CN102603585B - N-phenyl-2-mercaptobenzamide derivatives, preparation method and application thereof - Google Patents

N-phenyl-2-mercaptobenzamide derivatives, preparation method and application thereof Download PDF

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CN102603585B
CN102603585B CN201110022759.6A CN201110022759A CN102603585B CN 102603585 B CN102603585 B CN 102603585B CN 201110022759 A CN201110022759 A CN 201110022759A CN 102603585 B CN102603585 B CN 102603585B
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phenyl
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benzamide derivatives
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sulfydryl
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李锐
魏于全
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Sichuan University
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Abstract

Belonging to the technical field of chemical medicines, the invention specifically relates to N-phenyl-2-mercaptobenzamide derivatives, a preparation method and application thereof. Technically, the invention aims to provide a category of new compounds, N-phenyl-2-mercaptobenzamide derivatives, the structural of which is shown as formula I. The N-phenyl-2-mercaptobenzamide derivatives shown in formula I of the invention take the accessory protein Vif (virus infection factor) as a target, and protects the natural antiviral ability of APOBEC3G (apolipoprote in B mRNA-editing enzyme catalytic polypeptidelike3G) through inhibiting the functions of the Vif, thus providing a new choice for treatment of HIV-1.

Description

N-phenyl-2-sulfydryl benzamide derivatives and its production and use
Technical field
The invention belongs to technical field of chemical medicine, particularly N-phenyl-2-sulfydryl benzamide derivatives and its production and use.
Background technology
Acquired immune deficiency syndrome (AIDS), namely acquired immunity authority syndromes (acquired immunodeficiency syndrome, ADIS) be by HIV virus infection cause based on the syndromes of T cell immunodeficiency.Acquired immune deficiency syndrome (AIDS) originates from Africa, after bring the U.S. into by immigrant, since in June, 1981 confirms acquired immune deficiency syndrome (AIDS) first, acquired immune deficiency syndrome (AIDS) is rapid spread in the world, and the whole world is existing more than 5,300 ten thousand people's infected by HIV so far, and existing more than 2,000 ten thousand people are dead.High infection rate and sickness rate make sufferer's life-span decline, and bring great disaster to society and economy.
HIV is a kind of RNA viruses, belongs to retrovirus, and radius is about the spherical of 120 nanometers.HIV is divided into two kinds of hypotypes, HIV-1 and HIV-2, and its genome that most of AIDS patient is infected by HIV-1 is in the world made up of about 9200bp.Gene main code 3 structural protein Gag, Pol and Env, two kinds of Function protein Tat and Rev, and 4 kinds of accessory protein Vif (virion infectivity factor), Nef (negative regulator factor), Vpr (viral protein R) and Vpu (viralprotein U).
The current AntiHIV1 RT activity inhibitor gone on the market can be divided into 6 classes: nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitor, proteinase inhibitor, accessory receptor inhibitor, fusion inhibitor and integrase inhibitor, but not yet finds a kind of specifics for the treatment of acquired immune deficiency syndrome (AIDS) so far.Scientist Chinese descendant in America proposed to treat acquired immune deficiency syndrome (AIDS) by the antiviral conbined usage of three kinds or more, i.e. therapeuticcocktail of anti-retrovirals in 1996.This method by proteinase inhibitor and multiple antiviral used in combination, reduce the possibility of generation resistance of single drug, thus delay the course of disease, extend patient vitals, improve the quality of living.But HIV autoimmune is strong, be very easy to variation and produce Drug resistance strain, the inverase therefore developed based on novel targets is extremely urgent.Accessory protein also plays an important role in the existence and copying of HIV, and up to the present, there is no one in the medicine gone on the market for HIV accessory protein is target spot.Vif albumen finds the accessory protein relevant with the infection ability of virus the earliest.APOBEC3G (apolipoprote in B mRNA-editing enzyme catalytic polypeptidelike3G; Apolipoprotein B mRNA editing enzymes catalytic polypeptide sample albumen 3G) be a member of Isocytosine deaminase extended familys, there is natural HIV (human immunodeficiency virus)-resistant activity, research finds that the cytosine(Cyt) deamination of (-) cDNA that it can make HIV-1 reverse transcription be formed is uridylic, cause the sudden change of viral transcripts, thus reach the effect suppressing virus replication.But this activity is by VIF antagonism.If develop the inverase that can suppress VIF, enable APOBEC3G exercise normal function, so provide new selection by the treatment for anti-HIV-1.
