CN104926829A - Thieno miazines derivatives and preparation method and application thereof - Google Patents

Thieno miazines derivatives and preparation method and application thereof Download PDF

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CN104926829A
CN104926829A CN201510309662.1A CN201510309662A CN104926829A CN 104926829 A CN104926829 A CN 104926829A CN 201510309662 A CN201510309662 A CN 201510309662A CN 104926829 A CN104926829 A CN 104926829A
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various replacement
compound
hexa
thienopyrimidine
salt
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刘新泳
康东伟
展鹏
方增军
李震宇
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Shandong University
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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

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Abstract

The invention discloses thieno miazines derivatives and a preparation method and application thereof. The thieno miazines derivatives are compounds of which the structures are shown in the general formula I or pharmaceutically acceptable salts, esters or prodrugs of the compounds. The invention further provides the preparation method of the compounds as well as application of composition of one or more of the compounds to preparation of medicines for treating and preventing human immunodeficiency virus (HIV) infection.

Description

A kind of Thienopyrimidine analog derivative and its preparation method and application
Technical field
The invention belongs to organic compound synthesis and medical applications technical field, be specifically related to a kind of Thienopyrimidine derivative and preparation method thereof and the application as HIV-1 inhibitor.
Background technology
Acquired immune deficiency syndrome (AIDS) (Acquired Immune Deficiency Syndrome, AIDS) the great communicable disease of harm humans life and health has been become at present, its main pathogens is human immunodeficiency virus type 1 (Human Immunodeficiency Virus Type 1, HIV-1).Although Effective Anti reverse transcription therapy (Highly Active Antiretroviral Therapy, the survival time of enforcement significant prolongation patient HAART), but the problems such as the expense of resistance problems and poisonous side effect of medicine and prolonged administration of drugs, force investigator to research and develop the novel hiv inhibitor of high-efficiency low-toxicity.HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTIs) is the important component part of HAART therapy, such medicine has the advantage of high-efficiency low-toxicity, high specificity, but the defect easily producing resistance makes such medicine lose clinical potency rapidly, therefore the research and development of the NNRTIs of novel, efficient, low toxicity, wide spectrum anti-drug resistance are one of focuses of current inverase research.
Diaryl pyrimidine (diarylpyrimidine, DAPY) class is the HIV-1NNRTIs of a quasi-representative, has stronger HIV (human immunodeficiency virus)-resistant activity, also has good restraining effect to medicament-resistant mutation strain.In such medicine, etravirine (Etravirine) and rilpivirine (Rilpivirine) go on the market, but such compound water soluble is poor, oral administration biaavailability is lower, therefore such chemical structure is modified further, to finding that broad-spectrum high efficacy, bioavailability are good and the novel inverase with independent intellectual property right is significant.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of Thienopyrimidine analog derivative and preparation method thereof, present invention also offers the application of Thienopyrimidine analog derivative as HIV-1 inhibitor.
Technical scheme of the present invention is as follows:
1. Thienopyrimidine analog derivative
A kind of Thienopyrimidine analog derivative, or its pharmacy acceptable salt, ester or prodrug, have the structure shown in general formula I:
Wherein, between represented by dotted arrows A and B being is for being the one among singly-bound between double bond, B and D between double bond, A and B between singly-bound or B and D;
A is: S or C (U);
B is: S or C (V);
D is: S or C (W);
And A, B and D have and only have one for S;
Wherein U, V and W are independently separately: H, halogen, C 1-C 6alkyl, C 1-C 6alkoxyl group, C 2-c 6thiazolinyl, C 3-C 6cycloalkyl, O C 3-C 6cycloalkyl, phenyl, benzyl, trifluoromethyl, amino, hydroxyl, the hexa-member heterocycle of various replacement, the five-membered ring of various replacement;
Z is: F, F 2, OH, COOH, CONH 2, COOC 2h 5;
X is: the one among O, NH or S;
R 1, R 2, R 3be independently separately: H, halogen, cyano group, C 1-C 6alkyl, C 1-C 6alkoxyl group, C 2-c 6thiazolinyl, trifluoromethyl, amino, hydroxyl vinyl;
Ar is: substituted benzene ring, replace naphthalene nucleus, the hexa-member heterocycle of various replacement, the five-membered ring of various replacement, the hexa-atomic of various replacement five-membered ring, various replacement hexa-atomic hexa-member heterocycle, five yuan of various replacement and five-membered ring, the benzo five-membered heterocycle of various replacement or the benzo hexa-member heterocycle of various replacement.
