WO2016197589A1 - 一种噻吩并嘧啶类衍生物及其制备方法和应用 - Google Patents

一种噻吩并嘧啶类衍生物及其制备方法和应用 Download PDF

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WO2016197589A1
WO2016197589A1 PCT/CN2015/099924 CN2015099924W WO2016197589A1 WO 2016197589 A1 WO2016197589 A1 WO 2016197589A1 CN 2015099924 W CN2015099924 W CN 2015099924W WO 2016197589 A1 WO2016197589 A1 WO 2016197589A1
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substituted
heterocyclic rings
membered heterocyclic
various substituted
membered
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PCT/CN2015/099924
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French (fr)
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刘新泳
康东伟
展鹏
方増军
李震宇
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山东大学
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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

Definitions

  • the invention belongs to the technical field of organic compound synthesis and medical application, and particularly relates to a thienopyrimidine derivative, a preparation method thereof and application as an HIV-1 inhibitor.
  • AIDS Abundred Immune Deficiency Syndrome, AIDS
  • AIDS has become a major infectious disease that endangers human life and health. Its main pathogen is Human Immunodeficiency Virus Type 1, HIV-1.
  • HAART Highly Active Antiretroviral Therapy
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • NNRTIs are important components of HAART therapy, which have the advantages of high efficiency, low toxicity and specificity.
  • defects that are prone to drug resistance cause rapid loss of such drugs.
  • Clinical titer so the development of new, efficient, low-toxic, broad-spectrum anti-drug resistant NNRTIs is one of the hotspots of anti-HIV drug research.
  • Diarylpyrimidine is a typical class of HIV-1NNRTIs, which has strong anti-HIV activity and also has a good inhibitory effect on resistant mutant strains.
  • Etravirine and Rilpivirine have been marketed in this class of drugs, but the compounds are poorly water-soluble and have low oral bioavailability, so the chemical structure is further modified.
  • New anti-HIV drugs with broad spectrum and high efficiency, good bioavailability and independent intellectual property rights are of great significance.
  • the present invention provides a thienopyrimidine derivative and a process for the preparation thereof, and the invention also provides the use of a thienopyrimidine derivative as an HIV-1 inhibitor.
  • the dotted line represents a double bond between A and B, a double bond between B and D, a single bond between A and B, or a single bond between B and D;
  • A is: S or C (U);
  • B is: S or C (V);
  • D is: S or C (W);
  • A, B and D have one and only one is S;
  • U, V and W are each independently: H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, OC 3 -C 6 cycloalkyl, phenyl, benzyl, trifluoromethyl, amino, hydroxy, various substituted six-membered heterocyclic rings, various substituted five-membered heterocyclic rings;
  • Z is: F, F 2 , OH, COOH, CONH 2 , COOC 2 H 5 ;
  • X is: one of O, NH or S
  • R 1 , R 2 , and R 3 are each independently: H, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, trifluoromethyl, Amino group, hydroxycyanovinyl group;
  • 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 formula (b):
  • R 4 is H, CH 3 , COCH 3 , COOCH 3 , COOC 2 H 5 , COOH, SO 2 CH 3 or SO 2 CF 3 ;
  • R 5 is Cl, Br, Me, NHCH 3 , NHCOCH 3 , NHSO 2 CH 3 or NHSO 2 CF 3 .
  • 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 ratio of benefits to risks, 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 structural formula of the thienopyrimidine compound is one of the following:
  • R, U, V, W, Z and Ar are as defined in the above formula I.
  • thienopyrimidine derivatives are one of the following specific compounds:
  • the preparation method of the thienopyrimidine derivative is as follows: the 2,4-dichloro-substituted thienopyrimidine 1 is used as a starting material, firstly in a solution of N,N-dimethylformamide with substituted phenol, benzenethiol or The nucleophilic substitution of aniline produces intermediate 2; then intermediate 2 is reacted with N-Boc-4-aminopiperidine in dimethyl sulfoxide and subsequently deprotected by Boc group under trifluoroacetic acid to form key intermediate 4 Or Intermediate 2 undergoes a Buchwald-Hartwig coupling reaction to form intermediate 3 and then deprotected by BOC to give intermediate 4; finally this key intermediate 4 is in N,N-dimethyl
  • the target product is reacted with various substituted benzyl chloride or benzyl bromide in a formamide solution and potassium carbonate as a base; the synthesis route is as follows:
  • Reagents and conditions (i) substituted phenol, aniline or phenyl thiol, dimethylformamide, potassium carbonate, room temperature; (ii) N-Boc-4-aminopiperidine, dimethyl sulfoxide, potassium carbonate, 120 ° C; (iii) N-Boc-4-aminopiperidine, palladium acetate, 4,5-bis(diphenylphosphino)-9,9-dimethyloxaxime, cesium carbonate, 90 ° C, dioxane Hexacyclohexane; (iv) dichloromethane, trifluoroacetic acid, room temperature; (v) substituted benzyl chloride or benzyl bromide, dimethylformamide, potassium carbonate, room temperature.
  • the substituted phenol, aniline or phenyl thiol is mesitylene phenol, 2,6-dimethyl-4-cyanophenol, 2,6-dimethyl-4-(E)-cyanoethylene Phenol, mesitylene, 2,6-dimethyl-4-cyanoaniline, 2,6-dimethyl-4-(E)-cyanovinylaniline, mesitylene Alcohol, 2,6-dimethyl-4-cyanophenyl mercaptan, 2,6-dimethyl-4-(E)-cyanovinylphenyl mercaptan;
  • benzyl chloride or benzyl bromide as o-chlorobenzyl chloride, m-chlorobenzyl chloride, p-chlorobenzyl chloride, o-bromo bromide, m-bromo bromide, p-bromo bromide, o-fluorobenzyl bromide, m-fluorobenzyl bromide, p-fluorochloride Benzyl, 2,4-difluorobenzyl bromide, 3,4-difluorobromobenzyl, o-cyanobenzyl chloride, m-cyanobenzyl chloride, p-cyanochlorobenzyl, o-nitrobenzyl chloride, m-nitrobenzyl chloride, p-Nitrochlorobenzyl, o-methoxybenzyl chloride, m-methoxybenzyl chloride, p-methoxybenzyl chloride,
  • the room temperature of the invention is 20-30 ° C
  • Cell-level anti-HIV-1 (III B ), single-resistant mutants K103N, Y181C, Y188L and double-resistant mutant RES056 (K103N/Y181C) were obtained from the partial thienopyrimidine derivatives synthesized according to the above method. Active screening, with nevirapine (NVP), efavirenz (EFV), etravirine (ETV) and zidovudine (AZT) as positive controls. Their anti-HIV-1 activity and toxicity data are listed in Tables 1 and 2, respectively.
  • the thienopyrimidine derivatives of the present invention are a series of novel non-nucleoside HIV-1 inhibitors which exhibit a strong anti-HIV-1 wild strain and mutant activity. Most of the compounds inhibited the EC 50 values of wild-type strains and mutants to a nanomolar level. Among them, the activity of compound IA-1-2 was particularly prominent, and its EC 50 value for HIV-1 wild-type strain was the first generation of anti-AIDS. More than 150 times the drug nevirapine (NVP), it is more than twice as high as the latest generation of drug etravirine (ETV).
  • NTP drug nevirapine
  • ETV drug etravirine
  • Compound IA-1-2 also showed extremely high safety, and its selectivity index for HIV-1 wild strain was greater than 100,000, which was much higher than that of the marketed drug.
  • the compound IA-1-2 showed an inhibitory activity comparable to that of etravirine.
  • the single mutant strain Y188L its inhibitory activity was much higher than that of etravirine. More than 3 times.
  • the cytotoxicity of Compound IA-1-2 was much smaller than that of the positive drug (Table 2), resulting in the compound exhibiting a very high selectivity. Therefore, such thienopyrimidine compounds have further research and development value and can be utilized as a lead compound against HIV.
  • the thienopyrimidine derivatives of the present 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 thienopyrimidine derivative of the invention and one or more pharmaceutically acceptable carriers or excipients.