Summary of the invention
Technical problem to be solved by this invention is to provide the new compound N of a class-phenyl-2-sulfydryl benzamide derivatives, and structure is such as formula shown in I:
R 1for with 1 ~ 6 substituent phenyl, substituting group is independently H, nitro, C 1~ C 8alkyl or C 1~ C 8alkoxyl group;
R 2~ R 6be independently H, F, Cl, Br, OH, NO 2, NH 2or C 1~ C 8alkoxyl group;
R 7~ R 10be independently H, F, Cl, Br, OH, NH 2, CF 3, C 1~ C 8alkyl or C 1~ C 8alkoxyl group; And R 7~ R 10in have a substituting group at least for H;
n=0～2。
Preferably, N-phenyl-2-sulfydryl benzamide derivatives structure such as formula shown in I, R 1for with 1 ~ 6 substituent phenyl, substituting group is independently nitro, C 1~ C 8alkyl or C 1~ C 8alkoxyl group;
R 2~ R 6be independently H, F, Cl, Br, OH, NO 2, NH 2or C 1~ C 8alkoxyl group;
R 7~ R 10be independently H, F, Cl, Br, OH, NH 2, CF 3, C 1~ C 8alkyl or C 1~ C 8alkoxyl group; And R 7~ R 10in have a substituting group at least for H;
n=0～2。
Preferably, N-phenyl-2-sulfydryl benzamide derivatives structure such as formula shown in I, R 1for with 1 ~ 6 substituent phenyl, substituting group is independently nitro, C 1~ C 8alkyl or C 1~ C 8alkoxyl group;
R 2~ R 6be independently H, F, Cl, Br, NO 2or C 1~ C 8alkoxyl group, and R 2~ R 6in have a substituting group at least for H;
R 7~ R 10be independently H, F, Cl, Br, OH, NH 2, CF 3, C 1~ C 8alkyl or C 1~ C 8alkoxyl group; And R 7~ R 10in have a substituting group at least for H;
n=0～2。
Preferably, N-phenyl-2-sulfydryl benzamide derivatives structure such as formula shown in I, R 1for with 1 ~ 6 substituent phenyl, substituting group is independently nitro, C 1~ C 8alkyl or C 1~ C 8alkoxyl group;
R 2~ R 6be independently H, F, Cl, Br, NO 2or C 1~ C 8alkoxyl group, and R 2~ R 6in have a substituting group at least for H;
R 7~ R 10be independently H, F, Cl or Br; And R 7~ R 10in have a substituting group at least for H;
n=0～2。
Preferably, N-phenyl-2-sulfydryl benzamide derivatives structure such as formula shown in I, R 1for with 1 ~ 6 substituent phenyl, substituting group is nitro;
R 2~ R 6be independently H, F, Cl, Br, NO 2or C 1~ C 4alkoxyl group, and R 2~ R 6in have a substituting group at least for H;
R 7~ R 10be independently H, F, Cl or Br, and R 7~ R 10in have a substituting group at least for H;
n=0～2。
Preferably, N-phenyl-2-sulfydryl benzamide derivatives structure such as formula shown in I, R 1for p-nitrophenyl;
R 2~ R 6be independently H, F, Cl, Br, NO 2or C 1~ C 4alkoxyl group, and R 2~ R 6in have a substituting group at least for H;
R 7~ R 10be independently H, F or Cl, and R 7~ R 10in have a substituting group at least for H;
n=0～2。
Preferably, N-phenyl-2-sulfydryl benzamide derivatives structure such as formula shown in I, R 1for p-nitrophenyl;