Preferably, Ar is for having the substituted benzene ring of general formula (a) or general formula (b):
Wherein, R 4for H, CH 3, COCH 3, COOCH 3, COOC 2h 5, COOH, SO 2cH 3or SO 2cF 3; R 5for Cl, Br, Me, NHCH 3, NHCOCH 3, NHSO 2cH 3or NHSO 2cF 3.
" pharmacy acceptable salt " described in the present invention refers in reliable medical range of value, the salt of compound is suitable for contacting with people or more zootic tissue and without unsuitable toxicity, stimulation and anaphylaxis etc., there is quite reasonably income and risk ratio, normally water or oil solvable or dispersible, and can effectively for the purposes of its expection.Comprising pharmaceutically acceptable acid salt and pharmaceutically acceptable base addition salt, is here can do the purposes of expecting and compatible with the chemical property of formula I.The list of suitable salt see S.M.Birge etc., J.Pharm.Sci., 1977,66,1-19 page.
" prodrug " described in the present invention refers to pharmaceutically acceptable derivates, so that the biotransformation product of these derivative gained is the active medicines defined such as formula I.
Specifically, the structural formula of thienopyrimidines is one of following in the present invention:
Wherein, described in the same general formula I of R, U, V, W, Z and Ar.
Preferred further, Compound I A-1, IA-2, IA-3, IA-4, IA-5, IB-1, IB-2, IB-3, IB-4, IB-5 and IC-1, in IC-2, IC-3, IC-4, IC-5, Ar is general formula (a) or general formula (b).
Specifically, Thienopyrimidine analog derivative is one of following particular compound in the present invention:
2. the preparation method of Thienopyrimidine analog derivative
The preparation method of Thienopyrimidine derivative, step is as follows: the Thienopyrimidine 1 replaced with 2,4-dichloro, for initial feed, first generates intermediate 2 with fortified phenol, benzenethiol or aniline generation nucleophilic substitution in DMF solution; Then intermediate 2 reacts with N-Boc-4-amino piperidine and under trifluoroacetic acid condition, takes off Boc radical protection subsequently and generates key intermediate 4 in dimethyl sulfoxide (DMSO); Or intermediate 2 occur Buchwald-Hartwig (Buchwald-Hartwig) linked reaction generate intermediate 3 then de-BOC protection obtain intermediate 4; Under this key intermediate 4 last does the condition of alkali with salt of wormwood in DMF solution, react with various replacement benzyl chloride or bromobenzyl and generate target product; Synthetic route is as follows:
Reagent and condition: (i) fortified phenol, aniline or phenyl mercaptan, dimethyl formamide, salt of wormwood, room temperature; (ii) N-Boc-4-amino piperidine, dimethyl sulfoxide (DMSO), salt of wormwood, 120 DEG C; (iii) N-Boc-4-amino piperidine, palladium, 4,5-two (diphenylphosphine)-9,9-dimethyl xanthene, cesium carbonate, 90 DEG C, dioxane; (iv) methylene dichloride, trifluoroacetic acid, room temperature; V () replaces benzyl chloride or bromobenzyl, dimethyl formamide, salt of wormwood, room temperature.
