中间体F在三氯氧磷中以N,N-二甲基苯胺为碱氯化得到2,4-二氯四氢噻喃并嘧啶(G)，中间体G在碱性条件下与取代苯酚或苯胺反应得到中间体H，中间体H与相应的取代苯胺反应得到目标化合物；或与1-Boc-4-氨基哌啶反应，脱去Boc保护之后与相应的氯苄或溴苄反应得到目标化合物；
    合成路线如下：
    Figure PCTCN2016089710-appb-100006
    试剂和条件：(i)甲醇钠，碘化钾，甲醇，回流；(ii)甲醇钠，甲苯，105℃；(iii)甲基异硫脲硫酸盐，氢氧化钾，甲醇；(iv)醋酸/水，110℃；(v)三氯氧磷，N,N-二甲基苯胺，90℃；(vi)碳酸钾，N,N-二甲基甲酰胺，取代苯酚或苯胺；(vii)a)1-Boc-4-氨基哌啶，N,N-二异丙基乙胺，N-甲基吡咯烷酮，120-130℃；b)三氟乙酸/二氯甲烷，室温；c)取代溴苄或氯苄，碳酸钾，N,N-二甲基甲酰胺，室温；(viii)1-取代-4-氨基哌啶，N,N-二异丙基乙胺，N-甲基吡咯烷酮，120-130℃；(ix)4-氨基苯甲腈，2,2'-双-(二苯膦基)-1,1'-联萘，三(二亚苄基丙酮)二钯，1,4-二氧六环；
    所述的取代苯酚或苯胺为均三甲基苯酚、2,6-二甲基-4-氰基苯酚、(E)-2,6-二甲基-4-氰基乙烯基苯酚、均三甲基苯胺、2,6-二甲基-4-氰基苯胺或(E)-2,6-二甲基-4-氰基乙烯基苯胺；
    所述的取代溴苄或氯苄为邻氯氯苄、间氯氯苄、对氯氯苄、邻溴溴苄、间溴溴苄、对溴溴苄、邻氟氯苄、间氟氯苄、对氟氯苄、2,4-二氟溴苄、3,4-二氟溴苄、邻氰基氯苄、间氰基氯苄、对氰基氯苄、邻硝基氯苄、间硝基氯苄、对硝基氯苄、邻甲氧基氯苄、间甲氧基氯苄、对甲氧基氯苄、对甲磺酰基溴苄、对磺酰胺基溴苄、间磺酰胺基溴苄、对甲酰胺基溴苄、4- 溴甲基苯甲酸乙酯、4-溴甲基苯甲酸酰胺、3-溴甲基苯甲酸酰胺、N-(4-溴甲基苯基)甲磺酰胺；
    其中，R1、R2、R3、A、B、X的定义同上通式I或II所述。
  8. 一种如权利要求1-6任一项所述化合物在制备治疗和预防人免疫缺陷病毒(HIV)药物中的应用。
  9. 一种药物组合物，包含权利要求1-6任一项所述化合物和一种或多种药学上可接受载体或赋形剂。
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