  • the invention provides a novel structure of thienopyrimidine 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 thienopyrimidine 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.
  • the product was a white solid. Yield 87.5%, 178-180 °C.
  • Example 2 The operation was the same as in Example 1, except that the starting material used was 2,4-dichlorothieno[3,2-d]pyrimidine 18. Yield 67.7%, melting point 131-134 °C.
  • the product was a white solid, yield: 61.8%, m.p.
  • the product was a white solid, yield: 55.7%, m.p.
  • the product was a white solid, yield: 57.4%, mp.
  • the product was a white solid, yield: 65.3%, m.p. 133-136.
  • the product was a white solid, yield: 63.1%, mp.
  • the product was a white solid, yield: 63.1%, m.p.
  • the product was a white solid, yield: 50.7%, m.p.
  • the product was a white solid, yield: 59.6%, mp. 110-112.
  • the product was a white solid, yield: 42.7%, m.p.: 113-115.
  • the product was a white solid, yield: 45.7%, mp 221 - 224.
  • the product was a white solid, yield: 35.5%, m.p. 215-217.
  • the product was a white solid, yield: 58.9%, m.p. 260-262.
  • the product was a white solid, yield: 58.3%, m.p. 156-158.
  • the product was a white solid, yield: 54.1%, m.p. 192-194.
  • the product was a white solid, yield: 48.2%, m.p. 180-182.
  • the product was a white solid, yield: 56.2%, m.p. 165-167.
  • the product was a white solid, yield: 57.2%, mp 165-168.
  • the product was a white solid, yield: 47.3%, m.p. 181-183.
  • the product was a white solid, yield: 57.1%, m.p. 176-179.
  • the product was a white solid, yield: 55.4%, mp 185-191.
  • the product was a white solid, yield: 44.2%, m.p. 194-199.
  • the product was a white solid, yield: 53.2%, m.p. 122-125.
  • the product was a white solid, yield: 41.6%, m.p. 180-185.
  • the product was a white solid, yield: 48.9%, m.p. 176-180.
  • the product was a white solid, yield: 56.3%, m.p. 180-184.
  • the product was a white solid, yield: 39.5%, m.p. 172 - 175.
  • the product was a white solid, yield: 47.6%, m.p. 156-159.
  • the product was a white solid, yield: 45.9%, m.p. 147-150.
  • MTT is called brominated-3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium nitrogen (trade name: thiazole blue) and can be used to detect cell survival and growth.
  • the detection principle is: MTT can be combined with living intracellular succinate dehydrogenase to reduce water-insoluble blue-purple crystal formamidine deposited in cells, while dead cells do not have this function.
  • Dimethyl sulfoxide can dissolve the hyperthyroidism in the cells, and its absorbance (A) at 590 nm can be indirectly reflected by the microplate reader.
  • the amount of MTT crystal formation is proportional to the number of cells within a certain number of cells.
  • HIV-infected MT-4 cells develop lesions within a certain period of time (5-7 days)
  • an appropriate concentration of the compound solution to be tested is added to the HIV-infected MT-4 cell suspension for a period of time (5- After 7 days of culture, the activity of MT-4 cells was measured by MTT assay, and the anti-HIV activity of the target compound was obtained by obtaining a drug concentration (EC 50 ) which protects 50% of the cells from cytopathic effects.
  • EC 50 drug concentration
  • 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
  • EMV efavirenz
  • TMC125 etravirine
  • 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. Determined by a microplate reader Absorbance (A) at 590 nm.
  • MT-4 cell culture medium On a 96-well cell culture plate, add 50 ⁇ L of 1 ⁇ 10 4 MT-4 cell culture medium, and add 20 ⁇ L of MT-4 cells infected with HIV-1 (III B or RES056) or HIV-2 (ROD), respectively. Liquid (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, ETV, AZT represent the marketed drugs nevirapine, efavirenz, etravirine and zidovudine, respectively.
  • a CC 50 drug concentration at which 50% of MTT cells are pathological;
  • A represents compound SI > 10000,
  • B represents compound SI value of 1000-10000,
  • C represents compound SI ⁇ 1000;
  • X1 SI ⁇ 1 or 1;
  • NVP, EFV, ETV, AZT represent the marketed drugs nevirapine, efavirenz, etravirine and zidovudine, respectively.

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Abstract

本发明公开了一种噻吩并嘧啶类衍生物及其制备方法和应用，噻吩并嘧啶类衍生物是具有通式Ⅰ所示结构的化合物及其药学上可接受的盐、酯或前药，本发明还提供了化合物的制备方法，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)感染药物中的应用。

Description

一种噻吩并嘧啶类衍生物及其制备方法和应用 技术领域
本发明属于有机化合物合成与医药应用技术领域，具体涉及一种噻吩并嘧啶衍生物及其制备方法以及作为HIV-1抑制剂的应用。
背景技术