Described fortified phenol, benzenethiol or aniline are mesitylene phenol, 2,6-dimethyl-4-cyanophenol, 2,6-dimethyl-4-(E)-vinyl phenol, mesitylene base mercaptan, 2,6-dimethyl-4-cyano-phenyl mercaptan, 2,6-dimethyl-4-(E)-vinyl phenyl mercaptan, trimethyl aniline, 2,6-dimethyl-4-cyano-aniline, 2,6-dimethyl-4-(E)-Cyanoethenyl aniline;
Replace benzyl chloride or bromobenzyl be adjacent chlorobenzyl chloride, a chlorobenzyl chloride, 4-chlorobenzyl chloride, adjacent bromine bromobenzyl, a bromine bromobenzyl, to bromine bromobenzyl, adjacent fluorobenzyl chloride, a fluorobenzyl chloride, to fluorobenzyl chloride, 2; 4-difluorobenzyl bromide, 3,4-difluorobenzyl bromides, o-cyanobenzyl chloride, a cyano group benzyl chloride, to cyano group benzyl chloride, adjacent nitro benzyl chloride, a nitro benzyl chloride, p-nitrobenzyl chloride, O-methoxy benzyl chloride, meta-methoxy benzyl chloride, to methoxyl group benzyl chloride, to methylsulfonyl bromobenzyl, to sulfoamido bromobenzyl, to formamido-bromobenzyl, 4-(brooethyl) methyl benzoate.
Room temperature of the present invention is 20-30 DEG C.
3. the anti-HIV-1 wild strain of Thienopyrimidine analog derivative and mutant strain is active and application
The part Thienopyrimidine analog derivative synthesized according to the method described above is carried out to the anti-HIV-1 (III of cell levels b), the screening active ingredients of single medicament-resistant mutation strain K103N, Y181C, Y188L and two medicament-resistant mutation strain RES056 (K103N/Y181C), with nevirapine (NVP), Sustiva (EFV), etravirine (ETV) and zidovudine (AZT) for positive control.Their Anti-HIV-1 Active and toxicity data are listed in table 1 and table 2 respectively.
As can be seen from Table 1, Thienopyrimidine derivative of the present invention is the non-nucleoside HIV-1 inhibitor of a series of novel structure, shows extremely strong anti-HIV-1 wild strain and mutant strain activity.Overwhelming majority compound suppresses the EC of wild strain and mutant strain 50value reaches nmole rank, and wherein, the activity of Compound I A-1-2 is particularly outstanding, and it is to the EC of HIV-1 wild strain 50value is more than 150 times of first-generation anti-AIDS drug nevirapine (NVP), is more than 2 times of latest generation medicine etravirine (ETV).Compound I A-1-2 also shows high security, and it is greater than 100000, far away higher than marketed drug to the selectivity index of HIV-1 wild strain.To single mutation strain K103N and Y181C, Compound I A-1-2 shows the inhibit activities suitable with etravirine, and for single mutation strain Y188L, its inhibit activities exceeds etravirine far away, is more than 3 times of its inhibit activities.In addition, the cytotoxicity of Compound I A-1-2, much smaller than positive drug (table 2), causes this compounds exhibit to go out very high selectivity.Therefore such thienopyrimidines has the value of further research and development, and the lead compound that can be used as AntiHIV1 RT activity is used.
Thienopyrimidine derivative of the present invention can be used as the application of non-nucleoside HIV-1 inhibitor.Specifically, as HIV-1 inhibitor for the preparation of anti-AIDS drug.
A kind of anti-HIV-1 medicines composition, comprises Thienopyrimidine derivative of the present invention and one or more pharmaceutically acceptable carriers or vehicle.
The invention provides the brand-new Thienopyrimidine analog derivative of structure, its preparation method, its Anti-HIV-1 Active the selection result and the first Application in antiviral field thereof.Prove through overtesting, Thienopyrimidine analog derivative of the present invention can be used as HIV-1 inhibitor and applies and have very high using value.Specifically, as HIV-1 inhibitor for the preparation of anti-AIDS drug.
Embodiment
Contribute to understanding the present invention by following example, but content of the present invention can not be limited.