R 2~ R 6be independently H or C 1~ C 4alkoxyl group, and R 2~ R 6in have a substituting group at least for H;
R 7~ R 10be independently H, F or Cl, and R 7~ R 10in have a substituting group at least for H;
n=0～2。
Optimum, N-phenyl-2-sulfydryl benzamide derivatives structure such as formula shown in I, R 1for p-nitrophenyl;
R 2~ R 6be independently H or C 1~ C 4alkoxyl group, and R 2~ R 6in have a substituting group at least for H;
R 8for F or Cl, R 7, R 9and R 10for H;
n=0～2。
Further, the structure of N-phenyl-2-sulfydryl benzamide derivatives is such as formula shown in II:
Wherein R 2~ R 6be independently H, F, Cl, Br, OH, NO 2, NH 2or C 1~ C 8alkoxyl group;
R 7~ R 10be independently H, F, Cl, Br, OH, NH 2, CF 3, C 1~ C 8alkyl or C 1~ C 8alkoxyl group; And R 7~ R 10in have a substituting group at least for H;
R 11~ R 15be independently H, nitro, C 1~ C 8alkyl or C 1~ C 8alkoxyl group.
Preferably, the structure of N-phenyl-2-sulfydryl benzamide derivatives such as formula shown in II, R 2~ R 6be independently H, F, Cl, Br, NO 2or C 1~ C 8alkoxyl group, and R 2~ R 6in have a substituting group at least for H; R 7~ R 10be independently H, F, Cl, Br, OH, NH 2, CF 3, C 1~ C 8alkyl or C 1~ C 8alkoxyl group; And R 7~ R 10in have a substituting group at least for H; R 11~ R 15be independently H, nitro, C 1~ C 8alkyl or C 1~ C 8alkoxyl group.
Preferably, the structure of N-phenyl-2-sulfydryl benzamide derivatives such as formula shown in II, R 2~ R 6be independently H, F, Cl, Br, NO 2or C 1~ C 8alkoxyl group, and R 2~ R 6in have a substituting group at least for H; R 7~ R 10be independently H, F, Cl, Br, CF 3, C 1~ C 8alkyl or C 1~ C 8alkoxyl group; And R 7~ R 10in have a substituting group at least for H; R 11~ R 15be independently H, nitro, C 1~ C 8alkyl or C 1~ C 8alkoxyl group.
Further preferred, the structure of N-phenyl-2-sulfydryl benzamide derivatives such as formula shown in II, R 2~ R 6be independently H or C 1~ C 8alkoxyl group; And R 2~ R 6in have a substituting group at least for H;
R 7~ R 10be independently H, F, Cl or Br, and R 7~ R 10in have a substituting group at least for H;
R 11~ R 15be independently H or nitro, and R 11~ R 15in have a substituting group at least for H.
Optimum, the structure of N-phenyl-2-sulfydryl benzamide derivatives such as formula shown in II, R 2~ R 6be independently H or methoxyl group, and R 2~ R 6in have 1 or 2 substituting group to be methoxyl group;
R 8for F or Cl, R 7, R 9and R 10for H;
R 11~ R 15be independently H or nitro, and R 11~ R 15in have a substituting group at least for H.
Further, the structure of N-phenyl-2-sulfydryl benzamide derivatives is such as formula shown in III:
Wherein R 2~ R 6be independently H, F, Cl, Br, OH, NO 2, NH 2or C 1~ C 8alkoxyl group;
R 7~ R 10be independently H, F, Cl, Br, OH, NH 2, CF 3, C 1~ C 8alkyl or C 1~ C 8alkoxyl group; And R 7~ R 10in have a substituting group at least for H.