艾滋病(Acquired Immune Deficiency Syndrome,AIDS)目前已经成为危害人类生命健康的重大传染性疾病，其主要病原体是人免疫缺陷病毒1型(Human Immunodeficiency Virus Type 1,HIV-1)。尽管高效抗逆转录疗法(Highly Active Antiretroviral Therapy,HAART)的实施显著延长患者的生存时间，但是耐药问题和药物毒副作用以及长期服用药物的费用等问题，迫使研究者研发高效低毒的新型HIV抑制剂。HIV-1非核苷类逆转录酶抑制剂(NNRTIs)是HAART疗法的重要组成部分，该类药物具有高效低毒、特异性强的优点，然而易产生耐药性的缺陷使该类药物迅速丧失临床效价，因此新型、高效、低毒、广谱抗耐药性的NNRTIs的研发是目前抗HIV药物研究的热点之一。
二芳基嘧啶(diarylpyrimidine,DAPY)类是一类典型的HIV-1NNRTIs，具有较强的抗HIV活性，对耐药突变毒株也有很好的抑制作用。该类药物中依曲韦林(Etravirine)和利匹韦林(Rilpivirine)已经上市，但该类化合物水溶性较差，口服生物利用度较低，因此将该类化学结构进行进一步修饰，对发现广谱高效、生物利用度好且具有自主知识产权的新型抗HIV药物具有重大意义。
Figure PCTCN2015099924-appb-000001
发明内容
针对现有技术的不足，本发明提供了一种噻吩并嘧啶类衍生物及其制备方法，本发明还提供了噻吩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.噻吩并嘧啶类衍生物
一种噻吩并嘧啶类衍生物，或其药学上可接受的盐、酯或前药，具有通式I所示的结构：
Figure PCTCN2015099924-appb-000002
其中，虚线代表A与B之间为双键、B与D之间为双键、A与B之间为单键或者B与D之间为单键之中的一种；
A为：S或者C(U)；
B为：S或者C(V)；
D为：S或者C(W)；
并且A，B和D有且只有一个为S；
其中U，V和W各自为独立的为：H，卤素，C1-C6烷基，C1-C6烷氧基，C2-C6烯基，C3-C6环烷基，O C3-C6环烷基，苯基，苄基，三氟甲基，氨基，羟基，各种取代的六元杂环、各种取代的五元杂环；
Z为：F，F2，OH，COOH，CONH2，COOC2H5；
X为：O，NH或者S之中的一种；
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；
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。
优选的，Ar为具有通式(a)或者通式(b)的取代苯环：
Figure PCTCN2015099924-appb-000003
其中，R4为H，CH3，COCH3，COOCH3，COOC2H5，COOH，SO2CH3或SO2CF3；R5 为Cl，Br，Me，NHCH3，NHCOCH3，NHSO2CH3或NHSO2CF3。
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与风险比例，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。
本发明更为详细的，噻吩并嘧啶类化合物的结构式为下列之一：
Figure PCTCN2015099924-appb-000004
Figure PCTCN2015099924-appb-000005
Figure PCTCN2015099924-appb-000006
其中，R，U，V，W，Z和Ar同上通式I所述。
进一步优选的，化合物IA-1，IA-2，IA-3，IA-4，IA-5，IB-1，IB-2，IB-3，IB-4，IB-5和IC-1，IC-2，IC-3，IC-4，IC-5中，Ar为通式(a)或通式(b)。
本发明更为详细的，噻吩并嘧啶类衍生物为如下具体化合物之一：
Figure PCTCN2015099924-appb-000007
Figure PCTCN2015099924-appb-000008
2、噻吩并嘧啶类衍生物的制备方法
噻吩并嘧啶衍生物的制备方法，步骤如下：以2,4-二氯取代的噻吩并嘧啶1为初始原料，首先在N,N-二甲基甲酰胺溶液中与取代苯酚、苯硫醇或苯胺发生亲核取代生成中间体2；然后中间体2在二甲基亚砜中与N-Boc-4-氨基哌啶反应并随后在三氟乙酸条件下脱Boc基团保护生成关键中间体4；或者中间体2发生布赫瓦尔德-哈特维希(Buchwald-Hartwig)偶联反应生成中间体3然后脱BOC保护得到中间体4；最后此关键中间体4在N,N-二甲基甲酰胺溶液中和碳酸钾做碱的条件下，与各种取代氯苄或溴苄反应生成目标产物；合成路线如下：
Figure PCTCN2015099924-appb-000009
试剂及条件:(i)取代苯酚、苯胺或者苯基硫醇，二甲基甲酰胺，碳酸钾，室温；(ii)N-Boc-4-氨基哌啶，二甲基亚砜，碳酸钾，120℃；(iii)N-Boc-4-氨基哌啶，醋酸钯，4,5-双(二苯基膦)-9,9-二甲基氧杂蒽，碳酸铯，90℃，二氧六环；(iv)二氯甲烷，三氟乙酸，室温；(v)取代氯苄或溴苄，二甲基甲酰胺，碳酸钾，室温。
所述的取代苯酚、苯胺或者苯基硫醇为均三甲基苯酚，2,6-二甲基-4-氰基苯酚，2,6-二甲基-4-(E)-氰基乙烯基苯酚，均三甲基苯胺，2,6-二甲基-4-氰基苯胺，2,6-二甲基-4-(E)-氰基乙烯基苯胺，均三甲基苯基硫醇，2,6-二甲基-4-氰基苯基硫醇，2,6-二甲基-4-(E)-氰基乙烯基苯基硫醇；
取代氯苄或溴苄为邻氯氯苄、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、对甲酰胺基溴苄、4-(溴甲基)苯甲酸甲酯。
本发明所述的室温为20-30℃
3、噻吩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噻吩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K103N、Y181C、Y188L以及双耐药突变株RES056(K103N/Y181C)的活性筛选，以奈韦拉平(NVP)、依法韦伦(EFV)、依曲韦林(ETV)和齐多夫定(AZT)为阳性对照。它们的 抗HIV-1活性和毒性数据分别列于表1和表2中。
由表1可以看出，本发明的噻吩并嘧啶衍生物是一系列结构新颖的非核苷类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值达到了纳摩尔级别，其中，化合物IA-1-2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150倍以上，是最新一代药物依曲韦林(ETV)的2倍以上。化合物IA-1-2亦表现出了极高的安全性，其对HIV-1野生株的选择性指数大于100000，远远高于上市药物。对单突变株K103N和Y181C,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Y188L,其抑制活性远远高出依曲韦林，为其抑制活性的3倍以上。另外，化合物IA-1-2的细胞毒性远小于阳性药物(表2)，导致该化合物表现出非常高的选择性。因此该类噻吩并嘧啶类化合物具有进一步研究与开发的价值，可作为抗HIV的先导化合物加以利用。
本发明的噻吩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，包括本发明的噻吩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噻吩并嘧啶类衍生物、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。经过试验证明，本发明的噻吩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，但是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 PCTCN2015099924-appb-000010
合成路线二：
Figure PCTCN2015099924-appb-000011
合成路线三：
Figure PCTCN2015099924-appb-000012
合成路线四：
Figure PCTCN2015099924-appb-000013
实施例1：4-((2-(哌啶-4-胺)噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苯腈(10)的制备
Figure PCTCN2015099924-appb-000014
化合物10
称取4-羟基-3,5-二甲基苯腈(0.15g,1mmol)和碳酸钾(0.17g,1.2mmol)于5mL的N,N-二甲基甲酰胺(DMF)溶液中，室温搅拌15分钟，然后加入2,4-二氯噻吩并[3,2-d]嘧啶(0.21g,1mmol)继续室温搅拌2h(TLC检测反应完毕)。此时有大量的白色固体生成，慢慢地向其中加入25mL冰水，过滤，真空干燥箱干燥，得到白色固体即为化合物4-((2-氯噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苯腈，收率93.8％，熔点258-260℃。
称取化合物4-((2-氯噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苯腈(0.32g,1.0mmol)，N-Boc-4-氨基哌啶(0.24g,1.2mmol)与碳酸钾(0.28g,2mmol)于5mL的二甲基亚砜中，然后加热回流12小时。待反应冷却到室温以后，慢慢地将反应液滴加到20mL水溶液中，搅拌，有大量的黄色固体生成。过滤，干燥得粗品4-((2-(1-Boc-哌啶-4-胺)噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苯腈。称取该粗品(0.60g,1.21mmol)溶于4mL二氯甲烷中，然后慢慢地向其中加入三氟乙酸(0.74mL,10mmol)，室温条件下搅拌6小时(TLC检测反应完毕)。向反应液中加入10mL水，用饱和的碳酸氢钠水溶液调PH为9，二氯甲烷萃取(3×5mL)，饱和食盐水水洗，分取有机层，无水硫酸钠干燥。然后进行快速柱层析分离得到白色固体即为化合物4-((2-(哌啶-4-胺)噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苯腈。收率84.2％，熔点114-116℃。
1H NMR(400MHz,DMSO-d6,ppm)δ:8.20(d,1H,J＝5.4Hz,),7.72(s,1H),7.26(s,1H),6.92(s,br,1H),3.78(s,br,1H),2.89(s,br,2H),2.12(s.6H),1.74(m,2H),1.23(m,4H).ESI-MS:m/z 380.5(M+1)C20H21N5OS(379.15).