Synthetic route involved in embodiment is as follows:
Synthetic route one:
Synthetic route two:
The preparation of embodiment 1:4-((2-(piperidines-4-amine) thieno-[3,2-d] pyrimidine-4-yl) oxygen base)-3,5-dimethyl cyanophenyls (10)
Claim disubstituted-4-hydroxy-3,5-dimethyl cyanophenyl (0.15g, 1mmol) with salt of wormwood (0.17g, 1.2mmol) in DMF (DMF) solution of 5mL, stirring at room temperature 15 minutes, then 2 are added, 4-dichloro-thiophene also [3,2-d] pyrimidine (0.21g, 1mmol) continues stirring at room temperature 2h (TLC detection reaction is complete).A large amount of white solids is now had to generate, add 25mL frozen water wherein at leisure, filter, vacuum drying oven is dry, obtain white solid and be compound 4-((2-chlorothiophene is [3,2-d] pyrimidine-4-yl also) oxygen base)-3,5-dimethyl cyanophenyls, yield 93.8%, fusing point 258-260 DEG C.
Weigh Compound 4-((2-chlorothiophene also [3,2-d] pyrimidine-4-yl) oxygen base)-3,5-dimethyl cyanophenyl (0.32g, 1.0mmol), N-Boc-4-amino piperidine (0.24g, 1.2mmol) with salt of wormwood (0.28g, 2mmol) in the dimethyl sulfoxide (DMSO) of 5mL, then reflux 12 hours.After question response cool to room temperature, at leisure reaction solution is added drop-wise in the 20mL aqueous solution, stirs, have a large amount of yellow solids to generate.Filter, dry crude product 4-((2-(1-Boc-piperidines-4-amine) thieno-[3,2-d] pyrimidine-4-yl) oxygen base)-3,5-dimethyl cyanophenyls.Taking this crude product (0.60g, 1.21mmol) is dissolved in 4mL methylene dichloride, then adds trifluoroacetic acid (0.74mL, 10mmol) wherein at leisure, stirs 6 hours (TLC detection reaction is complete) under room temperature condition.In reaction solution, add 10mL water, adjust PH to be 9, dichloromethane extraction (3 × 5mL) with saturated sodium bicarbonate aqueous solution, saturated aqueous common salt is washed, and divides and gets organic layer, anhydrous sodium sulfate drying.Then carry out rapid column chromatography to be separated and to obtain white solid and be compound 4-((2-(piperidines-4-amine) thieno-[3,2-d] pyrimidine-4-yl) oxygen base)-3,5-dimethyl cyanophenyls.Yield 84.2%, fusing point 114-116 DEG C.
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)C 20H 21N 5OS(379.15).
The preparation of embodiment 2:2-(piperidines-4-amine)-4-(2,4,6-trimethylammonium phenoxy group) thieno-[3,2-d] pyrimidine (13)
Operation steps with embodiment 1, difference be starting raw material be 2，4，6-trimethyl phenol.
Product is white solid.Yield 87.5%, 178-180 DEG C.
1H NMR(400MHz,CDCl 3-d6,ppm)δ:7.73(d,1H,J＝5.4Hz,C 6-thienopyrimidine-H),7.19(d,1H,J＝5.3Hz,C 7-thienopyrimidine-H),6.90(s,2H,C 3,C 5-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,C 4-Ph”-CH 3),2.04-2.09(m,9H),1.46-1.54(m,2H).ESI-MS:m/z 369.5(M+1)C 20H 24N 4OS(368.17)
The preparation of embodiment 3: Compound I A-1
Weigh Compound 4-((2-(piperidines-4-amine) thieno-[3,2-d] pyrimidine-4-yl) oxygen base)-3,5-dimethyl cyanophenyl (10) (0.5mmol) is in 10mLDMF, Anhydrous potassium carbonate (0.14g is added after stirring and dissolving under room temperature condition, 1.0mmol) with the benzyl chloride replaced or bromobenzyl (0.6mmol), under room temperature condition, stir 12h (TLC detection reaction is complete).Decompression steams solvent, then in remaining substrate, adds 30ml ethyl acetate, saturated common salt solution washing 3 times, each 10mL, divides and gets organic layer, anhydrous sodium sulfate drying, filters, concentrated.Rapid column chromatography is separated and obtains target compound, and then recrystallization obtains target compound IA-1 in ethyl acetate-light petrol system.
With different substituted benzyls and 4-((2-(piperidines-4-amine) thieno-[3,2-d] pyrimidine-4-yl) oxygen base)-3,5-dimethyl cyanophenyl (10) obtains the target product of Compound I A-1-1 ~ IA-1-12 respectively with aforesaid method, partial results is as follows:
Operate the same, difference uses 4-methylsulfonyl bromobenzyl.