Preferably, the structure of N-phenyl-2-sulfydryl benzamide derivatives such as formula shown in III, R 2~ R 6be independently H, F, Cl, Br, NO 2or C 1~ C 8alkoxyl group, and R 2~ R 6in have a substituting group at least for H;
R 7~ R 10be independently H, F, Cl, Br, OH, NH 2, CF 3, C 1~ C 8alkyl or C 1~ C 8alkoxyl group; And R 7~ R 10in have a substituting group at least for H.
Preferably, the structure of N-phenyl-2-sulfydryl benzamide derivatives such as formula shown in III, R 2~ R 6be independently H, F, Cl, Br, NO 2or C 1~ C 8alkoxyl group, and R 2~ R 6in have a substituting group at least for H;
R 7~ R 10be independently H, F, Cl, Br, CF 3, C 1~ C 8alkyl or C 1~ C 8alkoxyl group; And R 7~ R 10in have a substituting group at least for H.
Further preferred, the structure of N-phenyl-2-sulfydryl benzamide derivatives such as formula shown in III, R 2~ R 6be independently H or C 1~ C 8alkoxyl group; And R 2~ R 6in have a substituting group at least for H;
R 7~ R 10be independently H, F, Cl or Br, and R 7~ R 10in have a substituting group at least for H.
Further preferred, the structure of N-phenyl-2-sulfydryl benzamide derivatives such as formula shown in III, R 2~ R 6be independently H or C 1~ C 4alkoxyl group, and R 2~ R 6in have a substituting group at least for H;
R 7~ R 10be independently H, F, Cl or Br, and R 7~ R 10in have a substituting group at least for H.
Optimum, the structure of N-phenyl-2-sulfydryl benzamide derivatives such as formula shown in III, R 2~ R 6be independently H or methoxyl group, and R 2~ R 6in have 1 or 2 substituting group to be methoxyl group;
R 8for F or Cl, R 7, R 9and R 10for H.
Second technical problem to be solved by this invention is to provide the preparation method of-2-of N-phenyl shown in formula I sulfydryl benzamide derivatives,
R 1for with 1 ~ 6 substituent phenyl, substituting group is independently H, nitro, C 1~ C 8alkyl or C 1~ C 8alkoxyl group;
R 2~ R 6be independently H, F, Cl, Br, OH, NO 2, NH 2or C 1~ C 8alkoxyl group;
R 7~ R 10be independently H, F, Cl, Br, OH, NH 2, CF 3, C 1~ C 8alkyl or C 1~ C 8alkoxyl group; And R 7~ R 10in have a substituting group at least for H;
When Y is Br, Z is SH; When Y is SH, Z is Br; N=0 ~ 2.
1) compd A and compd B are dissolved in DMF, with anhydrous K 2cO 3be catalyzer with copper powder, in 50 ~ 60 DEG C of reactions, be extracted with ethyl acetate reaction solution, the organic layer of extraction is concentrated to obtain crude product, crude isolate purifiedly namely obtains Compound C;
2) Compound C is dissolved in SOCl 2, in DMF, back flow reaction, adds anhydrous THF and stirs evenly after solvent evaporated, then adds Compound D and diisopropylethylamine reaction, be extracted with ethyl acetate after solvent evaporated, the organic layer of extraction is concentrated to obtain crude product, crude isolate purifiedly namely obtains product.
Step 1), 2) described separation purification method is column chromatography chromatogram.
The step 1) reaction times is 6 ~ 10 hours.Rear drying is washed with water before the organic layer extracted is concentrated.
Step 2) reflux time is 1 ~ 5 hour.The organic layer of extraction is concentrated front with dry after saturated common salt water washing.
The preparation method of-the 2-of N-phenyl shown in formula II sulfydryl benzamide derivatives is identical with the preparation method of the sulfydryl of N-phenyl-2-shown in above-mentioned formula I benzamide derivatives, and just the structure of compd B is the structure of Compound C is
The preparation method of-the 2-of N-phenyl shown in formula III sulfydryl benzamide derivatives is identical with the preparation method of the sulfydryl of N-phenyl-2-shown in above-mentioned formula I benzamide derivatives, and just the structure of compd B is the structure of Compound C is
3rd technical problem to be solved by this invention is to provide the purposes of the sulfydryl of N-phenyl-2-shown in formula I, formula II or formula III benzamide derivatives, shown in external HIV virus strain experiment results proved formula I, N-phenyl-2-sulfydryl benzamide derivatives has stronger AntiHIV1 RT activity effect, and toxicity is low, its TI (therapeutic index, therapeutic index) is greater than 200.