实施例2：2-(哌啶-4-胺)-4-(2,4,6-三甲基苯氧基)噻吩并[3,2-d]嘧啶(13)的制备
Figure PCTCN2015099924-appb-000015
化合物13
操作步骤同实施例1，所不同的是起始原料用的是2,4,6-三甲基苯酚。
产物为白色固体。收率87.5％，178-180℃。
1H NMR(400MHz,CDCl3-d6,ppm)δ:7.73(d,1H,J＝5.4Hz,C6-thienopyrimidine-H),7.19(d,1H,J＝5.3Hz,C7-thienopyrimidine-H),6.90(s,2H,C3,C5-Ph”-H),4.89(d,1H,J＝7.4Hz,NH),3.77(s,1H,NH),3.20(d,2H,J＝12.6Hz),2.74-2.76(m,2H),2.32(s,3H,C4-Ph”-CH3),2.04-2.09(m,9H),1.46-1.54(m,2H).ESI-MS:m/z 369.5(M+1)C20H24N4OS(368.17)
实施例3：2-(哌啶-4-胺)-4-(2,6-二甲基-4-氰基乙烯基苯氧基)噻吩并[3,2-d]嘧啶(17)的制备
Figure PCTCN2015099924-appb-000016
称取4-羟基-3,5-二甲基苯甲醛(4.02g,26.7mmol)和碳酸钾(5.04g,36.6mmol)于150mL的N,N-二甲基甲酰胺(DMF)溶液中，室温搅拌15分钟，然后加入2,4-二氯噻吩并[3,2-d]嘧啶(5.0g,24.4mmol)继续室温搅拌1h(TLC检测反应完毕)。此时有大量的白色固体生成，慢慢地向其中加入250mL冰水，过滤，真空干燥箱干燥，然后在氯仿中重结晶得到白色固体即为化合物4-((2-氯噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苯甲醛14，收率95.0％，熔点219-220℃。
氰甲基磷酸二乙酯(0.4mL,2.4mmol)溶解到10mL的二氯甲烷中，冰浴条件下向此反应液中慢慢的加入叔丁醇钾(0.27g,2.4mmol)，冰浴搅拌30min。然后向此混合溶液中滴加溶于 10mL二氯甲烷的4-((2-氯噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苯甲醛(0.5g,1.5mmol)溶液，冰浴2h后改问室温搅拌，10h后TLC检测反应完毕。过滤，水洗滤饼，干燥，然后在氯仿中重结晶得到关键中间体(E)-3-(4-((2-氯噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苯基)丙烯腈15，收率91.7％，熔点225-227℃。
称取化合物(E)-3-(4-((2-氯噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苯基)丙烯腈15(0.35g,1.0mmol)，N-Boc-4-氨基哌啶(0.24g,1.2mmol)与碳酸钾(0.28g,2mmol)于5mL的二甲基亚砜中，然后加热回流12小时。待反应冷却到室温以后，慢慢地将反应液滴加到15mL水溶液中，搅拌，有大量的黄色固体生成。过滤，干燥得粗品16。称取中间体16(0.60g,1.21mmol)溶于4mL二氯甲烷中，然后慢慢地向其中加入三氟乙酸(0.74mL,10mmol)，室温条件下搅拌6小时(TLC检测反应完毕)。向反应液中加入10mL水，用饱和的碳酸氢钠水溶液调PH为9，二氯甲烷萃取(3×5mL)，饱和食盐水水洗，分取有机层，无水硫酸钠干燥。然后进行快速柱层析分离得到白色固体即为2-(哌啶-4-胺)-4-(2,6-二甲基-4-氰基乙烯基苯氧基)噻吩并[3,2-d]嘧啶17。收率74.2％，熔点125-127℃。
1H NMR(400MHz,DMSO-d6,ppm)δ:8.16(d,1H,J＝4.0Hz),7.60(d,1H,J＝16.0Hz),7.49(s,2H),7.25(s,1H),6.89(s,1H),6.42(d,1H,J＝16.0Hz),4.01(dd,1H,J＝12.0,8.0Hz),3.76(s,1H,NH),2.68-2.74(m,2H),2.09(s,6H),1.76-1.83(m,2H),1.16-1.45(m,4H).ESI-MS:m/z 580.4(M+1),C20H21N5OS(379.15)。
实施例4：4-((2-(哌啶-4-胺)噻吩并[2,3-d]嘧啶-4-基)氧基)-3,5-二甲基苯腈(21)的制备
Figure PCTCN2015099924-appb-000017
操作同实施,例1，所不同的是所用初始原料为2,4-二氯噻吩并[3,2-d]嘧啶18.收率67.7％，熔点131-134℃。
1H NMR(400MHz,DMSO-d6)δ7.35(d,J＝5.5Hz,1H),7.31(s,2H),7.27(d,J＝5.9Hz,1H),7.08(s,1H),3.77(s,1H),3.72(s,1H),2.69(d,J＝37.2Hz,2H),2.10(s,6H),1.70-1.86(m, 2H),1.18-1.48(m,4H).ESI-MS:m/z 380.4(M+1),C20H21N5OS(379.15)。
实施例5：化合物IA的制备
称取化合物4-((2-(哌啶-4-胺)噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苯腈(10)(0.5mmol)于10mLDMF中，室温条件下搅拌溶解后加入无水碳酸钾(0.14g,1.0mmol)与取代的氯苄或溴苄(0.6mmol)，室温条件下搅拌12h(TLC检测反应完毕)。减压蒸出溶剂，然后向残留底物中加入30ml乙酸乙酯，饱和食盐水溶液洗涤3次，每次10mL，分取有机层，无水硫酸钠干燥，过滤，浓缩。快速柱层析分离得到目标化合物，进而在乙酸乙酯-石油醚体系中重结晶得到目标化合物IA-1。
以不同的取代苄基和4-((2-(哌啶-4-胺)噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苯腈(10)用上述方法分别制得化合物IA-1-1～IA-1-12的目标产物，部分结果如下：
Figure PCTCN2015099924-appb-000018
IA-1-1
操作同上，所不同的是使用4-甲砜基溴苄。
产物为白色固体，收率：52.4％，熔点＞300℃。
1H NMR(400MHz,DMSO-d6,ppm)δ:8.18(d,1H,J＝5.3Hz),7.86(d,2H,J＝8.2Hz),7.71(s,2H),7.54(d,2H,J＝8.2Hz),7.24(s,1H),6.88(s,1H),4.02(d,1H,J＝7.2Hz),3.17-3.19(m,7H),2.71(s,2H),2.10(s,6H),1.38-1.44(m,2H),1.14-1.19(m,2H).ESI-MS:m/z 548.4(M+1),570.5(M+Na).C28H29N5O3S2(547.69)。
Figure PCTCN2015099924-appb-000019
IA-1-2
操作同上，所不同的是使用对溴甲基苯磺酰胺。
产物为白色固体，收率：50.3％，熔点223-225℃。
1H NMR(400MHz,DMSO-d6,ppm)δ:8.18(d,1H,J＝5.3Hz),7.76(d,2H,J＝8.3Hz),7.72(s,2H),7.45(d,2H,J＝8.2Hz),7.29(s,2H),7.25(s,1H),6.87(s,1H),4.02(d,1H,J＝7.2Hz),3.48(s,2H),2.72(s,2H),2.10(s,6H),1.69-1.79(m,2H),1.39-1.44(m,2H),1.16-1.19(m,2H).ESI-MS:m/z 549.5(M+1),C27H28N6O3S2(548.50)。
Figure PCTCN2015099924-appb-000020
IA-1-3
操作同上，所不同的是使用对氟溴苄。
产物为白色固体，收率：61.8％，熔点＞300℃。
1H NMR(400MHz,DMSO-d6,ppm)δ:8.34(d,1H,J＝5.3Hz),8.20(d,2H,J＝8.3Hz),7.72(s,1H),7.35(d,2H,J＝8.2Hz),7.28(s,2H),4.03(d,1H,J＝7.2Hz),3.47(s,2H),2.72(s,2H),2.12(s,6H),1.72-1.76(m,2H),1.39-1.43(m,2H),1.15-1.18(m,2H).ESI-MS:m/z 488.5(M+1),C27H26FN5OS(487.59)。
Figure PCTCN2015099924-appb-000021
IA-1-4
操作同上，所不同的是使用4-氯甲基吡啶盐酸盐。
产物为白色固体，收率：51.3％，熔点154-156℃。
1H NMR(400MHz,DMSO-d6,ppm)δ:8.48(d,1H,J＝5.3Hz),8.20(d,2H,J＝8.3Hz),7.72(s,1H),7.57(d,2H,J＝8.2Hz),7.28(s,2H),4.02(d,1H,J＝7.2Hz),3.48(s,2H),2.73(s,2H),2.12(s,6H),1.70-1.76(m,2H),1.37-1.43(m,2H),1.17-1.18(m,2H).ESI-MS:m/z 471.5(M+1),C26H26N6OS(470.59)。