Product is white solid, yield: 52.4%, fusing point > 300 DEG C.
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).C 28H 29N 5O 3S 2(547.69)。
Operate the same, difference uses brooethyl benzsulfamide.
Product is white solid, yield: 50.3%, fusing point 223-225 DEG C.
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),C 27H 28N 6O 3S 2(548.50)。
Operate the same, difference uses fluorine bromobenzyl.
Product is white solid, yield: 61.8%, fusing point > 300 DEG C.
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),C 27H 26FN 5OS(487.59)。
Operate the same, difference uses 4-chloromethyl pyridine hydrochloride.
Product is white solid, yield: 51.3%, fusing point 154-156 DEG C.
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),C 26H 26N 6OS(470.59)。
Operate the same, difference is use 2,4-difluorobenzyl bromide.
Product is white solid, yield: 55.7%, fusing point > 300 DEG C.
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),C 27H 25F 2N 5OS(505.17)。
Operate the same, difference uses methylsulfonyl benzyl chloride.
Product is white solid, yield: 57.4%, fusing point 92-95 DEG C.
1H NMR(400MHz,CDCl 3-d6,ppm)δ:7.87(d,2H,J＝8.3Hz,C 3,C 5-Ph’-H),7.70(d,1H,J＝5.4Hz,C 6-thienopyrimidine-H),7.53(d,2H,J＝8.1Hz,C 2,C 6-Ph’-H),7.16(d,1H,J＝5.4Hz,C 7-thienopyrimidine-H),6.90(s,2H,C 3,C 5-Ph”-H),5.02(s,1H,NH),3.58(s,2H,N-CH 2),3.06(s,3H,SO 2-CH 3),2.74-2.76(m,2H),2.32(s,3H,C 4-Ph”-CH 3),1.93-2.09(m,11H),1.42-1.51(m,2H).ESI-MS:m/z 537.6(M+1),559.5(M+Na),C 28H 32N 4O 3S 2(536.19)。
Operate the same, difference uses bromomethyl-benzoic acid methyl ester.
Product is white solid, yield: 52.7%, fusing point 97-100 DEG C.
1H NMR(400MHz,CDCl 3-d6,ppm)δ:7.97(d,2H,J＝8.2Hz,C 3,C 5-Ph’-H),7.70(d,1H,J＝5.4Hz,C 6-thienopyrimidine-H),7.39(d,2H,J＝8.1Hz,C 2,C 6-Ph’-H),7.17(d,1H,J＝5.6Hz,C 7-thienopyrimidine-H),6.90(s,2H,C 3,C 5-Ph”-H),5.10(s,1H,NH),3.53(s,2H,N-CH 2),2.73-2.76(m,2H),2.31(s,3H,CO 2-CH 3),1.91-2.09(m,14H),1.41-1.49(m,2H).ESI-MS:m/z517.6(M+1),533.5(M+Na),C 29H 32N 4O 3S(516.22)
Operate the same, difference uses 4-fluorine bromobenzyl.
Product is white solid, yield: 65.3%, fusing point 133-136 DEG C
1H NMR(400MHz,CDCl 3-d6,ppm)δ:7.71(d,1H,J＝5.4Hz,C 6-thienopyrimidine-H),7.29(m,2H),7.17(d,1H,J＝5.4Hz,C 7-thienopyrimidine-H),7.02(t,2H,J＝8.6Hz),6.90(s,2H,C 3,C 5-Ph”-H),4.86(s,1H,NH),3.50(s,2H,N-CH 2),2.73-2.78(m,2H),2.32(s,3H,C 4-Ph”-CH 3),1.94-2.09(m,11H),1.40-1.51(m,2H).ESI-MS:m/z 477.5(M+1),C 27H 29FN 4OS(476.20)。
Operate the same, difference uses 3-fluorine bromobenzyl.
Product is white solid, yield: 63.1%, fusing point 140-142 DEG C.