Pharmaceutical composition, it is with the sulfydryl of N-phenyl-2-shown in formula I, formula II or formula III benzamide derivatives for activeconstituents, adds customary adjuvant composition.
4th technical problem to be solved by this invention is to provide intermediate used time prepared by the sulfydryl of N-phenyl-2-shown in formula I, formula II or formula III benzamide derivatives, and structure is such as formula shown in IV:
Wherein, R 1for with 1 ~ 6 substituent phenyl, substituting group is independently H, nitro, C 1~ C 8alkyl or C 1~ C 8alkoxyl group;
R 7~ R 10be independently H, F, Cl, Br, OH, NH 2, CF 3, C 1~ C 8alkyl or C 1~ C 8alkoxyl group; And R 7~ R 10in have a substituting group at least for H;
n=0～2。
-the 2-of N-phenyl shown in formula I sulfydryl benzamide derivatives is for target spot with accessory protein Vif (viral infective agent); by the natural anti-virus ability suppressing the function of Vif to protect APOBEC3G, the treatment for anti-HIV-1 provides new selection.
Embodiment
The preparation of embodiment 1 N-(2-p-methoxy-phenyl)-2-(4-nitrophenylsulfenyl) benzamide derivatives
For the chloro-N-of chemical compounds I a:5-(2-p-methoxy-phenyl)-2-(4-nitrophenylsulfenyl) benzamide, synthetic route is as follows:
1, the chloro-2-of 5-(4-nitrophenylsulfenyl) benzoic preparation:
After chloro-for 5-2-bromo-benzoic acid (0.235g, 1mmol) and p-Nitrobenzenethiol (0.202g, 1mmol) mixing, join in 10ml DMF, then add anhydrous K 2cO 3(0.069g, 0.5mmol) and copper powder (0.032g, 0.5mmol), reacting by heating liquid, to 55 DEG C, stirs 8 hours, is cooled to room temperature.Be extracted with ethyl acetate 3 times, organic layers with water washes 7 times, anhydrous MgSO 4drying, concentrated, crude product uses column chromatography purifying and namely obtains product (0.177g), productive rate 57%.
1H NMR(400MHz，DMSO-d 6)：7.052(d，J=8.4，1H)，7.351(m，1H)，7.576(d，J=8.8，2H)，7.671(s，1H)，7.968(d，J=2.4，1H)，8.208(d，J=8.4，1H)，13.104(br，1H)。
2, the preparation of the chloro-N-of 5-(2-p-methoxy-phenyl)-2-(4-nitrophenylsulfenyl) benzamide:
Chloro-for 5-2-(4-nitrophenylsulfenyl) phenylformic acid (0.54g, 1.8mmol) is dissolved in 10ml SOCl 2in, be heated to 77 DEG C of backflows 3 hours, be cooled to room temperature, be spin-dried for SOCl 2, add the anhydrous THF stirring at room temperature of 15ml, then add ORTHO ANISIDINE (0.123g, 1mmol) with diisopropylethylamine (0.903g, 7mmol), reaction 3 was as a child spin-dried for THF, be extracted with ethyl acetate 3 times, organic layer saturated aqueous common salt washes 1 time, anhydrous MgSO 4drying, concentrated, crude product uses column chromatography purifying and namely obtains product (0.298g), productive rate 72%.
1H NMR(400MHz，CDCl 3)：3.799(S，3H)，6.870(d，J=8，1H)，6.669(m，1H)，7.084(m，1H)，7.278(m，2H)，7.492(m，2H)，7.772(s，1H)，8.073(d，J=8.8，2H)，8.360(s，1H)，8.376(s，1H)。ESI-MS:[M+H] +m/z 415.