Figure PCTCN2015099924-appb-000022
IA-1-5
操作同上，所不同的是使用2,4-二氟溴苄。
产物为白色固体，收率：55.7％，熔点＞300℃。
1HNMR(400MHz,DMSO-d6,ppm)δ:8.20(d,1H,J＝5.4Hz),7.67-7.70(m,2H),7.39(d,1H,J＝6.4Hz),7.24(m,1H),7.14(td,1H,J＝10.2,2.5Hz),7.02(td,1H,J＝8.4,2.1Hz),6.89(s,1H),4.13-4.15(m,1H),3.45(s,2H),2.74(s,2H),2.11(s,6H),1.33-1.84(m,2H),1.35-1.42(m,4H).ESI-MS:m/z 506.3(M+1),C27H25F2N5OS(505.17)。
Figure PCTCN2015099924-appb-000023
IA-1-6
操作同上，所不同的是使用对甲磺酰基氯苄。
产物为白色固体，收率：57.4％，熔点92-95℃。
1H NMR(400MHz,CDCl3-d6,ppm)δ:7.87(d,2H,J＝8.3Hz,C3,C5-Ph’-H),7.70(d,1H,J＝5.4Hz,C6-thienopyrimidine-H),7.53(d,2H,J＝8.1Hz,C2,C6-Ph’-H),7.16(d,1H,J＝5.4Hz,C7-thienopyrimidine-H),6.90(s,2H,C3,C5-Ph”-H),5.02(s,1H,NH),3.58(s,2H,N-CH2),3.06(s,3H,SO2-CH3),2.74-2.76(m,2H),2.32(s,3H,C4-Ph”-CH3),1.93-2.09(m,11H),1.42-1.51(m,2H).ESI-MS:m/z 537.6(M+1),559.5(M+Na),C28H32N4O3S2(536.19)
Figure PCTCN2015099924-appb-000024
IA-1-7
操作同上，所不同的是使用对溴甲基苯甲酸甲酯。
产物为白色固体，收率：52.7％，熔点97-100℃。
1H NMR(400MHz,CDCl3-d6,ppm)δ:7.97(d,2H,J＝8.2Hz,C3,C5-Ph’-H),7.70(d,1H,J＝5.4Hz,C6-thienopyrimidine-H),7.39(d,2H,J＝8.1Hz,C2,C6-Ph’-H),7.17(d,1H,J＝5.6Hz,C7-thienopyrimidine-H),6.90(s,2H,C3,C5-Ph”-H),5.10(s,1H,NH),3.53(s,2H,N-CH2),2.73-2.76(m,2H),2.31(s,3H,CO2-CH3),1.91-2.09(m,14H),1.41-1.49(m,2H).ESI-MS:m/z517.6(M+1),533.5(M+Na),C29H32N4O3S(516.22)
Figure PCTCN2015099924-appb-000025
IA-1-8
操作同上，所不同的是使用4-氟溴苄。
产物为白色固体，收率：65.3％，熔点133-136℃
1H NMR(400MHz,CDCl3-d6,ppm)δ:7.71(d,1H,J＝5.4Hz,C6-thienopyrimidine-H),7.29(m,2H),7.17(d,1H,J＝5.4Hz,C7-thienopyrimidine-H),7.02(t,2H,J＝8.6Hz),6.90(s,2H,C3,C5-Ph”-H),4.86(s,1H,NH),3.50(s,2H,N-CH2),2.73-2.78(m,2H),2.32(s,3H,C4-Ph”-CH3),1.94-2.09(m,11H),1.40-1.51(m,2H).ESI-MS:m/z 477.5(M+1),C27H29FN4OS(476.20)。
Figure PCTCN2015099924-appb-000026
IA-1-9
操作同上，所不同的是使用3-氟溴苄。
产物为白色固体，收率：63.1％，熔点140-142℃。
1H NMR(400MHz,CDCl3-d6,ppm)δ:7.68(d,1H,J＝5.4Hz,C6-thienopyrimidine-H),7.37(t,1H,J＝6.1Hz,C5-Ph’-H),7.22(t,1H,J＝6.0Hz,C4-Ph’-H),7.17(d,1H,J＝5.3Hz,C7-thienopyrimidine-H),7.10(t,1H,J＝7.4Hz,C6-Ph’-H),7.03(t,1H,J＝9.5Hz,C2-Ph’-H), 6.88(s,2H,C3,C5-Ph”-H),5.05(s,1H,NH),3.57(s,2H,N-CH2),2.78-2.80(m,2H),2.31(s,3H,C4-Ph”-CH3),1.92-2.08(m,11H),1.41-1.48(m,2H).ESI-MS:m/z 477.5(M+1),C27H29FN4OS(476.20)。
Figure PCTCN2015099924-appb-000027
IA-1-10
操作同上，所不同的是使用3-氰基溴苄。
产物为白色固体，收率：63.1％，熔点99-102℃
1H NMR(400MHz,CDCl3-d6,ppm)δ:7.72(d,1H,J＝5.4Hz,C6-thienopyrimidine-H),7.64(s,1H,C2-Ph’-H),7.58(t,2H,J＝9.0Hz,C4-Ph’-H),7.44(t,1H,J＝7.7Hz,C5-Ph’-H),7.17(d,1H,J＝5.3Hz,C7-thienopyrimidine-H),6.90(s,2H,C3,C5-Ph”-H),5.14(s,1H,NH),3.51(s,2H,N-CH2),2.72-2.75(m,2H),2.32(s,3H,C4-Ph”-CH3),2.09(s,9H),2.93(s,2H),1.42-1.50(m,2H).ESI-MS:m/z 484.6(M+1),506.5(M+Na),C28H29N5OS(483.21)。
Figure PCTCN2015099924-appb-000028
IA-1-11
操作同上，所不同的是使用4-氯甲基吡啶盐酸盐。
产物为白色固体，收率：50.7％，熔点135-137℃
1H NMR(400MHz,CDCl3-d6,ppm)δ:8.54(d,2H,J＝5.9Hz,C2,C6-pyridine-H),7.71(d,1H,J＝5.4Hz,C6-thienopyrimidine-H),7.28(d,2H,J＝6.6Hz,C3,C5-pyridine-H),7.18(d,1H,J＝5.4Hz,C7-thienopyrimidine-H),6.90(s,2H,C3,C5-Ph”-H),4.86(s,1H,NH),3.50(s,2H,N-CH2),2.74-2.77(m,2H),2.32(s,3H,C4-Ph”-CH3),1.95-2.09(m,11H),1.44-1.52(m,2H).ESI-MS:m/z 460.6(M+1),482.6(M+Na),C26H29N5OS(459.21)。
Figure PCTCN2015099924-appb-000029
IA-1-12
操作同上，所不同的是使用2,4-二氟溴苄。
产物为白色固体，收率：59.6％，熔点110-112℃.
1HNMR(400MHz,CDCl3-d6,ppm)δ:7.70(d,1H,J＝5.4Hz,C6-thienopyrimidine-H),7.36(dd,1H,J1＝15.1Hz,J2＝8.3Hz C5-Ph’-H),7.17(d,1H,J＝5.3Hz,C7-thienopyrimidine-H),6.90(s,2H,C3,C5-Ph”-H),6.75-6.85(m,2H),4.89(d,1H,J＝7.3Hz,NH),3.52(s,2H,N-CH2),2.75-2.78(m,2H),2.32(s,3H,C4-Ph”-CH3),2.09-2.17(m,9H),1.93-1.95(m,2H),1.39-1.47(m,2H).ESI-MS:m/z 495.5(M+1),517.6(M+Na),C27H28F2N4OS(494.20)。
Figure PCTCN2015099924-appb-000030
IA-1-13
操作同上，所不同的是使用对磺酰胺基溴苄。
产物为白色固体，收率：53.6％，熔点211-213℃.
1H NMR(400MHz,DMSO-d6,ppm)δ:8.16(d,1H,J＝4.0Hz),7.77(d,2H,J＝12.0Hz),7.60(d,1H,J＝16.0Hz),7.49(s,2H),7.45(d,2H,J＝8.0Hz),7.32(d,2H,J＝4.0Hz),7.25(s,1H),6.89(s,1H),6.42(d,1H,J＝16.0Hz),4.01(dd,1H,J＝12.0,8.0Hz),3.48(s,2H),2.68-2.74(m,2H),2.09(s,6H),1.76-1.83(m,2H),1.16-1.45(m,4H).ESI-MS:m/z 575.4(M+1),C29H30N6O3S2(574.18)。
Figure PCTCN2015099924-appb-000031
IA-1-14
操作同上，所不同的是使用对砜甲基溴苄。
产物为白色固体，收率：42.7％，熔点113-115℃.