1H NMR(400MHz,CDCl 3-d6,ppm)δ:7.68(d,1H,J＝5.4Hz,C 6-thienopyrimidine-H),7.37(t,1H,J＝6.1Hz,C 5-Ph’-H),7.22(t,1H,J＝6.0Hz,C 4-Ph’-H),7.17(d,1H,J＝5.3Hz,C 7-thienopyrimidine-H),7.10(t,1H,J＝7.4Hz,C 6-Ph’-H),7.03(t,1H,J＝9.5Hz,C 2-Ph’-H),6.88(s,2H,C 3,C 5-Ph”-H),5.05(s,1H,NH),3.57(s,2H,N-CH 2),2.78-2.80(m,2H),2.31(s,3H,C 4-Ph”-CH 3),1.92-2.08(m,11H),1.41-1.48(m,2H).ESI-MS:m/z 477.5(M+1),C 27H 29FN 4OS(476.20)。
Operate the same, difference uses 3-cyano-benzyl bromide.
Product is white solid, yield: 63.1%, fusing point 99-102 DEG C
1H NMR(400MHz,CDCl 3-d6,ppm)δ:7.72(d,1H,J＝5.4Hz,C 6-thienopyrimidine-H),7.64(s,1H,C 2-Ph’-H),7.58(t,2H,J＝9.0Hz,C 4-Ph’-H),7.44(t,1H,J＝7.7Hz,C 5-Ph’-H),7.17(d,1H,J＝5.3Hz,C 7-thienopyrimidine-H),6.90(s,2H,C 3,C 5-Ph”-H),5.14(s,1H,NH),3.51(s,2H,N-CH 2),2.72-2.75(m,2H),2.32(s,3H,C 4-Ph”-CH 3),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),C 28H 29N 5OS(483.21)。
Operate the same, difference uses 4-chloromethyl pyridine hydrochloride.
Product is white solid, yield: 50.7%, fusing point 135-137 DEG C
1H NMR(400MHz,CDCl 3-d6,ppm)δ:8.54(d,2H,J＝5.9Hz,C 2,C 6-pyridine-H),7.71(d,1H,J＝5.4Hz,C 6-thienopyrimidine-H),7.28(d,2H,J＝6.6Hz,C 3,C 5-pyridine-H),7.18(d,1H,J＝5.4Hz,C 7-thienopyrimidine-H),6.90(s,2H,C 3,C 5-Ph”-H),4.86(s,1H,NH),3.50(s,2H,N-CH 2),2.74-2.77(m,2H),2.32(s,3H,C 4-Ph”-CH 3),1.95-2.09(m,11H),1.44-1.52(m,2H).ESI-MS:m/z 460.6(M+1),482.6(M+Na),C 26H 29N 5OS(459.21)。
Operate the same, difference is use 2,4-difluorobenzyl bromide.
Product is white solid, yield: 59.6%, fusing point 110-112 DEG C.
1HNMR(400MHz,CDCl 3-d6,ppm)δ:7.70(d,1H,J＝5.4Hz,C 6-thienopyrimidine-H),7.36(dd,1H,J 1＝15.1Hz,J 2＝8.3Hz C 5-Ph’-H),7.17(d,1H,J＝5.3Hz,C 7-thienopyrimidine-H),6.90(s,2H,C 3,C 5-Ph”-H),6.75-6.85(m,2H),4.89(d,1H,J＝7.3Hz,NH),3.52(s,2H,N-CH 2),2.75-2.78(m,2H),2.32(s,3H,C 4-Ph”-CH 3),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),C 27H 28F 2N 4OS(494.20)。
Embodiment 4: the external AntiHIV1 RT activity active testing of target compound
Test philosophy
The screening of Compound ira vitro HIV (human immunodeficiency virus)-resistant activity adopts mtt assay.MTT full name is bromination-3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazoliumbromide nitrogen (trade(brand)name: tetrazolium bromide), can be used for the survival and growth detecting cell.Cleaning Principle is: MTT can be combined and is reduced to water-insoluble bluish voilet crystallization first a ceremonial jade-ladle, used in libation and is deposited in cell by succinodehydrogenase in the cell of living, and dead cell there is no this function.Dimethyl sulfoxide (DMSO) can first a ceremonial jade-ladle, used in libation in dissolved cell, detects by microplate reader the quantity that its absorbancy (A) value at 590 nm indirectly can reflect viable cell.Within the scope of certain cell count, the amount that MTT crystallization is formed is directly proportional to cell count.