The synthetic route of synthetic method reference I a of I b.The obtained fluoro-2-of 5-(4-nitrophenylsulfenyl) is benzoic 1hNMR (400MHz, DMSO-d 6): 7.372 (m, 1H), 7.433 (m, 1H), 7.494 (d, J=8.8,1H), 7.718 (m, 1H), 7.821 (d, J=4.4,1H), 8.196 (d, J=8.8,1H), 8.248 (d, J=8.8,1H), 13.664 (br, 1H)
The obtained fluoro-N-of 5-(2-p-methoxy-phenyl)-2-(4-nitrophenylsulfenyl) benzamide 1h NMR (400MHz, CDCl 3): 3.771 (S, 3H), 6.859 (d, J=8,1H), 6.965 (m, 1H), 7.078 (m, 1H), 7.246 (m, 3H), 7.552 (m, 1H), 7.618 (m, 1H), 8.061 (d, J=8.8,2H), 8.369 (d, J=7.2,1H), 8.451 (S, 1H).ESI-MS:[M+H] +m/z 399.
Activity experiment:
The Anti-HIV-1 Active of international experimental technique to medicine is adopted to detect according to SFDA " inverase non-clinical pharmacodynamic study technical director's principle (2006) ".Activity Results is as shown in table 1, and wherein CC50 and EC50 has done twice mensuration respectively.
Table 1
As can be seen from Table 1, Compound I a, Ib have the ability of vitro inhibition HIV-1 activity, particularly the ability of Compound I a vitro inhibition HIV-1 activity is stronger, its toxicity is low simultaneously, there is high therapeutic index, thus can be used in preparing the new anti HIV-1 virus micromolecular inhibitor acting on HIV-1 accessory protein VIF.

Claims (5)

1. the N-phenyl-2-sulfydryl benzamide derivatives shown in formula III, is characterized in that:
Wherein, R 2~ R 6be independently H or methoxyl group, and R 2~ R 6in have 1 or 2 substituting group to be methoxyl group; R 8for Cl, R 7, R 9and R 10for H.
2. the preparation method of the phenyl of N-shown in claim 1-2-sulfydryl benzamide derivatives,
R 1for p-nitrophenyl; R 2~ R 6be independently H or methoxyl group, and R 2~ R 6in have 1 or 2 substituting group to be methoxyl group; R 8for Cl, R 7, R 9, R 10for H;
When Y is Br, Z is SH; When Y is SH, Z is Br; N=0;
1) compd A and compd B are dissolved in DMF, with anhydrous K 2cO 3be catalyzer with copper powder, in 50 ~ 60 DEG C of reactions, be extracted with ethyl acetate reaction solution, the organic layer of extraction is concentrated to obtain crude product, crude isolate purifiedly namely obtains Compound C;
2) Compound C is dissolved in SOCl 2, in DMF, back flow reaction, adds anhydrous THF and stirs evenly after solvent evaporated, then adds Compound D and diisopropylethylamine reaction, be extracted with ethyl acetate after solvent evaporated, the organic layer of extraction is concentrated to obtain crude product, crude isolate purifiedly namely obtains product.
3. the phenyl of N-shown in claim 1-2-sulfydryl benzamide derivatives is preparing the purposes in anti-AIDS drug.
4. pharmaceutical composition, it is with the phenyl of N-shown in claim 1-2-sulfydryl benzamide derivatives for activeconstituents, adds customary adjuvant composition.
5. intermediate used during N-phenyl-2-sulfydryl benzamide derivatives shown in preparation claim 1, structure is such as formula shown in IV:
R 1for p-nitrophenyl; R 2~ R 6be independently H or methoxyl group, and R 2~ R 6in have 1 or 2 substituting group to be methoxyl group; R 8for Cl, R 7, R 9, R 10for H;
n＝0。
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