1H NMR(400MHz,DMSO-d6,ppm)δ:8.16(d,1H,J＝8.0Hz),7.87(d,2H,J＝8.0Hz),7.60(d,1H,J＝16.0Hz),7.54(d,2H,J＝8.0Hz),7.49(s,2H),7.25(s,1H),6.89(s,1H),6.41(d,1H,J＝20.0Hz),3.67-3.78(m,1H)),3.53(s,2H),3.34(s,2H),2.68-2.73(m,2H),2.08(s,6H),1.76-1.83(m,2H),1.26-1.48(m,4H).ESI-MS:m/z 575.3(M+1),C30H31N5O3S2(574.18)。
Figure PCTCN2015099924-appb-000032
IA-1-15
操作同上，所不同的是使用对酰胺基溴苄。
产物为白色固体，收率：45.7％，熔点221-224℃.
1H NMR(400MHz,DMSO-d6,ppm)δ:8.16(d,1H,J＝8.0Hz),7.93(s,1H),7.82(d,2H,J＝8.0Hz),7.60(d,1H,J＝16.0Hz),7.49(s,2H),7.31-7.35(m,3H),7.25(s,1H),6.88(s,1H),6.42(d,1H,J＝16.0Hz),3.67-3.78(m,1H)),3.45(s,2H),2.68-2.73(m,2H),2.08(s,6H),1.88-1.99(m,2H),1.69-1.77(m,2H),1.34-1.53(m,2H).ESI-MS:m/z 539.5(M+1),C30H30N6O2S(538.22).
Figure PCTCN2015099924-appb-000033
IA-1-16
操作同上，所不同的是使用间酰胺基溴苄。
产物为白色固体，收率：35.5％，熔点215-217℃.
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝5.3Hz,1H),7.97(s,1H),7.80–7.74(m,2H),7.62(d,J＝16.6Hz,1H),7.49(s,2H),7.40(d,J＝6.9Hz,2H),7.35(s,1H),7.25(s,1H),6.88(s,1H),6.44(d,J＝16.7Hz,1H),3.73-3.76(m,1H),3.46(s,2H),2.74(s,2H),2.09(s,6H),1.93-2.00(m,2H),1.69-1.77(m,2H),1.35-1.45(m,2H).ESI-MS:m/z 539.5(M+1),C30H30N6O2S(538.22).
Figure PCTCN2015099924-appb-000034
IA-1-17
操作同上，所不同的是使用对氟溴苄。
产物为白色固体，收率：58.9％，熔点260-262℃.
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝5.3Hz,1H),7.62(d,J＝16.7Hz,1H),7.48(s,2H),7.32–7.23(m,3H),7.13(t,J＝8.8Hz,2H),6.88(s,1H),6.44(d,J＝16.7Hz,1H),3.71-3.75(m,1H),3.38(s,2H),2.71(s,2H),2.08(s,6H),1.92-1.99(m,2H),1.67-1.76(m,2H),1.32-1.42(m,2H).ESI-MS:m/z 502.4(M+1),C29H28FN5OS(501.22)。
Figure PCTCN2015099924-appb-000035
IA-1-18
操作同上，所不同的是使用间氟溴苄。
产物为白色固体，收率：58.3％，熔点156-158℃.
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝5.3Hz,1H),7.61(d,J＝16.6Hz,1H),7.48(s,2H),7.36(d,J＝6.7Hz,1H),7.25(s,1H),7.13-7.05(m,3H),6.89(s,1H),6.43(d,J＝16.7Hz,1H),3.71-3.75(m,1H),3.43(s,2H),2.72(s,2H),2.09(s,6H),1.77-1.92(m,4H),1.34-1.45(m,2H).ESI-MS:m/z 514.2(M+1),C29H28FN5OS(513.20)。
Figure PCTCN2015099924-appb-000036
IA-1-19
操作同上，所不同的是使用对溴溴苄。
产物为白色固体，收率：54.1％，熔点192-194℃.
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝5.3Hz,1H),7.62(d,J＝16.6Hz,1H),7.48-7.51(m,4H),7.22-7.24(m,3H),6.89(s,1H),6.44(d,J＝16.7Hz,1H),3.71-3.75(m,1H),3.37(s,2H),2.71(s,2H),2.08(s,6H),1.92-2.00(m,2H),1.75-1.77(m,2H),1.34-1.42(m,2H).ESI-MS:m/z 574.6(M+1),C29H28BrN5OS(573.12)。
Figure PCTCN2015099924-appb-000037
IA-1-20
操作同上，所不同的是使用间溴溴苄。
产物为白色固体，收率：48.2％，熔点180-182℃.
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝5.1Hz,1H),7.62(d,J＝16.5Hz,1H),7.49(s,2H),7.47–7.42(m,2H),7.27-7.29(m,3H),6.90(s,1H),6.44(d,J＝16.7Hz,1H),3.71-3.75(m,1H),3.42(s,2H),2.73(s,2H),2.09(s,6H),1.93-1.99(m,2H),1.75-1.77(m,2H),1.34-1.45(m,2H).ESI-MS:m/z 574.5(M+1),C29H28BrN5OS(573.12)。
Figure PCTCN2015099924-appb-000038
IA-1-21
操作同上，所不同的是使用邻溴溴苄。
产物为白色固体，收率：56.2％，熔点165-167℃.
1H NMR(400MHz,DMSO-d6)δ8.18(d,J＝5.2Hz,1H),7.65-7.56(m,2H),7.49(s,2H),7.43(d,J＝6.8Hz,1H),7.36(t,J＝7.4Hz,1H),7.27(s,1H),7.19(t,J＝8.2Hz,1H),6.92(s,1H),6.45(d,J＝16.7Hz,1H),3.76(s,1H),3.49(s,2H),2.78(s,2H),2.09(s,6H),1.93-1.99(m,2H),1.34-1.67(m,4H).ESI-MS:m/z 574.3(M+1),C29H28BrN5OS(573.12)。
Figure PCTCN2015099924-appb-000039
IA-1-22
操作同上，所不同的是使用邻氯氯苄。
产物为白色固体，收率：57.2％，熔点165-168℃.
1H NMR(400MHz,DMSO-d6)δ8.18(d,J＝5.2Hz,1H),7.62(d,J＝16.6Hz,1H),7.49(s,2H),7.42(d,J＝8.7Hz,2H),7.34-7.27(m,3H),6.91(s,1H),6.44(d,J＝16.7Hz,1H),3.74(s,1H),3.51(s,2H),2.68-2.77(m,2H),2.09(s,6H),1.72-1.78(m,2H),1.33-1.470(m,4H).ESI-MS:m/z 530.1(M+1),C29H28ClN5OS(529.17)。
Figure PCTCN2015099924-appb-000040
IA-1-23
操作同上，所不同的是使用对硝基溴苄。
产物为白色固体，收率：47.3％，熔点181-183℃.
1H NMR(400MHz,DMSO-d6)δ8.17-8.20(m,3H),7.64(s,1H),7.56(d,J＝8.3Hz,2H),7.49(s,2H),7.25(s,1H),6.91(s,1H),6.44(d,J＝16.7Hz,1H),3.74(s,1H),3.56(s,2H),2.74(s,2H),2.09(s,6H),1.71-1.77(m,2H),1.23-1.45(m,4H).ESI-MS:m/z 541.3(M+1),C29H28N6O3S(540.19)。
Figure PCTCN2015099924-appb-000041
IA-1-24
操作同上，所不同的是使用邻甲基溴苄。
产物为白色固体，收率：57.1％，熔点176-179℃.
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝5.3Hz,1H),7.62(d,J＝16.1Hz,1H),7.49(s,2H),7.26(s,1H),7.14-7.18(m,4H),6.88(s,1H),6.44(d,J＝16.7Hz,1H),3.75(s,1H),3.44(s,2H),2.63-2.74(m,2H),2.30(s,3H),2.08(s,6H),1.72-1.77(m,2H),1.22-1.39(m,4H).ESI-MS:m/z 510.4(M+1),C30H31N5OS(509.22)。
Figure PCTCN2015099924-appb-000042
IA-1-25
操作同上，所不同的是使用对甲基溴苄。
产物为白色固体，收率：55.4％，熔点185-191℃.