Due to HIV MT-4 cell within a certain period of time (5-7 days) can pathology be there is; therefore in the MT-4 cell suspension of HIV, add the compound solution to be detected of proper concn; through after a while (5-7 days) cultivation after; with MTT assay MT-4 cell viability, obtain protection 50% cell and avoid cytopathic drug level (EC 50) activity of the AntiHIV1 RT activity of target compound can be drawn.Obtain the concentration (CC that target compound makes the cell generation pathology of 50% non-infected by HIV simultaneously 50), calculate choosing coefficient (selectivity index, SI=CC 50/ EC 50).
Test material and method
(1) HIV-1 (III b), HIV-2 (ROD) strain, various HIV-1 persister: provided by Rega institute of medical college of Belgian Univ Louvain.
(2) MT-4 cell: provided by Rega research institute of medical college of Belgian Univ Louvain.
(3) MTT: purchased from American Sigma company.
(4) sample preparation: sample is dissolved in DMSO before use and is made into proper concn, and do 5 times of dilutions with distilled water, each 5 extent of dilution.
(5) positive control drug: nevirapine (NVP), efavirenz (EFV), etravirine (TMC125), zidovudine (AZT).
(6) testing method: join in HIV MT-4 cell suspension after diluted sample, through using MTT colorimetric method for determining cell viability after a period of time, by the absorbancy recorded in microplate reader at 590 nm (A) value, calculates EC 50, CC 50and SI.
(7) MTT colorimetry: add after sample solution cultivates for some time, MTT solution (5mg/ML) 20 μ L is added to every hole, continue to cultivate after some hours, abandon staining fluid, and 150 μ L DMSO are added to every hole, abundant mixing, by the absorbancy measured in microplate reader under 590nm (A) value.
Experimental technique
On 96 porocyte culture plates, add 50 μ L containing 1 × 10 4mT-4 cell culture fluid, then add 20 μ L infected by HIV-1 (III respectively bor RES056) or the MT-4 cell suspension of HIV-2 (ROD) (every milliliter containing 100 times of CCID 50) or blank cultures (toxicity test), then add testing compound solution or the positive control medicine of different concns, each concentration designs 3 multiple holes.Then cell is at 5%CO 2atmosphere, cultivates 5 days at 37 DEG C, adds 20 μ L (5mg/mL) MTT solution in each hole, continue cultivation 2 hours, then add DMSO, use the optical density of microplate reader assaying reaction solution at 540nm place, the cell proliferation rate P% under computerized compound different concns.Establish blank and drug control group and positive drug control group, the cell of computerized compound protection 50% thus avoids the cytopathy desired concn (EC that HIV induces simultaneously 50).The calculating of selectivity index: SI=CC 50/ EC 50.
Anti-HIV-1 (the III of cell levels has been carried out according to the part Thienopyrimidine analog derivative of above-mentioned experimental technique to synthesis b), the screening active ingredients of single mutation strain K103N, Y181C, Y188L and double-mutant strain RES056 (K103N/Y181C), Activity Results is as shown in table 1.
The structure of table 1 part IA series compound and reference drug and Anti-HIV-1 Active (MT-4 cell) thereof
Note: aeC 50: protect the MT-4 cell of 50% infected by HIV-1 to avoid cytopathic compound concentration; A representation compound EC 50<10nM, B representation compound EC 50value is 10-100nM, C representation compound EC 50>100nM; NVP, EFV, ETV, AZT represent marketed drug nevirapine, Sustiva, etravirine and zidovudine respectively.
The cytotoxicity of table 2 part IA series compound and reference drug and selectivity index (MT-4 cell)
Note: acC 50: make the drug level during MTT cell generation pathology of 50%; A representation compound SI>10000, B representation compound SI value is 1000-10000, C representation compound SI<1000; X1:SI>=1 or <1; NVP, EFV, ETV, AZT represent marketed drug nevirapine, Sustiva, etravirine and zidovudine respectively.