1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝5.2Hz,1H),7.61(d,J＝16.4Hz,1H),7.47(s,2H),7.24(s,1H),7.08-7.14(m,4H),6.85(s,1H),6.43(d,J＝16.7Hz,1H),3.71(s,1H),3.46(s,2H),2.71(s,2H),2.27(s,3H),2.07(s,6H),1.91-1.99(m,2H),1.71-1.74(m,2H),1.34-1.38(m,2H).ESI-MS:m/z 510.3(M+1),C30H31N5OS(509.22)。
Figure PCTCN2015099924-appb-000043
IA-1-26
操作同上，所不同的是使用对甲酸乙酯基溴苄。
产物为白色固体，收率：44.2％，熔点194-199℃.
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝5.2Hz,1H),7.92(d,J＝8.1Hz,2H),7.62(d,J＝16.6Hz,1H),7.48(s,2H),7.42(d,J＝7.9Hz,2H),7.25(s,1H),6.89(s,1H),6.44(d,J＝16.7Hz,1H),4.31(q,J＝7.1Hz,2H),3.75(s,1H),3.48(s,2H),2.72(s,2H),2.08(s,6H),1.92-2.00(m,2H),1.72-1.76(m,2H),1.42-1.47(m,2H),1.32(t,J＝7.1Hz,3H).ESI-MS:m/z 568.4(M+1),C32H33N5O3S(567.23)。
Figure PCTCN2015099924-appb-000044
IA-1-27
操作同上，所不同的是使用邻氰基溴苄。
产物为白色固体，收率：53.2％，熔点122-125℃.
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝5.3Hz,1H),7.80(d,J＝7.7Hz,1H),7.68(t,J＝7.5Hz,2H),7.54(d,J＝6.9Hz,1H),7.49(s,2H),7.46(d,J＝7.6Hz,1H),7.26(s,1H),6.91(s,1H),6.43(d,J＝16.7Hz,1H),3.74(s,1H),3.59(s,2H),2.74(s,2H),2.09(s,6H),1.72-1.76(m,2H),1.33-1.44(m,4H).ESI-MS:m/z 521.6(M+1),C30H28N6OS(520.20)。
Figure PCTCN2015099924-appb-000045
IA-1-28
操作同上，所不同的是使用间氰基溴苄。
产物为白色固体，收率：41.6％，熔点180-185℃.
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝5.3Hz,1H),7.71(d,J＝5.9Hz,2H),7.59-7.65(m,2H),7.54(t,J＝7.7Hz,1H),7.49(s,2H),7.25(s,1H),6.90(s,1H),6.44(d,J＝16.7Hz,1H),3.75(s,1H),3.48(s,2H),2.71-2.77(m,2H),2.09(s,6H),1.72-1.77(m,2H),1.33-1.44(m,4H).ESI-MS:m/z 521.2(M+1),C30H28N6OS(520.20)。
Figure PCTCN2015099924-appb-000046
IA-1-29
操作同上，所不同的是使用对氰基溴苄。
产物为白色固体，收率：48.9％，熔点176-180℃.
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝5.3Hz,1H),7.78(d,J＝8.2Hz,2H),7.62(d,J＝16.6Hz,1H),7.48(d,J＝6.5Hz,4H),7.25(s,1H),6.90(s,1H),6.43(d,J＝16.7Hz,1H),3.74(s,1H),3.50(s,2H),2.71(s,2H),2.09(s,6H),1.72-1.76(m,2H),1.33-1.44(m,4H).ESI-MS:m/z521.2(M+1),C30H28N6OS(520.20)。
Figure PCTCN2015099924-appb-000047
IA-1-30
操作同上，所不同的是使用对氯氯苄。
产物为白色固体，收率：56.3％，熔点180-184℃.
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝5.3Hz,1H),7.62(d,J＝16.5Hz,1H),7.48(s,2H),7.36(d,J＝8.3Hz,2H),7.28(d,J＝8.2Hz,2H),7.25(s,1H),6.88(s,1H),6.44(d,J＝16.7Hz,1H),3.72(s,1H),3.39(s,2H),2.70(s,2H),2.08(s,6H),1.92-2.00(m,2H),1.68-1.76(m,2H),1.37-1.44(m,2H).ESI-MS:m/z 530.5(M+1),C29H28ClN5OS(529.17)。
Figure PCTCN2015099924-appb-000048
IA-1-31
操作同上，所不同的是使用2-氯甲基吡啶盐酸盐。
产物为白色固体，收率：39.5％，熔点172-175℃.
1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝4.6Hz,1H),8.17(d,J＝5.3Hz,1H),7.75(t,J＝8.4Hz,1H),7.61(d,J＝16.6Hz,1H),7.48(s,2H),7.39(d,J＝7.6Hz,1H),7.24(d,J＝6.5Hz,2H),6.90(s,1H),6.43(d,J＝16.7Hz,1H),3.74(s,1H),3.54(s,2H),2.76(s,2H),2.09(s,6H),1.92-1.97(m,2H),1.68-1.77(m,2H),1.33-1.47(m,2H).ESI-MS:m/z 497.3(M+1),C28H28N6OS(496.20)。
Figure PCTCN2015099924-appb-000049
IA-1-32
操作同上，所不同的是使用3-氯甲基吡啶盐酸盐。
产物为白色固体，收率：47.6％，熔点156-159℃.
1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝4.7Hz,2H),8.17(d,J＝5.2Hz,1H),7.62(d,J＝16.6Hz,1H),7.48(s,2H),7.28(d,J＝4.1Hz,2H),7.24(s,1H),6.90(s,1H),6.43(d,J＝16.7Hz,1H),3.75(s,1H),3.45(s,2H),2.71(s,2H),2.08(s,6H),1.92-1.99(m,2H),1.72-1.78(m,2H),1.39-1.47(m,2H).ESI-MS:m/z 497.4(M+1),C28H28N6OS(496.20)。
Figure PCTCN2015099924-appb-000050
IA-1-33
操作同上，所不同的是使用4-氯甲基吡啶盐酸盐。
产物为白色固体，收率：45.9％，熔点147-150℃.
1H NMR(400MHz,DMSO-d6)δ8.46(s,2H),8.17(d,J＝5.3Hz,1H),7.67(d,J＝7.2Hz,1H),7.62(d,J＝16.6Hz,1H),7.48(s,2H),7.35(dd,J＝7.6,4.8Hz,1H),7.25(s,1H),6.89(s,1H),6.44(d,J＝16.7Hz,1H),3.73(s,1H),3.45(s,2H),2.72(s,2H),2.08(s,6H),1.92-2.00(m,2H),1.67-1.76(m,2H),1.36-1.43(m,2H).ESI-MS:m/z 497.3(M+1),C28H28N6OS(496.20)。
Figure PCTCN2015099924-appb-000051
IA-2-1
操作同上，所不同的是使用对磺酰胺基溴苄。
产物为白色固体，收率：54.5％，熔点241-243℃.
1H NMR(400MHz,DMSO-d6)δ7.78(d,J＝8.0Hz,2H),7.71(s,2H),7.46(d,J＝8.0Hz,2H),7.35(d,J＝5.5Hz,1H),7.31(s,2H),7.27(d,J＝5.9Hz,1H),7.08(s,1H),3.72(s,1H),3.49(s,2H),2.69(d,J＝37.2Hz,2H),2.10(s,6H),1.70-1.86(m,2H),1.18-1.48(m,4H).ESI-MS:m/z549.5(M+1),C27H28N6O3S2(548.17)。
实施例4：目标化合物的体外抗HIV活性测试
测试原理
化合物体外抗HIV活性筛选采用MTT法。MTT全称为溴化-3-(4,5-二甲基-2-噻唑基)-2,5-二苯基四唑氮(商品名：噻唑蓝),可用于检测细胞的存活和生长。检测原理为：MTT可以与活的细胞内琥珀酸脱氢酶结合还原为水不溶性的蓝紫色结晶甲瓒沉积在细胞中，而死细胞并无此功能。二甲基亚砜可以溶解细胞中的甲瓒，用酶标仪检测其在590nm下的吸光度(A)值可以间接的反映活细胞的数量。在一定的细胞数范围内，MTT结晶形成的量与细胞数成正比。
由于HIV感染的MT-4细胞在一定时间内(5-7天)会发生病变，因此向HIV感染的MT-4细胞悬浊液中加入适当浓度的待检测化合物溶液，经过一段时间(5-7天)的培养后，用MTT分析法测定MT-4细胞活力，得到保护50％细胞免于细胞病变的药物浓度(EC50)即可得出目标化合物的抗HIV的活性。同时得到目标化合物使50％未感染HIV的细胞发生病变的浓度(CC50),计算出选择系数(selectivity index，SI＝CC50/EC50)。
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(TMC125)、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。
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或者RES056)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。
按照上述实验方法对合成的部分噻吩并嘧啶类衍生物进行了细胞水平的抗HIV-1(IIIB)，单突变株K103N、Y181C、Y188L以及双突变株RES056(K103N/Y181C)的活性筛选，活性结果如表1所示。
表1部分IA系列化合物和参考药物的结构及其抗HIV-1活性(MT-4细胞)
Figure PCTCN2015099924-appb-000052
Figure PCTCN2015099924-appb-000053
Figure PCTCN2015099924-appb-000054
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、ETV、AZT分别代表上市药物奈韦拉平、依法韦伦、依曲韦林和齐多夫定。
表2部分IA系列化合物及参考药物的细胞毒性及选择指数(MT-4细胞)
Figure PCTCN2015099924-appb-000055
注：aCC50:使得50％的MTT细胞发生病变时的药物浓度；A代表化合物SI>10000，B代表化合物SI值为1000-10000，C代表化合物SI<1000；X1：SI≥1或者<1；NVP、EFV、ETV、AZT分别代表上市药物奈韦拉平、依法韦伦、依曲韦林和齐多夫定。

Claims (7)

  1. 一种噻吩并嘧啶类衍生物，或其药学上可接受的盐、酯或前药，其特征在于，具有通式I所示的结构：
    Figure PCTCN2015099924-appb-100001
    其中，虚线代表A与B之间为双键、B与D之间为双键、A与B之间为单键或者B与D之间为单键之中的一种；
    A为：S或者C(U)；
    B为：S或者C(V)；
    D为：S或者C(W)；
    并且A，B和D有且只有一个为S；
    其中U，V和W各自独立的为：H，卤素，C1-C6烷基，C1-C6烷氧基，C2-C6烯基，C3-C6环烷基，O C3-C6环烷基，苯基，苄基，三氟甲基，氨基，羟基，各种取代的六元杂环、各种取代的五元杂环；
    Z为：F，F2，OH，COOH，CONH2，COOC2H5；
    X为：O，NH或者S之中的一种；
    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；
    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. 权利要求1所述的化合物，其特征在于，通式I中的Ar为具有通式(a)或者通式(b)的取代苯环：
    Figure PCTCN2015099924-appb-100002
    其中，R4为H，CH3，COCH3，COOCH3，COOC2H5，COOH，SO2CH3或SO2CF3；R5为Cl，Br，Me，NHCH3，NHCOCH3，NHSO2CH3或NHSO2CF3。
  3. 权利要求1或2所述的化合物，其特征在于，结构式为下列之一：
    Figure PCTCN2015099924-appb-100003
    Figure PCTCN2015099924-appb-100004
    Figure PCTCN2015099924-appb-100005
    其中，R，U，V，W，Z和Ar同上通式I所述。
  4. 权利要求3所述的化合物，其特征在于，为如下具体化合物之一：
    Figure PCTCN2015099924-appb-100006
    Figure PCTCN2015099924-appb-100007
  5. 权利要求1所述的化合物的制备方法，步骤如下：以2,4-二氯取代的噻吩并嘧啶1为初始原料，首先在N,N-二甲基甲酰胺溶液中与取代苯酚、苯硫醇或苯胺发生亲核取代生成中间体2；然后中间体2在二甲基亚砜中与N-Boc-4-氨基哌啶反应并随后在三氟乙酸条件下脱Boc基团保护生成关键中间体4；或者中间体2发生布赫瓦尔德-哈特维希偶联反应生成中间体3然后脱BOC保护得到中间体4；最后此关键中间体4在N,N-二甲基甲酰胺溶液中和碳酸钾做碱的条件下，与各种取代氯苄或溴苄反应生成目标产物；合成路线如下：
    Figure PCTCN2015099924-appb-100008
    试剂及条件:(i)取代苯酚、苯胺或者苯基硫醇，二甲基甲酰胺，碳酸钾，室温；(ii)N-Boc-4-氨基哌啶，二甲基亚砜，碳酸钾，120℃；(iii)N-Boc-4-氨基哌啶，醋酸钯，4,5-双(二苯基膦)-9,9-二甲基氧杂蒽，碳酸铯，90℃，二氧六环；(iv)二氯甲烷，三氟乙酸，室温；(v)取代氯苄或溴苄，二甲基甲酰胺，碳酸钾，室温。
  6. 一种如权利要求1-4任一项所述化合物在制备治疗和预防人免疫缺陷病毒药物中的应用。
  7. 一种药物组合物，包含权利要求1-4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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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111793074A (zh) * 2020-07-23 2020-10-20 山东大学 K-5a2化合物的晶型及其制备方法和应用
US11225491B2 (en) * 2018-04-12 2022-01-18 Shan Dong University Thiazolo-pyrimidine HIV-1 reverse transcriptase inhibitor, preparation method therefor, and uses thereof
CN114588158A (zh) * 2022-03-14 2022-06-07 武汉工程大学 吲哚哌啶嘧啶类衍生物在制备新型冠状病毒抑制剂中的应用

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106117242B (zh) * 2016-06-27 2018-08-03 山东大学 四氢噻喃并嘧啶类衍生物及其制备方法与应用
CN106831814B (zh) * 2017-02-15 2018-11-23 山东大学 一种噻吩并[3,2-d]嘧啶类HIV-1逆转录酶抑制剂及其制备方法和应用
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CN108440560B (zh) * 2018-04-26 2019-09-27 山东大学 一种K-5a2前药及其制备方法与应用
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CN117618336B (zh) * 2024-01-26 2024-04-12 山东齐都药业有限公司 K-5a2原位凝胶制剂及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000027825A1 (en) * 1998-11-10 2000-05-18 Janssen Pharmaceutica N.V. Hiv replication inhibiting pyrimidines
CN1541215A (zh) * 2001-08-13 2004-10-27 ղɭҩҵ���޹�˾ 抑制hiv的嘧啶衍生物
CN104530078A (zh) * 2015-01-27 2015-04-22 山东大学 一种噻吩并[3,2-d]嘧啶衍生物及其制备方法与应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7595324B2 (en) * 2006-11-09 2009-09-29 Ardea Biosciences, Inc. Substituted thieno[3,2-D]pyrimidines as HIV inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000027825A1 (en) * 1998-11-10 2000-05-18 Janssen Pharmaceutica N.V. Hiv replication inhibiting pyrimidines
CN1541215A (zh) * 2001-08-13 2004-10-27 ղɭҩҵ���޹�˾ 抑制hiv的嘧啶衍生物
CN104530078A (zh) * 2015-01-27 2015-04-22 山东大学 一种噻吩并[3,2-d]嘧啶衍生物及其制备方法与应用

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11225491B2 (en) * 2018-04-12 2022-01-18 Shan Dong University Thiazolo-pyrimidine HIV-1 reverse transcriptase inhibitor, preparation method therefor, and uses thereof
CN111793074A (zh) * 2020-07-23 2020-10-20 山东大学 K-5a2化合物的晶型及其制备方法和应用
CN111793074B (zh) * 2020-07-23 2021-10-26 山东大学 K-5a2化合物的晶型及其制备方法和应用
WO2022016836A1 (zh) * 2020-07-23 2022-01-27 山东大学 K-5a2化合物的晶型及其制备方法和应用
CN114588158A (zh) * 2022-03-14 2022-06-07 武汉工程大学 吲哚哌啶嘧啶类衍生物在制备新型冠状病毒抑制剂中的应用
CN114588158B (zh) * 2022-03-14 2023-09-05 武汉工程大学 吲哚哌啶嘧啶类衍生物在制备新型冠状病毒抑制剂中的应用

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