Claims (7)

1. a Thienopyrimidine analog derivative, or its pharmacy acceptable salt, ester or prodrug, is characterized in that, has the structure shown in general formula I:
Wherein, between represented by dotted arrows A and B being is for being the one among singly-bound between double bond, B and D between double bond, A and B between singly-bound or B and D;
A is: S or C (U);
B is: S or C (V);
D is: S or C (W);
And A, B and D have and only have one for S;
Wherein U, V and W are independently separately: H, halogen, C 1-C 6alkyl, C 1-C 6alkoxyl group, C 2-c 6thiazolinyl, C 3-C 6cycloalkyl, O C 3-C 6cycloalkyl, phenyl, benzyl, trifluoromethyl, amino, hydroxyl, the hexa-member heterocycle of various replacement, the five-membered ring of various replacement;
Z is: F, F 2, OH, COOH, CONH 2, COOC 2h 5;
X is: the one among O, NH or S;
R 1, R 2, R 3be independently separately: H, halogen, cyano group, C 1-C 6alkyl, C 1-C 6alkoxyl group, C 2-c 6thiazolinyl, trifluoromethyl, amino, hydroxyl vinyl;
Ar is: substituted benzene ring, replace naphthalene nucleus, the hexa-member heterocycle of various replacement, the five-membered ring of various replacement, the hexa-atomic of various replacement five-membered ring, various replacement hexa-atomic hexa-member heterocycle, five yuan of various replacement and five-membered ring, the benzo five-membered heterocycle of various replacement or the benzo hexa-member heterocycle of various replacement.
2. compound according to claim 1, is characterized in that, the Ar in general formula I is for having the substituted benzene ring of general formula (a) or general formula (b):
Wherein, R 4for H, CH 3, COCH 3, COOCH 3, COOC 2h 5, COOH, SO 2cH 3or SO 2cF 3; R 5for Cl, Br, Me, NHCH 3, NHCOCH 3, NHSO 2cH 3or NHSO 2cF 3.
3. the compound described in claim 1 or 2, is characterized in that, structural formula is one of following:
Wherein, described in the same general formula I of R, U, V, W, Z and Ar.
4. compound according to claim 3, is characterized in that, is one of following particular compound:
5. the preparation method of compound according to claim 1, step is as follows: the Thienopyrimidine 1 replaced with 2,4-dichloro, for initial feed, first generates intermediate 2 with fortified phenol, benzenethiol or aniline generation nucleophilic substitution in DMF solution; Then intermediate 2 reacts with N-Boc-4-amino piperidine and under trifluoroacetic acid condition, takes off Boc radical protection subsequently and generates key intermediate 4 in dimethyl sulfoxide (DMSO); Or intermediate 2 occur Buchwald-Hartwig linked reaction generate intermediate 3 then de-BOC protection obtain intermediate 4; Under this key intermediate 4 last does the condition of alkali with salt of wormwood in DMF solution, react with various replacement benzyl chloride or bromobenzyl and generate target product; Synthetic route is as follows:
Reagent and condition: (i) fortified phenol, aniline or phenyl mercaptan, dimethyl formamide, salt of wormwood, room temperature; (ii) N-Boc-4-amino piperidine, dimethyl sulfoxide (DMSO), salt of wormwood, 120 DEG C; (iii) N-Boc-4-amino piperidine, palladium, 4,5-two (diphenylphosphine)-9,9-dimethyl xanthene, cesium carbonate, 90 DEG C, dioxane; (iv) methylene dichloride, trifluoroacetic acid, room temperature; V () replaces benzyl chloride or bromobenzyl, dimethyl formamide, salt of wormwood, room temperature.
6. the application of compound in preparation treatment and prevention human immunodeficiency virus medicine as described in any one of claim 1-4.
7. a pharmaceutical composition, comprises compound described in any one of claim 1-4 and one or more pharmaceutically acceptable carriers or vehicle.
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